Information about HH

Medical Articles

What is a
Hypothalamic
Hamartoma?

An Expert Speaks Out About HH
by Dr Kore Liow, of Kansas University

The Role of the Hypothalamus
An informative tutorial about the vital role of the hypothalamus in maintaining the body's status quo

The Endocrine System
Learn more about the importance of the endocrine system, hormones and the hypothalamus

MRI Scans of
"The Real Deal"
Actual MRI film of HH

January 2001 Neurosurgery Article by Rosenfeld, Harvey & the RCH Team

See a full description of
Seizure Types

Back to
HHUGS Home Page

• HH and Gelastic Epilepsy (general articles)

• HH and Precocious Puberty

• HH and Pallister-Hall Syndrome

• HH and Other Conditions

• Surgery on HH

Coppola G, Spagnoli D, Sciscio N, Russo F, Villani RM (2002) Gelastic seizures and low-grade hypothalamic astrocytoma: a case report. Brain & Development, 24(3): 183-6.
The typical, well recognized childhood epilepsy syndrome caused by hypothalamic hamartoma is characterized by early-onset, stereotyped attacks of uncontrollable laughter, frequent refractory seizures with progressive cognitive deterioration and severe behavioral problems. Here, we report a 17-year-old patient with gelastic phenomenon started in the neonatal period, later on associated with drug resistant polymorphic seizures, intellectual deficit and behavioral disorders, who improved by partial resection of an expected hypothalamic hamartoma that, in turn, resulted to be a hypothalamic low-grade astrocytoma.
(Department of Pediatrics, Clinic of Child and Adolescent Neuropsychiatry, Second University of Naples, Via Pansini 5, 80131 Naples, Italy)

Debeneix C, Bourgeois M, Trivin C, Sante-Rose C, Brauner R. (2001) Hypothalamic hamartoma: comparison of clinical presentation and magnetic resonance images. Hormone Research, 56(1-2):12-8.
Hypothalamic hamartoma (HH) is one of the most frequent causes of organic central precocious puberty (CPP). We compared the clinical presentation and the magnetic resonance images (MRI) of 19 patients with HH aged 5.7 +/- 4.1 (SD) years at the first endocrine evaluation. They had isolated CPP (group 1, n = 9), CPP plus gelastic seizures (group 2, n = 5), isolated seizures (group 3, n = 4), and 1 patient was asymptomatic. All patients without neurological symptoms (group 1 and the asymptomatic patient) had pedunculated lesion (diameter 6.4 +/- 3.6 (3-15) mm), suspended from the floor of the third ventricle. All patients with neurological symptoms (groups 2 and 3) had sessile lesion (diameter 18.3 +/- 9.6 (10-38) mm, p = 0.0005 compared to the others), located in the interpeduncular cistern with extension to the hypothalamus. Seven patients were overweight. The growth hormone peak, free thyroxine, cortisol and prolactin concentrations, and the concomitant plasma and urinary osmolalities were normal in all the cases evaluated. The mean predicted or adult heights of 10 patients treated 5.2 +/- 3.3 years for CPP with gonadotropin hormone releasing hormone (GnRH) analog were -0.3 +/- 1.7 SD, similar to their target height -0.1 +/- 0.9 SD. The clinical presentation of HH depends on its anatomy: small and pedunculated HH are associated with CPP, while large and sessile HH are associated with seizures. The hypothalamic-pituitary function in these cases is normal, which suggests that the absence of CPP is not due to gonadotropin deficiency. GnRH analog treatment preserves the growth potential in those with CPP.
(Pediatric Endocrinology, Universite Rene Descartes and Hopital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris, France)

Hoshida T, Sakaki T (2002) Laughter and mirth in epilepsy. NeuroImage Human Brain Mapping 2002 Meeting.
Epileptic symptomatology, which is demonstrated by abnormal excitement of normal brain function in human, provides important information for unraveling brain function and the relationship between the neuronal network. As it is thought that the mind is a reflection of brain activities, what pathways in the brain are involved in the processing of emotion is an interesting question. The relationship between brain and mind is one of the most excitable and expectant results in the 21st Century. It is known that some epilepsy patients demonstrate gelastic seizures, and electrical cortical stimulations induce laughter with or without mirth. We studied the mechanism and network of laughter and mirth in epilepsy patients.
RESULTS: Epileptic foci in patients associated with gelastic seizures were located in the left temporal lobe in three, hypothalamus in one, right parietal lobe in one, and undetermined in one patient. In two patients with hypothalamic hamartoma and right parietal lobe epilepsy with tuberous sclerosis, their seizures demonstrated mirth. Three of five patients, who underwent brain mapping using chronically implanted electrodes, elicited facial expression of laughter. Right cingulum stimulation induced tonic movement of the right nasolabial fold. This area was thought to be a cingulate motor one. Right insular cortical stimulation showed tonic movement of the left nasolabial fold, and left supplementary motor area stimulation demonstrated bilateral tonic movement of the face, resembling natural laughter. Two patients with right and left temporal lobe epilepsies showed laughter with happiness and loud voice after stimulation of the middle temporal gyrus. This kind of laughter and mirth were confirmed on another day.
CONCLUSIONS: The cingulum (ipsilateral side), insular cortex (contralateral side), and supplementary motor area (bilateral side) are of primary importance in relation to the facial expression of laughter and are thought to be relay areas to produce laughter. Hypothalamus and middle temporal gyrus are involved in processing emotional aspects of laughter. These five areas and other cortical and subcortical areas, may be the limbic system and brain stem, connect and relate for producing a unique emotion in humans, i.e. laughter and mirth.

Hosokawa K, Fujiwara J, Ikeda H, et al (1967) Two cases of laughter epilepsy. Clin Neurol, 7: 161.
No abstract available.

Iwasa H, Shibata T, Mine S, Koseki K, Yasuda K, Kasagi Y, Okada M, Yabe H, Kaneko S, Nakajima Y. (2002) Different patterns of dipole source localization in gelastic seizure with or without a sense of mirth. Neuroscience Research - Supplement, 43(1): 23-9.
Dipole source localization corresponding to interictal spikes were estimated using EEG dipole tracing with a realistic three-shell head model in three patients with cryptogenic gelastic epilepsy. The dipole sources in two patients, whose gelastic seizures were accompanied by a subjective feeling of mirth, were estimated in the right or left medio-basal temporal regions. In the other patient, with gelastic seizures without a sense of mirth, the dipole sources were localized in the right frontal region corresponding to the anterior cingulate. The results suggest that the neural activities in hippocampal regions are involved with the generation of gelastic seizures with a sense of mirth and those in the cingulate might be associated with the motor act of laughter.
(Department of Neuropsychiatry, School of Medicine, Hirosaki University, Japan) 

Luo S, Li C, Ma Z (2001) The diagnosis and treatment of hypothalamic hamartoma in children. Chung-Hua i Hsueh Tsa Chih (Chinese Medical Journal), 81(4): 212-5(In Chinese).
Our objective is to investigate the diagnosis and treatment of hypothalamic hamartoma in children. Eighteen cases of hypothalamic hamartoma in children, including 9 boys and 9 girls, were examined with CT and MRI. Eleven cases underwent operation. Post-operation follow-up was conducted for 0.5 approximately 6 years. The main clinical features of hypothalamic hamartoma were precocious puberty and gelastic seizures, some combine with other kinds of seizures, mental retardation or congenital abnormalities. The effective rate of surgery was 91%; patients with simple precocious puberty were cured. We conclude that microsurgery is the first choice of treatment for hypothalamic hamartoma.
(Department of Neurosurgery, Tiantan Hospital, Beijing, China)

Razzaq AA, Chishti MK (2001) Giant hypothalamic hamartoma and associated seizure types. Journal of the Pakistan Medical Association, 51(8): 296-8.
No abstract available.
(Department of Surgery, Section of Neurological Surgery, Aga Khan University Hospital, Karachi)

Stecker M, Kita M. Paradoxical response to Valproic Acid in a patient with a hypothalamic hamartoma. http://www.theannals.com/abstracts/volume32/November/1168
A 25-year-old African-American woman with a hypothalamic hamartoma had an electroencephalogram (EEG) that demonstrated frequent bursts of generalized spike and wave activity. The prevalence of spike and wave activity increased dramatically and the patient became increasingly somnolent as valproic acid was added to carbamazepine and phenobarbital therapy. Her EEG and mental status changes resolved when the valproic acid was discontinued. There was a strong positive correlation between the prevalence of spike and wave activity and the valproic acid concentration, but not between spike and wave activity and the concentrations of carbamazepine or phenobarbital. Although this is a complex case, it is clear that the addition of valproic acid produced an increase in spike and wave activity. Possible mechanisms and pathophysiologic significance of this paradoxical effect are discussed in light of the differences between this epileptic syndrome and the primary generalized epilepsies.

Striano S, Meo R, Bilo L, Cirillo S, Nocerino C, Ruosi P, Striano P, Estraneo A (1999) Gelastic epilepsy: symptomatic and cryptogenic cases. Epilepsia, 40 (3): 294-302.
Our purpose was to describe the etiology, characteristics, and clinical evolution of epilepsy in patients with gelastic seizures (GSs). Nine patients whose seizures were characterized by typical laughing attacks were observed between 1986 and 1997. Patients were selected based on electroencephalogram (EEG) or video-EEG recordings of at least one GS and on magnetic resonance imaging (MRI) study. Five patients were affected by symptomatic localization-related epilepsy (LRE), with four of the patients' disorders related to a hypothalamic hamartoma (HH) and one to tuberous sclerosis (TS) without evident hypothalamic lesions. In four patients (the cryptogenic cases) MRI was negative also in these cases, clinical and EEG data suggested a focal origin of the seizures. The epileptic syndrome in the HH cases was usually drug-resistant, and was surgically treated in two of the patients. The patient with TS became seizure free with vigabatrin. In the cryptogenic cases, the ictal, clinical, and EEG semiology were similar to the symptomatic cases: the clinical evolution was variable, with patients having transient drug resistance or partial response to treatment. No cognitive defects were observed in the cryptogenic patients. None of the nine patients had precocious puberty. We confirm the frequent finding of HHs in GSs and further underline how GSs may also be observed in patients without MRI lesions and with normal neurologic status. In these patients, clinical and EEG seizure semiology is similar to symptomatic cases, but the clinical evolution is usually more benign.
(Department of Neurological Sciences, Epilepsy Center, Federico II University, Naples, Italy)

Striano S, Striano P, Cirillo S, Nocerino C, Bilo L, Meo R, Ruosi P, Boccella P, Briganti F. (2002) Small hypothalamic hamartomas and gelastic seizures. Epileptic Disorders, 4(2): 129-33.
Our purpose is to describe the clinical history of patients with gelastic seizures (GSs) related to small-size hypothalamic hamartomas (HHs), and to show some of these unusual seizures. Patients with GSs and the MRI finding of HH < 1 cm diameter. Ictal EEG or video EEG are required. Three patients, among 6 with GSs and HH, had a small sessile HH. None of them had a history of precocious puberty, nor any relevant cognitive defects. All patients suffered from other seizure types, in addition to GSs. GSs were drug-resistant in all cases. Since small, not easily recognizable HHs may be present in patients with GSs, a careful MRI study of the hypothalamic, infundibular and mammillary bodys areas is mandatory in these cases (published with videosequences).
(Department of Neurological Sciences, Epilepsy Center, Federico II University, Naples, Italy)

Sturm JW, Andermann E, Berkovic SF (2000) “Pressure to laugh”: an unusual epileptic syndrome associated with small hypothalamic hamartomas. Neurology, 54 (4): 971-73.
Gelastic seizures are the hallmark of the epilepsy syndrome associated with hypothalamic hamartomas. Patients typically develop cognitive deterioration and refractory seizures. The authors describe three patients with small hypothalamic hamartomas without these features and thus identify a mild end to the clinical spectrum. All had the unusual symptom of "pressure to laugh," often without actual laughter. This symptom could be dismissed as psychogenic but should be recognized as a clue to the presence of this unusual lesion
(Department of Neurology, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia)

Wakai S, Nikaido K, Nihira H, Kawamoto Y, Hayasaka H. (2002) Gelastic seizure with hypothalamic hamartoma: proton magnetic resonance spectrometry and ictal electroencephalographic findings in a 4-year-old girl. Journal of Child Neurology,17(1): 44-6.
Gelastic seizure is a rare symptom often associated with hypothalamic hamartoma. We present here a 4-year-old girl with gelastic epilepsy caused by hypothalamic hamartoma and report the magnetic resonance spectrometry and electroencephalographic (EEG) findings. At the age of 2 1/2 years, she developed brief, repetitive laughing attacks or mixed attacks with laughing and crying, which were refractory to carbamazepine. An interictal EEG showed intermittent slow waves in the left frontocentral region and sporadic positive sharp waves in the left centroparietal area. Ictal EEG demonstrated dysrhythmic theta activity in the left central area 3 seconds after the onset of laughing. Brain magnetic resonance imaging demonstrated a large sessile mass, isointense to gray matter, in the region of the hypothalamus, suggesting hypothalamic hamartoma. Proton magnetic resonance spectrometry of the hypothalamic hamartoma revealed a significant reduction of the N-acetylaspartate/serum creatinine ratio. The altered chemical shift imaging with magnetic resonance spectrometry in our patient suggests a biochemical abnormality in the tissue of the hypothalamic hamartoma. Moreover, this abnormal function of the hamartoma tissue might be closely related to epileptogenesis because the time difference between the ictal laughter and the subsequent EEG changes in the ictal EEG does not support the idea that the activated cortex is the epileptogenic focus.
(Department of Pediatrics, Sapporo Medical University School of Medicine, Japan)

HH and Precocious Puberty

Acilona Echeverria V, Casado Chocan JL, Lopez Dominguez JM, Aguilera Navarro JM, Marques Martin E, Munoz Villa C (1994) Gelastic seizures, precocious puberty and hypothalamic hamartomas. A case report and the contributions of Single Photon Emission Computed Tomography (SPECT). Neurologia, 9 (2): 61-4.
We present a patient with gelastic seizures, precocious puberty and a hypothalamic hamartoma. The diagnostic method of choice for hypothalamic hamartoma is new generation MRI. The characteristic MRI images along with lack of growth during the course of disease indicates a diagnosis of hamartoma firmly with no need for pathological studies. Although the physical nature of gelastic seizures in this syndrome is a subject of dispute, SPECT findings point to activity at a distance from nerve routes connecting the hypothalamus to the cortical regions (the temporal region in this case). Prognosis improves if the various components of the syndrome are treated early and when dysgenesis is less extensive.
(Servico de Neurologia, Hospital Universitario Virgen del Rocio, Sevilla)

Alikchanov AA, Petrukhin AS, Mukhin K Yu, Nikanorov A Yu (1998) Gelastic epilepsy, hypothalamic hamartoma, precocious puberty, and agencies of the corpus callosum: a new association. Brain & Development, 20 (4): 239-41.
We describe a boy who has gelastic epilepsy, precocious puberty, hypothalamic hamartoma, and agenesis of the corpus callosum. We believe that this is the first documented case in which agenesis of the corpus callosum has been associated with hypothalamic hamartoma and gelastic epileptic syndrome in a child.
(Department of Computed Tomography, Russian Childcare Hospital, Moscow)

Alvarez-Garijo JA, Albiach VJ, Vila MM, Mulas F, Esquembre V (1983) Precocious puberty and hypothalamic hamartoma with total recovery after surgical treatment. Case Report. Journal of Neurosurgery, 58 (4): 583-85.
No abstract available.

Alvarado J, Lopez JM (2001) Hypothalamic hamartoma causing precocious puberty: A case report. Revista Medica de Chile, 129 (10):1179-82
Hypothalamic hamartomas are non neoplastic lesions that may cause precocious puberty with or without complex seizures, personality disorders and mental retardation. We report a 14 years old male that had a precocious puberty at the age of 11 and a prolonged episode of altered sensorium with automatism, that was diagnosed as a complex seizure. Physical examination showed a sexual development classified as Tanner stage III-IV, a height of 168 cm and a weight of 61 kg. Neurological examination was normal. A CAT scan showed a 13 x 13 x 9 mm mass in the suprasellar cistern, between the infundibulum and the brain stem, without exerting a mass effect over adjacent structures. It was diagnosed as an hypothalamic hamartoma.

Ames FR, Enderstein O (1980) Gelastic epilepsy and hypothalamic hamartoma. South African Medical Journal, 58 (4): 163-65.
The clinical, electro-encephalographic and neuroradiological findings in 2 boys with gelastic epilepsy are described. Both patients had hypothalamic masses thought to be hamartomas, and 1 had precocious puberty. These 2 cases are compared with a previously published case of gelastic epilepsy with a left temporal focus. It was not possible to differentiate the hypothalamic lesions from the left temporal lesion on clinical grounds. The laughter in the hypothalamic group did not lack affect, as described by some other authors. Interictal EEGs in the patients with hypothalamic lesions showed generalized wave-spike activity, whereas localized abnormality was present in the patient with a left temporal EEG focus. Ictal recordings were the same in both groups. The combination of gelastic epilepsy and precocious puberty is rare. Only 10 cases have been reported in the literature, our patient being the 11th.

Arisaka O, Negishi M, Numata M, Hoshi M, Kanazawa S, Oyama M, Nitta A, Suzumuara H, Kuribayashi T, Nakayama Y (2001) Precocious puberty resulting from congenital hypothalamic hamartoma: persistent darkened areolae after birth as the hallmark of estrogen excess. Clinical Pediatrics, 40 (3): 163-7.
No abstract available
(Department of Pediatrics, Dokkyo University School of Medicine, Mibu, Tochigi, Japan)

Berningstall GN (1985) Gelastic seizures, precocious puberty and hypothalamic hamartoma. Neurology, 35: 1180-83.
The concurrence of gelastic (laughing) seizures and precocious puberty has been reported in 18 patients, including 2 described here. At least 10 patients had hypothalamic hamartomas. Improvements in cerebral imaging permit noninvasive diagnosis. Surgical intervention in seven of these patients was of little diagnostic or therapeutic benefit.

Biswas K, Kapoor A, Jain S, Ammini AC (2000) Hypothalamic hamartoma as a cause of precocious puberty in neurofibromatosis type 1: patient report. Journal of Pediatric Endocrinology, 13 (4): 443-4.
Precocious puberty resulting from hypothalamic hamartoma is well known. Neurofibromatosis type 1 can also present with precocious puberty. However, hypothalamic hamartoma as the cause of precocious puberty in patients with neurofibromatosis type 1 has never been described in the literature. This rare occurrence of these two together in a patient with precocious puberty is reported.
(Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi)

Cacciari E, Zucchini S, Carla G, Pirazzoli P, Cicognani A, Mandini M, Busacca M, Trevisan C (1990) Endocrine function and morphological findings in patients with disorders of the hypothalamo-pituitary area: a study with magnetic resonance. Archives of Disease in Childhood, 65 (11): 1199-202.
Evaluation of the sellar area was performed with magnetic resonance imaging in 101 patients (age range 0.8-27 years) with hypopituitarism, isolated diabetes insipidus, hypogonadotrophic hypogonadism, and central precocious puberty. The hypopituitary patients (n = 70) included multiple pituitary deficiency (n = 23), pituitary deficiency with diabetes insipidus (n = 5), and isolated growth hormone deficiency (n = 42). The patients with multiple pituitary deficiency showed pathological morphological findings in all cases, with stalk and posterior lobe always involved. The group with associated diabetes insipidus had abnormal stalk in four of five cases and posterior lobe not visible in all cases. Only five of 42 (12%) patients with isolated growth hormone deficiency had abnormalities of the sellar area. In two out of four patients with isolated diabetes insipidus posterior lobe was not seen. All patients with hypogonadotrophic hypogonadism (three with Kallmann's syndrome, one Prader-Willi syndrome, and two idiopathic hypogonadism) appeared normal. In precocious puberty (n = 21) the three patients with onset of symptoms before age 2 years exhibited a hypothalamic hamartoma, whereas in the others with onset of puberty between age 2 and 7 the magnetic resonance image was normal in 17 of 18 patients. The probability of finding a pathological magnetic resonance image was considerably high in our patients with multiple pituitary deficiency, isolated diabetes insipidus, and precocious puberty with very early onset of symptoms. On the contrary, purely functional abnormality is suggested in most patients with isolated growth hormone deficiency, hypogonadotrophic hypogonadism, and precocious puberty with later onset of symptoms.

Cassio A, Cacciari E, Zucchini S, Balsamo A, Diegoli M, Orsini F (2000) Central precocious puberty: clinical and imaging aspects. Journal of Pediatric Endocrinology, 13 Suppl 1: 703-8.
We review briefly the definition of central precocious puberty (CPP), and discuss early puberty and very early puberty. The association of hypothalamic hamartoma and empty sella with CPP is described. The contribution of new imaging techniques - CT, MRI and ultrasound in the differential diagnosis of CPP is discussed.
(Department of Pediatrics, University of Bologna, Italy)

Comite F, Pescovitz OH, Rieth KG, Dwyer AJ, Hench K, McNemar A, Loriaux DL, Cutler GB Jr (1984) Luteinizing hormone-releasing hormone analog treatment of boys with hypothalamic hamartoma and true precocious puberty. Journal of Clinical Endocrinology & Metabolism, 59 (5): 888-92.
A long-acting analog of LRH (LRHa) has been shown to suppress pituitary gonadotropin and estradiol secretion to prepubertal levels in girls with idiopathic true precocious puberty. We treated six boys, aged 1-6 yr, with true precocious puberty due to hypothalamic hamartoma for 6-24 months with daily sc injections of LRHa. The patients had enlarged testes (6-25 ml), Tanner stage II-IV pubic hair, facial and axillary hair, increased growth rate, and an advanced bone age. Frequent erections occurred in all patients. Computed tomography of the head showed abnormalities characteristic of hypothalamic hamartoma (0.5-3 cm in diameter) in each boy. Each patient had measurable LH and FSH levels, with pulsed nocturnal secretion, and pubertal LH and FSH responses to LRH. Serum testosterone was in the range for normal adult men (200-600 ng/dl). LRHa significantly decreased basal LH (P less than 0.005) and FSH levels (P less than 0.01), LRH-stimulated gonadotropin levels (P less than 0.005), and serum testosterone levels (P less than 0.005). Testis size decreased significantly (P less than 0.005). Annualized growth velocity (centimeters per yr) decreased significantly compared to the pretreatment growth rate (P less than 0.01). Bone age advancement per yr slowed significantly during the course of LRHa treatment (P less than 0.01). Pubic hair, facial hair, and erections decreased in all patients. LRHa is an effective treatment for boys with precocious puberty associated with hypothalamic hamartoma. Chronic therapy will be required, however, to assess the ultimate effect of LRHa.

Commentz JC, Helmke K (1995) Precocious puberty and decreased melatonin secretion due to a hypothalamic hamartoma. Hormone Research, 44 (6): 271-5.
Hypothalamic hamartomata are benign malformations of the brain consisting of heterotopic nervous tissue, and are often associated with precocious puberty and gelastic seizures in early childhood. We report for the first time the melatonin plasma values of a girl with central precocious puberty and gelastic seizures due to a hypothalamic hamartoma. The melatonin plasma levels were low for the chronological age but appropriate for the pubertal status, making a causal relationship between lowered melatonin plasma levels and precocious puberty possible.
(Department of Pediatrics UKE, University of Hamburg, Germany)

Culler FL, James HE, Simon ML, et al (1985) Identification of gonadotropin-releasing hormone in neurons of a hypothalamic hamartoma in a boy with precocious puberty. Neurosurgery, 17: 408-12.
We have studied a 3 1/12-year-old boy who presented with a hypothalamic mass and precocious puberty. His history suggested a course of isosexual precocity progressing from birth. Gelastic seizures also began at an early age. Endocrine evaluation revealed normal thyroid-stimulating hormone and growth hormone secretion, elevated basal and stimulated prolactin concentrations, and luteinizing hormone responses to sequential intravenous injections of gonadotropin-releasing hormone (GnRH) that were pubertal in pattern and magnitude. A needle biopsy of the mass recovered tissue that contained neurons histologically similar to those found in the normal hypothalamus, and the mass was characterized as a hypothalamic hamartoma. Immunohistochemical staining of this tissue with anti-GnRH antiserum demonstrated positive staining for GnRH immunoreactivity in neurons. This suggests a neurosecretory pathogenesis for the precocious puberty found in patients with hamartomas in the hypothalamic region.

Curatolo P, Cusmai R (1986) Gelastic seizures, precocious puberty and hypothalamic hamartoma. Neurology, 36 (3): 443-4.
No abstract available.

Curatolo P, Cusmai R, Finocchi G, Boscherini B (1984) Gelastic epilepsy and true precocious puberty due to hypothalamic hamartoma. Developmental Medicine & Child Neurology, 26 (4): 509-27.
A new case of gelastic epilepsy and precocious puberty due to hypothalamic hamartoma is reported. After long-term medical treatment there was no observable neurological or endocrinological improvement and the clinical outcome was poor. The authors consider that early surgery for hamartoma should be reconsidered.

Dammann O, Commentz JC, Valdueza JM et al (1991) Gelastic epilepsy and precocious puberty in hamartoma of the hypothalamus. Klinische Padiatrie, 203 (6): 439-47 (in German).
Four cases of hypothalamic hamartoma leading to gelastic epilepsy, precocious puberty and behavioural disorders are reported. Cerebral neuroradiologic examinations revealed a tumor-like mass attached to the hypothalamus in the region of the mamillary bodies in all cases. Precocious puberty developed in the two girls at 4 and 13 months but in neither of the two boys, who both suffered behaviour disturbances in the form of aggressive outbursts. A total resection of the tumors of both boys led to histologic confirmation of hamartoma. One boy was free of seizures upon follow-up, whereas seizure frequency in the other boy was reduced, while his aggressivity increased. The cases are discussed in context of current therapeutic conceptions of gelastic epilepsy and central precocious puberty.
(Universitatskinderklinik Hamburg-Eppendorf, Germany)

Date I, Yagyu Y, Mino S, Ohhashi T (1985) Hypothalamic hamartoma with precocious puberty – a case report. No Shinkei Geka – Neurological Surgery, 13 (6) 633-8 (in Japanese).
A case of hypothalamic hamartoma with precocious puberty is presented and the literature of reported cases is reviewed. An 8-year-old boy was admitted to our hospital because of precocious puberty and mental retardation. His genital development was Tanner's stage 4 and pubic hair was Tanner's stage 3. Bone age was 11 years. Plain CT showed an isodense mass in the suprasellar cistern which was not enhanced following contrast administration. Metrizamide CT cisternography showed a filling defect in the suprasellar cistern. Endocrinological evaluation revealed high levels of serum luteinizing hormone (LH) and testosterone with a marked response of LH to LH-RH injection. A left frontotemporal craniotomy was performed and the tumor was partially removed. The tumor was gray, firm and well-circumscribed with poor vascularity. Postoperatively, a right oculomotor palsy and transient diabetes insipidus developed. He was discharged ambulatory one month later. Serum LH and testosterone returned to normal and the response of LH to LH-RH injection became normal. Hamartoma was diagnosed on histological examination. Electron micrographic study showed numerous dense granules with approximately 0.1 mu in diameter, in which Judge proved LH-RH by immunofluorescent study in 1977. Our case supports the hypothesis that hypothalamic hamartoma may cause precocious puberty by autonomous secretion of LH-RH and we consider that neurosurgical treatment is recommended.

De Brito VN, Latronico AC, Arnhold U, Lo LS, Domenice S, Albano MC, Fragoso MC, Mendonca BB (1999) Treatment of gonadotropin dependent precocious puberty due to hypothalamic hamartoma with gonadotropin releasing hormone agonist depot. Archives of Disease in Childhood, 80 (3): 231-4.
The gonadotropin releasing hormone (GnRH) secreting hypothalamic hamartoma (HH) is a congenital malformation consisting of a heterotopic mass of nervous tissue that contains GnRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle. HH is a well recognised cause of gonadotropin dependent precocious puberty (GDPP). Long term data are presented on eight children (five boys and three girls) with GDPP due to HH. Physical signs of puberty were observed before 2 years of age in all patients. At presentation with sexual precocity, the mean height standard deviation (SD) for chronological age was +1.60 (1.27) and the mean height SD for bone age was -0.92 (1.77). Neurological symptoms were absent at presentation and follow up. The hamartoma diameter ranged from 5 to 18 mm and did not change in six patients who had magnetic resonance imaging follow up. All patients were treated clinically with GnRH agonists (GnRH-a). The duration of treatment varied from 2.66 to 8.41 years. Seven of the eight children had satisfactory responses to treatment, shown by regression of pubertal signs, suppression of hormonal levels, and improvement of height SD for bone age and predicted height. One patient had a severe local reaction to GnRH-a with failure of hormonal suppression and progression of pubertal signs. It seems that HH is benign and that GnRH-a treatment provides satisfactory and safe control for most children with GDPP due to HH.
(Developmental Endocrinology Unit, Sao Paulo University Medical School, Brazil)

Deonna T, Ziegler AL (2000) Hypothalamic hamartoma, precocious puberty and gelastic seizures: a special model of “epileptic” developmental disorder. Epileptic Disorders, 2 (1): 33-7.
Based on a review of the literature and a detailed longitudinal single case study of a child with early onset gelastic seizures and hypothalamic hamartoma, the authors review the arguments suggesting that the acquired cognitive and behavioral symptoms seen in the majority of cases of this special epileptic syndrome result from a direct effect of the seizures. The early neurobehavioral profile of the case presented in this paper and that of a previous study is particular and combines features of a pervasive developmental and an attention deficit disorder which are probably closely related to the particular location of the epilepsy and its spread from the hypothalamus.
(Pediatric Department, CHUV, Lausanne, Switzerland)

De Sanctis V, Corrias A, Rizzo V, Bertelloni S, Urso L, Galluzzi F, Pasquino AM, Pozzan G, Guarneri MP, Cisternino M, De Luca F, Gargantini L, Pilotta A, Sposito M, Tonini G (2000) Etiology of central precocious puberty in males: the results of the Italian Study Group for Physiopathology of Puberty. Journal of Pediatric Endocrinology, 13 Suppl 1: 687-93.
We reviewed the hospital records of 45 boys, followed in 13 pediatric departments throughout Italy, who had undergone computed tomography and/or magnetic resonance imaging for central precocious puberty (CPP). Twenty-seven patients (60%) had idiopathic CPP and 18 (40%) neurogenic CPP. A hamartoma of the tuber cinereum was found in six patients (33%). All patients with hypothalamic hamartoma had earlier onset of symptoms than patients with idiopathic CPP. Five patients (27%) were affected by type 1 neurofibromatosis, two had ependymoma and five patients had an intracranial anomaly. Basal LH and basal and peak LH/FSH ratio were greater, but not significantly, in boys with neurogenic CPP than in boys with idiopathic CPP. The highest LH peak levels were observed in patients with hamartoma; however,no correlation was observed between LH peak and the size of the hamartomas. In addition, bone age at diagnosis was more advanced in patients with hamartoma than in patients with other conditions. In conclusion, gonadotrophin-dependent precocious puberty may be of idiopathic origin or may occur in association with any CNS disorder. Further studies are needed in order to evaluate the effects of nutritional, environmental and psychosocial factors on the timing of sexual maturation, to explain the high incidence of idiopathic CPP in our male patients.
(Division of Pediatric and Adolescent Medicine, Azienda Ospedaliera Arcispedale S. Anna, Ferrara, Italy)

Feilberg Jorgensen N, Brock Jacobsen B, Ahrons S, Starklink H (1998) An association of hypothalamic hamartoma, central precocious puberty and juvenile granulosa cell tumour in early childhood. Hormone Research, 49 (6): 292-4.
A case of central precocious puberty from infancy due to a hypothalamic hamartoma and associated with an ovarian juvenile granulosa cell tumour is presented. Central precocious puberty was diagnosed by gonadotropin stimulation tests and LHRH agonist therapy was successful. A MR scan, but not a CT scan, demonstrated the hypothalamic hamartoma. The possible influence of early LH stimulation for the development of the granulosa cell tumour is discussed.
(Department of Paediatrics, Odense University Hospital, Denmark)

Feuillan PP, Jones JV, Barnes K, Oerter-Klein K, Cutler GB Jr (2000) Boys with precocious puberty due to hypothalamic hamartoma: reproductive axis after discontinuation of gonadotropin-releasing hormone analog therapy. Journal of Clinical Endocrinology & Metabolism, 85 (11): 4036-8.
Hypothalamic hamartoma is an important cause of precocious puberty in boys. Although the GnRH analogs are known to be effective therapy, there are few studies of the recovery of the pituitary-gonadal axis following long-term treatment. To this end, we studied 11 boys with HH after 8.8+/-3.2 yr (range, 4.0-12.6) of treatment with the GnRH agonist D-Trp6,Pro9,NEt-LHRH. The patients' levels of LH and FSH, testosterone, testis volume, and body mass index were compared with those of six normal boys in pubertal stage IV-V. We found that the patients' mean +/- SD peak GnRH-stimulated LH and FSH had returned to the normal range by 1 yr after stopping therapy. Whereas testosterone returned to normal levels by 1 yr, the patients' testis volume remained smaller than normal until 2 yr after therapy. Ultrasonography revealed diffuse, punctate, echogenic foci in the testicular parenchyma of two patients; these were first observed during GnRH agonist therapy and persisted unchanged after discontinuation of treatment. Neither of these two patients reported pain or testicular discomfort, no mass or irregularity was detected by manual examination in either patient at any time, and levels of beta-hCG and alpha1-fetoprotein were normal. By 4 yr after therapy, all patients had pubertal stage V pubic hair; their body mass index was not different from that of the normal boys at any time point. The dimensions of the patients' hamartomas did not change during or after therapy, and no patient reported new neurological symptoms or signs suggestive of an enlarging lesion at any time during or after discontinuation of treatment. Two families did report episodes of emotional lability and truancy as the patients reentered puberty after discontinuation of treatment.
(Developmental Endocrinology Branch, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland, USA)

Feuillan PP, Jones JV, Barnes K, Oerter-Klein K, Cutler GB Jr (1999) Reproductive axis after discontinuation of gonadotropin-releasing hormone analog treatment of girls with precocious puberty: long term follow-up comparing girls with hypothalamic hamartoma to those with idiopathic precocious puberty. J Clin Endocrinol Metab, 84 (1): 44-9.
Although the GnRH agonist analogs have become an established treatment for precocious puberty, there have been few long term studies of reproductive function and general health after discontinuation of therapy. To this end, we compared peak LH and FSH after 100 microg sc GnRH, estradiol, mean ovarian volume (MOV), age of onset and frequency of menses, body mass (BMI), and incidence of neurological and psychiatric problems in 2 groups of girls: those with precocious puberty due to hypothalamic hamartoma (HH; n 18) and those with idiopathic precocious puberty (IPP; n = 32) who had been treated with deslorelin (4-8 microg/kg x day, s.c.) or histrelin (10 microg/kg x day, s.c.) for 3.1-10.3 yr and were observed at 1, 2, 3, and 4-5 yr after discontinuation of treatment. The endocrine findings were also compared to those in 14 normal perimenarcheal girls. There were no differences between the HH and IPP groups in age or bone age at the start of treatment, at the end of treatment, or during GnRH analog therapy. We found that whereas the peak LH level was higher in HH than in IPP girls before (165.5 +/- 129 vs. 97.5 +/- 55.7; P < 0.02) and at the end (6.8 +/- 6.0 vs. 3.9 +/- 1.8 mIU/mL; P < 0.05) of therapy, this difference did not persist at any of the posttherapy time points. LH, FSH, and estradiol rose into the pubertal range by 1 yr posttherapy in both HH and IPP. However, the mean posttherapy peak LH levels in both HH and IPP groups tended to be lower than normal, whereas the peak FSH levels were not different from normal, so that the overall posttherapy LH/FSH ratio was decreased compared to that in the normal girls (HH, 2.7 +/- 0.3; IPP, 2.6 +/- 0.1; normal, 5.2 +/- 4.8; P < 0.05). The MOV was larger in HH than IPP at the end of treatment (3.7 +/- 3.5 vs. 2.0 +/- 1.2 mL; P < 0.05) and tended to increase in both groups over time to become larger than that in normal girls by 4-5 yr posttherapy (HH, 14.9 +/- 12.9; IPP, 7.6 +/- 2.2; normal, 5.4 +/- 2.5 mL; P < 0.05). Whereas the onset of spontaneous menses varied widely in both groups, once menses had started, the HH group had a higher incidence of oligomenorrhea. Pelvic ultrasonography revealed more than 10-mm hypoechoic regions in 4 HH patients, 15 IPP patients, and 3 normal girls, all of whom were reporting regular menses. Live births of normal infants were reported by 2 HH and 2 IPP patients, and elective terminations of pregnancy were reported by 1 HH and 2 IPP patients. BMI was greater than normal in HH and IPP both before treatment and at all posttherapy time points and tended to be higher in the HH patients. Marked obesity (BMI, +2 to +5.2 SD score) was observed in 5 HH and 6 IPP patients, 1 of whom had a BMI of +2.5 SD score and developed acanthosis nigricans, insulin resistance, and hyperglycemia. Seizure disorders developed during GnRH analog therapy in 5 HH and 1 IPP patient, and 2 additional HH girls developed severe depression and emotional lability posttherapy. Although the mean anterior-posterior dimension of the hamartoma was larger in the HH patients with seizure than in those who were seizure free (1.7 +/- 1.2 vs. 0.9 +/- 0.4 cm; P < 0.05), no change in hamartoma size was observed either during or after therapy, and no patient has reported the onset of a seizure disorder posttherapy. Other than a tendency toward a larger MOV, a higher incidence of oligomenorrhea, obesity, and frequency of neurological disorders, recovery of the reproductive axis after GnRH analog therapy was not markedly different in HH compared to IPP. Continued follow-up of these patients may determine whether the decreased LH responses and increased BMI in both groups compared to those in normal girls remain clinically significant problems.
(Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA)

Gaggero R, Baglietto MP, Boragno F, et al (1991) Epilepsy with laughing seizures, hypothalamic hamartoma and precocious puberty. Contributions of MRI, computed EEG topography (CET) and ambulatory EEG (A-EEG). Minerva Pediatrica, 43 (12): 801-10 (in Italian).
The concurrence of gelastic (laughing) seizures, hypothalamic hamartoma and precocious puberty constitutes a well defined epileptic syndrome in children; moreover mental retardation, neuropsychological deterioration and behavioral disorders have been often observed in these patients. In two cases we studied by means of MRI the appearance and the site of the hamartoma (in the posterior part of the hypothalamus with extension toward the third ventricle). The EEG study was performed by means of repeated recordings, of Computed EEG Topography (CET) and of Ambulatory EEG (A-EEG): in both patients during interictal periods paroxysmal EEG discharges prevailing in temporal or fronto-temporal regions and slight abnormalities of the background activity in the same areas were detected. Laughing seizures were recorded in each patient particularly by means of A-EEG: in case 1 bursts of high-voltage activity ("theta" waves) followed by depression of the background rhythm and by irregular spike discharges located in left temporal region were observed; in patient 2 irregular generalised spike discharges followed by slow waves or by depression of the background activity were seen. The presence of local abnormalities in both patients can support the hypothesis that the cortex, especially of the temporal anterior lobe, is involved in the origin of the laughing seizures. The significance of the mechanisms of secondary generalization as regards the seriousness of the epilepsy and of the mental impairment in these patients is also suggested.
(Divisione e Cattedra di Neuropsichiatria Infantile, Istituto G. Gaslini, Universita di Genova)

Hadjilambris K, Fahlbusch R, Heinze E (1986) True precocious puberty of a girl with hamartoma of the CNS successfully treated by operation. European Journal of Pediatrics, 145 (1-2): 148-50.
A girl with precocious puberty due to a hypothalamic hamartoma is presented. At the age of 0.41 years vaginal bleeding was documented and signs of puberty were noted: PHIII, BII according to Tanner. The bone age was 1.3 years, and height velocity rose from the 50th to 90th percentile. Plasma concentrations of LH (5.85 mU/ml), FSH (3.29 mU/ml), growth hormone (30 ng/ml), and oestradiol (90 pg/ml) were elevated. The results of a neurological examination including an EEC recording as well as a skull roentgenogram, were unremarkable. The visual evoked potentials were grossly abnormal. A native and contrast CT scan visualized a tumour close to the suprasellar cisterna reaching the chiasma opticum. At the age of 1.2 years the tumours was removed. Histologically the tissue was identified as a hamartoma. Immediately after the operation vaginal bleeding ceased, pubertal development regressed, bone age did not advance any further, the visual evoked potentials normalized and the contrast CT did not show any tumour mass. The levels of LH, FSH, growth hormone and oestradiol 4 months post operation were decreased as follow: LH: 1.14 mU/ml, FSH: 0.70 mU/ml, GH: 15.1 ng/ml, oestradiol: 10 pg/ml. However, there was an increase of FSH (3 mU/ml) 1 year after the operation. No secondary sexual characters reappeared.

Hamilton RL (1997) Case of the month. July 1996 – precocious puberty. Brain Pathology, 7 (1): 711-2.
A 4 year old girl presented with precocious puberty. She had pubic hair, breast buds and showed a height and weight well above the 95th percentile. An MRI scan of the head revealed a discrete mass in the tuber cinereum which was surgically removed. Microscopic examination showed a hypothalamic hamartoma. The clinical, radiologic and microscopic findings in this case are "classic" for hypothalamic hamartoma Other clinical presentations are discussed. The patient's symptoms have regressed following surgery and there has been no regrowth in six months.
(University of Pittsburgh School of Medicine, Division of Neuropathology, PA, USA)

Harada K, Yoshida J, Wakabayashi T, Okabe H, Sugita K (1995) A super long-acting LH-RH analogue induces regression of hypothalamic hamartoma associated with precocious puberty. Acta Neurochirurgica, 137 (1-2): 102-5.
We treated a 1-year-old female with a hypothalamic hamartoma and precocious puberty with leuprolide acetate depot, a super long-acting hormone-releasing hormone analogue (Tap-144-SR; [D-Leu6-[des-Gly10-NH2] LH-RH ethylamide acetate). The infant's major symptoms were genital bleeding and gynaecomastia. The LH-RH analogue (30 micrograms/kg) was injected subcutaneously once every 4 weeks. Clinical and laboratory manifestations of precocious puberty showed marked improvement. A follow-up after 16 months of treatment, the size of the tumour decreased significantly and remained unchanged for 2 years of further follow-up. To the best of our knowledge, this is the first hypothalamic hamartoma case in whom a decrease of tumour size under treatment with LH-RH analogue has been documented. But, because diagnosis of hamartoma is only based on neuroradiological and not on histological examinations, the possibility of a gangliocytoma cannot be excluded with certainty.
(Department of Neurosurgery, Nagoya University School of Medicine, Japan)

Hochman HI, Judge DM, Reichlin S (1981) Precocious puberty and hypothalamic hamartoma. Pediatrics, 67 (2): 236-44.
A 3-year-old boy with true precocious puberty and hamartoma of the hypothalamus is described. Preliminary diagnosis was established by the presence of unusually advanced puberty and skeletal age without other evidence of central nervous system dysfunction, elevated blood gonadotropin and testosterone concentrations, and positive computed tomography scans. Pneumoencephalography further delineated the tumor. Hypothalamic-pituitary-gonadal and adrenal functions were studied. Release of gonadotropins after the injection of synthetic luteinizing hormone-releasing hormone and the suppression of luteinizing hormone and of testosterone by oral fluoxymesterone were comparable to maximal responses of normal men. The diagnosis was confirmed by histologic and electron microscopic study of an excised portion of the tumor. Immunofluorescence studies indicated the presence of luteinizing hormone-releasing hormone in the hamartoma and radioimmunoassays detected thyroid-stimulating hormone-releasing hormone and somatostatin. The hamartoma resembles an autonomously functioning accessory hypothalamus. The ectopic neuroendocrine pathways, however, are responsive to hormonal stimulation and feedback. The clinical, endocrinologic, and pathologic features of published cases of precocious puberty and hypothalamic hamartoma are reviewed. Advanced or rapidly progressive true precocious puberty in the very young with elevated concentrations of blood gonadotropins and gonadal steroids and positive pneumoencephalography appear to be characteristic.

Hsiao PH, Tsai WY, Lee JS, Liu HM, Hsieh FJ (1992) Hypothalamic hamartoma and precocious puberty: report of a case. Journal of the Formosan Medical Association, 91 (10): 1017-20.
Hypothalamic hamartoma is reported to be associated with precocious puberty. Here, the authors present a seven-year-old girl whose onset of puberty occurred at the age of two. Under the impression of idiopathic precocious puberty, cyproterone acetate was initially tried. Since the effect of her medication was not satisfactory, it was discontinued at the age of five years and 11 months. However, rapid advance of bone age and vaginal spotting recurred after the withdrawal of treatment. She was re-evaluated at the age of six, and a magnetic resonance image (MRI) study of the head revealed a hypothalamic hamartoma. At that time, a long-acting analog of luteinizing hormone-releasing hormone (LHRHa), leuprolide acetate, was prescribed. Her secondary sex characteristics regressed and her hypothalamic-pituitary-gonad axis was suppressed after treatment. The clinical presentation, mechanism and treatment of precocious puberty caused by hypothalamic hamartomas are fully discussed in this report.
(Department of Pediatrics, National Taiwan University Hospital, Taipei, R.O.C.)

Ishii T, Sato S, Anzo M, Sasaki G, Hasegawa T, Tamai S, Matsuo N (1999) Treatment with a gonadotropin-releasing-hormone analog and attainment of full height potential in a male monozygotic twin with gonadotropin-releasing-hormone-dependent precocious puberty. European Journal of Pediatrics, 158 (11): 933-5.
We report on a pair of male monozygotic twins, one unaffected and the other affected with gonadotropin-releasing hormone (GnRH)-dependent precocious puberty, and discuss the role of treatment with a GnRH analog in the attainment of full height potential in GnRH-dependent precocious puberty. At 1.6 years of age, the affected twin was studied for tall stature (+3.8 SD), and was diagnosed as having GnRH-dependent precocious puberty due to a hypothalamic hamartoma of the tuber cinereum. He was treated with oral cyproterone acetate (110-170 mg/m(2) daily) from 1.8 through 5. 0 years of age, with oral cyproterone acetate and intranasal buserelin acetate (700-900 microg/m(2) daily) from 5.0 through 7.5 years, and with intranasal buserelin acetate alone (1100- 1400 microg/m(2) daily) from 7.5 through 12.6 years. He attained a final height of 171.0 cm at 14.9 years of age (+0.10 SD) and his twin 170. 0 cm at 15.3 years of age (-0.10 SD), with their target height being 174.5 +/- 9.0 cm. This study indicates that GnRH analog treatment may preserve near full height potential in some patients with GnRH-dependent precocious puberty.
(Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan)

Judge JM, Kulin HE, Page R, Santen R, Trapukdi S (1977) Hypothalamic hamartoma: a source of luteinizing hormone-releasing factor in precocious puberty. New England Journal of Medicine, 296 (1): 7-10.
The presence of a hypothalamic hamartoma and precocious puberty in a 19-month-old boy provided an opportunity to study their relation. Excised tissue had the ultrastructural characteristics of an independent neuroendocrine unit -- i.e., neurons containing neurosecretory granules and blood vessels with fenestrated endothelium and double basement membranes. Immunofluorescence studies using specific antibody to luteinizing-hormone-releasing factor showed antigenicity to the factor in the hamartoma. The testicular-hypothalamic-pituitary axis was tested. Clomiphene unresponsiveness suggested a lack of maturation of central-nervous-system events characteristic of normal puberty. The negative feedback system between gonad and brain was intact but partially resistant to steroid suppression. These studies suggest that hypothalamic hamartomas may cause precocious puberty by autonomous production and release of luteinizing-hormone-releasing factor into vessels that communicate with the pituitary portal blood system.

Kammer KS, Perlman K, Humphreys RP, Howard NJ (1980) Clinical and surgical aspects of hypothalamic hamartoma associated with precocious puberty in a 15-month-old boy. Child's Brain, 7 (3): 150-7.
A case is reviewed of precocious puberty associated with hypothalamic hamartoma in a 15-month-old boy. The authors believe this to be the first documented case in which significant reductions occurred in the level of serum testosterone and in the result of the luteinizing hormone-releasing hormone (LHRH) infusion test following surgical removal of the tumor. Such surgery appears to be safe when a planned microsurgical course is employed.

Katayama H, Miyao M, Kobayashi S, Yanagisawa M, Yokota H, Mashiko T, Masuzawa T (1993) A case of hypothalamic hamartoma with gelastic seizures, precocious puberty, poly- and syndactyly. No to Hattatsu (Brain & Development), 25 (4): 341-6 (in Japanese).
We reported a 6-month-old boy, patient of hypothalamic hamartoma with a rare association of poly- and syndactyly, which developed gelastic seizures and precocious puberty. His birth was complicated by poly- and syndactyly in both hands and polydactyly in both feet, but other physical signs were normal. At 5 month of age, he visited our hospital because of a suspected seizure. On admission, physical and neurological examinations revealed increased size in penis and testes, and delayed psychomotor development. Gelastic seizures occurred up to 100 times a day, and were resistant to many anticonvulsants. Ictal EEG showed bursts of generalized high voltage slow waves. His serum LH and testosterone levels were elevated for his age. Brain CT and MRI demonstrated a hypothalamic mass lesion, which proved to be hamartoma by biopsy.
(Department of Pediatrics, Jichi Medical School, Tochigi)

Koelfen W, Wentz J (1991) Precocious puberty and laugh attacks. Monatsschrift fur Kinderheilkunde, 139 (8): 479-81 (in German).
A 7 year old girl presented with precocious puberty and ictal laughter. Brief, repetitive, stereotyped attacks of laughter were the first manifestation of the epileptic syndrome. Stages of puberty were noted as B III-IV and PH II according to Tanner. X-rays showed a bone age of 11 years and the weight increased from the 50th beyond 97th percentile. Plasma concentrations of LH, FSH, testosterone and Ostradiol were elevated. The CT scan was normal and a magnetic resonance imaging showed an hypothalamic hamartoma. The control of the seizures control and social adjustment were poor. MR scanning 3 years later showed no change in the size of the lesion.
(Universitats-Kinderklinik, Mannheim)

Kyuma Y, Kuwabara T, Chiba Y, Yamaguchi K, Sekido K, Yagishita S (1986) Controlling precocious puberty – surgical excision of hypothalamic hamartoma causing precocious puberty. No Shinkei Geka – Neurological Surgery, 14 (9): 1095-103 (In Japanese)
Among the causes of precocious puberty, hypothalamic hamartoma comprises a small percentage. However, the frequency of precocious puberty in the presence of hypothalamic hamartoma is quite high. Recently, results of surgery in 14 cases of hypothalamic hamartoma were reported. Precocious puberty completely subsided in three cases and slight improvement was achieved in another three cases. We performed surgery in four patients with hypothalamic hamartomas, with the goal of decreasing the symptoms of precocious puberty. The patients were two females (aged 1 yr, 3 mo and 6 mo) and two males (aged 3 yr, 7 mo and 1 yr, 9 mo). The main symptoms were precocious puberty and mental retardation of varying degrees. The males had excessive growth of body and external genitalia, while the females had genital bleeding and premature breast development. In each case, computed tomographic scans disclosed a round, isodense mass in the interpeduncular cistern, attached to the base of the hypothalamus. Contrast enhancement was negative. Endocrinologically, in case 1, testosterone was 92.6 ng/ml, FSH was 16 mIU/ml, and LH was 2.2 mIU/ml. Although LH was within normal limits, it overresponded to LH-RH stimulation. In case 2, estrogen was 13.5 ng/day, LH was 5.2 mIU/ml, FSH was 5.3 mIU/ml, and LH showed an exaggerated response to LH-RH stimulation. In case 3, testosterone was 362 ng/ml, LH was 8.8 mIU/ml, FSH was 4.8 mIU/ml, and LH showed an abnormally high response to LH-RH stimulation. In case 4, LH was 18.4 mIU/ml, FSH was 12.0 mIU/ml, and both hormones were stimulated abnormally strongly by LH-RH.

List CF, Dowman CE, Bagchi BK, Bebin J (1958) Posterior hypothalamic hamartomas and gangliogliomas causing precocious puberty. Neurology, 8: 164-74.
No abstract available.

Mahachoklertwattana P, Kaplan SL, Grumbach MM (1993) The luteinizing hormone-releasing hormone-secreting hypothalamic hamartoma is a congenital malformation: natural history. Journal of Clinical Endocrinology & Metabolism, 77 (1): 118-24.
The LHRH-secreting hypothalamic hamartoma (HH), a congenital malformation consisting of a heterotopic mass of nervous tissue that contains LHRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle, can cause true or central precocious puberty (TPP). We have suggested that it functions as an ectopic LHRH pulse generator independent of the central nervous system inhibitory mechanism that normally restrains the hypothalamic LHRH pulse generator. TPP associated with a hamartoma has all of the hormonal hallmarks of puberty, including a pubertal pattern of pulsatile LH and a pubertal plasma LH response to LHRH administration. Little is known about the natural history of HH. We present long term data on 10 children (5 females and 5 males) with TPP due to HH. Physical signs of puberty were observed at a mean age of 2.2 +/- 1.6 yr (range, 0.5-5.1). Two of 10 had a pedunculated mass, and 8 of 10 had a sessile mass. The hamartoma varied in diameter from 4-25 mm and did not change with time (3.5-8.7 yr). Four patients have a seizure disorder, 3 with gelastic seizures (1 with mental retardation) and 1 with tonic-clonic seizures. The shape of the hamartoma, sessile or pedunculated, did not correlate with the occurrence of seizures. At presentation with sexual precocity, the mean height SD for chronological age was +3.5 +/- 0.4, the mean height SD for bone age was -1.9 +/- 0.4, and the mean bone age SD for chronological age was +6.8 +/- 0.7. Baseline data were comparable to those of 10 females with idiopathic TPP. Nine of 10 HH patients and all idiopathic TPP patients were treated with a LHRH agonist. The response to therapy was excellent in both groups and indistinguishable. Nine of 10 HH children attend school regularly and, aside from those with seizures, have no neurological handicap. While surgical resection of the hamartoma has been recommended, it carries an increased risk of morbidity and mortality and, if removal is incomplete, does not arrest the sexual precocity. In our experience, LHRH agonist therapy for TPP due to HH is the preferable approach.
(Department of Pediatrics, University of California San Francisco, USA)

Matustik MC, Eisenberg HM, Meyer WJ (1981) Gelastic (laughing) seizures and precocious puberty. American Journal of Diseases of Children, 135(9): 837-8.
Gelastic (laughing) seizures are a rare phenomenon with fewer than 150 cases previously reported. These seizures have been reported to have a benign course in children. This article reviews the small subgroup of seven patients in whom such seizures were associated with precocious puberty and adds one additional case. When gelastic seizures are associated with precocious puberty, the patients often have mental retardation.

Minns RA, Stirling HF, Wu FC (1994) Hypothalamic hamartoma with skeletal malformations, gelastic epilepsy and precocious puberty. Developmental Medicine & Child Neurology, 36(26): 173-6.
A child is described who has skeletal malformations, gelastic epilepsy, precocious puberty and a hypothalamic hamartoma. The skeletal abnormalities were detected at birth, she developed gelastic epilepsy at the age of 3 years 5 months and precocious puberty at 3 years 8 months. A hypothalamic hamartoma was found on MRI. The precocious puberty has been successfully medically managed, though her seizures are difficult to control. The combination of all four features has not been described previously.

Money J, Hosta G (1967) Laughing seizures with sexual precocity: report of two cases. Johns Hopkins Medical Journal, 120: 326-36.
No abstract available.

Rappaport R, Brauner R (1989) Lack of adrenarche in two children with precocious puberty secondary to hypothalamic hamartoma. Hormone Research, 31 (5-6): 226-9.
Adrenarche, which occurs earlier than gonadarche in normal children, is marked by increases in plasma dehydroepiandrosterone and its sulfate (DHAS). Adrenarche and gonadarche can be dissociated in various situations, e.g. central precocious puberty, indicating that they are controlled by independent mechanisms. This report concerns 2 children with central precocious puberty secondary to hypothalamic hamartoma. Their plasma basal DHAS values, compared to other cases with central precocious puberty not secondary to hamartoma, remained low for chronological age and bone age over a follow-up of 6.3 (case 1) and 9.2 9.2 years (case 2): in case 1 (boy), DHAS was 9 micrograms/dl at chronological age 7.7 and bone age 13 years; in case 2 (girl), DHAS was 11 micrograms/dl for chronological age 10.5 and bone age 13.5 years. GH secretion was normal. Basal plasma cortisol levels as the levels during hypoglycemia and after corticotropin stimulation were all normal. These data suggest that hypothalamic hamartoma may affect the central control of adrenarche. They may also contribute to the diagnosis of hypothalamic hamartoma.
(Unit of Pediatric Endocrinology and Diabetes, Hopital des Enfants Malades, Paris, France)

Rivarola Belgorosky A, Mendilaharzu H, Vidal G (2001) Precocious puberty in children with tumours of the suprasellar and pineal areas: organic central precocious puberty. Acta Paediatrica, 90 (7): 751-6.
During the past 11 years, 115 children younger than 8/9 y of age (female/male) with tumours of the suprasellar or pineal areas were followed in our clinic to study the incidence of precocious puberty. In addition, type of central lesion, clinical characteristics and gonadotropic secretion were studied in order to elucidate the different mechanisms of gonadal activation. A control group of 21 patients with idiopathic precocious puberty and a control group of 10 age-matched patients with suprasellar tumours without precocious puberty were also studied. Precocious puberty associated with organic central lesions was found at diagnosis in 30 patients (26%), in 9 out of 48 patients with glial cell tumours (18.7%), 6 out of 9 patients with germ cell tumours (66.6%), 11 out of 11 patients with hypothalamic hamartomas (100%) and in 4 out of 4 patients with subarachnoid cysts or arachnoidocele (100%). Precocious puberty was not found in any of 36 patients with craniopharyngioma. With the exception of one patient with pineal germinoma, all lesions were localized to the suprasellar area. In all patients with hypothalamic hamartoma, precocious puberty was diagnosed before 4 y of age, while in most patients with the other lesions, it was diagnosed after this age. Height SDS, weight increase and advancement of bone age were similar in both idiopathic and organic central precocious puberty. Maximal LH responses to GnRH in idiopathic and organic central precocious puberty were similar except for germ cell tumours. Patients with suprasellar tumours without precocious puberty had lower maximal LH (but not FSH) responses to GnRH, with the exception of germ cell tumours. In the latter, elevation of serum beta-hCG indicates that this gonadotropin was responsible for gonadal stimulation. In hypothalamic hamartomas, the prepubertal hiatus in the activity of the GnRH pulse generator was absent. The mechanism of this failure in the inactivation of GnRH is unknown. Data suggest that in glial cell tumours and in subarachnoid cysts, an unknown factor, probably secreted by the tumours, advances the tempo of GnRH maturation. Therefore, the aetiology of organic central precocious puberty is multiple and is directly related to location and type of lesion. This clinical information suggests that the onset of puberty is not the result of the disruption of a putative pulse generator inhibitory influence but the consequence of secretion of stimulatory substances by the lesions.
(Endocrinology Service, Hospital de Pediatria Garrahan, Buenos Aires, Argentina)

Sallum J, Assis LM, Andrade AR, Zaclis J, Toledo SP, Mattar E (1977) Precocious puberty due to hypothalamic hamartoma. Amb; Revista Da Associacao Medica Brasileira, 23 (3): 93-6 (in Portugese).
No abstract available.

Takeuchi J, Handa H (1985) Pubertas praecox and hypothalamic hamartoma. Neurosurgical Review, 8 (3-4): 225-31.
Precocious puberty of cerebral origin is classified into pseudoprecocious puberty and true precocious puberty. Pseudoprecocious puberty is caused by HCG secreting tumours. True precocious puberty is caused by various hypothalamic diseases. Among them, hypothalamic hamartoma is the most common cause. Precocious puberty is caused by elevated blood pituitary gonadotropin concentration, secondary to the elevated hypothalamic LHRH secretion. The hypothalamic hamartoma is not infrequently associated with laughing (gelastic) seizures as well as convulsions. Diagnosis of a hypothalamic hamartoma is easily made by CT. Although the hypothalamic hamartoma is difficult to operate on, the value of surgery is stressed for treatment of precocious puberty. This is also confirmed by recent reports.

Takeuchi J, Handa H, Miki Y (1979) Precocious puberty due to hypothalamic hamartoma. Surgical Neurology, 111: 456-60.
A case of precocious puberty due to a hypothalamic hamartoma is presented. Concentrations of plasma LH and FSH, testosterone and its derivatives were found to be elevated. Circadian rhythms of LH were also observed. After removal of the mass, plasma LH and FHS concentrations declined to nearly half the preoperative levels.

Turanli G, Aynaci M, Yalnizoglu D, Renda Y (1996) Hypothalamic hamartoma with gelastic epilepsy, precocious puberty and polydactyly. Turkish Journal of Pediatrics, 38 (4): 533-6.
An entity including gelastic epilepsy, precocious puberty, polydactyly and a hypothalamic hamartoma type IIa is described in a 16-year-old female patient. Polydactyly was detected at birth, she developed precocious puberty at four years of age, and gelastic epilepsy was diagnosed at age seven. The precocious puberty was successfully treated medically and her treatment was discontinued at the age of 10 years, but the gelastic seizures were difficult to control. When the patient was 11 years old, MRI revealed a hypothalamic hamartoma. The combination of these four features is very rare in the literature.
(Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara)

Turjman F, Xavier JL, Froment JC, Tran-Minh VA, David L, Lapras C (1996) Late MR follow-up of hypothalamic hamartomas. Childs Nervous System, 12 (2): 63-8.
The absence of changes over time in the diagnostic features of suspected hypothalamic hamartomas is of paramount importance. Since magnetic resonance (MR) imaging is very sensitive to modifications in the brain parenchyma, a late MR follow-up study was performed in five children. In all cases, the diagnosis of hypothalamic hamartoma has been suspected on the basis of the association of central precocious puberty and the presence of a mass in the inferior aspect of the hypothalamus, demonstrated on previous MR studies. Late MR evaluation (after a mean of 39 months) demonstrated stability of the lesions in shape, size, and signal intensity. In three cases the lesions demonstrated a rim of isointense signal with a hyperintense center on T2-weighted sequences. In two cases a Chiari I malformation was found in association with the hypothalamic malformation. In one case a pineal cyst was demonstrated. These unusual findings are discussed. Late MR follow-up showed the absence of changes in the lesions over time, allowing the diagnosis to be confirmed.
(Department of Radiology, Hopital Neurologique, Lyon, France)

Unger F, Schrottner O, Haselsberger K, Korner E, Ploier R, Pendl G (2000) Gamma knife radiosurgery for hypothalamic hamartoma for patients with medically intractable epilepsy and precocious puberty. Report of two cases. Journal of Neurosurgery, 92(4): 726-31.
Hamartoma of the hypothalamus represents a well-known but rare cause of central precocious puberty and gelastic epilepsy. Due to the delicate site in which the tumor is located, surgery is often unsuccessful and associated with considerable risks. In the two cases presented, gamma knife radiosurgery was applied as a safe and noninvasive alternative to obtain seizure control. Two patients, a 13-year-old boy and a 6-year-old girl, presented with medically intractable gelastic epilepsy and increasing episodes of secondary generalized seizures. Abnormal behavior and precocious puberty were also evident. Magnetic resonance (MR) imaging revealed hypothalamic hamartomas measuring 13 and 11 mm, respectively. After general anesthesia had been induced in the patients, radiosurgical treatment was performed with margin doses of 12 Gy to 90% and 60% of isodose areas, covering volumes of 700 and 500 mm3, respectively. After follow-up periods of 54 months in the boy and 36 months in the girl, progressive decrease in both seizure frequency and intensity was noted (Engel outcome scores IIa and IIIa, respectively). Both patients are currently able to attend public school. Follow-up MR imaging has not revealed significant changes in the sizes of the lesions. Gamma knife radiosurgery can be an effective and safe treatment modality for achieving good seizure control in patients with hypothalamic hamartomas.

Uriarte MM, Klein KO, Barnes KM, Pescovitz OH, Loriaux DL, Cutler GB Jr (1998) Gonadotrophin and prolactin secretory dynamics in girls with normal puberty, idiopathic precocious puberty and precocious puberty due to hypothalamic hamartoma. Clinical Endocrinology, 49 (3): 363-8.
This study was designed to test the hypothesis that hypothalamic hamartoma causes precocious puberty through a different neuroendocrine mechanism than that of normal puberty or of idiopathic precocious puberty. We compared the pattern of gonadotrophin secretion among 4 girls with precocious puberty due to hypothalamic hamartoma, 27 girls with idiopathic precocious puberty, and 14 girls with normal puberty. All subjects were breast stage 3 or 4. Blood samples were obtained every 20 min for 4 h during the day (1.000 hours to 1400 h) and night (22.00 hours to 0200 h). LH, FSH, and prolactin were measured in each blood sample. Girls also underwent LHRH-stimulation with measurement of LH and FSH before and after stimulation. RESULTS: There were no significant differences in mean LH level, LH peak amplitude, or LH or FSH peak frequency during either the day or the night among the three diagnostic groups. However, the mean +/- SD LHRH-stimulated peak LH levels were greater in girls with hypothalamic hamartoma than in girls with normal puberty or with idiopathic precocious puberty (194 +/- 142 vs 85 +/- 60 or 66 +/- 54 IU/l, respectively, P < 0.05). The LHRH-stimulated peak FSH level in girls with hypothalamic hamartoma exceeded the level for the normal pubertal girls (31 +/- 19 vs 17 +/- 7 IU/l, P < 0.05), but not the level for the girls with idiopathic precocious puberty (25 + 12 IU/l). The peak LH to peak FSH ratio in the girls with hypothalamic hamartoma exceeded the ratio for the girls with idiopathic precocious puberty (7.3 +/- 3.9 vs 2.6 +/- 3.0 IU/l, P < 0.05), but not the ratio for the normal pubertal girls (5.0 + 2.9). There were no significant differences in mean prolactin level, peak amplitude or frequency, or in the ratio of mean night to mean day prolactin, among the 3 diagnostic groups. We conclude that spontaneous gonadotrophin and prolactin secretion are similar among girls with hypothalamic hamartoma, idiopathic precocious puberty, or normal puberty. However, the increased LHRH-stimulated peak LH in the girls with hypothalamic hamartoma suggests subtle differences in neuroendocrine regulation that may underlie their more rapid pubertal maturation.
(Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA)

Vaquero J, Carrillo R, Oya S, Martinez R, Lopez R (1985) Precocious puberty and hypothalamic hamartoma. Report of a new case with ultrastructural data. Acta Neurochirurgica, 74 (3-4): 129-33.
A new case of hypothalamic hamartoma associated with precocious puberty is presented. After reviewing the literature, 23 other cases appeared. The ultrastructural study of the present case revealed common features with other hamartomatous lesions of the central nervous system and with the gangliogliomas. The data suggest that these lesions are morphologically organized in a very similar manner despite their very different growing potential.

Wang A, Nakasu Y, Ichikawa M, Nakasu S, Handa J, Okumura K, Ohya N (1987) Hypothalamic hamartoma associated with precocious puberty. Case report. Neurologia Medico-Chirurgica, 27 (4): 336-40. (In Japanese).

No abstract available.

Weinberger LM, Grant FC (1941) Precocios puberty and tumors of the hypothalamus. Arch Intern Med, 67: 762-92.
No abstract available.

Williams M, Schutt W, Savage D (1978) Epileptic laughter with precocious puberty. Archives of Disease in  Childhood, 53: 965-6.
No abstract available.

Wolman L, Balmforth GV (1963) Precocious puberty due to a hypothalamic hamartoma in a patient surviving to late middled age. Journal of Neurology, Neurosurgery and Psychiatry, 26: 275-80.
No abstract available.

Zaatreh M, Tennison M, Greenwood RS (2000) Successful treatment of hypothalamic seizures and precocious puberty with GnRH analogue. Neurology, 55 (12): 1908-10.
Patients with hypothalamic hamartomas and precocious puberty may develop gelastic seizures that are resistant to conventional antiepileptic drug therapies. While treating precocious puberty in two such patients with long-acting GnRH analogue, the authors observed cessation of gelastic seizures. Although the mechanism is unclear, long-acting GnRH analogue should be considered as a possible therapy for gelastic seizures in patients with hypothalamic hamartomas.
(Department of Neurology and Pediatric Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA)

Zuniga OF, Tanner SM, Wild WO, Mosier HD (1983) Hamartoma of CNS associated with precocious puberty. American Journal of Diseases of Children, 137 (2): 127-33.
A male infant had precocious puberty and hamartoma of the CNS. Signs of puberty appeared and progressed from 6 months of age. A computed tomographic scan disclosed an interpedunculary tumor. A craniotomy was successfully performed at 11/2 years of age, and 90% of the tumor was removed. Histologically, the tissue was identified as a hypothalamic hamartoma. Pubertal development stopped. The patient is now 4 years 9 months old and well. Review of medical literature covering a span of 47 years showed 50 cases of hamartomas in or near the hypothalamus confirmed by surgical exploration or autopsy. The male-female ratio of hamartomas with precocious puberty derived from these data is 2:1. Convulsions, mental retardation, or behavioral disorders were present in 48% of the cases; 36% had precocious puberty.

HH and Pallister-Hall Syndrome

Biesecker LG, Kang S, Schaffer AA, Abbott M, Kelley RI, Allen JC, Clericuzio C, Grebe T, Olney A, Graham JM Jr (1996) Exclusion of candidate loci and cholesterol biosynthetic abnormalities in familial Pallister-Hall syndrome. Journal of Medical Genetics, 33 (11): 947-51.
Pallister-Hall syndrome (PHS) was originally described in 1980 in six sporadic cases of children with structural anomalies including hypothalamic hamartoma, polydactyly, imperforate anus, and renal and pulmonary anomalies. In 1993, the first familial cases were reported, including affected sibs and vertical transmission. Three of these families are sufficiently large to allow initial evaluation by linkage studies to candidate genes or loci. We have evaluated candidate loci for PHS based on three clinical observations. The first is a patient with PHS-like malformations, including a hypothalamic hamartoma, and an unbalanced translocation involving 7q and 3p. The second is a family with familial PHS where the founder's father had an autosomal dominant hand malformation previously mapped to 17q. The third is the phenotypic overlap of PHS and Smith-Lemli-Opitz syndrome. In this report, we exclude these loci as candidates for linkage to the PHS phenotype on the basis of lod scores of less than-2.0. We conclude that hypothalamic hamartoma is not specific to PHS and that the dominant hand malformation in one of the families was a coincidence. To evaluate the relationship of PHS to Smith-Lemli-Opitz syndrome, we analysed levels of cholesterol and intermediate metabolites of the later stages of cholesterol biosynthesis. There is no evidence of a generalised disorder of cholesterol biosynthesis in patients with familial PHS. On genetic and biochemical grounds, we conclude that PHS and Smith-Lemli-Opitz syndrome are not allelic variants of a single locus.
(National Institutes of Health, National Center for Human Genome Research, Bethesda, Maryland, USA)

Cheng K, Sawamura Y, Yamauchi T, Abe H (1993) Asymptomatic large hypothalamic hamartoma associated with polydactyly in an adult. Neurosurgery, 32 (3): 458-60.

A hypothalamic hamartoma is a congenital tumor-like neural malformation. It is usually seen in children and is associated with neuroendocrinological symptoms, seizures, or psychological impairments. An asymptomatic hypothalamic hamartoma in an adult is extremely rare. This report describes an asymptomatic adult with a large hypothalamic hamartoma associated with polydactyly in his feet. Both polydactyly and hamartoma are rare lesions; therefore, this may not be a coincidental presentation. It is thought to have occurred in the embryonic period presumably between 37 and 40 gestational days.

(Department of Neurosurgery, Hokkaido University School of Medicine, Sapporo, Japan)

Feuillan P, Peters KF, Cutler GB Jr, Biesecker LG (2001) Evidence for decreased growth hormone in patients with hypothalamic hamartoma due to Pallister-Hall syndrome. Journal of Pediatric Endocrinology, 14 (2): 141-9.
Pallister-Hall syndrome (PHS) is characterized by hypothalamic hamartoma, bifid epiglottis, and central or postaxial polydactyly. Familial transmission is autosomal dominant; isolated cases also occur. To screen for hypothalamic-pituitary dysfunction in PHS, we studied a 12 year-old boy (patient #1), and 14 additional patients (patients #2-14: 7M, 7F; ages 4-72 yr). We performed serial sampling of GH, LH/FSH, TSH, and cortisol from 20.00-08 00 h. At 08.00 h, we measured IGF-I, peak responses of LH and FSH after GnRH, and cortisol after ACTH. We found that 6/7 children, including patient #1, and 6/8 adults had low or absent spontaneous GH secretion and/or low levels of IGF-I. Patient #1 also had accelerated pubertal development, but no other patient had abnormalities of the pituitary-gonadal axis, and none of the 14 patients had an abnormal thyroid or adrenal axis. We conclude that decreased pituitary GH secretion is common in PHS, and may exist in the absence of other forms of endocrine dysfunction.
(Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA)

Galasso C, Scire G, Fabbri F, Spadoni GL, Killoran CE, Biesecker LG, Boscherini B (2001) Long-term treatment with growth hormone improves final height in a patient with Pallister-Hall syndrome. American Journal of Medical Genetics, 99 (2): 128-31.
Pallister-Hall syndrome is a disorder of development consisting of hypothalamic hamartoma, pituitary dysfunction, central polydactyly and visceral malformations. This disorder is inherited as an autosomal dominant trait and is caused by mutations of the GLI3 gene encoding a zinc finger transcription factor. We describe a case of Pallister-Hall syndrome with growth hormone neurosecretory dysfunction, successfully treated with growth hormone until attainment of final height. We conclude that children with Pallister-Hall syndrome and short stature be evaluated carefully for spontaneous somatotropic function and, if necessary, treated with growth hormone.
(Department of Pediatrics, Tor Vergata University, Rome, Italy)

Grebe TA, Clericuzio C (1996) Autosomal dominant inheritance of hypothalamic hamartoma associated with polysyndactyly: heterogeneity or variable expressivity? American Journal of Medical Genetics, 66 (2): 129-37.
We report on a two-generation family exhibiting dominant inheritance of complex polysyndactyly associated with hypothalamic hamartoma. These individuals have some manifestations of Pallister-Hall syndrome (PHS), but their phenotype is milder. The proposita is a 16-year-old girl with polysyndactyly of the hands and feet, short stature, and a large hypothalamic hamartoma. Her brother and father also have polysyndactyly and a hypothalamic mass on MRI scan. All three have normal appearance and intelligence, with normal pituitary function. Several other paternal relatives have polysyndactyly as well. We propose that this family may represent a clinically and perhaps genetically distinct entity from PHS, based on normal survival, normal intelligence, lack of endocrine dysfunction or facial anomalies, and few other structural malformations. Linkage analysis is in progress to determine whether this represents a benign form of PHS or a genetically separate condition. The phenotypic differences between these cases and classic PHS have important prognostic and recurrence risk implications.
(Department of Pediatrics, University of Arizona College of Medicine, Phoenix, USA)

Iafolla K, Fratkin JD, Spiegel PK, Cohen MM Jr, Graham JM Jr (1989) Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome). American Journal of Medical Genetics, 33 (4): 489-99.
We report one new case of congenital hypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome) and one case of a diencephalic nodule associated with craniofacial malformations. Based on a review of 11 cases of Pallister-Hall syndrome documented by pathological examination, two cases presumed by phenotype, three cases of hypothalamic hamartoma with craniofacial anomalies only, and several cases of related interest, we delineate the clinical, neuroradiologic, and neuropathologic manifestations which aid in differential diagnosis. Clinical manifestations in infants with Pallister-Hall syndrome included postaxial polydactyly with nail dysplasia, short nose with flat nasal bridge, apparently low-set, posteriorly angulated ears, kidney and lung anomalies, congenital heart defects, imperforate anus, and micropenis with undescended or hypoplastic testes in males. These manifestations were associated with varying degrees of panhypopituitarism and pituitary aplasia. In three cases of hypothalamic hamartoma associated with craniofacial anomalies only, the face resembled that of holoprosencephaly. Other cases of hypothalamic hamartoma have had associated palate or heart defects or presented with precocious puberty. Of the infants with a hypothalamic hamartoblastoma at autopsy, neuropathologic findings were consistent with a primitive neuroectodermal tumor. Surgical tissue from our sole survivor suggested such tumors might mature, and the tumor has not recurred. Neuroradiologic diagnosis may be difficult but should be attempted in infants with these clinical manifestations; due to the need for prompt initiation of appropriate therapy.
(Department of Maternal and Child Health, Dartmouth Hitchcock Medical Center, Hanover, New Hampshire)

Kang S, Allen J, Graham JM Jr, Grebe T, Clericuzio C, Patronas N, Ondrey F, Green E, Schaffer A, Abbott M, Biesecker LG (1997) Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. Journal of Medical Genetics, 34 (6): 441-6.
Pallister-Hall syndrome is a human developmental disorder that is inherited in an autosomal dominant pattern. The phenotypic features of the syndrome include hypothalamic hamartoma, polydactyly, imperforate anus, laryngeal clefting, and other anomalies. Here we describe the clinical characterisation of a family with 22 affected members and the genetic mapping of the corresponding locus. Clinical, radiographic, and endoscopic evaluations showed that this disorder is a fully penetrant trait with variable expressivity and low morbidity. By analysing 60 subjects in two families using anonymous STRP markers, we have established linkage to 7p13 by two point analysis with D7S691 resulting in a lod score of 7.0 at theta = 0, near the GLI3 locus. Deletions and translocations in GLI3 are associated with the Greig cephalopolysyndactyly syndrome. Although Greig cephalopolysyndactyly syndrome has some phenotypic overlap with Pallister-Hall syndrome, these two disorders are clinically distinct. The colocalisation of loci for these distinct phenotypes led us to analyse GLI3 for mutations in patients with Pallister-Hall syndrome. We have previously shown GLI3 mutations in two other small, moderately affected families with Pallister-Hall syndrome. The linkage data reported here suggest that these larger, mildly affected families may also have mutations in GLI3.
(National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA)

Kang S, Graham JM Jr, Olney AH, Biesecker LG (1997) GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nature Genetics, 15 (3): 266-8.
Pallister-Hall syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations. This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hall syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)), co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene. Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly syndrome (GCPS; M175700) although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3' of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.
(Laboratory of Genetic Disease Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA)

Killoran CE, Abbott M, McKusick VA, Biesecker LG (2000) Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis. Clinical Genetics, 58 (1): 28-30.
The polydactyly, imperforate anus, vertebral anomalies syndrome (PIV, OMIM 174100) was determined as a distinct syndrome by Say and Gerald in 1968 (Say B, Gerald PS. Lancet 1968: 2: 688). We noted that the features of PIV overlap with the VATER association and Pallister-Hall syndrome (PHS, OMIM 146510), which includes polydactyly, (central or postaxial), shortened fingers, hypoplastic nails, renal anomalies, imperforate anus, and hypothalamic hamartoma. Truncation mutations in GL13, a zinc finger transcription factor gene, have been shown to cause PHS. We performed a molecular evaluation on a patient diagnosed with PIV, whose mother, grandfather, and maternal aunt had similar malformations. We sequenced the GLI3 gene in the patient to determine if she had a mutation. The patient was found to have a deletion in nucleotides 2188-2207 causing a frameshift mutation that predicts a truncated protein product of the gene. Later clinical studies demonstrated that the patient also has a hypothalamic hamartoma, a finding in PHS. We concluded that this family had atypical PHS and not PIV. This result has prompted us to re-evaluate the PIV literature to see if PIV is a valid entity. Based on these data and our examination of the literature, we conclude that PIV is not a valid diagnostic entity. We conclude that patients diagnosed with PIV should be reclassified as having VACTERL, or PHS, or another syndrome with overlapping malformations.
(Genetic Disease Research Branch, NHGRI/National Institutes of Health, Bethesda, Maryland, USA)

Kujat C, Moringlane JR, Low M, Feiden W (1994) Familial association of hypothalamic hamartoma and polysyndactyly. Radiologe, 34 (11): 662-5 (in German)
Hypothalamic hamartomas are congenital malformations. The association between hypothalamic hamartomas and other dysplasias, including polydactyly, is known to be a neonatal lethal syndrome. We report on two patients (mother and son) with asymptomatic large hypothalamic hamartomas and polysyndactyly. The relationship of the patients suggests an autosomal dominant transmission.
(Institut fur Neuroradiologie, Universitatskliniken des Saarlandes, Homburg/Saar, Germany)

Low M, Moringlane JR, Reif J, Barbier D, Beige G, Kolles H, Kujat C, Zang KD, Henn W (1995) Polysyndactyly and asymptomatic hypothalamic hamartoma in mother and son: a variant of Pallister-Hall syndrome. Clinical Genetics, 48 (4): 209-12.
We report on a 53-year-old woman and her 20-year-old son who both presented with polysndactyly, without other external malformations or mental retardation. MRI imaging revealed, as an incidental finding, asymptomatic hypothalamic hamartomas in both patients. The siblings of both mother and son are unaffected. This family may represent an autosomal dominant variant of Pallister-Hall syndrome.
(Institute of Human Genetics, Saarland University, Homburg, Germany)

Ondrey F, Griffith A, Van Waes C, Rudy S, Peters K, McCullagh L, Biesecker LG (2000) Asymptomatic laryngeal malformations are common with patients with Pallister-Hall syndrome. American Journal of Medical Genetics, 94 (1): 64-7.
Pallister-Hall syndrome (PHS) comprises hypothalamic hamartoma, polydactyly, pituitary dysfunction, laryngotracheal cleft, imperforate anus, and other anomalies. Some patients with PHS have a bifid epiglottis, a rare malformation. Greig cephalopolysyndactyly syndrome (GCPS) comprises polydactyly with craniofacial malformations without the PHS malformations. Both disorders are caused by mutations in the GLI3 gene. Laryngoscopy on 26 subjects with PHS showed that 15 had a bifid or cleft epiglottis (58%) and none of 14 subjects with GCPS had a cleft epiglottis. The malformed epiglottis was asymptomatic in all of the prospectively evaluated subjects. One additional PHS subject was found to have bifid epiglottis and a posterior laryngeal cleft on autopsy. We conclude that bifid epiglottis is common in PHS but not GCPS. Posterior laryngeal clefts are an uncommon manifestation of PHS and are identified only in severely affected patients. The diagnosis of a bifid epiglottis should prompt a thorough search for other sometimes asymptomatic anomalies of PHS to provide better medical care and recurrence risk assessment for affected individuals and families.
(National Institute on Deafness and Other Communication Disorders, the National Institutes of Health, Bethesda, Maryland, USA)

Squires LA, Constantini S, Miller DC, Wisoff JH (1995) Hypothalamic hamartoma and the Pallister-Hall syndrome. Pediatric Neurosurgery, 22 (6): 303-8.
The Pallister-Hall syndrome (PHS) was initially described as the congenital hypothalamic 'hamartoblastoma' syndrome in 1980. Cardinal manifestations of the syndrome consist of a hypothalamic hamartoma and extracranial abnormalities, initially thought to be fatal in the perinatal period. The original pathologic description of these hypothalamic lesions were from infants who died in the perinatal period and revealed small cells of variable density which resembled primitive undifferentiated germinal cells and appeared to invade the hypothalamic nuclei, suggesting a neoplastic potential. Hypothalamic lesions have now been removed from older infants and children with this syndrome and reveal a more mature histologic appearance typical of a hypothalamic hamartoma. We present 2 new cases of PHS who underwent surgery and demonstrate the maturational nature of the hypothalamic lesion and the phenotypic variability of the syndrome.
(Department of Pediatrics, De Vos Children's Hospital, Michigan State University, Grand Rapids, USA)

Turanli G, Aynaci M, Yalnizoglu D, Renda Y (1996) Hypothalamic hamartoma with gelastic epilepsy, precocious puberty and polydactyly. Turkish Journal of Pediatrics, 38 (4): 533-6.
An entity including gelastic epilepsy, precocious puberty, polydactyly and a hypothalamic hamartoma type IIa is described in a 16-year-old female patient. Polydactyly was detected at birth, she developed precocious puberty at four years of age, and gelastic epilepsy was diagnosed at age seven. The precocious puberty was successfully treated medically and her treatment was discontinued at the age of 10 years, but the gelastic seizures were difficult to control. When the patient was 11 years old, MRI revealed a hypothalamic hamartoma. The combination of these four features is very rare in the literature.
(Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara)

HH and Other Conditions

Diaz LL, Grech KF, Prados MD (1991) Hypothalamic hamartoma associated with Laurence-Moon-Biedl syndrome. Case report and review of the literature. Pediatric Neurosurgery, 17 (1): 30-3.
A rare case of a patient with Laurence-Moon-Biedl syndrome associated with hypothalamic hamartoma is described. The English-language literature contains no cases of patients with this association. The clinical manifestations of this syndrome, those of hypothalamic hamartomas, and the appearance of the tumors on magnetic resonance images are discussed.
(Department of Neurological Surgery, School of Medicine, University of California, San Francisco, USA)

Fujiwara I, Kondo Y, Iinuma K (1999) Oral-facial-digital syndrome with hypothalamic hamartoma, postaxial ray hypoplasia of the limbs, and vagino-cystic communication: a new variant? American Journal of Medical Genetics, 83 (2): 77-81.
We report on a 20-month-old girl with hypothalamic hamartoma, left cerebral atrophy, tongue nodules, oral frenula, micrognathia, hypoplasia of the left ulna, the fibulae, and right tibia, polysyndactyly of the hands and feet, vagino-cystic drainage with hydrometrocolpos, megaloureters, and hydronephrosis, agenesis of urethra, complex partial seizures, and central precocious puberty. The differential diagnosis is discussed. We conclude that the malformation complex in this girl is an oral-facial-digital syndrome, but is different from any of the 11 known subtypes.
(Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan)

Goda M, Tashima A, Isono M, Hori S, Kimba Y (1999) A case of hypothalamic hamartoma associated with arachnoid cyst. Childs Nervous System, 15 (9): 490-2.
A 14-year-old girl presented with seizures. Radiological examinations revealed an arachnoid cyst in left middle fossa and a cystic mass in the interpeduncular cistern. The cyst was opened and the wall of the cyst and a mass were biopsied. The histological findings were characteristic of an arachnoid cyst and hamartoma, respectively. A hypothalamic hamartoma associated with an arachnoid cyst is comparatively rare; however, such a case may help clarify the genesis of this malformation.
(Department of Neurosurgery, Oita Medical University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan)

Kahane P, Di Leo M, Hoffmann D, Munari C (1999) Ictal bradycardia in a patient with hypothalamic hamartoma: a stereo-EEG study. Epilepsia, 40 (4): 522-7.
Little is known about bradycardia and cardiac asystole which occur during partial epileptic seizures, especially whether they relate to ictal involvement of well-defined cortical areas. Several reports based on simultaneous electrocardiographic and intracranial depth electroencephalographic monitoring have shown that either the fronto-orbital cortex or the amygdalohippocampal complex could be responsible for such cardiac variations. We performed stereo-EEG recordings in a patient with refractory localization-related epilepsy associated with a hypothalamic hamartoma. We found that other cortical areas, such as the frontocentral region and the temporal neocortex, can contribute to the genesis of ictal bradyarrhythmia. Second, the lesion per se, although located within the hypothalamus, is not involved with this phenomenon.
(Neurosciences Department, Grenoble Hospital, France)

Liow K, Weissenberger A, Dell M, Fratelli C, Zametkin A (in press) Characteristics of Aggression in HHUGS (Hypothalamic Hamartoma with Uncontrolled Gelastic Seizures).. Supplement to Epilepsia.
The syndrome of HHUGS (Hypothalamic Hamartoma with Uncontrolled Gelastic Seizures) is characterized by gelastic (laughing) seizures, congenital malformation of hypothalamic hamartoma (HH), cognitive deterioration and associated behavioral problems. Although interictal rage has often been described in this syndrome, no systemic study has been done to characterize it.
METHODS: Twelve children with Magnetic Resonance Imaging (MRI) evidence of HH and neurophysiologic evidence of gelastic seizures were systemically interviewed using the Vitello Aggression Scale. A sibling similar in age was also interviewed using same testings regimen. Affective aggression characteristics tested using the following criteria: (1)non-profitable damaging of own property; (2)completely out of control when aggressive; (3)exposes self to physical harm when aggressive; (4)is aggressive without a purpose; (5)aggression is unplanned; (6)is aggressive in front of other people; (7)fights with stronger children; (8)expresses remorse after aggression. Predatory aggression characteristics tested using the following: (1)can control own behavior when aggressive; (2)very careful to protect self when aggressive; (3)tries to get something from being aggressive; fights with weaker children.
RESULTS: 11 of the 12 affected children (91.6%) completed the interview. Majority of affected children presented with affective aggressive characteristics (18.2% with 7 of 8 characteristics, 27.3% with 6 of 8, another 18.2 % with 5 of 8, 9% with 4 of 8 and 27% do not present with affective aggression characteristics). Only 1 patient (9%) present with all 4 predatory aggression characteristics, 18.2% with 2 of 4. 3 patients (27.2%) did not show any affective or predatory aggression characteristics. All control subjects showed no characteristics of affective or predatory aggression.
CONCLUSIONS: Results show that the rage or aggression in HHUGS are of the affective type, indicating that it is an impulsive and sudden response and not premeditated or motivated by ill will toward victim as in predatory aggression. The study further supports the theory that a relationship exists between hypothalamus and aggression.

Nishio S, Morioka T, Hamada Y, Kuromaru R, Fukui M (2001) Hypothalamic hamartoma associated with an arachnoid cyst. Journal of Clinical Neuroscience, 8 (1): 46-8.
A hypothalamic hamartoma associated with an arachnoid cyst in an 8-year-old boy is reported herein. He presented with precocious puberty, and neuroimaging studies demonstrated a solid mass in the prepontine cistern and a huge arachnoid cyst in the left cranial fossa. The mass appeared isointense to the surrounding cerebral cortex on T1-weighted magnetic resonance images, hyperintense on T2-weighted images, and was not enhanced after administration of Gd-DTPA. The patient underwent a left frontotemporal craniotomy and a cyst-peritoneal shunt was inserted. Histological features of the cyst wall and the mass were characteristic of an arachnoid cyst and hamartoma, respectively. While a hypothalamic hamartoma associated with an arachnoid cyst is rare, such a case may help clarify the geneses of both anomalous lesions.
(Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Japan)

Prasad S, Shah J, Patkar D, Gala B, Patankar T (2000) Giant hypothalamic hamartoma with cystic change: report of two cases and review of the literature. Neuroradiology, 42 (9): 648-50.
We describe the MRI findings in two patients with giant hypothalamic hamartomas with cystic areas. Cystic change within hypothalamic hamartomas is rarely reported in the literature.
(Department of Radiology, Boston, MA 02114, USA)

Stecker MM, Kita M (1998) Paradoxical response to valproic acid in a patient with hypothalamic hamartoma. Annals of Pharmacotherapy, 32 (11): 1168-72.
We report a patient who developed the paradoxical effect of increasing electrical seizure activity and confusion with initiation of valproic acid therapy. A 25-year-old African-American woman with a hypothalamic hamartoma had an electroencephalogram (EEG) that demonstrated frequent bursts of generalized spike and wave activity. The prevalence of spike and wave activity increased dramatically and the patient became increasingly somnolent as valproic acid was added to carbamazepine and phenobarbital therapy. Her EEG and mental status changes resolved when the valproic acid was discontinued. There was a strong positive correlation between the prevalence of spike and wave activity and the valproic acid concentration, but not between spike and wave activity and the concentrations of carbamazepine or phenobarbital. Although this is a complex case, it is clear that the addition of valproic acid produced an increase in spike and wave activity. Possible mechanisms and pathophysiologic significance of this paradoxical effect are discussed in light of the differences between this epileptic syndrome and the primary generalized epilepsies.
(Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, USA)

Stephan MJ, Brooks KL, Moore DC, Coll EJ, Goho C (1994) Hypothalamic hamartoma in oral-facial-digital syndrome type VI (Varadi syndrome). American Journal of Medical Genetics, 51 (2): 131-6.
Oral-facial-digital syndrome (OFDS) type VI (Varadi syndrome) is an autosomal recessive trait of orofacial anomalies, cerebellar dysgenesis, and polysyndactyly. Developmental anomalies of the posterior fossa, including cerebellar hypoplasia and variants of the Dandy-Walker complex, are the most common central nervous system malformations reported in patients with this syndrome. We report hypothalamic hamartoma, supernumerary maxillary incisor, and precocious puberty in a boy with OFDS type VI. We propose that hypothalamic hamartoma is an occasional manifestation of OFDS type VI.
(Department of Pediatrics, Madigan Army Medical Center, Tacoma, WA, USA)

Stroh B, Rimell FL, Mendelson N (1999) Bifid epiglottis. International Journal of Pediatric Otorhinolaryngology, 47 (1): 81-6.
Bifid epiglottis is a rare congenital defect that is often associated with other congenital annomalies. The most common defect associated with a bifid epiglottis are anomalies of the hands and/or feet (90%) while the most dangerous and potentially lethal anomaly if not recognized and treated are hypothalamic hamartomas and hypopituitarism (50%). A bifid epiglottis will often result in severe respiratory distress secondary to laxity of the cartilage and chronic aspirations, which may require surgical intervention. We present the case of a 10-week-old child who was sent for evaluation of stridor and aspiration. Office laryngoscopy demonstrated a true bifid epiglottis and further evaluation demonstrated a hypothalamic hamartoma consistent with Pallister-Hall syndrome. Management of our case as well as those previously presented in the literature are reviewed.
(Department of Pediatrics, University of Minnesota and Hennepin County Medical Center, Minneapolis, USA)

Tsugu H, Fukushima T, Nagashima T, Utsunomiya H, Tomonaga M, Mitsudome A (1998) Hypothalamic hamartoma associated with multiple congenital abnormalities. Two patients and a review of reported cases. Pediatric Neurosurgery, 29 (6): 290-6.
We report 2 patients with hypothalamic hamartoma associated with multiple congenital abnormalities and analyze 42 (including our own) reported cases, including our 2 cases, of hypothalamic hamartoma or hypothalamic hamartoblastoma with multiple congenital abnormalities, to understand the timing of their occurrence and clarify the prognosis. To this end, we classified them into lethal and nonlethal cases. We found poly- and syndactyly, cleft or high-arched palate and nose abnormalities to be important manifestations of this syndrome. Major organ abnormalities and CNS and endocrine abnormalities occurred frequently among the lethal cases, very likely indicative of a disturbance of embryogenesis between gestational days 34-37 and thus implicated in a negative prognosis.
(Department of Neurosurgery, School of Medicine, Fukuoka University, Fukuoka, Japan)

Surgery on HH

Delande O, Rodriguez D, Chiron C, Fohlen M. (2001) Successful surgical relief of seizures associated with hamartoma of the floor of the fourth ventricle in children: report of two cases. Neurosurgery, 49(3): 726-30; discussion 730-1.
Our objective is to discuss the physiopathology and surgical handling of seizures due to hamartoma of the floor of the fourth ventricle in two children. Two girls aged 3 years at the time of their operations presented with seizures due to a lesion of the floor of the fourth ventricle. The seizures began within the first days of life and consisted of hemifacial contraction, then head deviation, blinking of the eyelids, and intermittent dysautonomic manifestations. The interictal neurological condition seemed normal in one patient and showed a slight development delay in the other. An ictal electroencephalogram showed slow waves in the posterior areas. A magnetic resonance imaging scan revealed a mass that remained unchanged on serial examinations bordering the fourth ventricle, with an isointense signal on T1-weighted sequences and high-intensity signals on T2-weighted sequences without gadolinium enhancement. An ictal single-photon emission computed tomographic scan showed hyperperfusion in the lesion in both girls. The operation consisted of resection and disconnection of the lesion. An electrical recording was obtained in one patient during the operation while she was anesthetized; the recording, made by means of a depth electrode with five contacts inside the lesion, indicated that repetitive theta rhythmic discharges were present. Neuropathology was consistent with a hamartoma. In both girls, the seizures disappeared after their operations, and antiepileptic drugs were withdrawn (follow-up periods, 8 and 3 yr, respectively). Considering the results of single-photon emission computed tomography, the intralesional electrical record, and the relief of seizures after the operation, we postulate that the seizures arose from inside the lesion. This particular kind of noncortical seizure is similar to gelastic seizure due to hypothalamic hamartoma.
(Pediatric and Epilepsy Neurosurgery Department, Foundation Ophtalmologique A. de Rothschild, Paris, France).

Freeman JL, Harvey AS,, Rosenfeld JV, Wrennall JA, Bailey CA, Berkovic SF (in press) Evolution and postoperative resolution of symptomatic generalized epilepsy in children with hypothalamic hamartomas Supplement to Epilepsia.
The syndrome of hypothalamic hamartoma (HH) and gelastic epilepsy (GE) has been proposed as a model for symptomatic generalized epilepsy (SGE), with spike-wave (SW) and decremental EEG patterns and mixed generalized seizures developing in an age-dependent fashion in many patients.
Methods: Of 17 children with intractable GE who underwent detailed neurological evaluation prior to transcallosal resection/disconnection of HH at our center since 1997, 12 (age 4-17 yrs) had features of SGE defined as the presence of tonic and other generalized seizures, abundant interictal SW, generalized decremental or fast ictal rhythms, and neurobehavioral disturbance. Interictal scalp EEG recordings were performed 1-113 weeks (median 1) before and 1-17 weeks (median 2) after surgery. Interictal SW was measured as a percentage (SW%) of 5-minute samples of awake and asleep EEG for each patient, and the preoperative and first postoperative EEGs compared. In 7 patients, intraoperative EEG was recorded by depth electrode from the HH prior to resection and simultaneously from the frontotemporal scalp and exposed frontal cortex before, during and after resection.
Results: Onset of gelastic seizures was at 0-18 mths (mean 3); 6 had neonatal onset. Complex partial features developed between 0.3-7 yrs (mean 4) and tonic features between 1-9 yrs (mean 6). 11 had normal development in the first year of life. Preoperatively, intellectual impairment was present in all and behavioral disturbance in 9. Several children had normal EEGs in early life. Preoperatively, all had abundant interictal SW, with slow SW in 9 and continuous SW during sleep in 5. SW was recorded intraoperatively over the scalp and cortex before, during and after HH resection in 6/7 cases. None of the HH depth recordings showed SW or other epileptiform patterns. Postoperatively (mean follow-up 15 mths), tonic seizures ceased in 10 patients and 5 are seizure free. Early behavioral improvement (e.g. alertness and speech) occurred in all and continued in 10. SW activity was markedly reduced in 9 patients awake and in 7 asleep. Mean SW% for the group decreased from 14% to 4% awake and from 43% to 19% asleep. All 6 in whom awake SW was abolished had cessation of tonic seizures and sustained behavioral improvement; later EEGs performed at 4-41 mths in 3 showed continued absence of SW.
Conclusions: Resolution of SGE clinical features after HH resection is associated with a marked reduction in interictal SW activity, which may be the basis of the neurobehavioral improvements. Whereas seizures in this syndrome arise from the HH, interictal SW does not and is most likely a secondary thalamocortical phenomenon.

Harvey AS,  Freeman JL, Rosenfeld JV, Zacharin M, Wrennall JA, Bailey CA, Berkovic SF (in press) Postoperative course and seizure outcome following transcallosal resection of hypothalamic hamartoma in seventeen children with intractable gelastic epilepsy. Supplement to Epilepsia.
Surgical treatment of hypothalamic hamartomas (HH) causing gelastic epilepsy is being increasingly advocated, although optimal surgical approach and long-term outcome remain uncertain.
17 children aged 4-17 yrs underwent stereotactically-assisted, transcallosal, interforniceal, trans-3^rdventricular resection of HH at our center since 1997. Seizure onset was at 0-34 mths (14<6). All had gelastic seizures with/without complex partial features; 12 developed symptomatic generalized epilepsy (SGE) with tonic seizures and prominent spike-wave EEG patterns. Additional problems included precocious puberty (9), intellectual impairment (13), aggressive (11) and obsessive/autistic (5) behavior. Seizures were multiple daily in 16 and refractory to anticonvulsants (17), ketogenic diet (4), vagal nerve stimulator (2), partial subfrontal HH resection (2), thermocoagulation (1) and frontal corticectomy (1). All HH were sessile (size: 7x9x2mm to 26x30x39mm) with an intraventricular component. 7 were small and predominantly (>90%) intraventricular. Hypothalamic attachment was unilateral (6), predominantly unilateral (6) or bilateral (5). Seizure, neurobehavioral and endocrine status are reported 1-45 (mean 14) mths after surgery.
RESULTS: 10 patients had 95-100% resection of the HH and 7 had 25-90% resection with complete or partial disconnection. 10 patients are seizure-free on reduced or no treatment (follow up 1-35 mths), 5 had >90% seizure reduction, 1 had 75% reduction and 1 had <50% reduction. Only 2 children had persistent major disabling seizures. Postoperative findings included a small thalamic infarct occurred in 2 (mild residual hemiparesis in 1), appetite stimulation (9, persistent in 3), short-term memory complaints (6, persistent in 3), low thyroid or growth hormone (2), and transient somnolence (7), hypernatremia (Na⁺>150)(8), temperature instability (3) and 3^rd nerve paresis (1). Precocious puberty remained in 7. 15 had marked improvements in behavior and quality of life (QOL). Seizure freedom was not associated with age at onset, pubertal status, HH size/attachment, age at surgery or >95% resection. Normal intellect (p=0.09) and absence of SGE (p=0.04) were associated with seizure freedom.
CONCLUSION: Complete or near complete transcallosal resection/disconnection of HH can be achieved relatively safely. HH characteristics determine technical aspects of the surgery, but do not predict outcome. Although normal intellect and absence of SGE predicted seizure freedom, improvements in seizures, quality of life and behavior occurred in most children.

Luo S, Li C, Ma Z, Zhang Y, Jia G, Cheng Y. (2002) Microsurgical treatment for hypothalamic hamartoma in children with precocious puberty. Surgical Neurology, 57(5): 356-62; discussion 362.
We review the surgical treatment of hypothalamic hamartoma causing precocious puberty. Six children (three girls and three boys) with precocious puberty secondary to hypothalamic hamartoma were recruited for our study. The mean age of the patients was 30 months old (range 13 months to 5 years), and the mean age of the onset of puberty was 7.3 months. All patients were treated by microsurgery. All patients had higher then normal stature, body weight, bone growth, and serum levels of sexual hormones. The boys presented with mature external genitalia, pubic hair, frequent erection, and acne, while the girls presented with growth of breasts and menarche. Magnetic resonance image (MRI) revealed an isointense mass below the tuber cinereum extending into the supersellar and interpeduncular cistern, ranging from 4 to 12 mm in diameter, consistent with pedunculate hamartoma. The hamartoma was removed completely via a right pterional approach. The symptoms and signs of precocious puberty resolved completely, and sexual hormone levels decreased to the pre-pubertal range in all six patients without any postoperative complications. We report a series of six children with hypothalamic hamartoma-induced precocious puberty who underwent microsurgical treatment. All of them recovered completely to their age-appropriate state. Microsurgery is a good choice of treatment for pedunculate hypothalamic hamartoma.
(Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China)

Mottolese C, Stan H, Bret P, Berlier P, Lapras C (2001) Hypothalamic hamartoma: the role of surgery in a series of eight patients, Child's Nervous System, 17 (4/5): 229-38.
Hypothalamic hamartoma are rare lesions. We report a new series of eight patients treated for precocious puberty (six cases) or gelastic seizures (two cases). Surgical resection was total in four cases (three pediculated and one sessile). Precocious puberty was controlled by surgical treatment in all cases. Gelastic seizures were controlled by medical treatment, but the patients did not become seizure free. We observed no mortality and no endocrinological or visual morbidity. The fact that a vascular "rete mirabilis" was observed on the surface of the lesion in our surgical material is an argument favoring a vascular mechanism in precocious puberty. Coagulation of this vascular structure can help control precocious puberty. Our series confirms that the hypothalamic hamartoma can be surgically treated when patients fail to respond to medical treatment, when the length of the treatment cannot be tolerated by the children and their families, and when there are uncontrolled gelastic seizures.

Palmini A, Chandler C, Andermann F, Costa Da Costa J, Paglioli-Neto E, Polkey C, Rosenblatt B, Montes J, Martinez JV, Farmer JP, Sinclair B, Aronyk K, Paglioli E, Coutinho L, Raupp S, Portuguez M. (2002) Resection of the lesion in patients with hypothalamic hamartomas and catastrophic epilepsy. Neurology, 58(9): 1338-47.
Patients with hypothalamic hamartomas (HH) often have severe refractory epilepsy, incapacitating behavioral abnormalities, and cognitive decline. Attempts to control the seizure disorder by resection of apparently epileptogenic mesial temporal or other cortical structures have failed consistently. Our objective is to report a series of 13 patients in whom the hamartoma itself was resected. All patients underwent preoperative evaluation between ages 2 and 33 years and had subtotal or complete resection of the hamartoma. Follow-up ranged from 1 to 5.5 years (mean: 2.8 y). Preoperatively, all patients had variable combinations of gelastic, complex partial, and generalized seizures. Eight had drop attacks. In addition, all had marked behavior abnormalities and cognitive impairment. Postoperatively, two patients are completely seizure-free and 11 are either seizure-free or have achieved a greater than 90% reduction of drop attacks and generalized tonic-clonic seizures. However, minor gelastic, complex partial, and atypical absence seizures have persisted in 11 patients, although at significantly reduced rates. In addition, there has been a dramatic improvement in behavior and cognition. Three patients had an anterior thalamic and one a capsular infarct, which left only minimal long-term deficits. Exact location of the lesion in relation to the interpeduncular fossa and the walls of the third ventricle correlated with extent of excision, seizure control, and complication rate. CONCLUSION: Resection can alleviate both the seizures and the behavioral and cognitive abnormalities of hypothalamic hamartomas, but complications are frequent.
(Porto Alegre Epilepsy Surgery Program, Hospital Sao Lucas da PUCRS, Brazil)

Regis J, Bartolomei F, Rey M, Hayashi M, Porcheron D, Chauvel P, Peragut JC. (2002) Gamma knife radiosurgery for the treatment of severe epilepsy. Revue Neurologique, 158(4): 405-11 (in French).
The Gamma Knife radiosurgery is a neurosurgical approach having now demonstrated well its efficiency, its low morbidity and its comfort in the treatment of numerous neurosurgical disorders. These advantages of this type of intervention make it a method of great interest in functional neurosurgery and quite particularly in surgery of epilepsy. French experience is a pionner one in this domain. If for several years the positive evolution of the epilepsy associated to brain lesions had been noticed after the Gamma Knife radiosurgical treatment, the use of this approach in surgery of the epilepsy is systematically estimated since 1993. Data are today available concerning the surgical treatment of the epilepsies originating in temporomesiale area without occupying process, epilepsies associated to hypothalamic hamartomas and epilepsies associated to cavernous angiomas or to low grade gliomas. The quality of the epileptological result obtained in these various indications associated to a very reduced morbidity lets suppose that the Gamma Knife radiosurgery could indeed have tomorrow a place within the sample group of surgical approaches dedicated to the treatment of severe epilepsies. However, a larger number of treated patients and a more prolonged follow-up remains necessary to estimate in a more definitive way this approach.
(Service de Neurochirurgie Fonctionnelle et Stereotaxique, Hopital Timone, Marseille France)

Rosenfeld JV, Harvey AS, Freeman JL, Zacharin M, Wrennall J (in press) Transcallosal resection oh hypothalamic hamartoma in seventeen children with intractable gelastic epilepsy: surgical technique and outcome.
Surgical treatment of hypothalamic hamartomas (HH) to control gelastic epilepsy has been regarded as hazardous and unachievable. 17 children aged 4 -17 yrs with refractory epilepsy underwent stereotactically-assisted, transcallosal, interforniceal, trans-3rd ventricular resection of HH since 1997.  Follow up is 1-45 (mean 14) mths. 10 patients had 95-100% resection of the HH and 7 had 25-90% resection with complete or partial disconnection. Early postoperative problems included appetite stimulation (9), somnolence (7), short-term memory complaints (6), Na+>150 (8), low thyroid or growth hormone (2) and temperature instability (3). A small thalamic infarct occurred in 2 (mild residual hemiparesis in 1) and a transient 3rd nerve palsy in 1. Ongoing problems included weight gain (3), memory dysfunction (3) and salt-water imbalance (1). 10 patients are seizure-free on reduced or no treatment, 5 have >90% seizure reduction, 1 has 75% reduction and 1 has <50% reduction. Only 2 children had persistent major disabling seizures. All but 2 had marked improvements in behavior and quality of life (QOL). Seizure freedom was not associated with age at onset, PP, HH size/attachment, age at surgery or >95% resection; normal intellect (p=0.09) and absence of SGE (p=0.04) were associated with seizure freedom. We conclude that complete or near complete transcallosal resection/disconnection of HH can be achieved relatively safely. HH characteristics determine technical aspects of the surgery, but do not predict outcome. The surgeon must avoid injury to the forniceal / mammillary / thalamic pathways and deep perforators. Although normal intellect and absence of SGE predicted seizure freedom, improvements in seizures, QOL and behaviour occurred in most children.

Sgouros S, Natarajan K, Richard Walsh A, Rolfe EB, Hockley AD (1998) Computer simulation of a neurosurgical operation: craniotomy for hypothalamic hamartoma. Child's Nervous System, 14 (7): 322-7.
Although magnetic resonance imaging has revolutionised the management of intracranial lesions with improved visualisation of anatomical structures, it only produces two-dimensional images, from which the clinician has to extrapolate a three-dimensional interpretation. Several approaches can be used to create 3D images; the discipline of image segmentation has encompassed a number of these techniques. Such techniques allow the clinician to delineate areas of interest. The resulting computer-generated outlines can be reconstructed in a three-dimensional arrangement. Although a plethora of "generic" segmentation techniques exist, we have developed a refined form, dependent on general and particular properties of the anatomical structures under investigation. High-contrast structures such as the ventricles and external surface of the head are found by using a localised adaptive thresholding technique. Less definable structures, with poor or nonexistent signal change across neighbouring structures, such as brain stem or pituitary, are found by applying an "energy minimisation"-based technique. To demonstrate the techniques we used the example of an 8-year-old boy with uncontrolled gelastic seizures due to a hypothalamic hamartoma, who is being considered for surgery. We were able to demonstrate the anatomical relationships between the hypothalamic hamartoma and adjacent structures such as optic chiasm, brain stem and ventricular system. We were subsequently able to create a video, reproducing the stages of craniotomy for excision of this tumour. By creating true 3D objects, we were able at any stage of the simulation to visualise structures situated contralaterally to the approaching surgical dissector. These 3D representations of the structures can be either invisible or opaque, in order to afford 3D localisation as the "virtual" surgical dissection proceeds. The clinical application of such techniques will enable surgeons to improve their understanding of anatomical relations of intracranial lesions and has obvious implications in image-guided surgery.
(Department of Neurosurgery, Birmingham Children's Hospital, United Kingdom)

What is a Hypothalamic Hamartoma?

An Expert Speaks Out About HH

The Role of the Hypothalamus

The Endocrine System

MRI Scans of "The Real Deal"

Full Description of Seizure Types

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