Alopecia: Syndromes of Genetic Significance

THE JOURNAL OF I NVESTIGATIVE DERMATOLOGY

Copyright © 1973 by The Williams & Wilkins Co. Vol. 60, No.6

Printed in U.S.A.

ALOPECIA: SYNDROMES OF GENETIC SIGNIFICANCE*

SIGFRID A. MULLER, M.D.

INTRODUCTION

E:~ccept for common baldness, the loss of axillary , pubtc, and body hair in the aged (especially in postmenopausal women) and the absence of hair growth in t he testicular feminization syndrome or other simi lar rare conditions, most cases of a lopeci~ are not directly related to hormonal factors. In _hirsutism, on t he other hand, hormona l relationship~ are important. Again, in hirsut ism histopathologic exam inat ion of the hairs in sk in biopsies or exammation of plucked ha irs is rarely clinically useful, whereas in a lopecia, espec ial ly when the scalp Is affected, careful exam ination of such ha irs o~en helps to estab lish or co nfirm t he clinical ~hagnosis. Such exam inations have not been done m many types of alopecia.

It _is also important t hat t he anatomy, basic physiOlogy of hair growth , hair cycles, as well as t he_ variable sensitivity and responses of t he hair folhcle to a variety of drugs and stresses be evaluated (Fig. 1). These points a re very well covered in s uch basic texts as t hose of Montagna and. Ellis (1958) , Montagna and Dobson (1969) , Ebhng and Rook (1968), and Munro (1971) and in t~e papers of Kligman (1959, 1961), Van Scott and h1s colleagues (1957), and Crounse and Van Scott (~960) . I shall limi t myself primarily to a discusSIOn of (1) the various forms of congenital a lopecia and assoc iated syndromes wherein loss of hair is a feature, (2) common baldness (or androaenetic alopecia) in men a nd women , and (3) alopecia areata in which important genetic influences have b~~n reported or suspected. Although t he susceptibihty to loss of ha ir in numerous other conditions (e._g .? telogen or anagen effluv ium and hypothyroidism) and in response to infectious agents such as de~matophyte infections may have significant genetic aspects, only scanty information is avail able. I ha ll a lso exc lude many dermatologic diseases. such as lupus erythematosus, sc leroderma, ~ar~01d, or blistering disorders because they only Incidenta lly involve hair-bearing areas and be·cause pi lary involvement is a secondary phenomenon.

SYNDROMES OF ALOPEC IA (TABLE I)

Congenital Alopecia

AloP_ecia congenita uniuersalis. This category of alopecia has caused cons iderable confusion . Pat ients were included in this category if they showed al?~ecia at birth and no other abnorma li ty. The clinical differentiation between t his process and alopecia areata occurri ng in t he neonatal period may be unclea r a nd argumen ts for their simila rity

• From the Department of Dermatology Mayo Clini c Rochester, Minnesota 55901. ' '

475

have been propounded. However, the hairs in alopecia a reata are distinctively involved as noted in hair pluck specimens and in sca lp biopsies. We can only specu late about t he pathogenetic mec han isms in a lopecia congeni ta universa lis, but partial or complete failure of development of the primary epithelial hair germ to develop is one possibility. The cases of Tillman (1952) , Linn (1964) , Pajtas (1950), and probably those of Shy and Treister (1968) appear to fall in to this category; but sca lp biopsies were not reported except in an undetermined number of Pajtas's cases. The other cases frequently referred to in the li terature probably fit best into t he hidrotic type of ectodermal dysplasia .

Linn (1964) reported two isolated cases of congenital a lopecia: a boy a nd a girl, born of unrelated parents in Australia, who had experienced a tota l absence of hair since birth except for a few normal eyelashes; the children were otherwise normal. Biopsies were not done. Tillman (1952) reported on two fami lies who seemed to provide t he best evidence for a recessive mode of inheritance. In one family, a brother and sister (index cases), both completely bald but born of normal parents, married siblings who were thei r fir t cousins but also born of norma l parents; on ly t he male sib ling was bald. All 5 children of the marriaae of the two hairless persons were bald. One of these children married a normal person and had 2 normal chil dren . T he marriage of the other person (index case) produced 11 children of whom 4 were bald. One of t he normal children married and had 5 normal offspring. Two of the bald children married normal persons and had normal children.

The index case of Tillman 's second family had parents who were firs t cousins. The patemal grandmother had lost her hair at 13 years of age. Because no examination of the hairs was reported, the possibility remains that the co ndi t ion was congeni tal a lopecia areata. In Czechoslovakia Pajtas (1950) observed four generations of a family consisting of 147 members, 22 of whom had inherited a lopec ia as an incompletely dominant tra it with similar numbers of each sex affected. The family members were otherwise well and of normal intelligence. A few ski n biopsies showed t he sk in glands and a rrectores pilorum muscles to be normal and hyal ini zed perifollicular connective t issue to be present. A few normal hairs were also seen.

Special mention should be made of a fami ly observed by S hy and Treister (1968) and reviewed briefly by McKusick (1968) in which 6 of 13 siblings had congeni ta l a lopecia universa lis as an isolated trait without ab normalities of t he teeth na ils, or sweat glands. Porter's cases (thi s issue) may a lso fit best here.

476 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

B

FIG. 1. A: Plucked normal human scalp ha irs in a nagen phase in water (unstained; x 20). B: Plucked norma l

human sca lp hairs in anagen a nd telogen (nitro blue tetrazolium stai n; x 16). C: Plucked hairs from margin of plaque of alopecia areata in 26-year-old man . Note tapering proximal tips of anagen hairs and a norma l te logen hair (unstained ; x 20). D: Tapering hair roots from case of anagen effl uvium in 22-year-old woman treated with

azathioprine ( x 16).

Hereditary hypotrichosis (Marie Unna type). Increasing evidence indicates that the Marie Unna type of hereditary hypotrichosis is a clinically distinctive autosomal dominant gene mutation in which the only abnormality is alopecia. Excellent summaries a nd fami ly studies of this condition, published by Stevanovic (1970), Peachey and Wells (1971) , and Solomon et at. (1971), indicate that it is more common than was previously believed. Affected family members are usually born with little or no hair; but the scalp hair generally becomes more profuse in early childhood and develops into characteristically coarse, twisted hairs like those of a horse 's tail (Stevanovic, 1970). The alopecia not uncommonly becomes more severe at puberty , especially on the vertex and at the periphery of the scalp. Folliculitis sometimes occurs but not to the same degree as in folliculitis decalvans. The general body hair, eyebrows, and eyelashes are sparse or absent. Solomon and associates (1971) have postulated that the hair abnormality is basically a defect in the hair shaft. The abnormal hairs are flat , ribbon-like , and twisted at irregular intervals. Studies of scalp biopsies by light microscopy were not distinctive, but electron microscopy studies showed intracellu-

Jar fractures of the cuticular cells, increased interfibrillar matrix, and fractures of the cortica l and medullary cells. Thus, this condition could perhaps more accurately be classified as " Alopecia Associated With Deformities of the Hair Shaft " but this has not been done because of the frequently hairless condition at birth and the delayed development of the characteristically coarse , twisted scalp hairs.

Unclassified types. The case reported by Stevanovic (1959) probably belongs more correctly in the hidrotic ectodermal dysplasia group because in addition to total alopecia, keratoderma of the palms and soles and severely dystrophic nails were present in the index case and his two sons. The da ughter had norma l scalp hair but no eyelashes; she also had keratoderma. The two siblings with sparse scalp hair, syndactyly , and retinal degeneration reported by Albrectsen and Svendsen (1956) should be classified separately, at least for the present. Moynahan's brief report (1962) of a boy with total absence of hair, epilepsy, and mental retardation is also unique and distinctive because the alopecia present at birth in the proband 's brother, father, and maternal aunt improved after 2 to 4 years of age.

ALOPEC IA

TABLE I

Syndromes of genetic significance in alopecia

I. Congeni ta l a lopec ia A. Un ive rsa l B. Hereditary hypot richos is: Marie Unna type C. Unclassified types D . Locali zed

l. Aplas ia cutis congenita 2. Alopecia triangular is congeni ta lis

II. Ectodermal dysplasia A. Hidrotic B . Anhidrotic

III. Congeni ta l syndromes in which hypotri chosis is less constant or less we ll defined A . Autosomal recessive condi t ions

l. Cockayne's syndrome 2. Werner's synd rome 3. Progeria 4. Rothmund 's syndrome 5. Dyskeratos is congeni ta 6. Sec kel's syndrome 7. Cartilage-hair hypoplasia 8 . Marinesco-Sjogren syndrome 9 . Conradi 's syndrome

10. Acroderm atiti s enteropathica 11 . Tricho- rhino- phalangeal syndrome 12. Homocyst inuria 13. Lamellar ichthyosis 14. ? Hartnup 's disease 15. 'J Citrullinemia

B. Autosomal dominant conditions 1. Pachyonychia congeni ta 2. Ha llerm an- Streiff syndrome 3. Oculodentod igita l syndrome 4. Treacher- Collins syndrome 5. Poplitea l- web syndrome

C. X -linked dominant disorders l. Oral- fac ial- di gita l syndrome 2. ln continent ia pigmenti 3. Focal dermal hypoplas ia

D. X- linked recessive disorders 1. Keratos is fo lli culari s spin ulosa deca lvans cum ophiasi

E . Ch,·o mosomal a berrations 1. Down 's syndrome 2. Trisomy A

IV. Alopecia assoc iated with deformities of ha ir shaft A. M onilethrix B . P ili te rt i C . Bjornstad 's syndrome D. Trichorrhexis nodosa E . Kinky hair syndrome F. Polli tt 's syndrome G. B rown's syndrome (trichoschisis with a lternati ng birefringe nce) H. Arginosuccinicaciduria I. Netherton's disease and varia nts

V. Common baldness VI. Alopecia areata

VII. Misce ll aneous A. Genera li zed a lopecia due to hamartomas of hair folli cle B. Universal atrichia with papular les ions C. Locali zed pectora l, abdomi nal, and crura l a lopecia D. Organoid hamartomas of sca lp

477


Cockayne (1933), who reviewed t he literature extensive ly before 1933 an d sum ma rized the previous ly reported cases, distinguished between dominant a nd recessive forms of a lopec ia congeni ta. Ne it her form appeared to be homogeneous. In iso lated and fa milia l cases, the patients freq uently had norma l ha ir on other parts of the body; one had numerous keratinized follicular cysts, two had hypop lastic nails, and one had t hickened palms and soles. Other patients had thickened nai ls a nd notched teeth . Almost a ll t he cases were reported in t he 19th or ea rly part of t he 20th cent ury, a fact that makes eva luation more difficult.

The cases of a lopec ia congen ita with suspected dom inan t inheritance reviewed by Cockayne generally were associated with a bnormali t ies of the nai ls or sebaceous glands . One extensive ped igree was associated with hair that was normal at birth but fell out in early childhood. In 1881 he summarized the report of a fami ly of completely ha irless Australian a borigines who were otherwise norma l and hea lthy.

Suffi ce it to say t hat t he unclass ified types are ra re. Further documentation of t he histopathologic a nd associated clinical findings and a complete genetic work-up a re needed to make a diagnosis or to estab lish t hese d isorders as separate entities as well as to recognize t he variabi li ty of their expression .

Localized forms of congenital alopecia. Aplasia cutis congenita (congenital defect of scalp ): This

rare disorder is listed here because it not infrequently involves the scalp. The most striking clinical feature after hea ling is circumscribed cicatricia l a lopec ia most commonly seen near the mid line over the vertex of t he scalp. The defects, which usually in volve only the skin and subcuta neous t issues, vary in size from a pinhead to several centimeters in dia meter and usua lly have sharp punched-out margins which , at birt h, may appear as granulation t issue without any appendages (Anderson and Novy, 1942). Frank and Ruby (1957) , Rauschkolb and Enriquez (1962) , Resnik et a l. (1965), and Bart et a l. (1966) reviewed t he condi t ion and pointed out t hat a lthough reports of fam ili a l involvement are few , t hey usually occur in a parent and child , a nd thus suggest dominan t inherita nce. However, Gedda and associates (1963) reported an affected boy and girl born of consanguineous parents. Rarely, other abnormali t ies have been reported wi th t he disorder . T hey include clubbing of hands a nd feet , congeni ta l heart disease, absent digits, hareli p, cleft palate, hemangiomas, and assoc iated underlying skull defects. Miller et a l. (1970) a nd Guthrie et al. (1971) reported sca lp defects associated with t risomy 13 and with deletion of a portion of chromosome 4. In at least a fo urt h of t he cases t he defects a re seen in t he midline and may a lso be associated wi t h underlying bony defects.

Hodgeman et a l. (1965) reported congeni ta l scalp defects in otherwise normal twin sisters wi t h

underlyi ng bony defects and reviewed six previous ly reported cases. T he bony d efect hea led spontaneously in 5 and 7 months, and cicatrix was formed in t he soft t issues of the sca lp in 4 weeks . There is no adeq uate exp lanation of t he defects. T he ma in compli cation, secondary infection, has occasiona lly resul ted in meningit is (Frank a nd Ruby, 1957).

Alopecia triangularis congenitalis: Only a few cases of this rare form of nonscarring congeni tal alopec ia have been reported. Described by Sabouraud (1932) , it occurs as nonscarring tria ngular patches of te mporal a lopecia with t he base of the tr iangle toward t he forehead at t he a nterior hair margin : The borders are sometimes not well defined, the triangle extends onto the sca lp for about 1- ~ inches, and the condition is eit her unilateral or bilateral. It has no specia l s ignificance, but it should be distinguished from a lopec ia areata. On two occasions I have seen it as a n incidental findi ng (Fig. 2); I suspect it is not as rare as the literature ind icates . No familia l association of the condi tion has been reported (Can iza res, 1941· Huriez and Desmons, 1961).

Ectodermal Dysplasia

In two ma in forms of ectodermal dysplasia, a lopecia or sparse hair is an important clinical feature: t he hidrotic type, which is inherited as an autosomal dominant trait, and t he an hidrotic form, wh ich is an X-linked recess ive, though women occasiona lly have partial expression of the condi t ion. Kerr and associates (1966) reported that t he evidence for an autosomal variety of the latter remains inconclusive. Confusion has a risen probab ly beca use more t ha n one type of hidrotic ectodermal dysplasia ex ists, though t he Clouston type is t he principa l vari ety. On the other hand , Passarge et a l. (1966) reported a family in a n inbred group in rural Kentucky where a utosomal recess ive inherita nce was suggested , t hough t he condi t ion wa clinica lly simila r to the X- linked form. Likewise , Crump and Danks (1971) reported t he cases of a boy a nd a girl where autosomal recess ive inherita nce was probable.

Hidrotic ec todermal dysplasia. T his type is much commoner than t he anhidrot ic form and most patients a re of French-Canadia n or French origin. Willia ms and Fraser (1967 ) reported follow-up genetic studies of Clouston 's origi na l affected fami ly a nd several other cases including an American fami ly of French-Canadian origin. Of 453 offspring of an affected and an unaffected parent, 240 were affected. Calculat ions showed a satisfactory fit for autosomal dominant inheritance with equal numbers of men and women affected .

The principa l clin ica l features includ e dy -t rophic na ils, scant or absent hair , and several types of denta l anomalies . Less common fi ndings include hyperkeratosis of the palms and sole , patchy hyperpigmentation, epilepsy, deafnes , menta l deficiency, polydactyly, syndactyly, and

ALOPECIA 479

. F 1c. 2. Unilater-a l a lopecia tria ngula ris congeni ta l is of left frontote mpora l sca lp in a 14-year-old girl. P resent s ince birth without change. Congeni ta l dislocation of left hip a lso present.

sensorineura l hearing loss . Diagnos is becomes difficult when only an isolated finding , such as peg teeth or an absent tooth, is present. Sweat and se baceous gla nds function normally , but the relative frequency of sebaceous fo lli cles a nd pilosebaceous structures has not been inve tigated. The alopecia resem bles t hat of t he anhidrotic type and is rarely co mplete. Commonly t he ha ir is soft, short, a nd parse; men need to shave only infrequently. Lowry et a l. (1966) indicated t he variabi lity of expression in a patient who had normal ha ir growth a nd an affected offspring who was bald. As many as 20 percent of the affected patients may have normal ha ir (C louston , 1929). Fertili ty is not impaired as is indicated by Wil liams and Fraser (1967). The dental anoma lies may be of diagnostic va lue w hen other findings are minimal. Reed et a l. (1970) gro up t his type as a disorder of keratin izat ion, but it is difficu lt to explain all the findings on this basis. Certa inly ep idermal keratinization has not been shown to be ab norma l.

Anhidrotic ectodermal dysplasia. In t his condition, wh ich occurs in almost a ll racia l grou ps, the phenotype is so consistent and remarkable that affected patien ts resemble one a nother much more

strongly t han they resemb le their re lat ives . The first manifestation of the condi t ion is heat intolerance. Reed et a l. (1970) summarized the clinica l spectrum of t he condition noting that there may be only a gross defici ency rather than an absolu te absence of sweat glands. Alopecia, dental anomalies, and characteristic fac ies a re the principa l features. Nai ls are rare ly, if ever, significantly dystrophic, unlike those in t he hidrotic fo rm. Histologically, hypop las ia of t he appendages is clearly evident in t he skin and perhaps a lso in the mucous membranes of the respiratory and gast rointestinal tract. As a consequence , se rious resp iratory infections, chronic bronchitis, hoarseness, and atrophic rhiniti s can resu lt. Sub norma l intelligence and numerous minor abnormalities, in cluding atopic disorders, have occasiona lly been seen. Previously , on ly a few patients surv ived past puberty; thus, it is difficu lt to estab lish a ny pedigrees (De Si lva, 1989; Reed et a l. , 1970) . Puberty occurs normally in survivors and hair growth sometimes increases at this time, a lthough pigmentation of the hair is deficient. In some patients, body and sexual hair is completely absent (De Si lva, 1939).

480 THE JO URNA L OF INVESTIGATIVE DERMATOLOGY

Kerr and colleagues (1966), who investigated the gene effect in ca rriers of t he disorder, noted especia lly minor degrees of part ial anodont ia and va riably diminished sweat-gland activity. They found the ha ir norm al, a lt hough hypotrichosis has been noted in female carriers of t he gene (Richa rds and Ka pl an , 1969).

Congenital Syndrom es in Which Hypotrichosis Is a M inor or Less Well-Defined Manifestation

In ma ny syndromes, hypotrichos is or a lopec ia may be an associated minor ma nifestat ion a lt hough no obvious defect of kerat in ization in the hair has been reported. Alopec ia is rarely distinct ive in itself (ra re except ions will be men tioned later), a nd usually deta il ed descript ions or biopsies of hair have not been ca rried out . Some disorders such as t he Marin esco-Sjogren syndrome may belong in the category associated wi t h hair shaft deformi t ies (Fig. 1), but the present grouping is a convenient one espec ia lly for the less well-defin ed ty pes of hypotri chos is whi ch a re seen as pa rt of a complex congeni ta l syndrome. Various modes of inheri tance are noted in Table I.

Autosomal recessive conditions. In Cockayne's syndrome, t he ha ir, whi ch tends to be sparse in childhood, shows some gray ing a nd relat ively minor changes in growt h (S mi t h, 1970). Patients wit h Werner's syndrome have norm al a moun ts of ha ir un t il late adolescence when premature and p rogressive loss of sca lp hair is followed by generalized loss of ha ir . T he skin is atrophi c and ta ut, mimickin g sc leroderm a, and hypogonadism develops rapidl y. Genera li zed ar teri osc lerosis is present (Thannhauser, 1945; Epstein et a l. , 1966). Children who have progeria frequent ly have tota l a lopecia, t hough it may not be evident in t he first year of life. Genera lized hypop las ia develops, in vo lving t he skin , subcutaneous fat, na ils, teeth, a nd bones. The patients a re ra rely taller t han a 5-year-old child and usually die in childhood or adolescence of a rteri oscleros is (S mi t h, 1970). In Rothm und 's syndrome t he scalp ha ir is fin e and sparse or com plete ly abse nt ; freq uent ly t he body ha ir is absent. In 50 percent of the cases , eyebrows and eye lashes are a bsent (Rook et a l. , 1959 ; Butterworth and Strean, 1962). T he ty pe of sca lp a lopec ia has not been determined , but t he ha ir loss is not a ndrogen-dependent since hy pogonadism is usua lly present . Thus, common ba ldness is not a pa rt of these conditions .

T he scalp hair of patients wi t h dys kera tos is congeni ta is often sparse, fin e, and prematurely gray. Patients wit h t he bird -headed dwa rf syndrome (Seckel, 1960) have va ria ble degrees of ha iriness; fo ur of Seckel's patients ha d hypert richosis, b ut M cKusick et a l. (1967) reported two a ffected s ist ers wi t h defini te genera li zed hypotri chosis. This is an important example of opposite phenotypes , which should be resolved to prevent confusion in t he classification of t hese dwarfs .

In t he ca rt ilage- hair hypopiasia synd ro me, t he characte ristic hair phenotype is ove rsha dowed by a characteristic type of dwa rfism origina lly reported in Amish populations but later found in nonAmish populations as well (Smi th, 1970). T he hair is genera lly sparse, fragile , fin e, and s ilky. The light color, short ness , and sma ll caliber of t he sca lp ha irs probably create an impress ion of exaggerated spars ity; however,· in some cases McKusick et a!. (1965) noted a lmost complete ba ldness. The ha ir tends to darken wit h aging. The body ha ir is simila rly affected , and since no hormona l a bnormali t ies a re present, sexua l development is normal.

In t he Marinesco-Sjogren syndrome, t he sca lp ha ir is sparse, fin e, hypopigmented , a nd shor t, and axi lla ry, fac ia l, a nd pu bic ha ir a re sparse. The significance of t he a lopec ia is not known (M ari nesco et a l. , 1931; Norwood, 1964). P orter (this iss ue) · observed short, spa rse scalp ha ir in 3 of 5 siblings wi t h t hi s condi t ion in whom t richoschi is wi t h a lternating birefrin ge nce was present.

In severa l reported cases of Conradi's syndrome, patients had assoc iated icht hyotic- like sk in in vo lvement during infancy which gradua lly cleared. Al t hough Rook and Wells (1968) desc ri bed t he hair as norm al, S mi t h (1970) reported that patchy a lopec ia of t he sca lp wi t h coarse ha irs is frequ ent ly seen . Reed (persona l communication, 1971) a lso noted pili torti. All ansmi t h a nd Senz (1960) reported cases of patchy sca lp a lopecia a nd poss ibly diffuse thinning.

Acrodermatit is en teropathi ca is characterized by part ia l or complete loss of sca lp hair, eye brows, a nd eye lashes (a ll present at birt h) du ring the acute phase of the syndrome in in fa ncy; after t reatment wi t h diiodohydroxyquin (Diodoquin ) a ll ha ir regrows completely (Wells and Win kel mann , 1961) .

Sparse, fine, light -colored sca lp ha ir is characteristic of the ra re tri cho-rhino- pha langea l syn drome. The frontote mpora l areas a re most severely in vo fved , and t he latera l eye brows a re thinned. The eye lashes may or may not be normal. Microsco pi c exa mination of the ha irs shows periodic fl attening wit h ret1ected li ght and some sligh t variation in thi ckn ess, neither of whi ch are str iking. Usually t he na il s a re t hinned . Other characterist ic feat ures include moderate retardation of growth, a pea r-sha ped nose, a nd typica l de formit ies of t he fingers wit h cone-shaped ep iphyses (Gorlin et a l. , 1969) .

Abnorm ali t ies of ha ir phenoty pe in homocys tinuri a have not been emphasized , but ap parently mild a lopec ia res ul ts in fi ne, dry, light-colored hair (S chimke et a l. , 1965).

In patients wi t h lamell ar icht hyos is, patchy cicatricia l a lopecia of t he sca lp, wh ic h is not di stinctive, occas ionally develops during childhood or adolescence (Longhin et a l. , 1968; Va ndersteen , 1970). In addi t ion, Porte r and Lobi tz (1970) reported fragil e ha irs wi t h atrophi c bulbs in cit rul -

ALOPECIA 481

linemia and fine fragile scalp hair in patients with Hartnup 's disease . Hair phenotypes should be characterized more completely in these diseases since little is known about t hei r importance.

Autosomal dominant conditions. Patients with pachyonychia congenita frequently have sparse, friable, kinky hair on the scalp , but t he hai r elsewhere may be entirely normal (S hrank, 1966; Soderquist a nd Reed , 1968). Patients with the Hallerman-Streiff syndrome have s ignificant hypotrichosis, especially of the scalp and eyebrows, where t he hair tends to thin and be li ght-colored; occasionally the pubic and axi ll ary ha ir is normal. The skin is usually atrophic (Falls and Schull , 1960; Solomon and Silver, 1970) . This disorder is usually the result of a single autosoma l dominant mutation.

The ocu lodentodigita l synd rome, which is characterized principally by microphthalmos , enamel hypoplasia, and deformity of: the fingers, is occasionally associated with dry, lusterless, short hairs in the sca lp which have not been characterized further (Gorlin et a l. , 1963b).

The Treacher-Collins syndrome (mandibulofacial dysostosis) is mentioned here because about 50 percent of the patients have partial to tota l absence of t he lower eye lashes. However , one-fourth of the patients have projection of the sca lp hair onto t he lateral part of t he cheek (Rovin et a!., 1964; Sm ith , 1970).

The popliteal- web syndrome is a complex condition that consists principally of cleft lip and palate , lip pits, skeletal anoma li es, genital anomalies, and web bing of the palpebrae, mouth, perineum, and popliteal fossae; it has a lso been associated with an absence of eye hair and short, spa rse, dry , hypopigmented scalp hair. The complete syndrome is present only infrequently because t he expressivity is variable (Rosel li and Gulienetti , 1961; Hecht and Jarvinen , 1967).

X -linked dominant disorders. In add it ion to multiple anomalies, patients with the oral-facialdigita l syndrome freq uent ly have diffuse scalp alopecia characterized by coarse, lusterless, brittle , and broken-off hairs above the sca lp line. Scalp biopsies show diminution of hair follicles , early keratinous cysts, and greatly diminished to absent sebaceous glands (Doege et a l. , 1964; Solomon et al., 1970).

A recent report of patients with incontinen tia pigmenti described patchy, atrophic scalp alopecia in 18 of 26 patients, a much higher incidence t ha n previously reported (Carney and Carney, 1970) . Children afflicted with t he rare syndrome of focal dermal hypoplasia (Goltz- Gorlin syndrome) sometimes have diffuse sparse hair on the sca lp, eyebrows, and eyelashes, or focal atrophic a lopecia on the sca lp (Goltz et al., 1962; Gorlin et al. , 1963a; Beurey et a l. , 1969).

X -linked recessiue inheritance. The only condition in this category is keratosis follicularis spinulosa decalvans cum ophiasi, an extremely rare

disorder in which affected patients have an ophiasic pattern of alopecia in one or more winding streaks on the sca lp and sparse eye and beard hair (McKusick, 1968) in addition to th ickening of the skin of the neck, ears, eyelids, and t he palms and soles. The significance of the spiny follicular keratosis in the causation of the alopecia is not clear .

Chromosomal aberrations. A minor feature of Down's syndrome (trisomy 21) is fine, soft, sca lp ha ir that is often sparse, a lthough baldness is not seen. The sexual hair is straight (Smith, 1970) . Partial a lopecia of the scalp is a lso associated with t he sporadic ill-defined trisomy A syndrome (Porter and Lobitz , 1970).

Alopecia Associated With Deformities of Hair Shaft

In a sense, th is category is not inclusive enough because most disorders of a lopecia are probably due to abnormalities of keratinization. However , I have included t hose disorders wherein deformities of t he hair shaft are grossly visible. These are characterized by variable expressivity, e.g. , some persons at birth have various degrees of a lopecia, whereas others do not have significant a lopecia and hence are detected on ly incidentally in family studies .

Monilethrix is an autosomal dominant trait in which the ha ir shaft is uniformly beaded. A few sporad ic cases have been reported (Fig. 3A). The intensity of t he beading and the relative numbers of affected hairs are variable in a kindred (Baker, 1962; Solomon and Green, 1963). Fractures occur in the internodal areas deficient in hair matrix. The hairs are usually short and frequent ly emerge from horny follicular papules. Sometimes almost total or patchy baldness is seen. In some patients the hair loss is not significant whereas in others the condition is often confused with pili torti. In its pure form no other abnorma li ties are seen although all the ·body hair may be affected. Some patients improve after puberty. Sometimes baldness is noted at birth , but the hair shaft abnormali ty may not become evident until some years later. In polarized light, monilethrix hairs have a characteristic appearance (Fig. 3B), which may be helpful in diagnosis if typica l beading is not easily seen .

Pili torti is a developmental defect in which the hair shaft is twisted 180° on its own ax is at more or less irregular intervals (Fig. 3C ). C linically the disorder resembles monilethrix and rarely these cond itions are noted together. Althoug h a lopecia is frequently not severe, it is sometimes almost tota l at birth , and the hair-shaft defects become more apparent with aging. In many cases, t he fragility of the hair gradually improves wit h adolescence (Fig. 3D) (Ronchese, 1932; Hillier et al., 1940; Nichamin, 1958). Twice as many women as men are said to be affected , but t his may be a soc iologic sampling error. Pili torti is listed as an autosoma l dominant disorder by McKusick (1968). Occasion ally severe trichotillomania is confused clinically

482 THE JO URN AL OF INVESTIGATIVE DERMATOLOG Y

Frc. 3 . A: Sporad ic case of moni lethri x ma nifesting as m ild a lopecia in a 3-year-o ld hea lt hy gi rl. B: Affected ha ir

of (A) viewed in pola ri zed li ght ( X 40). C: Twisted ha ir of pili tort i viewed in refl ected li ght ( x 45). D: Sixteen-yea r-old

girl wi t h pili to rt i and moderate a lopec ia. E : Severe t ri chot illoma nia in a 6-yea r-old girl unde rgoing psychothera py .

wi t h a lopec ia due to eit her monil ethri x or pili tort i (Fig. 3E), bu t ca reful exa mination of t he ha irs or a sca lp biopsy is di agnostic (Muller and Winkelmann , 1972).

An in creas ing number of cases of pili tort i have been reported in which cochlea r- type deafn ess is an assoc iated de fect (Bjornstad ' synd rome) . In a ll th e reported cases, t he deafness has been bilatera l and its severi ty is directly related to the more

severe ha ir defects (Reed et a l. , 1967) . Unlike pili tor t i, it is listed as a n autosoma l recess ive d isorder (McKusick, 1968).

As in monilethrix and pili tort i, ha ir in trichorrhexis nodosa sometimes appea r beaded to the na ked eye. Actua lly , however, t he nodal swelling. represe nt brushlike fr actures provoked by t rauma . Although this type of brea kage in norm al persons is proba bl y due to severe t raum a (C hernosky and

ALOPECIA 483

Owens, 1966), susceptibili ty could be familial. Multiple nodes as well as broken hairs a re seen .

The prev iously discussed ha ir phenotypes of monil ethrix, pili tort i, and trichorrhex is nodosa may be assoc iated in differen t degrees wit h severa l syndromes of cons idera ble morbidi ty in which the hair d efect can provide a help fu l diagnostic clue. These include Menkes' syndrome, Pollitt's syndrome, arginosucci ni cac iduria, and etherton's syndrome. The occurrence of t ri chorrhex is nodosa in Apert's syndrome has a lso be~n reported (Porter and Lob itz, 1970).

At least 15 cases of Menkes' syndrome, a fatal syndrome of X-linked recess ive inheri tance, have been reported. The principal features are se izures and severe neurolog ic impa irm ent, which usua lly begin within a mont h or two of birth and progress to decerebration. A number of other abnormalities have a lso been noted, such as microcephaly and micrognathy, bu t severe a lopecia is perhaps t he most interesting accompa nying anomaly (Menkes et a l. , 1962; Bray, 1965; Aguil ar et al., 1966). The scalp hai r, usua lly normal at birth , becomes fr iable, sparse, and kinked within a few weeks. Pili torti , monilethrix , and trichorrhexis nodosa have a ll been reported toget her; but someti mes only one principa l kind of hair defect, usually pili tort i, is present. Aguilar and col leagues (1966) have proposed t hat a specific inherited metabolic defect causes derangement of lipid in t he brain and possibly also in t he hair , si nce lipid monolayers are thou ght to play an important part in the orientation of the keratin fiber. They reported an unusua l autofluo rescence in t he hair shafts a nd t he Purkinje cells.

Mention should be made of Pollitt's syndrome. The isolated report by Pollitt and colleagues (1968) described a brother and sister, 3 and 5 years of age, with mild menta l a nd physica l reta rdation . The scalp hair was sparse , the hai r shafts cou ld eas ily be broken, and they showed tr ichorrhexis nodosa and pili tort i . Biochemical examination of the hairs disclosed a considerab le decrease in cystine content, which ref1ected a deficiency in su lfur-rich proteins, though plasma and urinary levels of cystin e were norm al.

In Brown's syndrome (Brown et al., 1970), t he scalp hair resembles t hat in Pollitt 's syndrome, i.e., both had low levels of sulfur-ri ch protein. The only abnorm a li ty in t he child reported by Brown et al. , h owever, was the fragile ha irs, which appeared norma l in ordinary li ght but had a lternating bands of birefringence when viewed with polarized light.

o doubt the latter case represents a different disorder but it suggests an additiona l method of class ify ing ha ir ab normali t ies by their content of sulfur-rich proteins.

A rginosuccinicaciduria is characteri zed by men tal retardation, convulsions, and hepato mega ly beginn ing in infancy. Many of the patients have normal hai r, but a num ber of cases have been reported wherein short, sparse hai rs most noticea-

bly on t he scalp have been a prominent feature. Fragile hairs, trichorrhex is nodosa, and monilethrix have been reported. Hair abnormalities were a finding in 5 of t he first 10 cases studied. Some patients are only mild ly mentally retarded or of normal in telligence (Levin et a l. , 1961; Crounse, 1962; Efron et al. , 1965; Efron and Hoefnagel, 1966). The metabolic defect is the absence of arginosucc inase and t he excretion of large amounts of arginosuccinic acid in t he urine with a resultant fai lure of the orni t hine- urea cycle and ammonia in tox ication. The possibility of relative deficiencies of the enzymes in one t issue but not in the others has been proposed as an exp lanation of the variability of the findings. S ince large amou nts of arginine are "found in hair and citrul line is present only in the in tern al root sheath and medull a of ha irs, it is understandable how a defective synt hesis of protein could result in fragi le hairs, t hough an exact exp lanation for this disease is not yet known (Sotos and Boggs, 1970).

Netherton's disease is characteri zed by congenital ichthyosis, hair-shaft deformities, and sparse sca lp ha irs, freq uently an atopic diathesis, and rarely an inconstant am inoaciduria. Arguments have ar isen about the type of icht hyosis described by Netherton since severa l cases of icht hyos is linearis circumf1exa (ILC) with these hair defects have been reported (Altman and Stroud, 1969). Hurwitz and associates (1971) suggested t hat, in Netherton 's original case, a combination of lamellar ichthyosis and tr ichorrhexis in vaginata was present. In other forms of ichthyosis , bamboo hairs may a lso be seen.

I am not certain whether Netherton 's disease and ILC are variants of t he same disorder or separate ent ities, but I do agree with Hurwi tz and colleagues (1971) that ha ir-shaft abnormali t ies are seen in a variety of ichthyotic disorders. The typica l finding is that of bamboo hairs with jointlike deformities in ball and socket ar rangement (trichorrhex is invaginata) . Pili torti was a lso seen in at least 4 patients (Marshall and Brede, 1961). Vilanova and De Moragas's patient (1964) had only tr ichorrhex is nodosa , whereas Stevanovic (1969) reported other hair changes, including a rope like appearance , cha nges in the shape and ca liber of the hair, and abrup t changes in the archi tecture of the hai r.

Thi increased frag ili ty of the ha ir is usually manifested by sparse sca lp hair at birth which usually stays s hort without cutting, a lthough some lengthen ing of t he hai r and fewer deformities are sometimes seen with aging (Gianotti , 1969). All the body hair may be affected in various degrees . Reports show t hat a preponderance of girls have t his disease, an indication of a sex- linked domi nant in heritance . Porter and Starke (1968) noted severa l stillborn males in an affected kindred. Nevertheless, because of t he possible heterogeneity of the syndrome (Hurwi tz et a l. , 1971) , a definite mode of inheritance cannot be postulated until the


associated ichthyotic condition has been diagnosed or until more definite diagnostic cri teria have been est a blished.

Tay's recen t report (1971) is s ignifi cant in thi s regard . In a Chinese family in Singapore, two brothers and a sister in a s ibship of 7 children were affected and were charact erized by nonbullous congenita l icht hyos iform erythroderm a, sparse ha ir with pili tort i and trichorrhex is nodosa-like lesions, and mental and growt h reta rdation. No other systems were affected . Clearly t his was not Ne therton's syndrome, bu t T ay contended it had many features t hat resembled it and reinforced t he hypothesis of Hurwi tz and assoc iates (1971) a bout the heterogenei ty of Netherton's disease .

Co mmon Baldness (Pattern A lopecia, Premature Alopec ia , Androgenetic A lop ecia, Se borrheic A lopecia )

Al t hough everyone is fa miliar wi th t he phenomenon of common baldness, in some mild cases and in aged individu a ls it is diffi cult to diagnose. Since there is no defini te characteristic that will positive ly identify this disorder, ge netic studies have proved difficul t and somewhat unreli able. Hamil to n's criteria (1951) are useful in men but less so in women. Most investigators accept t he common ident ity of pat tern alopecia in men and women and the expansion of t he syndrome to include diffuse t hinning of t he ha ir in women (Maguire and Kl igman, 1963; Lud wig, 1964; S mi th and Wells, 1964; P apa a nd Kli gman , 1965; Vadasz and Debreczeni , 1967; Sala mon, 1968) .

Clinical findings. A gradual M-shaped fronta l recession of the hair margin is frequent ly foll owed by the deve lopment of a bald spot on t he posterior crown in men. Enlargement and confluence then progress to a fin al stage where only a periphera l frin ge of scalp hair remains. Women wi th masculi ni zing syndromes or idiopathic hirsui t ism may have a similar loss of hair . Clinica lly common baldness in women is usually more diffuse and severe in the frontocentral scalp (Fig. 4A) and only rarely, if ever, progresses to a smooth pate (Figs. 4B and 4C). A few older women ex perience a thinning of t he scalp ha ir on t he crown only, bu t whether this is related to common baldness is not yet known (Ludwig, 1964, 1968; Vadasz and Debreczeni , 1967) . T he deve lopmen t of typica l male pattern a lopec ia in women is so un common t hat, when present , it indicates t he need for excluding endocrinologic abnormali t ies, part icularly when signs of masculini zation a re also present. T ables II a nd III summari ze my unpu b lished studi es and compare t he principal clinica l findin gs in a group of 50 men and 50 women wit h common ba ldness seen at t he Mayo Clinic in 1963 and 1964.

Testosterone is necessary fo r t he phenotypi c ex pression of common baldness, but it is not understood why s imilar androgenic stimulation results in hirsut ism or a lopecia elsewhere on t he body. Recent studi es focus ing on t he regiona l

variat ions in end-organ sens itivi ty have been re viewed in t he preceding paper.

Prevalence. There is ge neral agree ment a bout the prevalence of common baldness a mong young and middle-aged Caucas ian men in whom the expression of t he t ra it increases wit h aging. However, the signifi cance of t he extremely high figures reported in aged populations rema ins undetermined . Figures fo r the t hird , fourth , and fift h decades proba bly are more meaningful. T hus, Hamil ton (195 1) reported an overall preva lence of common baldness a mong 47 percent of t he men in t hese t hree decades wi t h an in crease to a bout 80 percent among men in t he seven th and eighth de cades. Buechner and co lleagues (1964) reported an overa ll incidence of 82 percent, bu t t hey divided t he condi t ion into two sub types in which hair was principa lly lost anteriorly or about the vertex. Snyd~r and Yingling (1935) noted a prevalence of 43 percent of male common baldness. Beek's study (1 950) of 1,000 men also gave high preva lence rates for common baldness. Only 34 percent of t he men between 35 and 44 years of age were bald , bu t thi s increased to 55 percent in the next decade and to 80 percent among men 65 years of age or older. Beek grouped calvities frontalis separately, noting a prevalence of this condi t ion of 98, 100, and 100 percent for these same decades, res pec tively. E ven though Hamil ton (1951) ins isted on strict cri teria for the diagnos is of common baldness, it is generall y acce pted that everyone 's scalp hair thins wit h aging and that the common baldness phenotype in the aged cannot be determined accurately. Prevalence fi gures for those years beyond the fift h and sixth decades should probably be held as unreliable fo r the t ime bein g.

The condi t ion is t hought to be less frequent in Negroes . Estimates for common ba ldness include 25 percent by Buec hner et a!. (1964), bu t Setty (1970) noted t hat 74 percent of Negro men do show some evidence of common baldness t hough his cri teria for di agnosis were not as strict as t hose of Hamil ton (1951). Nonbaldness, however, was seen in 26 percent of Negro men but in only 6 percent of Caucas ian men. Baldness was noted in a bout 15 percent of Chinese men (Ha mil ton, 1951). Figures for American Indians and Eskim os are not ava il able, t hough t here is genera l agreement t hat these rac ial groups have t he lowest occurrence of com mon baldness .

Prevalence of common baldness in wo men is ha rder to determine, probably because it is so re adily masked or perhaps even confused wit h other types of a lopec ia. Early investigators, applying similar clin ica l cri teri a as in ma le- patterned alopecia for t he di agnos is in wom en, noted a preva len ce of 8 percent (Snyder and Yingling, 1935) and 19 percen t (Ha mil ton , 1951) . Likewise. Smith and Wells reported (1964) similar prevalence ra tes in a ge neral Caucasian population. I kn ow of no studies done in non- Caucas ian women , bu t I would ex pect t he fi gures to be considerably

ALOPECIA 485

FIG. 4. A: Female type of common ba ldness seen in a 29-yea r-old hea lthy woman. Onset 4 years prev iously . B: Ma le type of common baldness in 37-yea r-old woman who is otherwise hea lthy except for irregular menstrual cycles . Hirsu tis m wa not present. C: Male type of common baldness in 46-year-old woman with idiopathic hirsutism of severa l year ' duration .

lowe r , as is t rue for the ma le type. Beek's study (1950) of 1,000 Caucas ian wo men was instructive in t h at only 9 percen t of t he wom en between 35 and 44 year s of age were ba ld. This fi gure increased to 39 p e r ce nt in t he next decade a nd to 75 percen t in wo m e n 65 yea rs of age or older. For ca lvities fro n talis , t he preval ence rates were 27 , 73, a nd 92 percen t fo r the same age groups, respectively. This also s u ggests to me the greater re li ab ili ty of t he diagn osis of common ba ldness in younger a nd middl e - aged women .

Gen etics. T he inheri tance of common ba ldness has not been settled . E a rly stud ies of Os born (1916), Snyder a nd Yingling (1935), a nd Ha rri s (1947 ) s uggested t hat common ba ldness is inherited as a n a u toso ma l domin a nt tra it in men bu t as a recess ive t ra it in women ; thus, it is a sex- limi te d tra it. Co mm on ba ldness deve lo ped only in wo men who h a d inheri ted a doubl e dose of t he gene. Roo k

(1965) s uggested that co mm on ba ldness deve lops in heterozygo us women with pathologica lly high levels of androgens. Other possibili t ies reviewed by Cockayne (1933) were those of a n X- linked recessive tra it or even inherita nce t hrough a Y chromoso me. H owever, wit h better und ersta nd ing of the disorder and pedigree a nalyses, t he latte r two suggestions have been rejected . The most recen t study was that of Sa la mon (1968) who ca me to t he co nclusion t hat common ba ldness is inheri ted as a sex-controlled, au tosoma l do min an t character ; bu t he admi tted t hat t he wea k po in t of t he hypothesis was the ina bil ity to determine t he "'zygos ity" of a n affected perso n .

S mit h a nd Wells (1964) suggested t hat t he wide va riat ions in t he ma nifestation of co mm on ba ld ness indicate genet ic mechanisms akin to those fo r he ight a nd we ight wi t h e it her severa l genes or a s ingle gene a nd modify in g genes at work . T hey

486 THE J OUR NA L OF INVESTIGATIVE DERMATOLOGY

TABLE 11

Chronologie comparison of progression of common boldness in moles and females

Time

Onset Consul tat ion

Average age. years

Males Fe ma les

Cond it ion full y deve loped

Teens 25 + 45 +

20s 35+ 60 +

TABLE III

Clinical comparison of common baldness in males and females

Factor

Incidence Severi ty Appeara nce. Patte rn

P rogress ion Complete denu

dation Sym ptomatol

ogy

Ma le Pe ma le

Common Common Mi ld to extrem e Mild to extreme Readily apparent Eas ily masked Diffuse; frontopari - Diffuse ; fron tocen-

eta l and crown tra l Ra pid or slow Slow Common Rare

Ra re Occasiona l tenderness and t ightness of scalp

noted that among women with t he severest degrees of a lopecia , who wou ld be t he most likely to be homozygous, a higher incidence of a lopecia in their parents was lackin g. T heir studies excluded Xlinked recessive and autosoma l recess ive inheri tance and favo red a mul t ifactori a l genetic mec hanism wi t h a part ially do minant gene for common ba ldness in both men and wo men. T he seve ri ty of t he disord er showed no consta nt relation to the incidence or ex tent in other members of the family; t hus the modifying genes were suggested to be inherited independently of t he principal gene.

Unfort un ately, there are no data to confirm any of these hypotheses. Perhaps, un t il more defini te st ud ies are done, it wo uld be best to admi t ignorance and state t hat comm on ba ldness tends to run in families.

Histopathology . Histologica ll y t here is an ascending, ob li terative fibrosis of the hai r fo llicle sheaths (Maguire and Kligman, 1963) so that the ha ir bulbs are small er and occur more superfi cia ll y in t he dermis of the sca lp . The involvement of ha ir is manifested clinically by t he sheddin g of increased numbers of te logen hairs because of short ened anagen cycles and randomly distribu ted num bers of short, t hin , hypopigmented ha irs contrasting wi t h rela ti vely un affected long, thick ha irs in t he genetica lly sensit ive regions of t he scalp . In men, this progresses to hairlessness, whereas in women it is ra rely seen.

Associated conditions. Ha mil ton and assoc iates (1969) refuted Harri s's cla im (1947) tha t men with

common baldness are more hirsute t han others . Setty (1 970), however, provided new data that support Harris's study jn both Caucas ia n and Negro men. Salamon (1968) and Ha mil ton (1951) reported a poss ibly significant increased association of common baldness with t he a bsence of hair on the latera l lower part of t he legs.

No correlat ion was found between common baldness and myocardi a l infarctions, severi ty of acne scarring, or insani ty (Snyder and Yingling, 1935: H amil ton et a l. , 1969 ). However, Buechner et a!. (1964) proposed that whi te males with coronal ba ldness are four t imes more resistant to t he development of bronchogenic carcinoma than t hose wi t h abundant sca lp hair a nd are slightly less susceptible to the development of emphysema. Their studies a lso suggested an increased susceptibili ty to coronary artery disease and a shortened li fe-s pan for men with common baldness. T hese cla ims should be invest igated furt her to be proved or disproved even though t he ge nera l fee ling is one of disbelief. In agreement with Auerbach (1968) , I have noted normal serum iron levels and iron-binding capac it ies in wo men wi th common bald ness.

Alopecia A reata

Clinica l features . This disord er is characterized by single or multiple discrete or confluent c ircular or ova l plaques of asymptomatic, nonscarring alopec ia occurrin g most commonly on t he scalp of healthy persons bu t a lso on hairy skin anywhere. Occas ionally t he condi t ion progresses to general ized hairlessness . Most of t he cases are mild, with normal regrowth of hair after a few months. a lt hough ini t ia l at tempts at formation of ha ir may produ ce fine, nonpigmented hair (Fig. 5A) . Exclamation point hairs are usually seen in vari able numbers at t he margins of the bald areas (Fig. 1C). They are distinctive , short, and pigmented , taper ing down to a trophi c roots . Dystrophic cha nges in fin gernails a lso are comm only seen . Estimates of t he progress ion to a lopecia totali s vary fro m 1 to 30 percent depending on the selection of cases a nd t he length of follow- up (Anderson, 1950; Walker and Rothma n, 1950; Muller a nd Winkelm ann , 1963). Permanent regrowth of ha ir after t he development of a lopecia tota lis is infrequent (Mul ler and Winkelmann , 1963) .

The disease occurs most commonly in t he t hird , fo urth, and fi ft h decades of li fe and affects equal numbers of each sex. The average age at onset is 36 years for the mild cases bu t 23 years for individuals wi th more severe in volvement. Approximately 20 percent of the cases are children in whom the disease tends to be more severe t han in adul ts (Figs. 5B and 5C). T able IV shows t he early age at onset of the disease in some patients in a series reported from t he Mayo Clinic (Mull er and Win kelm ann , 1963) and emphasizes the possible area of confusion between thi s diso rder and alopecia congeni tal is.

Estim ates of the preva lence of the disease in a

ALOPECIA 487

I

II

ill

2

D 0 alopecia areata 0 atopy )Zfdead

FIG. 5 . A: Alopecia areata of 2 yea rs' duration in a 53-year-old ma n. Regrowing wi t h nonpigmented hairs. Band C: Norma l regrowth of scalp hair in 7-yea r-old boy with onset of a lopecia a reata 2 yea rs previously and severe loss of hair at age 9 yea rs. D: Pedigree of a family wi th a lopecia areata (courtesy of Dr. Hymie Gordon). E : Alopecia areata in a 42-year-old ma n. Began 5 months after onset of Graves' disease.

T ABLE IV

Age at onset of alopecia areata (158 children)

Age, years Tota l is Part ia l is

0- 2 10 4 3-6 23 26 7- 10 22 21

11- 15 31 21

Swedis h population are 30- 100 per 100,000 population (Gip et a l. , 1969) . Anderson (1950) estim ates that 2 percent of 15,000 pa tients seen in a derma to logic clinic during a 5-year period had t he disorder.

Gen e tic aspec ts. A previous review (Muller and Winkelmann , 1963) of 736 patients with a lopec ia areata, as well as other reports (Sa bouraud , 1932; Anderson, 1950) , indicated a fa mili a l incidence of abou t 10 percent; when a lopecia tota lis was present, t h e incidence increased to 18 percent. In our stud y , one parent and a child were affected in 18 case s and only siblings were affected in 21. Two pair s of identi cal twins were affected as were one

fraternal pair plus two other twins of undetermined type. Several other reports indicate involve ment through two or t hree generations (An derson , 1950 ; Simons, 1964). Anderson (1950) reported 22 famil ia l cases in his study of 134 patients. A parent and offspring were affected in 7 instances and a nother sibling in 8. In volve ment of a parent and grandparent was seen once. Hendren (1949), Turncliff (1931), and Barsky and Gigli (1961) each reported the occu rrence of a lopec ia areata in a pair of twins ; bu t Hendren's report may have been t hat of tri chotillomania, a neurotic ha bit disord er not un commonly confused wit h a lopec ia areata.

Our data suggest that t he lesions in a lopec ia areata do not fo rm and resolve in t he usual sense ; rat her, its chroni city and high rate of recurrences suggest t hat t he di sease represents a cont inuous potent ia l reactivity of t he pilary uni ts. It has been difficul t to assess the heri ta bili ty of a lopecia areata since our data are sketchy. The pedigree of a fa mily with affected members in three generations was recently studied by us (Fig. 5D) ; the index case was a 28-year-old woma n. Des pi te some bas is for argu ing t hat t his case shows t ransmission of alopec ia

488 THE JO URNA L OF INVESTIGATIVE DERMATOLOGY

areata as an a utoso mal dominan t t rai t wi th incom plete penetra nce, I believe it and others like it sim ply ill ustrate unusual examples of a clusterin g of cases in a family, since most patien ts do not have affected relatives . Our previous studies (Mul ler and Winkelm ann , 1963) are consistent wi t h mul t ifactori al causation since affected patients wi t h earlier ages at onset tended to have more affected relatives and were more severely involved . M ore deta iled studi es will be needed to establish t his t hes is defini t ive ly.

Histopathology. Evidence suggests t hat hair growt h is restra ined in the a nagen phase . The numbers of te logen hairs a re a lso increased, proba bly as a secondary phenomenon. Characteristic microsco pic features are lymphocytic infl ammatory infil t rat ion of t he connective t issue sheath en ve loping affecte d hair bulbs a nd a trophic anage n ha irs (Van Scott, 1958; Van Scott and Eke!, 1958). F igure 1C illustrates t he value of studying plucked ha irs in a lopec ia areata. Affected ha irs can be seen to taper rapidly to a " spear po int" prox im ally whereas other hairs may recover . In questiona ble cases, scalp biops ies may be diagnostic.

Associated diseases. T he incidence of vit iligo and thyroid disorders (Fig. 5E ) increases, but its significance is unkn own (Muller and Winkelmann , 1963; Cunliffe et a l. , 1969).

T here may be a n increased assoc iation wi t h atopic disease, bu t data t hus fa r are not conclusive. T he lymphocytic inflamm atory in filt ration of the connective t issue sheath enve loping affected hair bulbs, t he favorable response to cort icosteroid therapy, and t he increased frequ ency of associat ion wi t h t he above disorders suggest t hat possibly autoimmune mechanisms a re a t fa ul t .

Miscellaneous

I include here four ty pes of a lopecia, two of which are of in terest because of t heir simila ri ty to a lopecia areata universa lis and a lopec ia congeni ta. They illustrate we ll the need for histopathologic study of t he hair.

T he first type was reported by Brown and associates (1969) in a 32-year- old Negro woma n who developed a lopec ia of the sca lp when she was 20 years of age and later universal a lopecia. Skin co lored papul ar les ions were ini t ia lly a minor feature noted on the face only. She was seen by a number of dermato logists a ll of whom made a clinical di agnosis of "alopec ia areata " un t il 25 skin biopsies from mul t iple sites uniformly showed occult hair follicle hamartomas at the site of biopsies. The tumors did not penetrate in to the skin . The ma in concern was whether t his condi t ion represen ted a variant of mul t iple trichoe pi theliomas. The patient, in addi t ion , had myasthenia gravis, suspected lu pus erythematosus, aminoaciduri a, a nd an enlarged sella turcica. There was a question of whether a patern al aun t had had a similar disord er.

In a second type, Damste a nd Prakken (1954)

reported three simil ar cases of uni versal a lopec ia wit h pa pular lesions, and subsequen tly a fourth case (Loewnethal and P rak ken, 1961) was repor ted. All four patients were female, and three of them were born wi th rela ti ve ly normal ha ir which was shed in the neonatal period ; the fourth child was born with sparse ha ir. Widespread pap ular lesions were noted by the ages of 5, 8, 9, and 18 years, t hough t he exact t imes of onset we re not men t ioned . No other ectoderm al defects were reported . T he fa mily history of one patient is notab le because t wo of her sisters were similarly bald but had died at 3 mont hs and 5 mon t hs of age . Histolog ically, t he papules were folli cular cysts. each wit h a hyperk eratotic orifi ce fill ed wit h kerat in . Small cysts were situated deeper in the co rium . The widespread papular lesions were interpreted as dysplasia of the pilose baceous system and a re lat ionship to t richoepi t helioma was postulated : The au thors were not certa in whether the pa pular lesions were pri mary or second ary to a lopecia or an unrelated phenomenon. Nevertheless, the possibili ty of genera li zed dys plasia of the pilose baceous organs should be considered , as in t he case reported by Brown and assoc iates (1969).

The t hird type, organoid ha martomas (nevus sebaceo us of J adasso hn ), usually is present at birth and involves t he sca lp in about 70 percent of t he cases. These hamartomas occas ionally may be as large as 9 em in diameter but usua lly they a re cons idera bly sma ll er (M ehregan a nd Pinkus , 1965) . In infancy the lesions are characteri zed by a circumscribed area of a lopecia in which t he skin shows a mild , smooth, ye llowish , waxy thickening. Puberty initiat es the next phase in which epi t helial hyperplasia, se baceous gland hyper t rophy, and apocrine glands predominate . In ma ny patients. secondary ep itheli a l neoplasias subsequent ly develop in t he lesions. No instances of fa milia l occurrence have been reported to my knowledge . This les ion is included because of rare, sporadic reports of its assoc iation wit h cerebra l defects in cludin g epil epsy a nd mental retardation which have been summari zed by Wilson J ones and Hey! (1970).

A fourth type, in volving circula r bare areas in regions of pilos ity on t he chest and a bdomen, has been described in Caucasian ma les by Setty (1961 , 1966), es pecia lly in more hirsute individuals . T he bare areas overlie each pectora l musc le and average 9- 10 em in di ameter. The um bilica l bare areas average 2- 11 em in diameter and are cen tered a bove, below, or a bout the umbili cus. Among 607 Caucasian males, 5 had pecto ra l and um bilical bare areas, while 28 had only t he umbilica l bare areas. Setty (1961) also poin ted out similar bu t small bare areas on eit her side of t he chin as dis tinctive features of cer ta in beard pa t terns. N o significance other than an t hropologic was given to these alopecic areas, and their unresponsiveness to androgenic pilar stimulation has not been investi gated.

ALOPECIA 489

COMMENTS

Much more needs to be learned about the ca uses of hair loss and the syndromes of a lopecia. For t h at matter, much m ore inform ation is needed about a lmost all aspects of n ormal hair physiology. Additional clinical a nd histopathologic data and suitable gene t ic studies should provide muchneeded knowledge about many alopecic conditions and should improve our clinical acumen, should indicate basic pathogenetic mechanisms or even new treatment approaches, and should improve the quality of genetic counseling.

Surely, in every abnormal condition, the hair should be looked at carefully. At the Mayo Clinic a laboratory report form has been designed for

'plucked hairs examined with dissectin g, light, and polarizing microscopy. This form is included in the permanent medical laboratory report sheet in the patient's chart. It has helped other physicians in diagnosing and treating medical problems not directly related to the alopecia. Our experience has increased considerably as a result of the greater numbers of referrals for this purpose. The value of scalp or skin biopsies cannot be overe mphasized as sources of information in the study of alopecic syndromes.

Finally, newer methods of investigation should be utilized whenever possible, e.g. , scanning electron microscopy, electron microprobe x-ray microanalysis, neutron activation analysis, tensile a_nd friction measurements, and amino acid analyS IS. Additional insights into a number of medical disorders in which alopecia is either a maj or or a minor feature could be achieved by the direct application of currently available research techniques to the analysis of the affected hairs themselves.

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Alopecia: Syndromes of Genetic Significance

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