THE COLOR OF THE HAIR

V. Katsiboulas M.D., D. Rigopoulos M.D., A. Katsambas M.D.

UNIVERSITY OF ATHENS,

DEPARTMENT OF DERMATOLOGY,

A. SYGROS HOSPITAL, ATHENS, GREECE

Address for correspondence:

KATSIBOULAS VASSILIOS

1, KATECHAKI str. & MESOGEION Ave.

115.25 ATHENS

GREECE

FAX. (+003216910000)

TEL. (+003216913333)

e-mail address : vassdoc@panafonet.gr

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...,çlèe d' Aèhnç ouranoèen ` pro gar hke èea leukïlenoò `Hrh `ámöù omùò èumù öhleousa te kõdomenç te ` stç d' opióèen, xanèhò de komçò ele Pçleéùna oiù öainomenç: tùn d' allùn ou tiò orato: èambçsen d' Achleuò, meta d' etrapet', autika d' egnù

.êlthe d' Athênê ouranothen: pro gar hêke thea leukôlenos Hêrê amphô homôs thumôi phileousa te kêdomenê te: stê d' opithen, xanthês de komês hele Pêleïôna oiôi phainomenê: tôn d' allôn ou tis horato: thambêsen d' Achileus, meta d' etrapet', autika d' egnô

..Minerva came down from heaven (for Juno had sent her in the love she bore to them both), and seized the son of Peleus by his yellow hair, visible to him alone, for of the others no man could see her;. (Homer ILIAD book I; 194-199).

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...enèá mesaipolioò per eùn Danaoisi keleusaò Idomeneuò Trùessi metalmenoò en öobon ùrse. Ðeöne gar Oèruonça Kabçsoèen endon eonta, oò ra neon polemoio meta kleoò eilçlouèei,...

.....entha mesaipolios per eôn Danaoisi keleusas Idomeneus Trôessi metalmenos en phobon ôrse. pephne gar Othruonêa Kabêsothen endon eonta, hos rha neon polemoio meta kleos eilêlouthei,

And now Idomeneus, though his hair was already flecked with grey,called loud on the Danaans and spread panic among the Trojans as he leaped in among them............

(Homer ILIAD book XIII; 360-365).

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.........CLEOPATRA For the most part, too, they are foolish that are so. Her hair, what color?

Messenger

Brown, madam: and her forehead As low as she would wish it………

(William Shakespeare’s ANTONY AND CLEOPATRA Act 3, Scene 3)

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INTRODUCTION

GENETICS

Hair color and the control mechanisms of the process of melanin pigmentation are under genetic influence 22,23,24. Responsible are four, at least, gene loci which are probably allelic 25 and changes in pigmentation are important markers of genetic aberrations. Melanin pigmentation is related to four biologic processes: 1) formation of melanosomes in melanocytes; 2) melanization of melanosomes in melanocytes; 3) secretion of melanosomes into keratinocytes and 4) transport (by keratinocytes) of melanosomes within lysosome-like organelles 26,27,28,29. Dominance may play a small role in the case of hair color, while it seems to be absent in eye-color. There are no sufficient indications of X-linked factors for both characters 30. The follicular melanocytes’ mitosis and melanosome production and transfer occur only during the anagen phase of the hair cycle and respond to the Melanocyte Stimulating Hormone (MSH) 1,10. Three different types of MSH have been identify: alpha, beta, gamma that there are small peptides consisting of 12-18 aminoacids, produced from the intermediate lobe of the pituitary gland and deriving from a common precursor peptide, pro-opiomelanocortin 1. Alpha-MSH binds to melanocytes in binding sites that seem to be present only on melanin synthesizing melanocytes and is thought to stimulate melanogenesis through a cyclic-AMP-dependent mechanism. The follicles of senile white hair, which do not contain active melanocytes, are short of binding sites 31. The switch of melanogenesis would be significantly controlled by structural and functional availability of vesiculoglobular bodies which are encoded or associated with HMSA-5 (69 kDa) glycoprotein. This HMSA-5 protein shares a significant homology with gp75 "b-locus" protein. However, because of the hypothesis that vesiculoglobular bodies carry post- (and pre-) tyrosinase regulatory factors involving in both pheo- and eumelanogenesis, the term "b-protein" which focuses only on eumelanogenesis may not be applied to HMSA-5 32. NATURAL COLOR VARIETY

RACIAL-ETHNIC VARIATION

The racial and ethnic differences are obvious in the different races and ethnic groups. Volumic density of pigment in human hair is differentiate in hair samples from the head, chest, armpits, and pubis in residents of Asia, Africa, Latin America, and the regions of the former USSR 33. Hair color and shape are separately inherited 34. RED HAIR (rutilism)

Red hair color is due to pheuemalanin and the incidence among the general population varies from 0.3% in Northern Germany to 11% in some regions of Scotland. The MSHR gene cannot be solely responsible for the red hair phenotype and variances in the MSHR gene are necessary but not always sufficient, for red hair production. Three alleles are associated with red hair color expression 35. Red hair often darkens with age1,7. High UV sensitivity is associated with high phaeomelanin and low eumelanin levels, and point to the eumelanin/phaeomelanin ratio as a novel chemical parameter that could be used for predicting individuals at high risk for skin cancer and melanoma 27. In humans, melanocortin 1 receptor variants are associated with red hair and fair skin. In addition, melanocortin 1 receptor variants are a risk factor, possibly independent of skin type, for melanoma susceptibility 22. Some authors suggest an association between the occurrence of natural red hair and those factors that lead to the development of endometriosis36. Red hair men are also considered as unattractive compared to other hair colors 37. A distinct esthetic/sexual preference exists among men for blondes over brunettes38.

HETEROCHROMIA

Heterochromia of hair is the presence of more than one distinct color of hair in the same person. A color difference between scalp hair and a mustache or sideburns is not uncommon. Pubic and axillary hair and eyebrows and eyelashes are often darker than scalp hair in a fair-haired person. Rarely, a circumscribed patch of hair of different colors occurs. Diffuse heterochromia of black and red scalp hair has been reported in a father and son 39. In general scalp hair darkens with age. Rarely, a circumscribed patch of hair occurs of different color due to pathological reasons, (irregularly alternating segmentation of hair into dark and light bands, in some cases of iron deficiency anaemia 6) or due to genetic predisposition. Are of several types (very dark hair growing from a melanocytic naevus or white hair from naevus depigmentosus 40). Can also be hereditary, usually autosomal dominant heterochromia, as a result of somatic mosaicism, the white forelock of piebaldism, the “flag sign” forelock in Kwashiorkor 41, or as a finding of protein deficiency 1,42. White forelock has been reported also in Down's syndrome 43 *.

MINERALS, CHEMICALS, TRACE ELEMENTS AND DRUGS IN HAIR

Hair analysis comprises the determination of minerals, trace elements and drugs. Besides a number of advantages hair analysis is impaired by the difficulty to distinguish between endogenous and exogenous sources of metals in hair. Except for methylmercury, there are no critical limit values for trace elements in hair available. Aluminium in hair is of no value in environmental medicine. For assessment of cadmium and inorganic arsenic exposure hair analysis is only suitable as a screening method based on large populations. Monitoring of lead in hair is a valuable screening method also for small groups, especially for children. Based on toxicokinetics and under consideration of practicability the optimal biomarker of methylmercury exposure is the hair concentration. For other mercury compounds hair analysis is of lower significance. Nicotine and cotinine measurements in hair provide a practical and proper method for estimating environmental tobacco smoke exposure and to validate smoker status in epidemiological studies 44. Testing hair has been used since two hundred years for arsenic determination. Today the development of new methods like gas chromatography/mass spectrometry has permitted numerous applications based on the analysis of organic substances trapped in hair. Useful conclusions can be taken by hair analysis and used in several fields, such as screening procedure of psychiatric patients, management of epileptic patients, for monitoring neuroleptics, as evidence of gestational drug exposure, hair nicotine as a marker of passive exposure to tobacco; detection and clinical survey of heroin addict, evaluation of pharmaceutical exposure, hair analysis as a tool of clinical diagnosis, hair analysis for compliance monitoring 45. More than one mechanisms are proposed to explain the incorporation of drugs into hair. Drugs enter hair only by passive diffusion from the blood stream into the growing cells at the base of the hair follicle, according to one of them. More recent experimental findings suggest that drugs probably enter hair from multiple sites, via multiple mechanisms, and at various times during the hair growth cycle. A more complex model is proposed in which drugs and metabolites are incorporated into hair during formation of the hair shaft (via diffusion from blood to the actively growing follicle), after formation (via secretions of the apocrine and sebaceous glands), and after hair has emerged from the skin (from the external environment). Further, drugs can be transferred to hair from multiple body compartments or pools located in tissues surrounding the hair follicle. These mechanisms can also be drug-specific46. The incorporation of some drugs from sweat into elder hair regions and the slow removal by washing are also discussed 47. Human scalp hair retains the past dosage history over a rather long period of time, acting as 'tape-recorder'. Each 1-cm length of hair contains the drug approximately corresponding to the amount ingested over a 1-month period when the hair is cut into 1-cm lengths successively from the scalp end. However, the hair growth rate is variable both within and between subjects and the hair has its own growth cycle 48. Has also the ability of radioligand binding with cocaine. Melanin was considered the most likely binding site for cocaine in hair and because the concentration of melanin is much greater in dark than in light hair, scatchard analysis indicated that dark hair had a 5- to 43-fold greater binding capacity than light hair. Differences in radioligand binding between hair types appeared to be due to differences in the density of binding sites formed by melanin in hair 49. Other drugs or their metabolites can also be identified in hair fibers and the natural hair color is an important parameter in the evaluation of drug concentration in hair. Hair samples of grizzled patients with permanent medical treatment by amitriptyline, carbamazepine, chlorprothixene, diclofenac, doxepine, indomethacine, maprotiline or metoclopramide, haloperidol 50, and with a chronic heroin and cocaine abuse were separated into white and pigmented fibers and both fractions were independently investigated by GC-MS. The concentrations in the white fibers were smaller than in the pigmented ones for the most of the samples investigated 51.The method can be useful in investigating overdose deaths and previous histories of drug use and abuse. The "first" or occasional intake of heroin, can also be determined, which could be a contributing factor to the overdose death, because of lack of tolerance 52,53. Cannabis concentration was found to be higher in pubic hair than in scalp hair 54. Hair would also be a good specimen for disclosure of drug history of fenethylline (FNT) and for discrimination between (FNT) use and amphetamine (AP) abuse 55. Detection in hair of other drugs or their metabolites is also possible (phencyclidine (PCP) and its two major metabolites, 1-(1-phenylcyclohexyl)-4-hydroxypiperidine (PCHP) and trans-1-(1-phenyl-4-hydroxycyclohexyl)-4'-hydroxypiperidine (t-PCPdiol)56, benzodiazepines and other psychotropic drugs 57 ). The synthetic opioid methadone58 and stanozolol, an anabolic androgenic steroid occasionally abused by athletes 59, can also be traced in hair. Measuring uric acid in hair can be available for the metabolic control in hyperuricemia 60,61. It has been found that antimicrobial quinolones (ofloxacinone48 and temafloxacin62) are detectable in hair, even after a short exposure to them, fentanyl from head hair samples obtained from surgery patients who received the medicine during anesthesia 63, the antimycotic triazole, fluconazole, during and after administration 64, and chlorpromazine (CPZ) which resulted being in white hairs much lower (< 10%) than in black hairs, suggesting that the strong affinity of CPZ for hair melanin may explain the accumulation in black hair 65. Phencyclidine (PCP) 66, lysergic acid diethylamide (LSD) 67, ecstasis 68 and their metabolites, too, can be detected in human hair. After multiple and single doses administration of codeine the medicine can revealed in the hair 69,70. The in vitro incorporation of benzoylecgonine is proportional to melanin content in the hair 71. Arsenic can be also traced in hair after long term drinking of arsenic contaminated water72. Uranium concentrations in hair of non-exposed and occupationally exposed persons, shows some promise as an indicator of exposure 73. Mercury has also been traced in human hair, sometimes related with occupational use (in dentists exposed to mercury used in dental restorations)74 but not always related to environmental mercury concentrations75. The content of antimony in human scalp-hair doesn’t seem to represent an indicator of the external absorption from soil. The rate of transfer of antimony from the soil to humans in the exposure case seemed to be very low 76. In both sexes, total and organic mercury concentrations were significantly higher in gray hair than in dark hair but no difference was observed between dark hair and gray hair for the concentration of inorganic mercury 77. Manganese dioxide in dust, is trapped in hair, reduced by the components of sweatand follows the diffusion of manganese into the hair shaft. Population with a high exposure to manganese can be affected by the neurological condition of Groote Eylandt Syndrome 78. The differences in hair metal contents of mercury (Hg), lead (Pb), cadmium (Cd) , copper (Cu), calcium (Ca), magnesium (Mg), sodium (Na) and potassium (K), iron (Fe), manganese (Mn), aluminum (Al), barium (Ba), calcium (Ca), selenium (Se), boron (B), titanium (Ti), arsenic (As), chromium (Cr), tin (Sn), strontium (Sr)79, in hair samples are due to differences in community lifestyle (dietary, environmental or occupational intake) 80,81. Zinc (Zn) levels in hair increased with age, and then Zn levels decreased with age from the puberty group to elderly group (61-70 yr). The hair lead (Pb) levels are the lowest in newborns, increased with age from newborn to infant (1-2 yr), and then decreased with age from infant to the elderly. The hair Pb and Zn levels are inversely related in various age groups, suggesting that there is possibly antagonism between Pb and Zn in the human body. The hair Pb levels of subjects living in urban area, except for newborns, are higher than those of subjects residing in the rural area. No difference revealed in the hair Zn contents in populations residing in urban and rural areas 82. Hair color influences Cu concentrations in both males and females. In males, white hair contains less Cu than black hair; in females, white hair's Cu levels are significantly lower than those of dark blond, red, light brown, and brown hair. There are no significant differences in Zn concentrations with respect to different hair colors, in either males or females 83. Some researchers believe that hair color, in young boys, shows no significant differences in Zn and Cu concentrations but a significantly higher concentration for Zn:Cu is revealed in boys with black hair than in the other color groups. Correlation between mineral content (Zn and Cu) and melanin is low and nonsignificant, except for Zn in hair color ranging from 0-100 melanin units (r = -0.34, P less than 0.05). Hair color change in children may be important in estimation of mineral nutritional status 84,85. In female hair the content of zinc, copper, nickel, manganese and lead, is higher than in male hair independently of color. Blond hair has the lowest concentration values of the elements studied independently of sex. The maximum amount of these metals is found generally in black hair, followed by red and brown hair. Age seems to have a different influence, with the copper element decreasing appreciably in brown and blond female hair as the age of the subjects increased 86. The hair segment analysis of nicotine indicates that environmental nicotine is the dominating contributor to the overall nicotine found in hair both from smokers and non-smokers 87. In hair samples obtained from 36 smokers, who had smoked > or = 3 years, there was a significant positive correlation between the concentration of nicotine and the number of cigarettes consumed daily. The nicotine content of white hair was much less than that of black hair collected from the same subjects with grizzled hair 88. The nicotine content in hair is proportional to the number of cigarettes consumed daily48. The determination of caffeine concentration in the plasma and hair of subjects consuming normal daily amounts of caffeine-containing beverages provides a practical assessment of individual liver metabolic capacity 89. The diabetics' hair is more heavily glycosylated than normal and there is a correlation between hair glycosylation and the concentration of glycosylated haemoglobin in the diabetics 90.

HAIR COLOR ALTERATIONS DUE TO SYSTEMIC USE OF DRUGS

A wide variety of drugs have been implicated in causing hair color changes but very few have data to support a true relationship 91. Some systemic drugs alter hair color by interfering with the eumelanin or phaeomelanin pathway. In others the mechanism is not known 1. Chloroquine and cancer chemotherapeutic agents have the best evidence to support an association. Chloroquine interferes with phaeomelanin synthesis. It affects only blonde and red-haired individuals and the changes are completely reversible1. Hypopigmentation of hair and freckles occurred in a patient receiving chloroquine sulfate therapy who suffered from severe congenital renal failure that presumably increased plasma and tissue levels of the drug 92. Long term therapy with chloroquine and hydroxychloroquine can turn the hair in white in blonde and red-haired men93. Hyperpigmentation of hair has also been reported after chemotherapy 94. Horizontal pigmented bands developing within the hair of a patient on intermittent high-dose methotrexate chemotherapy is presented, in a case report 95. Tamoxifen has also been reported to induced hair color changes 96. A case of a 45-year-old woman who took, when she was 34 years old, for a period of 25 months a silver-containing pharmacological product (colloidal silicon with 0.5 percent of silver) in order to treat an intestinal dyspepsia with diarrheic episodes. After few months she developed a cutaneous greyish-blue irreversible pigmentation extending over the whole body, nails, hair, and the oral and gingival mucosae 97. For other drugs, such as p-aminobenzoic acid, calcium pantothenate, anthralin, chinoform, mephenesin, minoxidil, propofol, valproic acid, and verapamil their direct association with hair color changes is not yet confirmed. Drug-induced causes should be considered in any patient with unexplained hair color changes 91.

HAIR COLOR ALTERATIONS DUE TO EXTERNAL OR TOPICAL USE OF DRUGS OR OTHER ELEMENTS

Dithranol 98 and chrysarobin (anthrone derivative), antipsoriatic drugs can stain light colored or grey hair in mahogany brown, probably due to an increase in plasma of the 5-S-cysteinyldopa (5-S-CD) 98. Resorcin, formerly used in a variety of skin diseases, turns black or white hair color in yellow or yellowish-brown. Resorcin has the tendency to stain selectively elastic fibres in several human tissues 47. Today is used, combined with other elements, as biological adhesive (GRF) glue in cardiovascular operations 99. Increasing brown discoloration of all nails and previously fair hair in short period was found in a patient using water with a high iron content for washing. A high iron content was detected in the discolored parts of the hair 100. Mephenesin, a glycerol ether used for diseases with muscle spasms, causes pigmentary loss in dark-haired people91. Triparanol, an anticholesterolaemic drug, and fluorobutyrophenone, an antipsychotic drug, both interfere with keratinization and cause hypopigmentation and sparse hair. Minoxidil and diazoxide, are two potent antihypertensive agents, both cause hypertrichosis and darkening of hair. The color produced by diazoxide is reddish. Minoxidil darkens hair mainly converting vellus hair to terminal hair. Hydroquinone and phenylthiourea interfere with tyrosine activity, causing hypopigmentation of skin and hair 1,91.

GREEN HAIR

An unusual dermatologic condition usually due to the deposition of copper in the hair, from exogenous sources, mostly been reported in patients with blond hair as a consequence of increased concentrations of copper in domestic or swimming pool water. Other predisposing factors include previous hair damage (mechanical, sun exposure, bleaching, dyeing, waving), frequent contact with chlorinated water (swimming pools), or use of alkaline shampoos 101,102. Green hair discoloration can also be provoked by selenium sulfide 103, and can disappeared after the use of a penicillamine containing shampoo 104.

COLOR CHANGES DUE TO NATURAL AND TOPICAL FACTORS

Natural hair color changes may occur during lifetime due to biochemical changes and is no longer believed that an individual is producing only one type of melanin, eumelanins or phaeomelanins throughout life 105. The terminal part of the hair along its shaft appears lighter than the rest (the normal “weathering”) due to the many interfaces deriving of cortex disruption and followed from internal reflection and refraction of light. The white color of hair seen when melanin is absent is an optical effect due to reflection and refraction of the incident light from various interfaces at which zones of different refractive index are in contact in the hair shaft 1,9. Skin whitening has been associated with the application of hair rinses and permanent and semipermanent hair colors, but their effect on hair color is not yet clear 106. Irreversible hair matting, is a rare, acquired hair disorder, created during hair shampooing. Light and electron microscopy showed dramatic permanent twisting and bending of the hairs through 180 degrees. This bending and entanglement of hairs of varying widths (felting) seemed to be the main reason for the hairs becoming so dramatically knotted together 107. Cobalt workers get bright blue hair and a deep blue tint may be seen in indigo handlers. Yellowish hair color can be noticed in white- or grey-haired heavy smokers due to tar in cigarette smoke. Yellow hair staining may also occur from picric acid and dithranol. Trinitrotoluene (TNT) workers sometimes develop yellow skin and reddish brown hair 1. Ormones like estrogenes and progesterone, probably increase hair color 1. Bleaching of hair has been reported after use of carbamide perhydrate 108 *, benzoyl peroxide acne lotions 109 * and valproic acid 110 *. Red hair staining after application of chinoform 111 *.

GREY HAIR

Greying of hair (canities) is the most notable of the manifestations of the ageing process. This also represents a main characteristic of individual’s description. The age of onset is primarily genetically predisposed, being different in different races, ethnic groups and sexes. In whites appears earlier than black people and in Japanese people, earlier in men than women. The beard and moustache areas commonly become grey before scalp and body hair. On the scalp, temples usually start greying first 1. Age estimation by appearance of grey hair in pubic area is proposed by researchers 112. Greying of the hair is due to progressive loss of melanocytes from the hair follicles113 and a decline in the number of melanosomes synthesized, leading to reduced pigmentation114. The larger medullary spaces of older people may contribute to the process, decrease and eventual cessation of tyrosinase activity in the lower bulb 115. Autoimmunity has been suggested participating in the pathogenesis of greying; grey hair certainly has an association with autoimmune diseases, anemias and metabolic disorders 116,117,118. In human mitochondrial DNA (mtDNA), in hair follicles, deletions occur and accumulate during human ageing 119. Temporal concentration variations of the short-lived, isotope-producing elements Br, Ca, Cl, Cu, I, Mg, Mn, Na, S, and Zn over time, in pigmented and white hair is also established 120 . Grey hair may temporarily darken after inflammatory processes, after electron-beam-induced alopecia, and after some chemotherapy regimens 121. In a patient with long-standing Parkinson's disease his white hair turned grey and darkened 8 months after the addition of carbidopa to his established levodopa (L-dopa) therapy and 4 months after the introduction of bromocriptine 122. Reappearance of black hair after 40 years is reported following erosive candidiasis of the scalp 123. Familial grey hair appeared to be in higher than expected frequency as one of clinical and metabolic characteristics of Parkinsonian patients whose illness started before the age of 40 116. Premature grey hair, associated with anemia, hyperpigmented skin, paresthesia, recurrent aphthous ulcers and epistaxis is reported in the literature 117, eventually proved to be a case of vitamin B12 deficiency. Due to the rarity of this deficiency, the diagnosis may be overlooked. Therapeutic response to vitamin B12 was dramatic 124,125.

TURNING WHITE OVERNIGHT, IS IT POSSIBLE?

The first reported episode of rapid whitening of the hair is recorded in the Talmud. Historical examples include Sir Thomas Moore and Marie Antoinette whose hair became grey over the night before their execution 1. This process can be explained as a two-step process. The first step involves the rapid development of white hair due to vitiligo or alopecia areata 126. The second step involves the apparent sudden whitening of the scalp hair due to either simultaneous lingthening of the white hair or selective loss of the dark hair. In fact, the hair that is perceived as suddenly whitening was already white 127,128. Immunofluorescence microscopy of biopsy material showed prominent deposits of IgG and IgM in a granular pattern in the epithelium of the lower portions of hair follicles in a case of a patient presenting rapid whitening of scalp hair in a three-month period with a diffuse, subtotal alopecia. The cause of this patient's loss of hair color may be different from others described as having rapid whitening of scalp hair because of alopecia areata or vitiligo 151. The process normally130 is progressive and permanent, ongoing with ageing. Repigmentation is reported in cases related with alopecia areata 126, vitiligo and metabolic disorders when the underlying disease is affronted 117,131,132. Rapid progression of whitening and loss of hair in 2 months period was the first manifestation of amyloidosis in a 67-year-old male patient 133.

Premature greying

Premature greying of hair is consider when the onset of greying is before 20 vears of age in whites and 30 years of age in blacks, probably with a genetic predisposition and occasionally occurs as an isolated autosomal dominant condition. Premature greying of hair is associated with pathological conditions on the basis of genetic linkage 1. Can be the early sign of pernicious anaemia, as serum iron also is important in the kinetics of melanogenesis within the follicular melanocytes 6, hyperthyroidism and, less commonly, hypothyroidism. Pernicious anemia, premature greying, reversible immunodeficiency and hypoadrenalism where simultaneously presented in a case of primary hypoparathyroidism 134 *. Distal lipoatrophy with canities, stunted somatic growth, painful muscle cramps and hypoplastic uterus is presented in the literature as a unique report 135*. Premature canities is an inconstant charateristic of the Rothmund - Thomson syndrome which is a rare, autosomal recessive disorder associated with characteristic cutaneous changes, sparse hair, juvenile cataracts, short stature, skeletal defects, dystrophic teeth and nails, and hypogonadism. Mental retardation is unusual. An increased incidence of certain malignancies has been reported. Clonal or mosaic chromosome abnormalities and abnormalities in DNA repair mechanisms have been reported in some cases136. Correlation with gastrointestinal abnormalities have also been reported 137. In a recent case-control study, premature hair greying was found to be associated with osteopenia, suggesting that this might be a clinically useful risk factor for osteoporosis 138. Some researchers are suggesting that premature graying of the hair is associated with premature cardiovascular disease. It should probably be regarded as a coronary risk factor and used to identify patients at increased risk 139,140. Other study performed to see if early graying was associated with increased morbidity, earlier age at death, and specific cause of death, provide no evidence to support the contention that early gray hair is a risk factor 141. In one case a patient with Darier’s disease presented jouvenile canities 142. "Asymmetric gray hair" phenomenon has been suggested as a clinical sign in the diagnosis of syringomyelia 143*. Canities and vitiligo can be complicating factors in interferon therapy for hepatitis C 144 *. Gray hair, is also presented in patients with ataxia-telangiectasia (A-T), also called Louis-Bar (L-B) syndrome, with the characteristic telangiectasias and vitiligo, impetigo, recurrent herpetic gingivostomatitis, hirsutism, lipoatrophyprogeroid changes and hyper- and hypopigmented macules 145. Cerebellar ataxia begins in infancy with a slowly progressive course. In the late stages free walking and standing are no longer possible. Progressive atactic speech disorders and cerebellar atrophy are also presented 146. Individuals with this form of ataxia are more susceptible to sinus and lung infections and may also develop tumors (neoplasia) 121,147. Very early greying hair can be a symptom in premature ageing syndromes of as a result of the accelerated ageing procedures 148. Hutchinson-Gilford progeria syndrome , a very rare progressive disorder of childhood characterized by premature aging (progeria). Growth delays occurring in the first year of life resulting in short stature and low weight, deterioration of the layer of fat beneath the skin (subcutaneous adipose tissue), and characteristic craniofacial abnormalities including an abnormally small face, underdeveloped jaw (micrognathia), unusually prominent eyes, and/or a small, "beak-like" nose. In addition, during the first year or two of life, scalp hair, eyebrows, and eyelashes may become sparse, and veins of the scalp may become unusually prominent. Additional symptoms and physical findings may include joint stiffness, repeated nonhealing fractures, a progressive aged appearance of the skin, delays in tooth eruption (dentition), and/or malformation and crowding of the teeth. Individuals with the disorder typically have normal intelligence. In most cases, affected individuals experience premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), potentially resulting in life-threatening complications. Hutchinson-Gilford Progeria Syndrome is thought to be due to an autosomal dominant genetic change (mutation) that occurs for unknown reasons (sporadic) 149. and Werner's syndrome (pangeria), that begins in adolescence or early adulthood and results in the appearance of old age by 30 to 40 years of age. Physical characteristics associated with the disorder may include short stature, prematurely aged appearance of the skin, premature balding, cataract, and/or other abnormalities. Werner Syndrome is thought to be inherited as an autosomal recessive genetic trait 148,149, 150. As a non-constant symptom may be also presented in other, rare progeroid syndromes such as : Wiedemann-Rautenstrauch syndrome (also known as Neonatal Progeroid Syndrome) an extremely rare genetic disorder characterized by an aged appearance at birth (neonatal progeroid appearance). Growth delays before and after birth (prenatal and postnatal growth retardation), subcutaneous lipoatrophy, causing the skin to appear abnormally thin, fragile, and wrinkled. In addition, for reasons that are not understood, abnormal deposits of fat may accumulate around the buttocks, the anogenital area and flanks. Affected infants and children also have distinctive malformations of the craniofacial area including an unusually prominent forehead (frontal bossing) and sides of the skull (parietal bossing), causing the head to appear abnormally large (pseudohydrocephalus). Unusually small, hypoplastic bones of the face and abnormally small facial features, a small "beak-shaped" nose that becomes more pronounced with advancing age, and/or sparse scalp hair, eyebrows, and/or eyelashes. Most infants and children also have unusually thin arms and legs, abnormally large hands and feet, progressive neurological and neuromuscular abnormalities, varying degrees of mental retardation and severe delays in the acquisition of skills requiring the coordination of mental and muscular activities (psychomotor retardation). In addition, in many cases, affected infants and children are prone to repeated respiratory infections that may result in life-threatening complications. The syndrome is inherited as an autosomal recessive genetic trait 151,152. GAPO syndrome, with white eyelashes153) . The onset of greying hair can be the first symptom of other pathological entities as in dystrophia myotonica 1, or in other cases a non constant symptom, as in Wolf-Hirschhorn syndrome, an extremely rare disorder due to deletions on chromosome 4p16 154. Major symptoms may include extremely wide-set eyes (ocular hypertelorism) with a broad or beaked nose, microcephaly, low-set malformed ears, mental and growth deficiency, cardiac defects, and seizures). In some cases antibody deficiencies are reported 155. Cri du Chat syndrome, A rare chromosomal disorder that is apparent at birth, is characterized by a distinctive high, shrill, mewing, "kitten-like" cry during infancy. This distinctive cry becomes less pronounced during late infancy. Other findings and symptoms may include low birth weight and failure to grow at the expected rate. Distinctive abnormalities of the craniofacial area including microcephaly, widely spaced eyes (ocular hypertelorism), and an unusually small jaw (micrognathia) and mental retardation, due to contiguous gene deletion resulting from hemizygous deletions of chromosome 5p156. and Book's syndrome 1. Grey hair can be also be presented in rare syndromes as in : 1)spastic paraparesis, mental retardation, and cutaneous pigmentation disorder, presented in four siblings of a family with a highly consanguineous background with an unusual combination of muscle wasting, microcephaly, skeletal deformities, and hypopigmented and hyperpigmented lesions and graying of the hair 157 and 2) in a new familial syndrome that affected young women with a very peculiar phenotype, poikilodermia and hair greying, and idiopathic nonarteriosclerotic cerebral calcifications. A marked, progressive hyalinosis involving capillaries and often arterioles and small veins of the digestive tract, kidneys, and calcified areas of the brain. Diarrhea, rectal bleeding, malabsorption, and protein-losing enteropathy were the main and lethal clinical problems. Hypertension, and mild proteinuria, peripheral retinal ischemic syndrome and chorioretinal scars and a subarachnoid hemorrhage, due to a right sylvian aneurism, also occurred in both sisters and was lethal for one of them 158.

HAIR COLOR CHANGES DUE TO PATHOLOGICAL REASONS

Changes in the shape and color of hair are mentioned in malabsorption syndromes like: acrodermatitis enteropathica, dermatitis herpetiformis, Whipple disease, Cronkhite-Canada syndrome, dermatogenic enteropathy and abnormalities that occur as complication from the surgery treatment for obesity improvement 159. Hair color changes result from alterations in melanin production and from changes in the hair structure, altering its optical properties. A variety of genetic, metabolic, nutritional, and acquired disorders result in hair color changes. When the underlying defect can be corrected, hair color usually returns to normal. The flag sign can occur as a result of nutritional insults 85 or due to medications. Most drug-induced changes in hair color result in lighter hair color, although PABA and some chemotherapy regimens have darkened hair 121.

Tuberous sclerosis

Is a rare genetic multisystem disorder characterized by the appearance of characteristic benign tumors in various areas of the body, seizures, and mental retardation. Other findings and symptoms may include developmental delays; characteristic skin lesions (e.g., adenoma sebaceum), lesions in the eyes (ocular), uncontrollable involuntary muscle spasms (myoclonic jerking), and/or learning disabilities. The range and severity of associated symptoms and findings may vary greatly from case to case. Tuberous Sclerosis is inherited as an autosomal dominant genetic trait. Two genes have been identified that may cause this disorder. One disease gene, the TSC1 gene, is located on the long arm of chromosome 9 (9q34). The other gene, the TSC2 gene, has been located on the short arm of chromosome 16 (16p13.3)160. Approximately 65 percent of the cases of Tuberous Sclerosis occur as a result of a spontaneous genetic change (new mutation). The disease can be bilateral and can have an early onset 161. A tuft of white scalp hair is a useful new sign of tuberous sclerosis in the newborn and young child, and the hair should be examined as carefully as the skin when early 'organic' seizures are unexplained 162,163.

AIDS

Four black men with the acquired immunodeficiency syndrome (AIDS) demonstrated profound alterations in hair patterns two to three years after their first symptoms appeared. The hair became longer, lighter, softer, and silky, and it was occasionally discolored 164.

Segmented heterochromia

A newly recognized disorder of black scalp hair is described as the irregular alternating segmentation of hair into dark and light bands,in 15-year-old girl who had segmented heterochromic scalp hair in association with iron-deficiency anemia. The clinical and laboratory investigations support the view that low serum iron levels play a critical role in reducing eumelanogenesis and in the possible failure of melanin transfer. The segmented heterochromic hair recovered completely after iron supplementation (Canities segmentata sideropaenica) 6.

Hypopigmentation in Prader-Willi (PWS) and Angelman (AS) syndromes.

Hypopigmentation in PWS and AS syndromes is characterized by light skin, reduced retinal pigment, low hairbulb tyrosinase activity, and incomplete melanization of melanosomes, due to interstitial deletions of the proximal long arm of one chromosome 15 (q11-q13). PWS usually results from a paternal deletion of 15q11-q13 or maternal disomy for chromosome 15. Hypopigmentation is the result of deletion of the P gene in the context of PWS 165. Electron microscopic examination of hairbulb melanocytes showed normal melanosome and melanocyte architecture and number, but reduced melanin formation, with many stage II and III premelanosomes but few stage IV fully melanized melanosomes 29,166,167,168. Angelman syndrome is an extremely rare disorder characterized by congenital mental retardation, the absence of speech, unprovoked laughter, unusual facial features, and muscular abnormalities. Children with this disorder smile often and easily and may have episodes of excessive laughter. This syndrome was first described as the Happy Puppet Syndrome. This term is now obsolete. On the basis of molecular findings, the Angelman syndrome (AS) patients can be classified into the following 4 groups : familial cases without deletion, familial cases with submicroscopic deletion, sporadic cases with deletion, and sporadic cases without deletion. The molecular deletion, which commonly extended from D15S9 to D15S12, although not all deletions are identical. In other groups of patients deletion involves only 2 loci, D15S10 and GABRB3. Among sporadic and familial cases without deletion, no uniparental disomy was found and most of them were shown to inherit chromosomes 15 from both parents (biparental inheritance). Most clinical manifestations, including neurological signs and facial characteristics, were not distinct in each group except for hypopigmentation of skin or hair. Familial cases with submicroscopic deletion were not associated with hypopigmentation 169.

Prader-Labhart-Willi syndrome

Hypopigmentation, behavioral problems, significant differences in hair color, sun sensitivity and dental abnormalities are the main characteristics of the PLWS. Individuals with the deletion frequently had lighter hair color, more sun sensitivity, and fairer complexion than did either other family members or nondeletion PLWS patients. No significant differences in biochemical findings (phenylalanine, tyrosine, catecholamines, or beta-melanocyte-stimulating hormone) were found between deletion and nondeletion PLWS patients or between hypopigmented and normally pigmented patients. The data suggest that a gene(s) controlling the activity of tyrosinase or other enzymes required for melanin production is located on proximal 15q168,170.

Menkes' disease

Is a genetic disorder of copper metabolism beginning before birth. Copper accumulates in excessive amounts in the liver, and is deficient in most other tissues of the body. Structural changes occur in the hair, brain, bones, liver and arteries. Is a sex-linked recessive disease (abnormal X chromosome) 171. It is manifested in the first year of life with severely retarded mental and physical development, convulsions, a particular phenotype and abnormalities of the hair, bones and arteries. Diverticula of the bladder mucosa and serosa, as well as cortical atrophy and malformed cerebral vessels can also be associated with the disease 41. Hair abnormalities consisting of pili torti and white hair, and low levels of serum copper (Cu) and ceruloplasmin. Is also called kinky hair or steely hair syndrome and is caused by abnormal Cu metabolism. The kinky hair formation results from low activity of sulfhydryl oxidase, which is a Cu enzyme172. In very bright portions of hair eumelanin’s and pheomelanin’s levels are only half those of normal. After subcutaneous administration of copper-histidinate for 2 months, his scalp hair changed to dark brown 173.

Partial yellow scalp hair

Partial yellow coloration of the scalp hair has been reported, due to decreament of eumelanin content, in the yellow hair, whereas the pheomelanin content was normal. Patient suffers of congenital hypomelanosis with a segmental pattern on the left abdomen, whorl-like pattern on the back; mosaic pattern on the chest, right abdomen, and proximal extremities. (Nevus depigmentosus systematicus with partial yellow scalp hair) 174 .

ANEMIAS

Serum iron also is important in the kinetics of melanogenesis within the follicular melanocytes 6. Two Latin-American patients, one with congenital and one with acquired pernicious anemia, had reddish hair while they were cobalamin deficient. With appropriate treatment, the new hair growth assumed its normal premorbid dark brown color 175. Hair depigmentation has also been reported in patients with pernicious anaemia, from Africa 176.

Cross syndrome

Cross syndrome has autosomal recessive inheritance177 and is characterized by oculocerebral syndrome and cutaneous hypopigmentation as first delineated by Cross in 1967 in three siblings of an inbred Amish family. The mixed pattern of hair pigmentation is an important diagnostic sign 178. The cases can be sporadic or with familial recurrence presenting deep mental retardation and spastic tetraplegia with athetoid movements 177,179.

Uveitis, poliosis, hypomelanosis, and alopecia in a patient with malignant melanoma.

The spontaneous development of bilateral uveitis, poliosis, hypomelanosis, and alopecia (Vogt-Koyanagi-Harada syndrome) in a 57-year-old woman following operation for metastatic malignant melanoma 180.

A case resembling the 'fleck retina of Kandori' with ectodermal peculiarities and macula degeneration.

The case of a 36-year-old woman followed-up for nine years is reported presenting unique, sharply-defined, irregular, yellow, large flecks of the retina combined with bilateral macula degeneration. The patient's rusty-red hair, enamel dysplasia, and ashen-gray skin color were also noted. It is the first case reported outside Japan 181.

Riyadh chromosome breakage syndrome : mental retardation with depigmentation of the skin and hair.

A recently described entity in 20-month-old infant with "silvery-blond" hair color, widespread confettilike depigmentation of the skin, and mental retardation. in lymphocytes and fibroblast cultures, increased spontaneous chromosome breaks and breaks induced by both mitomycin and gamma-irradiation. The sister chromatid exchange frequency was normal. This child probably represents a new chromosome breakage syndrome182. Ataxia-deafness-retardation syndrome First described in three brothers by Berman et al (1973), followed by a case of three sisters aged 16, 12 and 8 years from a consanguineous family. They present progressive spinocerebellar ataxia combined with moderate mental retardation, progressive sensorineural hearing loss and signs of both upper and lower motor neuron disease. In the family described here transmission of the disease appears to be linked with occurrence of red hair color 183.

Waardenburg syndrome (WS)

Waardenburg syndrome (WS) is a hereditary disorder that causes hypopigmentation and hearing impairment. Depending on additional symptoms, WS is classified into four types: WS1, WS2, WS3 and WS4. Mutations in MITF (microphthalmia-associated transcription factor) and PAX3, encoding transcription factors, are responsible for WS2 and WS1/WS3, respectively. MITF transactivates the gene for tyrosinase, and is critically involved in melanocyte differentiation. Absence of melanocytes affects pigmentation of the skin, hair and eyes, and hearing function in the cochlea. Hypopigmentation and hearing loss in WS2 are results of an anomaly of melanocyte differentiation caused by MITF mutations. PAX3 directly regulates MITF and the failure of this regulation due to PAX3 mutations causes the pigmentary and auditory symptoms in at least some individuals with WS1. The molecular mechanism by which PAX3 mutations cause the pigmentary and auditory disorders in WS1/WS3 is not yet clear 184.

Waardenburg syndrome type 1 (WS1)

Type 1 Waardenburg syndrome (WS1) is an autosomal dominant disorder characterized by dystopia canthorum, sensorineural deafness, and pigmentary disturbances 185. 17%-58% of the patients presenting a white forelock 186,187 .

Waardenburg syndrome type 2 (WS2)

Waardenburg syndrome type 2 (WS2) is a dominantly inherited syndrome of hearing loss, with no dystopia canthorum and pigmentary disturbances of reduced hair pigmentation, due to mutations affecting splice sites in the MITF gene located in the chromosome 3p12.3-p14.1188. Broad nasal root, heterochromic or hypochromic irides and synophrys are also presented in both types of the syndrome.

Woolf's Syndrome

Can present with pigmentary changes that are similar to Waardenburg syndrome. Woolf's syndrome also includes deafness. However, the distinguishing structural ophthomologic abnormalities of dystopia canthorum, broad nasal root, and synophrys are not found in Woolf's syndrome 186.

Reversible Hypopigmentation in Homocystinuria

Deficiency of cystathionine beta-synthase (CBS) is a genetic disorder of transsulfuration resulting in elevated plasma homocyst(e)ine and methionine and decreased cysteine. Homocyst(e)ine inhibits tyrosinase, the major pigment enzyme and the probable mechanism of this inhibition is the interaction of homocyst(e)ine with copper at the active site of tyrosinase. Affected patients have multisystem involvement, which may include light skin and hair 189.

Endocrine disorders resulting in early-onset obesity, adrenal insufficiency and red hair pigmentation.

The central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5) and the linkage of human obesity to chromosome 2 in close proximity to the precursor protein pre-pro-opiomelanocortin (POMC) locus, lead to the proposal of an association of POMC with human obesity. Patients with a defect in POMC function present early-onset obesity, adrenal insufficiency and red hair pigmentation 190.

Disordered pigmentation, spastic paraparesis and peripheral neuropathy

Three siblings in a Jordanian family presented with a distinctive syndrome consisting of disordered skin and hair pigmentation, progressive spastic paraparesis and peripheral neuropathy. Sural nerve biopsy revealed axonal degeneration and skin biopsy showed abnormal epidermal pigmentation. No underlying biochemical defect has been found in this previously undescribed neurocutaneous syndrome 191.

Spastic paraparesis, mental retardation, and cutaneous pigmentation disorder

The unusual combination of spastic paraparesis, muscle wasting, microcephaly, mental retardation, skeletal deformities, and cutaneous manifestations of hypopigmented and hyperpigmented lesions and graying of the hair, is reported in four siblings in a family with a highly consanguineous background. An autosomal recessive inheritance is probable 192.

Neuroectodermal melanolysosomal disease.

The syndrome identified in three consanguineous families who had common ancestors, and is characterized by profound dysfunction of the central nervous system, silver-leaden colored hair, abnormal melanosomes and melanocytes, and abnormal inclusion bodies in fibroblasts, bone marrow histiocytes and lymphocytes which appear to represent abnormal lysosomal bodies 193.

Chediak-Higashi syndrome

A rare recessive autosomal disease, a form of albinism, caused by mutations in a single gene encoding a protein of unknown function, called lysosomal-trafficking regulator 194. characterized by a decreased pigmentation and visual difficulties. Leukocyte abnormalities associated with Chediak-Higashi syndrome result in immune deficiencies. Affected individuals may have an increased susceptibility to infections and certain cancers 195. An African Kenyan female infant was born with very light skin and ashen grey, scanty hair. At 18 months she presented with a bluish skin pigmentation, hepatosplenomegaly, generalised lymphadenopathy and non-responsive fever. A bone marrow aspirate and peripheral blood examination done revealed characteristic features of the Chédiak-Higashi Syndrome. This is a rare disorder, to our knowledge not previously described in Africans 196.

Griscelli syndrome

Is a rare autosomal recessive disorder on chromosome 15q21 and is associated with mutations in the myosin-Va gene leading to disorders in organelle-transport machinery 197. Partial albinism with immunodeficiency defines this uncommon disorder characterized by pigmentary dilution (relatively light skin color) and variable immunodeficiency, presented with a silvery-gray sheen to the hair, large clumped melanosomes in hair shafts, and prominent mature melanosomes in cutaneous melanocytes with sparse pigmentation of adjacent keratinocytes. Immunologic abnormalities include impaired natural killer cell activity, absent delayed-type hypersensitivity, and impaired responses to mitogens and hypogammaglobulinemia. Acute phases of uncontrolled lymphocyte and macrophage activation, leads to death in the absence of bone-marrow transplantation 197. Recurrent infections may be present and neurological involvement varying from mild cognitive delay with a convulsive disorder to a fatal degenerative course is reported 198. The syndrome can be differentiated from Chediak-Higashi syndrome by pathognomonic features in light and electron microscopy in skin and hair, and absence of consistent granulocyte abnormalities. Symptoms may started in the newborn period 199. Cerebral involvement. hypotonia and motor retardation with increasing hepatosplenomegaly, have also been reported in a case 200,201. The Griscelli-Prunieras syndrome The case report of a six-year-old girl with silvered hair syndrome, of Griscelli-Prunieras variety, is presented. A hereditary sickness with regressive autosomic and distinguished by partial albinism and leukocytic alterations. The patient presented the acute phase of the sickness defined by: hepatosplenomegaly, thrombocytopenia, generalized lymphadenopathy, and systematic infection; the giant inclusions in bone marrow leukocyte and peripheric blood that are feature of Chediak-Higashi syndrome were not present in this case. The distribution of mote of melanin on the hair that in the Griscelli-Prunieras syndrome are six times bigger in the Chediak-Higashi syndrome202.

Marfan's syndrome

Marfan syndrome is an inherited disorder that affects the connective tissues of the heart and blood vessels (cardiovascular system). The musculoskeletal system (ligaments and muscles) is also affected. Major symptoms also include unusual height, large hands and feet, and involvement of the lungs and the eyes. The anatomical substrate of Marfan's syndrome is a degeneration of elastic fibres and disorganization of the collagen, due to mutation of genes localised on chromosome 15. The first of them (FBN1) codes for the main constitutive protein of the elastic tissue: fibrillin 1, present mainly in structures which must resist load and stress (aortic adventitia, the suspending ligament of the lens, skin); the second (FBN2) codes for fibrillin 2: responsible for the orientation of the elastin and mainly present in cartilage, the aortic media, the bronchi, and all tissues rich in elastin 203. The cutaneous expression of Marfan's syndrome is generally limited to striae distensae and a number of uncommon associations with other dermatologic disorders. It is reported a patient with Marfan's syndrome who presented with an acquired white forelock 204.

Hypohidrotic ectodermal dysplasia (HED)

Hypohidrotic ectodermal dysplasia (HED) can be distinguished in two types the X-linked form of HED (XLHED) autosomal recessive disorder (ARHED) 205. The disease involves abnormalities of tissues of ectodermal origin due to developmental disturbances in the embryonal state, including trichodysplasia, dental defects, onychodysplasia, and dyshidrosis, eczemas, thin, dry skin, typical facial features such as saddle-nose, unusually thick lips, and/or a large chin, deformity and periorbital wrinkling and pigmentation. Primarily characterized by partial or complete absence of certain sweat glands (eccrine glands), causing lack of or diminished sweating (anhidrosis or hypohidrosis), heat intolerance, and fever. Underdevelopment (hypoplasia) or absence (aplasia) of mucous glands within the respiratory and gastrointestinal (GI) tracts and, in some cases, decreased function of certain components of the immune system (e.g., depressed lymphocyte function, cellular immune hypofunction). Otolaryngologic problems and respiratory disease are also present. Mild mental retardation can also be present. Diagnosis of the syndrome can early be suspected in a child with recurrent fever of unknown etiology, thin blond hair, and anodontia. Patients have a life expectancy similar to that of the general population. Direct mutation detection would enable carrier detection in female relatives of sporadic cases, as well as help distinguish the X-linked form of HED (XLHED) from the rarer, clinically indistinguishable, autosomal recessive disorder (ARHED) 205. The X-linked recessive form of HED, also known as Christ-Siemens-Touraine syndrome, is the most frequent and widely documented form, caused by mutation in a novel transmembrane protein 206,207. Only a small minority of affected males can be diagnosed by direct mutation analysis and linkage analysis, in informative situations, is the only practical diagnostic option available 208. In autosomal dominant hypohidrotic ectodermal dysplasia (ADHED) by genetic linkage analysis researchers have mapped a gene for ADHED (EDA3) to the proximal long arm of chromosome 2 (q11-q13) 209.

Obstructive cardiomyopathy in a male dwarf with cryptorchidism

A case of a male dwarf with bilateral undescended testes and biventricular obstructive cardiomyopathy is reported. The clinical symptoms were choreoathetoid movements, chorioretinitis, bilateral nystagmus, and unusual red color of the hair, associated with some features of Turner phenotype. He presented lack of thyrotrophic stimulating hormone (TSH). Obstructive cardiomyopathy has been reported in cases of male and female Turner phenotype with normal chromosomes 210.

Familial defect in cellular chemotaxis associated with redheadedness and recurrent infection

The familial defect in polymorphonuclear leukocyte chemotaxis associated with redheadedness and recurrent infection in two of six siblings, not associated with a concurrent defect in leukocyte bactericidal activity. these These children experience recurrent infections, although immunoglobulin levels (IgG, IgA, IgM, and IgE) and complement components (total hemolytic complement, Clq, C3 and C3PA) are all within normal limits, mobility and phytohemagglutinin-stimulated lymphocyte transformation were also within normal limits. These studies demonstrate a familial PMN defect limited to leukocyte chemotaxis and associated with recurrent infection and possibly redheadedness 211.

Osteopathia striata associated with familial dermopathy and white forelock

Is reported the case of a white-Caucasian woman and her two daughters who developed osteopathia striata and a macular, hyperpigmented dermopathy. The skin lesions were not those most often associated with osteopathia striata, but appeared tgo be a unique dermatosis, which also included a hypopigmented forelock, probably inherited with X-linked or autosomal dominant transmission 212.

Syndrome of brittle cornea, blue sclera, and joint hyperextensibility

This rare autosomal recessive syndrome has variable expressivity. In some of the patients affected with the syndrome of brittle cornea, blue sclera, and hyperextensible joints (brittle cornea syndrome), two different may be distinguished: one includes 5 families, all of Tunisian Jewish origin and patients in this group also have red hair. In the second group, 9 families are from various ethnic origins and the affected patients in this group have a normal distribution of hair color. A possible explanation for the existence of these two different group of patients is that the locus of the gene responsible for the syndrome is closely linked to the locus for a gene responsible for hair color with linkage disequilibrium in Tunisian Jews (Sepharadim) 213.

Acquired ichthyosis, alopecia and loss of hair pigment associated with leiomyosarcoma

Is presented the case of a 70-year-old lady with acquired ichthyosis and leiomyosarcoma, one of the less frequently associated malignancies. An additional unusual finding was generalised thinning and loss of pigment affecting her hair. Scalp biopsy showed histological evidence of ichthyosis. Following resection of the tumour the ichthyosis resolved and there was regrowth of darker hair214.

Nevoid hypertrichosis

The case of a 23-month-old Caucasian girl with congenital circumscribed areas of deeply pigmented terminal hairs that gradually lost their pigment over the next two years, is presented in the literature. Physical examination revealed no other abnormalities 215.

Nevus depigmentosus systematicus with partial yellow scalp hair

A Japanese patient with congenital hypomelanosis of a segmental pattern on the left abdomen, whorl-like pattern on the back; mosaic pattern on the chest, right abdomen, and proximal extremities; and with yellow hair on a portion of the scalp. Chemical analysis of the yellow hair revealed decreased eumelanin content, whereas the pheomelanin content was normal 216.

Yellow forelock--a new neuro-ophthalmological sign.

A middle-aged man with a prominent yellow forelock complained of loss of vision in both eyes. He smoked his pipe avidly and drank a little Bourbon whisky daily. The nicotine content of the forelock (21.7 ng/mg) was 10 times that of the hair on his occiput (2.23 ng/mg). A yellow forelock when associated with isolated painless visual loss suggests tobacco amblyopia 217.

Progressive spastic paraparesis, vitiligo, premature greying, and distinct facial appearance

Is described progressive spastic paraparesis of the lower limbs in the presence of generalized vitiligo, premature graying of body hair, and distinct facial appearance in 3 patients whose parents are first cousins, considered as autosomal recessive trait. This neurocutaneous disorder is of unknown pathogenesis 218.

Albinism

Albinism connotes a large group of genetic disorders that are characterized by diminished ocular and oftentimes cutaneous pigmentation. These disorders are generally subclassified as oculocutaneous albinism (OCA) or ocular albinism (OA) based on the extent of their effects on the pigmentation of the skin and hair. Sometimes, different mutations in the same gene can cause OCA or OA 219. The pathologic gene mutations causing OCA can be divided according to the phenotype disorders manifesting. When a mutated tyrosinase gene produces inactive, less active, or temperature-sensitive tyrosinase, its phenotype is tyrosinase-negative (type I-A), yellow-mutant (type I-B), or temperature-sensitive (type I-TS) OCA, respectively. Mutation of the P gene encoding the tyrosine-transporting membrane protein probably occurs in tyrosinase-positive OCA (type II) 220. According to other researchers five types of oculocutaneous albinism (OCA) can be determined. Type IA (tyrosinase-negative) and type IB (yellow mutant) individuals had low or no measurable tyrosinase activity, and heterozygotes for these two types are detectable. Type II (tyrosinase-positive) individuals have moderate to high activity, and the heterozygotes for this type are not detectable. Type III (minimal pigment) individuals have low activity, and heterozygote levels are useful in detecting this type of OCA. Type VI (Hermansky-Pudlak syndrome) individuals have moderate to no measurable activity, and heterozygotes for this type cannot be detected 221. Hermansky-Pudlak Syndrome is a rare, hereditary disorder that consists of four characteristics: lack of skin pigmentation (albinism), blood platelet dysfunction with prolonged bleeding, visual impairment, and abnormal storage of a fatty-like substance (ceroid lipofuscin) in various tissues of the body. Oculocutaneous albinism consist of hereditary disorders in which there is a congenital absence or reduction of melanin in the skin, hair and eyes, with nystagmus, photophobia and reduced visual acuity. The body is unable to make melanin due to the functional absence of the enzyme tyrosinase. The disease is transmitted as an autosomal recessive character. Some writers suggesting six conditions distinguishable in relation to their frequency, and their clinical, biochemical, ultrastructural, and genetic characteristics. The attempt to identify the heterozygote has led to contradictory results. Abnormal transparency of the iris has only been observed in some heterozygotes, and this feature cannot be used to recognise carriers. The main problems are sensitivity to sunlight, with concomitant susceptibility to skin tumors, and collateral vision disturbances. Patients should avoid direct sunlight 222. Sometimes normally pigmented people who do not look like albinos can in fact be albinos. It appears that patients with autosomal recessive albinism can be normally pigmented, and patients with X-linked albinism can be severely hypopigmented. The prevalence for all forms of albinism is at least 1:15,000 and about 10% of the albinos have X-linked albinism 223. Autosomal recessive ocular albinism (AROA) is a disorder characterized by reduced pigmentation of the retina and iris, hypoplastic fovea, variably reduced visual acuity and nystagmus. Pigmentation of the skin and hair is normal, but is usually slightly lighter than in unaffected sibs related with abnormalities of the tyrosinase (TYR) gene 224. Clear ethnic differences are observed in the major form of tyrosinase-negative oculocutaneous albinism as well as in other forms of oculocutaneous albinism, cutaneous albinism and the very rare ocular albinism. Most interesting is the borderline between normal variation and abnormal forms, especially illuminated in rutilism or red headedness in Negroids and high frequencies of pigmentation anomalies without appreciable disadvantages for the carrier, e.g., the reddish skin of geographically isolated Papuans. The very differential frequencies of the occurrence of pigmentation anomalies in some populations are influenced as well by population genetic factors (isolation/inbreeding, founder-effect, heterosis) as also by socio-cultural factors (albinism as a marriage barrier, infanticide), and in some areas perhaps some kind of “negative selection” in which individuals with the character in question fail to reach reproductive age 225. By some writers was proposed to modify the albino definition as a hereditary and congenital inborn error of metabolism related to the pigment cell, characterized by anomalies of eyes, and hypopigmentation in most cases or absence of pigment in skin, hair, and eyes, and the characteristic neuro-anatomical consequences. Also to abandon the terms oculo-cutaneous albinism (OCA), and X-linked ocular albinism (XOA), and use the terms autosomal recessive albinism, and X-linked albinism instead 223.

Pseudoalbinism due to selenium deficiency.

Selenium levels were low in four children receiving long-term total parenteral nutrition (TPN) who developed erythrocyte macrocytosis (3/4), loss of pigmentation of hair and skin (2/4), elevated transaminase and creatine kinase levels (2/4), and profound muscle weakness (1/4). After 6 to 12 months of intravenous selenium supplementation, the two children with decreased pigmentation became darker skinned and their hair color changed from blonde to dark brown; a third child's hair, which had been blonde, also became darker. Transaminase and creatine kinase levels returned to near normal in those affected and, in the one child with severe myopathy, muscle weakness improved 226 .

Red or

rufous albinism Red or rufous albinism is a rare type of oculocutaneous albinism described, but not as yet fully investigated, in Africa and New Guinea. The combination of the unusual red skin color, ginger to reddish hair color, low sensitivity to sun damage, and minimal visual problems, in affected individuals, suggested that they form a group which is distinct from the brown and other types of albinism 227. The mode of inheritance was found to be recessive. Tyrosinase assays showed that rufous albinos are tyrosinase positive and on electron microscopy studies normal melanosomes and melanocytes were observed in hair bulbs and skin. Visual evoked potential testing did not show the gross decussation abnormalities of the optic pathway detected in other types of albinism. Rufous albinism might be at one end of the spectrum of types of oculocutaneous albinism 228.

Phenylketonuria

Is an autosomal recessive disorder in which the tissues are unable to metabolize phenylalanine to tyrosine because of phenylalanine hydroxylase deficiency due to base substitutions in exon 12 of the phenylalanine hydroxylase (PAH) gene229. Mental retardation fits and decreased pigmentation of the skin, eyes and hair occurs with eczema and dermographism. Black hair may become brown, reddish 230, or in older phenylketonurias may have pale blonde or grey hair. Tyrosine treatment causes darkening towards normal color within 12 months 1.

Poliosis

Is called the presence of a localized patch of white hair due to the absence or deficiency of melanin in a group of neighboring follicles.

Etiology

Molecular basis of congenital hypopigmentary disorders The melanocytes are of neural crest embryonic origin, migrate into specific target sites, synthesizing melanin(s) within a specialized organelle, transfers pigment granules to neighboring cells, and responds to various exogenous stimuli. The process of melanogenesis can be interrupted by mutations in many of the respective encoding genes and can result in hypopigmentary disorders of skin and hair. The specific transcription factors PAX3 and MITF (microphthalmia transcription factor) appear to play a regulatory role in early embryonic development of the pigment system and in associated diseases (Waardenburg syndromes). During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts. Lack or dysfunction of these receptors result in : Apert syndrome (acrocephalosyndactyly) 231, a rare inherited disorder characterized by premature closure of the bones of the skull (craniosynostosis) causing the head to appear long and pointed at the top (acrocephaly). Other features of this disorder include fusion or webbing (syndactyly) of the fingers and/or toes and unusual facial features such as widely spaced, protruding eyes and dental crowding. May be inherited as an autosomal dominant genetic trait, or sporadic. Hirschsprung syndrome (Aganglionosis involving the rectum or rectosigmoid or the left colon, the proximal colon or total colonic aganglionosis. Enterocolitis occurres in some cases76. Aganglionosis is due to loss of neural cell adhesion molecule inhibits neurocytes to migrate to aganglionic regions, and loss of nitric oxide can well explain the spasticity associated with the aganglionic region )232 and Piebaldism, respectively. Once the melanocyte resides in its target tissue, a plethora of melanocyte specific enzymes and structural proteins are coordinately expressed to form the melanosome and to convert tyrosine to melanin within it. Mutations in the genes encoding these proteins results in a family of congenital hypopigmentary diseases called oculocutaneous albinism (OCA). The tyrosinase gene family of proteins (tyrosinase, TRP1, and TRP2) regulate the type of eumelanin synthesized and mutations affecting them result in OCA1, OCA3, and slaty (in the murine system), respectively. The P protein, with 12 transmembrane domains localized to the melanosome, has no assigned function as of yet but is responsible for OCA2 when dysfunctional. There are other genetically based syndromes, phenotypically resembling albinism, in which the synthesis of pigmented melanosomes, as well as specialized organelles of other cell types, is compromised. The Hermansky-Pudlak syndrome (HPS) and the Chediak-Higashi syndrome (CHS) are two such disorders. Eventually, the functional melanocyte must be maintained in the tissue throughout life. In some cases it is lost either normally or prematurely. White hair results in the absence of melanocytes repopulating the germinative hair follicle during subsequent anagen stages. Vitiligo, in contrast, results from the destruction and removal of the melanocyte in the epidermis and mucous membranes 195.

Hereditary defects

Piebaldism (white spotting or partial albinism) is an autosomal dominant genetic disorder23 of pigmentation characterized by congenital white patches of skin and hair totally depigmented, which remain unchanged throughout life. The frontal white patch - the white forelock - may be the only sign 1. Melanocytes are lacking or are dramatically decreased in number, with abnormal shape and contain normal nonmelanized premelanosomes, and also premelanosomes and melanosomes of abnormal appearance 175. It is suggested that piebaldism-affected skin is immunologically different from normal skin 233. These hypopigmented regions can be the result of mutations of the KIT-gene (c-kit gene), which encodes the cell surface receptor transmembrane tyrosine kinase for an embryonic growth factor, the steel factor (SLF) 234. Several pathologic mutations of the KIT-gene have been identified in different patients with piebaldism and the correlation of these mutations with the associated piebald phenotypes has led to the recognition of a hierarchy of three classes of mutations that result in a graded series of piebald phenotypes 235. An heterozygous mutation of the c-kit gene encoding mast cell-stem cell growth factor receptor also contributes in inducing piebaldism 220. Sometimes is characterized by a white forelock and freckled depigmentation of the forehead, chin, ventral trunk and extremities. Normal pigmentation is found on the back, hands and feet. Within the non-pigmented areas may be present patches of hyperpigmentation 236. The melanin pigmentary abnormalities of the hair and skin in piebaldism, Waardenburg's syndrome, piebaldism with deafness, and piebaldism or Waardenburg's syndrome with aganglionosis of the gut were suggested as disorders belonging to the same category, considering them the results of defective development of the neural crest 237. These disorders of pigment cell development represent a subgroup of the neurocristopathies, involving defects of various neural crest cell lineages that include melanocytes, and many other tissues derived from the neural crest 238. Piebaldism can also be associated with other diseases like neurofibromatosis 1 (NF-1) 239. Successful repigmentation was achieved 6 to 8 months in 6 patients with three types of hypomelanosis (vitiligo, piebaldism, and albinism) by transplantation of fresh, autologous cultured epithelium with melanocytes, The autologous cultured epithelial grafting procedure is a promising treatment for patients with hypomelanosis 240.

Cartilage-hair hypoplasia

Cartilage-hair hypoplasia is an autosomal recessive metaphyseal chondrodysplasia with short-limbed short stature, hypoplastic hair, and defective immunity and erythrogenesis. Is manifested with increased ligamentous laxity, limited extension of the elbows, increased lumbar lordosis, thoracal deformity, genu varum, scoliosis, defective cellular immunity and increased susceptibility to infections and childhood anaemia. Hirschsprung disease can be associated with this entity 241. ABCD syndrome The case of a macrosomic newborn girl with albinism, a black lock at the right temporo-occipital region, and retinal depigmentation, bilateral deafness and a severe defect of intestinal innervation. Biopsy showed aganglionosis of the large intestine, and total absence of neurocytes and nerve fibers in the small intestine, indicating a total lack of sympathetic and parasympathetic innervation. The infant died of intestinal dysfunction at 5 weeks. She was the 14th child of consanguineous Kurdish parents. Four sibs of our patient had the same syndrome and died a few days after birth. The other 9 sibs are well, with an unremarkable phenotype. It represents a new neural crest syndrome with autosomal-recessive inheritance242.

Tiez's syndrome

Generalized 'white spot' loss of skin and hair pigment, complete deaf, mutism and eyebrow hypoplasia. Whether or not melanocytes are present in the affected areas remains controversial 1.

Vogt-Koyanagi-Harada syndrome

Is a rare disease of unknown origin that affects many body systems such as the eyes, ears, skin, and the meninges. The most noticeable symptom is a rapid loss of vision. There may also be neurological signs such as severe headache, vertigo, nausea, and drowsiness. Loss of hearing, alopecia and skin color may occur along with whitening of the hair and eyelashes (poliosis). Is also presented with uveitis, dysacousia, madarosis 243, although uncommon, Vogt-Koyanagi-Harada may affect young children, and may be severe 161.

A new white forelock (poliosis) syndrome with multiple congenital malformations in two siblings.

Two Jewish Ashkenazi male patients are reported as having a new syndrome consisting of a white forelock, distinct facial features associated with congenital malformations involving the eye, cardio-pulmonary and skeletal systems. The etiology of this disorder is probably genetic and transmitted either as an autosomal recessive or X-linked recessive conditions 244.

DIFFERENTIAL DIAGNOSIS OF piebaldism, naevus depigmentosus, vitiligo.

Epidermal melanocytes in different hypopigmentary disorders, from skin specimens from patients with piebaldism, naevus depigmentosus, and vitiligo, were examined by immunohistochemistry (cryosections), using monoclonal antibodies against the c-kit protein (YB5.B8) and melanosomes (TA99). In piebaldism, hypomelanotic epidermis contained only a few TA99-positive epidermal melanocytes and no detectable c-kit protein, in naevus depigmentosus the expression of c-kit protein was strong, and TA99 immunoreactivity was faint. In vitiligo lesions, no epidermal immunoreactivity for melanosomes or c-kit protein was found 233.

Physical hair changes

The new-formed unpigmented hair has yellowish color due to its dense keratine 9. Hairs on exposed parts may be bleached by sunlight 9.

Von Luschan's Chromatic Scale The equipment necessary for classification is: Von Luschan's chromatic scale for classifying the color of the skin. There are 36 opaque glass tiles for confronting the subject's skin-color. Martin's color grading scale for the color of the eyes. It consists of 16 glass eyes used to compare the color of the subject's eyes. Fisher's hair color chart consisting of 30 tufts of cellulose hair. (Museo di Storia Naturale.UNIVERSITÀ DEGLI STUDI DI FIRENZE, ITALY).

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