Trichothiodystrophy: Review of sulfur-deficient brittle hair syndromes and association with the ectodermal dysplasias

JOURNAL of the

A.meRiCaN ACaDemy OF

DerMaTOLOGY VOLUME 22

NUMBER 5

PART 1

MAY 1990

Continuing medical education Trichothiodystrophy: Review of sulfur-deficient brittle hair syndromes and association with the ectodermal dysplasias Peter H. Itin, MD,* and Mark R. Pittelkow, MD Rochester, Minnesota Trichothiodystrophy appears to represent a central pathologic feature of a specific hair dysplasia associated with several disorders in organs derived from ectoderm and neuroectoderm. The key finding is brittle hair with low sulfur content, but alternating dark and light bands under polarizing microscopy, trichoschisis, and absent or defective cuticle are additional important clues for the diagnosis of trichothiodystrophy. Our review of the literature revealed extensive associated findings in trichothiodystrophy. Classification of patients with trichothiodystrophy and other dysplasias isdifficult because diminution of sulfur-rich protein in hair is not a sufficient marker to allow precise differentiation, although several similar ectodermal dysplasias can be excluded by demonstration of abnormal sulfur content in hair of patients with trichothiodystrophy. Patients with trichothiodystrophy should have a thorough evaluation for other associated manifestations, including investigation of photosensitivity and DNA repair defects. Detection of low-sulfur brittle hair syndrome is also important for genetic counseling because the disease appears to be inherited in an autosomal recessive pattern. (J AM ACAD DERMAToL 1990;22:705-17.) Trichothiodystrophy (sulfur-deficient brittle hair), a rare hair disorder, is inherited as an autosomal recessive trait. 1-3 Only one case suggestive of an X-linked inheritance pattern has been reported." Clinically, the hair is dry and sparse and the hair shafts break easily with trauma. The hair color appears to be unaffected. No effective treatment for the brittle hair is known, but trauma should be min-

The CME articles arc made possiblethrough an educational grant from the Dermatological Division. Ortho Pharrnaccutical Corporation. From the Department of Dermatology, Mayo Clinic and Mayo Foundation. Supported by the Swiss National Science Foundation. Reprint requests: Mark R. Pittclkow, MD, Department of Dermatology, Mayo Clinic, 200 First St. SW, Rochester, MN 53905. "Dr. [tin is VisitingClinician at the Department of Dermatology. 16/2/18298

Fig. 1. Frontal view of patient: short, sparse hair. imized. Often, severe neuroectodermal disorders are associated but none is a constant feature' Sulfur-deficient brittle hair is a key finding and an objective marker for these associated autosomal re-

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Table I. Associated signs and symptoms reported Table I. Cont'd

with trichothiodystrophy Findings

Hair Axillary hair sparse Pubic hair sparse, body hair absent/sparse Few vibrissae + otic hair Nails Dysplasia Splitting Koilonychia Ridging Thickening Yellow discoloration, unguis inflexus Skin Ichthyosis Photosensitivity Xeroderma pigmentosum or defective DNA repair Collodion baby Erythroderma, eczema Hypohidrosis, lipoatrophia, follicular keratosis Pruritus, erythema, freckles Telangiectasia, folliculitis, hemangioma Cheilitis Hyperpigmented eyelids, pyoderma, palmar pustules, hypopigmented macules, parchmentlike skin Nervous system Retardation Spasticityjparalysis, ataxia, intention tremor Motor control impaired Pyramidal signs, muscle tone diminished, neurosensory hearing impairment, peripheral neuropathy Hyperreflexia, eye movements jerky, deep tendon reflexes absent Seizures, hemiparesis, tetraparesis, dysarthria, cerebellar deficiency, irritability /lethargy Morphologic changes and dysmorphia Growth retardation Microdolichocephaly/ microcephaly Receding chin

Reported cases (total No.)

8 7

5 43 15 13

7 3

2

30 16

13 9 8 5

4 3

2 1

69 5

4 3

2

59 21 12 Continued

Findings

Morphologic changes and dysmorphia Protruding ears Dental abnormalities Caries, thin-beaked nose, progeria Raspy high-pitched voice, enamel hypoplasia High-arch palate Single palmar crease, white plaques on tongue, frontal bossing, gingival hyperplasia, excessive palm crease Hypoplastic ears, preauricular pits, hemiatrophia faciale, change in proportions, polythelia, short neck, goiter, cleft ear lobes, bifid uvula, small mouth, macrocheilia, obstruction of the nose, cranial dysplasia, ear deformation not specified Maxillary hypoplasia Eyes Cataract Conjunctivitis Nystagmus Photophobia, epicanthic folds Retinal dystrophy Entropion, hypotelorism, exophthalmus, enophthalmus, esotropia, myopia, astigmatism, ectropion Retrobulbar hemangioma, chorioret II atrophy, retinal pigmentation, antimongoloid eye slant, tortuosity of retinal vessels, diminished red-green discrimination, strabismus, hypertelorism, ocular abnormalities (not otherwise specified) Pale optic disc Genitals Hypoplasia, cryptorchism Hypospadias Lungs Asthma Bronchiect pulmonary s adenorr Immune sys ztion Recurrent

Reported cases (total No.)

10 9 7 5

3 2

1

Several

13 7 5 4 3 2

1

Several

6 2 3 1

17 Continued

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Trichothiodystrophy 707

Table I. Cont'd Findings

Bones Pectus excavatum, pes valgus Range of motion limited, thoracic kyphosis Genu valgum, coxa valga, cubital/tibial valgus defect, ulnar deviation of finger, valgus deformity of great toe, contracture of finger, scoliosis, lumbosacral lordosis, zygodactyly Cardiovascular system Peripheral circulation impaired Vcntricular septal defect

Reported cases (total No.)

3

2

Fig. 2. Polarization microscopy of scalp hair shows alternating light and dark bands.

2 1

cessive ectodermal and neuroectodermal diseases, although isolated cases oftrichothiodystrophy without other defects have been reported.v? The spectrum of symptoms and signs reported to be associated with trichothiodystrophy is extensive (Table 0. In patients with trichothiodystrophy, hair abnormalities are the only obligatory and diagnostic findings that identify the sulfur-deficient neuroectodermal dysplasias.' Scalp hairs, eyebrows, and eyelashes are brittle, unruly, of variable lengths, easily broken, and generally feel dry' (Fig. 1). Light microscopy reveals clean transverse fractures through the hair shafts (trichoschisis), an irregular hair surface and diameter, and a decreased cuticular layer with twisting and a nodal appearance mimicking trichorrhexis nodosa.': 8, 9 The distal hair shafts often terminate in "brush breaks."! Polarizing microscopy with crossed polarizers shows a typical appearance of alternating light and dark bands, giving a "zigzag" or "tiger tail" pattern I, 2, 6, 8, 10-17 (Fig. 2). It has been reported to represent "alternating birefringence" but this terminology is incorrect because no fixed angle of light splitting is detected. The structural abnormality that causes the transverse bright lines is not known. However, Calvieri et aI.,18 by x-ray microanalysis, found an alternating content of sulfur along the length axis of the trichothiodystrophic hair. Scanning electron microscopy shows incomplete cuticles or absence of them and

Fig. 3. Scanning electron microscopy of scalp hair demonstrates almost total absence of the cuticular layer with longitudinal ridges.

longitudinal grooves 1-3, 6,8, 11-17, 19 (Fig. 3). Transmission electron microscopy demonstrates an abnormal arrangement of microflbrils.l? Absence of the exocuticula and the sulfur-rich A layer (outer aspect of the cuticle cell) causes cuticular weathering and weakness of the hair shaft. 20 Hair and nails are composed of proteins of two structural groups and multiple subgroups: (l) fila-

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Table II. Ectodermal symptom complexes with brittle hair and low-sulfur content or typical microscopic findings of trichothiodystrophy Author(s) (McKusick Catalog No.)

Pollitt et aL24

1968

(27555)

Brown et al.6 Tay37 (24217)

1970 1971

Porter-? (24880)

1971

Jackson et al. 2

1974

(23405)

Cantu et al.62

1975

(25836)

Baden et al.lO

1976

(23405)

Baden et al.lO

1976

Arbisser et a1. 67 Howell et a1. 71

1976

(21139)

Hernandez et al. 35

Features

Year

1979

(25836)

Mental and physical retardation; trichorrhexis nodosa Isolated brittle hair Ichthyosiform erythroderma, hair shaftabnormalities; mental andgrowth retardation Abnormal "birefringence"; trichoschisis in Marinesco-Sjogren syndrome Brittle hair; shortstature; intellectual impairment; decreased fertility Onychotrichodysplasia; chronic neutropenia; Brittle hair; intellectual impairment; decreased fertility; shortstature Low sulfur content in Marinesco-Sjogren syndrome Brittle hair; morphologic and biochemical hair abnormalities; mental deficit Onychotrichodysplasia; chronic neutropenia; mild mental retardation

·See also BIDS, Amish brittle hair syndrome. tSee also Tay syndrome.

Acronym/eponym

Pollitt syndrome Trichoschisis Tay syndrome

Amish brittle hair syndrome

BIDS syndrome

Sabinas syndrome

Continued

*Po!litt syndrome. §Trichothiodystrophy withxeroderma pigrnentosum.

mentous proteins that have lower sulfur content than the parent keratins (low-sulfur proteins), and (2) matrix proteins represented by two protein subgroups,onerich incystine (high-sulfur proteins) and the other rich in glycineand tyrosine (high-tyrosine proteinsj.!' As a rule, patients with trichothiodystrophy show an approximately 50%decrease in cystine/cysteine and sulfur of hair but often a total decrease to less than 10%of the normal value may be noted.1-3,10-13, 15,20,22-24 The nails may show a decrease in cystine and sulfur content. 1, J0,25,26 Urine and serum levels of these substances usually are normal. The composition of low-sulfur proteins of hair appears to be almost identical to that of control subjects with some variation in relative proportions/" The high sulfur-containing proteins are

altered qualitatively and especially the ultra-high sulfur-proteins are severely decreased.F: 27 In addition, there is an abnormal distribution of the sulfurrich, intennicrofibrillar, globular proteins of the cortex and the sulfur-rich proteins of the hair cuticle.20,28 Expression of abnormal genes that specifically affect sulfur-rich proteins of keratinization may be pathogenic. 22 Several different groups of trichothiodystrophy with the same sulfur-deficient, brittle hair phenotype and distinct associated ectodermal and neuroectodermal abnormalitiesexist. These patients appear to represent a subtype of the ectodermal dysplasias. Ectodermal dysplasiashave been defined as a developmental defect that, at the embryologic stage, affects primarily the ectoderm. Freire-Maia and

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Trichothiodystrophy 709

Table II. Cont'd Author(s) (McKusick Catalog No.)

Year

Features

Acronym/eponym

Price33 (23405*) Price et a1. 1 (23405*, 24217,t 27555,:1: 27873§) Corona-Rivera et a1. 36 (25836)

1979 1980

Low-sulfur-content hair; neuroectodermal disorders

Trichothiodystrophy

1981

ONMR syndrome

J orizzo et aP3 Crovatoet a1. 41 Diaz-Perez et a1. 47

1982 1983 1983

Yong et al,55 (27873) Hordinsky et a1. 4

1984 1987

Lehmann et a1.39

1988

Chapman'?

1988 1988

Onychotrichodysplasia; chronic neutropenia; mild retardation Ichthyosis + BIDS Photosensitivity + IBIDS Lamellar ichthyosis; photosensitivity; pruritus; brittle hair; increased urinary excretion of kynurenine + hydroxykynurenine Trichothiodystrophy; xeroderma pigmentosum Trichothiodystrophy; urea cycle dysfunction Trichothiodystrophy; heterogeneous DNA repair impairment; no photosensitivity Osteosclerosis + IBIDS Trichothiodystrophy; ultrastructural changes in keratinocytes

Pois et aI,51

Pinheirov- 30 suggested that at least two ectodermal structures (hair, teeth, nails, and sweat glands) should be affected in ectodermal dysplasias. Classification of patients with trichothiodystrophy and several other ectodermal dysplasias is difficult and occasionally incomplete because diminution of sulfur-rich protein is not a sufficient marker to allow precise differentiation, although several similar ectodermal diseases can be excluded by demonstration of abnormal sulfur content in hairs. Various acronyms and eponyms have been created to describe low-sulfur hair associated with neuroectodermal changes (Table II). Van Neste et a1. 5, 9 proposed a classification scheme for trichothiodystrophy according to increasing severity of findings in organs derived from ectoderm and/or neural crest: the isolated hair defect (A), accompanied by onychodystrophy (B), mental retardation (e.g., Sabinas syndrome) (C), and including findings of growth retardation (e.g., Amish brittle hair syndrome, and the

IBIDS PIBIDS syndrome

SIEIDS syndrome

brittle hair, intellectual impairment, decreased fertility and short stature syndrome [BIDS]) (D), ichthyosis (e.g., Tay syndrome and ichthyosis with BIDS [IBIDS]) (E), and photosensitivity (e.g., PIBIDS) (F). We also include another group (G) that includes patients with trichothiodystrophy and chronic neutropenia" Van Neste et a1. 27, 32 suggested that biochemical differences in the hair of patients with trichothiodystrophy might be related to clinical expressions of associated diseases. Two patients with a variant of trichothiodystrophy were reported with a decrease of high-sulfur proteins without major changes in the composition of amino acids.l? For the diagnosis of trichothiodystrophy we suggest that at least low sulfur content and one of the following findings must be present: trichoschisis, alternating light and dark bands by polarizing microscopy, or absent or severely damaged hair cuticle by scanning electron microscopy.

Journal of the American Academy of

710

Dermatology

[tin and Pittelkow

Table III. Results of analysis of hair in patients with trichothiodystrophy

Sulfur analysis, * electron microscopy, polarizing microscopy

I

No.of

patients

45

I

References (No.)

Electron microscopy polarizing microscopy Polarizing microscopy

21

1-3,6,7, 11·17, 20, 23-25,28, 31,34, 41,42,46,51, 55, 63, 64 2, 3, 42, 43, 47

9

4,37, 38,48,50,

Light microscopy] Electron microscopy Sulfuranalysis" Sulfur analysis, * electron microscopy No data available

5 2 5 2

65, 68 35,36,62 19,40 10,27 67

6

2,39,50

*Sulfur analysis:determination by amino acid analysis. electrondispersive, or x-ray microanalysis. [Trichorrhexis.

In our analysis of the literature we included all patients reported to have trichothiodystrophy or patients whohad two or more of the following fmdings: low sulfur or cystine hair content, alternating light and dark bands by polarizing microscopy, trichoschisis by light microscopy, and absent or severely altered hair cutide by scanning electronmicroscopy. Because the criteria for the diagnosis of trichothiodystrophy have been characterized only since 1979, we determined the methods of hair analysis using variouscriteria for patients with brittle hair found to represent the low sulfur hair syndrome (Table III). LITERATURE REVIEW

In 1979 and 1980, Price et al.1,33 created the term trichothiodystrophy to describe the abnormality of sulfur-deficient, brittle hair. Trichothiodystrophy was recognized as a marker for a neuroectodermal symptom complex.1, 5,25, 34 In addition to the typical findings ofbrittle, easilybroken, sparseand dry scalp hair, hypotrichosis and patchy alopeciaare frequent findings along with scarcity of eyelashes and eyebrows. Sparse axillary and pubic hair as well as diminished vibrissae and otic hairs also have been reported. Other body hair may be scant or absent.* *References

1,3,6,7, 11, 12,35,36.

Cutaneous abnormalities and disorders include ichthyosis, * collodion baby, 13, 16,23,34,38-40,48,50 follicular keratosis, 19, 24, 31,35, 51 erythroderl ,12,23,34,37.38 erythe 1122334 ma ' rna,' " eczema,t pruritus.P: 31, 47 hypoidrosis,l, 13, 37 cheilitis,": 52, 53 palmar pustulea" pyoderma19 and folliculiti . tIS, 24, 31 , 35 singlepalmar crease,25 ,40 excessive palm creases, 19,34 regional absence of subcutaneous fatty tissue, 13,37,46 photosensitivity,:j: and xeroderma pigmentosum(complementation group D) or impaired DNA repair.§ No increasein malignancies has been detected in patients with the isolatedfinding of impaired DNA repair and trichothiodystrophy. 57,58 Photosensitivity is frequently associatedwith ichthyosis. It has been suggested that photosensitivity does not affect patients with congenital ichthyosis but occurs in those with ichthyosis that develops later in infancy. However, cases oftrichothiodystrophy,congenitalichthyosis, and photosensitivity have been reported. 25, 34. 59 The photosensitivity in patients with trichothiodystrophy may be related to defective repair ofDNA,42,44,45, 50, 52, 54, 55 Usually, trichothiodystrophy patients without photosensitivity have normal DNA repair and synthesis51,60.61 but Lehmann et aI.39.58 and Blanchet-Bardon et aI.50 found abnormal DNA repair in these patients. Prenatal diagnosis by use of the DNA repair assay has been reported in some cases of familial trichothiodystrophy.so Hemangioma,1,62 telangiectasia.Urf freck42, les 53, 55 hyperpigmented eyelids, hypopigmented macules,55 and parchmentlike skin34are other cutaneousfindings reportedin patients with trichothiodystrophy. Nail dysplasia] is a frequent, but occasionally subtle, finding that includes longitudinal ridgingI,34-36 and horizontal splitting,1.3.7,16,42,46,62 thickening of the nail plate, 1, 13, 23, 34 yellow discoloration.l-v' and koilonychia.f Unguis inflexus was reported in two cases. 1. 19 These abnormalities appear to represent part of the ectodermal defect in affected patients. "References 1,

12-16.23,25,28, 34, 37-49. 1,4,12,24,31,43,46,50. :j:References 11, 12, [4,25,34,41-45,47,49,50,54,55. §References 5. 9, 39, 42, 44, 45, 50, 54-57. IIRcfcrences 1,3,4,7,13,14,19,23·25,34-36,38-46,49,51,62-64. lJIReferences 1, 7. 24, 31, 35, 36, 43, 62, 65.

[References

Volume 22 Number 5, Part 1

May 1990

Mental retardation* and delayed or arrested physicalmaturation t occurfrequently. Dysarthria, 1 spasticity,1,2,28,43 diplegia and quadriplegia,2, 43 hemiparesis or tetraparesis, 1,28 cerebellar deficiency 28 ataxia 16,42,43 pyramidal signs,25,43, 66 in. 1 25' . d tention" tremor.': 14,25,34 hyperreflexia,': impaire motor coordination,1, 25,46,66 absenceof deeptendon . reflexes,43,63 peripheral neuropathy, 28 "53 65 diirmnished muscle tone,40, 62, 63 neurosensory hearing impairment,12, 23, 53 jerky eye movements.t'' nystagmus,1,34,39,40,42 and seizures2,66 are among the reported neurologic signs in these patients. In addition, lethargy, irritability," and an unusuallysociable behavior have been reported.1, 59, 67 Growth retardation is frequently observed, and alteration in body proportions also may be associated with the disease complex.25 Progeria,I,14,37,46,51 polythelia.l'' microcephaly/ microdolichocephaly:j: and peculiar facies with receding chin,§ small thin or beaked nose,I,I6,25,3?,42,44,5I obstruction of the nose,48 goiter.i? protruding ears] hypoplastic ears,23 ear malformation not otherwise speciried.'" preauricular pits,36 clefted ear lobes,2 hemiatrophia faciale,"? small mouth,42,44 macrocheilia.l'' and frontal bossing'<'? have been described. Cranial dysplasia with no other specification was reported once.P Dental abnormalities.j] enamel hypoplasia12,24,25,63 and caries,1, 14,24,25,34,41,51 gingival hyperplasia,19,25 maxillaryhypoplasia,3high-arched palate,34, 51, 65 bifid uvula,36 and whiteplaquesonthe tongue/" are other signsin this syndrome. Occasionally, these patients may have a high-pitched, raspy voice. 1, 13,25,51 Ophthalmologic manifestations include epicanthic folds,I,51,65,67 antimongoloid eye slant.l? ectropion,12,38 entropion,35 conjunctivitis,I9,3I,35,62,67 hypotelorism,25, 34 hypertelorisrn.P enophthaImus,42,44, 52 exophthalmus1, 25 (inonecase caused by retrobulbar hemangioma1), cataract,': 11, 13,23,34, 39-4~!49 myopia,34,42 astigmatism,1,67 exophoria,34,66 strabismus.s chorioreti*References 1-4, 11-17,23-25,31,34-44,46,49-51,62,63,65-67. tReferences 1,2,4,11-17,23-25,31,34,37-46,49-51,63,65,66. :f:References 1, 11, 13, J6, 17,24, 25, 34,37,39,40,42,43,46,51,62,

63,66. §References 1, 12, 16,19,25,34,37,41-44,46. IIReferences 1, 13, 16,25,37,41-44,46,51. ~References

1, 12-14,24,25,31,34,42,44.

Trichothiodystrophy

711

nal atrophy,38 retinal dystrophy,3, 42 retinal pigmentation, 1pale optic disc.' photophobia,11,42,55 tortuosity of retinal vessels,3, 67 and diminished redgreen discrimination. 1 and cryptorDecreased fertility2,3 chism,2,23,25,40,46 hypoplasia of male 12• 17,23, 25,46 and female genitalia,13 hypospadias,63, 65 asthma1,23,34 and bronchiectasis.f congenital cystic pulmonary adenomatosis,14recurrentinfections, * and immunodeficiency' also have been reported. Orthopedic problemsincludegenu valgum,51 coxa valga,34 valgus deformity of the great toe,13 pes valgus,34, 36, 63 cubital and tibial valgus deformity,36 ulnar deviation of the fingers.l? contracture of a finger,12, zygodactyly,36 limited range of motion in large joints,25,34 pectus excavaturn.P: 36, 51 scoliosis.P thoracic kyphosis,25,51 and lumbosacral lordosis.51 In two patients, impairment of peripheral circulation was noted,24, 63 and in one case a ventricular septal defect was identified.e" Numerous abnormalities in laboratory values have been found including hyperammonemia and episodic hyperlysinemia" and increased urinary kynurenine and hydroxykynurenine excretion.f? Rarely, increased serum copper'" and zinc,34 hypergammaglobulinemia.l" increased 19B1,12,49 and IgG K chain M spike," decreased y-globulin7 and low IgA,34,36,42 decreased T4jT8 ratio," poor response of lymphocytes to mitogens," and Coombspositive anemia? have been documented. Chronic neutropenia with monocytosis I9,31,35,36.62 and disturbed intracellular killing caused by delayed and deficient oxygen consumption during ph agocytosiS l9,31 may coexist. Radiographic examination may reveal osteosclerosis-' and osteopetrosis of the axial skeleton and demineralization of the distal bones,I,34,40 diffuse demineralization of bones,25 and intracranial calcifications, 13, 37,46 The most important laboratory abnormalities are revealed by two-dimensional gel electrophoresis, amino acid analysis, electron-activated analysis, or x-ray microanalysis of hair and nail. Patients with trichothiodystrophy show an approximately 50% decrease of cystine and sulfur content in the highsulfur proteins of hair and in several cases a total decrease to less than 10% of the normal value may *References 7,14,19,31,34-37,39,40,42,44,46,51,62.

712 [tin and Pittelkow be noted. 1 Sulfur proteins are qualitatively and quantitatively altered, and there is an abnormal distribution of the sulfur-rich proteins in the cortex and hair cuticle.20, 22 Urinary and serum levels of sulfur and cystine/cysteine usually are normal, and gastrointestinal malabsorption has not been found. 24, 38 Adequate dietary intake has been demonstrated in several patients and it appears that the sulfur-deficiency state of hair and nails is induced by an inborn error of metabolism.6 , 22 Abnormal filaments in keratinocytes of a patient with trichothiodystrophy was demonstrated by electron microscopy.51 Gummer et al.20 suggested that the hair defect is the result of faulty biochemical steps in keratinization of the cuticle. Studies of incorporation of radiolabeled cystine into hair follicles failed to demonstrate defective amino acid transport in patients with trichothiodystrophy. J 1 Patients with ectodermal dysplasias and hair alterations of trichothiodystrophy can express abnormal structural or regulatory genes that specifically affect sulfur-rich proteins of keratinization. 22 Chromosomal analyses performed in several patients demonstrated normal karyotypes. In one patient with trichothiodystrophy, severe mental retardation, and neurologic findings, a deletionin the long arm of chromosome 14 was found? and a brain biopsy specimen of this patient showed abnormal cytoarchitecture.f" The term neurotrichosis for hair shaft abnormalities associated with neurologic disease was proposed by Coulter et a1. 66 in 1982. Mental deficiency has been described in several diseases associated with metabolic defects of sulfur-containingamino acids (e.g., homocystinuria). It is not known whether the associated defects of trichothiodystrophy are also due to the abnormal metabolism of sulfur proteins. Cystine-rich protein appears to be important in reproductive physiology. Spermatogenesis is linked to production of sulfurcontaining proteins.v? Decreased fertility has been described in patients with trichothiodystrophy and may be related to defective or deficient supply of cystine-rich proteins in other organs or tissues. Because the disease spectrum is wide, several eponyms and acronyms have been formulated to describe brittle hair combined with neuroectodermal abnormalities 70 (Table II). However, we believe that all these syndromes should be classified as subgroups of trichothiodystrophy.

Journal of the American Academy of Dermatology

In 1968, Pollitt et al.24 reported the first cases of trichorrhexis nodosa, lowsulfur content of hairs, and associated mental and physical retardation. Two years later, Brown et al.6 described a case of isolated trichoschisis, the typical abnormality of hairs shown by polarized light microscopy, and low sulfur content in hair. They also found a marked decrease in hair sulfur in a patient with hidrotic ectodermal dysplasia, and scanning electron microscopy revealed defective cuticle.P" No further clinical data were available for this case. T ay37 studied three patients with ichthyosiform erythroderma, hair shaft abnormalities, and mental and growth retardation; microscopic examination showed the typical changes of trichothiodystrophy. Several reports on Tay syndrome with low-sulfur hairs followed.J4, 16, 34, 45, 46, 54 In 1974, Jackson et al. 2 found a pedigree of 25 persons in an Amish kindred with brittle hair, short stature, intellectual impairment, decreased fertility, and low sulfur content of hair. The inheritance pattern was consistent with an autosomal recessive disorder. Cantu et a1. 62 subsequently reported a syndrome of onychotrichodysplasia with chronic neutropenia. In 1979, three similar cases were reported.P An additional patient with onychotrichodysplasia, chronic neutropenia, and mild mental retardation was presented and the acronym ONMR syndrome was created." Recently, a patient with onychotrichodysplasia, neutropenia, and normal intelligence was reported.l? Electron microscopy of hair showed the typical changes of trichothiodystrophy. Until recently these patients were not recognized as belonging to a part of the spectrum of trichothiodystrophy. We 3] have reported a patient with brittle hair, chronic neutropenia, and mild mental retardation. We documented sulfur-deficient brittle hair in this condition. In 1976, Arbisser et a1. 67 described the Sabinas syndrome, named after a town in Mexico where most of the patients lived. Their patients were found to have brittle hair, neuroectodermal dysplasia, and low sulfur content in hair. The same authors reported further cases in the following years." 1 Baden et al.' 0 used the acronym BIDS syndrome for brittle hair, intellectual impairment, decreased fertility, and short stature in association with low sulfur content in the hair. Their report described hairs with an

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"alternating birefringent pattern" when examined by polarization microscopy. Earlier references were reported by Brown et aI.6 and Jackson et al.2 Baden et al. J0 also documented a case of MarinescoSjogren syndrome with low sulfur content of the hair. Porter72 reported in 1971 a case of MarinescoSjogren syndrome with trichoschisis and abnormal "birefringence" by polarized light microscopy. Marinesco-Sjogren syndrome consists of oligophrenia, cerebellar ataxia, cataracts, short stature, and unruly hair. The main symptoms and signs, however, involve primarily nonectodermal tissues. The term trichothiodystrophy was proposed in 1979 and 1980 by Price et al.!: 33 to characterize the condition of patients with sulfur-deficient brittle hair and other neuroectodermal symptoms. They recognized sulfur deficiency as a possible marker for a special group of neuroectodermal diseases. Jorizzo et al.23 suggested the term IBIDS syndrome for ichthyosis-associated cases with the lowsulfur-content hair of BIDS. In 1983, Crovato et al." reported a low-sulfur-hair syndrome with photosensitivity and suggested the acronym PIBIDS syndrome, although photosensitivity in patients with trichothiodystrophy had been reported earlier or concurrently. I, 11,47 The patients of Diaz-Perez and Vasquez'? showed increased urinary excretion of kynurenine and hydroxykynurenic acid. Diaz-Perez and Vasquez" suggested that these substances may cause the photosensivity. Trichothiodystrophy in combination with xeroderma pigmentosum or decreased DNA repair has been documented. * Cytologically detectable chromosomal alterations (e.g., microdeletion) as possible cause for the association of xeroderma pigmentosum and trichothiodystrophy were not detected.I'' Friable hair with characteristic alternating light and dark bands in combination with hyperammonemia and episodichyperlysinemia has been reported more recently." On the basis of the severity of symptoms in relatives and urinary excretion of abnormal amino acids, an X-linked heritance was suggested, but an autosomal recessive pattern was not excluded. Chapman''? detected osteosclerotic abnormalities in a patient with trichothiodystrophy and proposed the acronym SIBIDS for osteosclerosis, ichthyosis, brittle hair, impaired intelligence, decreased fertility, "References 5, 9, 39, 42, 44, 45, 50, 52, 54-57, 59, 60, 70, 73, 74.

Trichothiodystrophy 713 and short stature. In the same year, Lehmann et al.39 investigated three patients who had trichothiodystrophy without photosensitivity. One had normal DNA repair, one had partially decreased DNA repair, and the third patient had severeimpairment of DNA repair but without clinical correlation. This was the firstobservation of abnormal DNA repair in patients without photosensitivity. Recently another patient with trichothiodystrophy and no clinical photosensitivity but reduced DNA repair was reported. 50 Previous patients with trichothiodystrophy but no photosensitivity showed normal DNA repair function.51, 60 On the basis of our scheme to define trichothiodystrophy, the following cases were excluded although they bore some similarity to trichothiodystrophy. Dupre and Bonafe 5 observed a case of keratosis follicularis decalvans (Siemens syndrome) with trichoschisis. After an initial report by Leupold." Happle 46 examined a hair sample from the same patient and demonstrated clean transverse fractures. Braun-Falco et al.77 reported two siblings with ichthyosis vulgaris, growth and mental retardation, hair dysplasia, recurrent infections, and malabsorption. Examination by light microscopy revealed trichoschisis. Salfeld and Lindley?" applied the term trichodysplasia to a patient with ichthyosis vulgaris and ectodermal dysplasia. The hair was brittle with clean transverse fractures and an undefined alteration was present, but absence of hair cuticle was not shown.78 Leonard et al.7 9 reported. a patient with late onset of generalized trichorrhexis nodosa after regular vigorous massage of the scalp. Amino acid analysis showed significantly decreased cysteine content. Electron microscopy revealed numerous small vacuoles in the endocuticle. It was concluded that the intrinsic defects allowed moderate physical trauma to cause trichorrhexis nodosa. DISCUSSION

Sulfur-deficient hair and nail have been described in a distinctivegroup of patients with brittle hair and frequently accompanying ectodermal and neuroectodermal dysplasias. Our review of the literature revealed 95 cases. Variably detailed clinical findings were available for 91 patients. Of the identified cases, 44 werein female patients and 47 were in male patients. In two cases prenatal diagnosis was made but no further clinical data were available. Signifi-

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cant findings (in eight or more cases) included growth and mental retardation, nail dysplasia with koilonychia and splitting, sparse axillary hair, collodion baby, ichthyosis and photosensitivity, defective DNA repair, erythroderma, eczema, cataracts, recurrent infections, mental and growth retardation with receding chin, protruding ears, dental abnormalities, and microcephaly (Table I). Low sulfur content of hair and characteristic abnormalities on light, polarizing, and electron microscopy are the only obligatory features in common among these patients. Other clinical manifestations varied significantly. Inheritance was in an autosomal recessive pattern with one exception that was suggestive for an X-linked genodermatosis." We emphasize the cumulative findings of the literature review showing that a single, isolated hair finding is not sufficient to establish the diagnosis of trichothiodystrophy. Morganti et al.80 found marked decreases in cystine and other amino acids in several patients with different types of ichthyosis. Another article reported three patients with Clouston's ectodermal dysplasia and normal sulfur content but cystine content of hydrolyzed hair was approximately 25% to 30% lower than that in control subjects." Moreover, amino acid content may vary with season and nutrition. A child with untreated kwashiorkor had subnormal sulfur content of hair. 82 After treatment, the value became normal. Cystine content in hair decreases remarkably after treatment with cold-waving lotions, depilatories, hair bleaching solutions, and synthetic organic hair dyes. 83 Although trichoschisis and alternating light and dark bands by polarizing microscopy are typical findings in trichothiodystrophy, they may occur in patients without the disorder. 64, 75, 84, 85 Ectodermal dysplasias have been classified as congenital diseases with the main manifestation expressed in tissues of ectodermal origin. As a rule, however, ectodermal dysplasias are not pure "onelayer diseases"; mesodermal and rarely endodermal dysplasias may coexist. Embryogenesis exhibits distinct tissue organizational fields, which interact in development of all germ layers. 86 Recently, a comprehensive and useful classification of ectodermal dysplasias was described.A 30 Characterized by disorders in two or more of the four basic ectodermal structures (hair, teeth, nails,

Journal of the American Academy of Dermatology

and sweat glands). Freire-Maia and Pinheiro'? created 34 subgroups representing 121 different conditions. Among the list of ectodermal dysplasias, we identified onychotrichodysplasia with neutropenia and the Sabinas brittle hair syndrome, but most of the disorders with trichothiodystrophy were not defined. We believe that trichothiodystrophy is a marker for a specific hair defect that may be associated with a variety of ectodermal disorders. There are overlaps among these ectodermal symptom complexes but unique aspects in the different groups of trichothiodystrophy exist. It is possible that the various clinical presentations represent different closely related or linked genetic alterations that regulate keratinization and sulfur content in the hair follicle because within pedigrees the associated findings are quite constant. There are isolated cases of trichothiodystrophy without other manifestations, which, by convention, are not classified within the ectodermal dysplasias according to the scheme of Freire- Maia and Pinheiro.P: 30 The phenotypic marker of trichothiodystrophy is low sulfur content of hair. Patients within the previously defined clinical groups A through G could be further categorized and included in the systematic designation of the ectodermal dysplasias. We suggest avoidance of the various acronyms and eponyms devised to characterize trichothiodystrophy associated with wide-ranging symptoms and signs because they emphasize only selected findings while excluding others. In the exhaustive catalog of Mendelian inheritance in humans by McKusick,87 Pollitt syndrome (catalog No. 27555), xeroderma pigmentosum and trichothiodystrophy (No. 27873), Tay syndrome (No. 24217), Amish brittle hair syndrome (No. 23405), Sabinas brittle hair syndrome (No. 21139), and onychotrichodysplasia with neutropenia (No. 25836) were included. Several literature citations were cross-referenced repeatedly, revealing that the syndromes are difficult to distinguish. The Marinesco-Sjogren syndrome (No. 24880) is not a primary ectodermal disease but these patients may have trichoschisis and low sulfur content of hair. Patients with congenitally brittle hair may represent a subgroup of ectodermal dysplasia, and sulfur analysis of hair should be performed routinely in these cases. When the criteria for the diagnosis of

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trichothiodystrophy are met, further medical evaluations and examinations are important. Investigation for photosensitivity and abnormal DNA repair may behelpfulalthough impaired DNA repairmay not necessarily be associated with photosensitivity Of the typical findings of xerodermapigmentosum.t? 50 Detection of low-sulfur-content hair also is important for genetic counseling because brittle hair syndromes appear to be inherited in an autosomal recessive pattern. Prenatal diagnosis can be madein some cases. Two women with trichothiodystrophy were reported recently.t" Both showed mental and growth retardation with microcephaly, protrudingears, and receding chin, with an erythematous papular facial rash. In addition, patient 1 had onychoschizia and ophthalmologic abnormalities. Patient 2 had seizures and keratosis pilaris. Examinationsofthe hair with polarizing light microscopy, scanning electron microscopy, and amino acid analysis showed the typical results of trichothiodystrophy. REFERENCES 1. Price VH, Odom RB, Ward WH, et al. Trichothiodystrophy, Sulfur-deficient brittle hair as a marker for a neuroectodermal symptom complex. Arch Derrnatol 1980; 116:1375-84. 2. Jackson CE, Weiss L, Watson JHL. "Brittle" hair with short stature, intellectual impairment and decreasedfertility:an autosomalrecessive syndrome in an Amish kindred. Pediatrics 1974;54:201-7. 3. Howell RR, Arbisser AI, Parsons DS, et al. The Sabinas syndrome. Am J Hum Genet 1981;33:957-67. 4. Hordinsky MK, Briden B, Berry SA. Friable hair, urea cycle dysfunction, and trichothiodystrophy. A newX-linked genodermatosis. Curr Probl Derm 1987;17:52-60. 5. Van Neste D, Miller X, Bohnert E. Clinicalsymptoms associated withtrichothiodystrophy. A review of theliterature withspecialemphasison lightsensitivityand the association withxerodermapigmentosum (complementationgroupD). In: Van Neste D, Lachapelle JM, Antoine JL, eds.Trends in human hair growth and alopecia research. Dordrecht: Kluwer Academic, 1989:183-93. 6. Brown AC, BelserRB, CrounseRG, et al.A congenital hair defect: trichoschisis with alternating birefringence and low sulfur content. J Invest Dermatol 1970;54:496-509. 7. Baden HP, Katz A. Trichothiodystrophy without retardation: one patient exhibitingtransient combinedimmunodeficiency syndrome. Pediatr Dermatol 1988;5:257-9. 8. VenningV, Dawber RPR, Ferguson DJP, et al. Weathering of hair in trichothiodystrophy. Br J Dermatol 1986; 114:591-5. 9. Van Neste D, Miller X, Bohnert E. Trichothiodystrophie. Ein kutanes Merkmal filr einen Symptomenkomplex von

Trichothiodystrophy 715 zunehmendem SchweregradmitBeziehung zu Xeroderma pigmentosum. Aktuel DermatoI1988;14:191-6. 10. Baden HP, Jackson CE, WeissL, et al. The physicochemical properties of hair in the BIDS syndrome. Am J Hum Genet 1976;28:514-21. 11. Van Neste D, Bore P. Trichothiodystraphie: une etude morphologique et biochimique. Ann Dermatol Venereal 1983;110:409-17. 12. Lucky PA, Kirsch N, Lucky AW, et al. Low-sulfur hair syndrome associatedwithUVB photosensitivity and testicular failure. J AM ACAD DERMATOL 1984;11:340-6. 13. Jorizzo JL, Crounse RG, WheelerCE Jr. Lamellarichthyosis, dwarfism, mental retardation, and hair shaft abnormalities. A link between the ichthyosis-associated and BIDS syndrome. J AM ACAD DERMATOL 1980;2:309-17. 14. Calvieri S, Giustini S, Nini G, et al. Trichothiodystrophy: two cases,In: Wilkinson DS, MascaroJM, OrfanosCE, et al., eds, Clinical dermatology: the CMD case collection, Stuttgart: Schattauer, 1987:65-6. 15. White MC, Hayes TJ. Trichothiodystrophy. J Assoc Mil DermatolI987;l3:4-6. 16, Motley RJ, Finlay AY. A patient with Tay's syndrome. Pediatr Dermatol 1989;6:202-5. 17. Przedborski S, Ferster A, SongM, et al. Brittlehair,intellectual impairment, decreased fertility and short stature (BIDS) syndrome in three sibs [Abstract]. J Neural 1985;232(supp):127. 18. Calvieri S, Zampetti M, CorboA. Preliminaryresults using a microanalysis systemon the hair of patients affected by trichothiodystrophy [Abstract]. Clin Exp Dermatol 1989;14:404. 19. Verhage J, Habbema L, Vrensen GFJM, et al. A patient with onychotrichodysplasia, neutropenia and normal intelligence. Clin Genet 1987;31:374-80. 20. Gummer CL, Dawber RPR, PriceVB. Trichothiodystrophy: an electron-histochemical studyof thehair shaft. Br J DermatoI1984;1l0:439-49. 21. Marshall Re, Gillespie JM. The keratin proteins of wool, horn and hooffrom sheep. AustJ BioI Sci 1977;30:389-400, 22. GillespieJM, Marshall RC. A comparison of the proteins of normal and trichothiodystrophic human hair. J Invest DermatoI1983;80:195-202. 23. Jorizzo JL, Atherton DJ, Crounse RG, et al. Ichthyosis, brittle hair, impaired intelligence, decreased fertility and short stature (IBIDS syndrome). Br J Dermatol 1982; 106:705-10. 24. Pollitt RJ, Jenner FA, Davies M. Sibs with mental and physical retardation and trichorrhexis nodosa with abnormal amino acid composition of the hair. Arch Dis Child 1968;43:211-6. 25. Meynadier J, Guillot B, Barneon G, et al. Trichothiodystrophie. Ann Dermatol Venereal 1987;114:1529-36. 26. Pollitt RJ, Stonier PD. Proteins of normalhair andof cystine-deficient hair from mentally retarded siblings. Biochern J 1971;122:433-44. 27. Van Neste D, Gillespie .TM, MarshallRC. Deficit pilaireen proteins matricielles hautement soufrees (high-sulfur protein deficient human hair): une variante de trichothiodystrophic [Abstract]. Nouv DermatoI1988;7(supp 1):50. 28. Gummer CL, Dawber RPR. Trichothiodystrophy: an ultrastructural study of the hair follicle, Br J Dermatol 1985;113:273-80.

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29. Freire-Maia N, Pinheiro M. Ectodermal dysplasias: a clinical and genetic study. New York: Alan R. Liss, 1984. 30. Freire-Maia N, Pinheiro M. Ectodermal dysplasias-i-some recollections and a classification. Birth Defects 1988;24:314. 31. Itin PH, Pittelkow MR. Trlchothiodystrophy with chronic neutropenia and mild mental retardation. J AM ACAD DERMATOL (In press.) 32. Van Neste D, Miller X, Bohnert E. Trichothiodystrophie: un marqueur cutane commun Ii un ensemble d'associations symptomatique de severite croissante avec mention particuliere pour la photosensibilite [Abstract]. Nouv Dermatol 1988;7(supp 1):48. 33. Price VH. Bruchiges Schwefelmangelhaar: trichothiodystrophic. In: Orfanos CE, ed. Haar und Haarkrankheiten. Stuttgart Gustav Fischer Verlag, 1979:413-21. 34. Kousseff BG, Esterly NB. Trichothiodystrophy: IBIDS syndrome or Tay syndrome? Birth Defects 1988;24:169-81. 35. Hernandez A, Olivares F, Cantu JM. Autosomal recessive onychotrichodysplasia, chronic neutropenia and mild mental retardation. Delineation of the syndrome. Clin Genet 1979;15:147-52. 36. Corona-Rivera E, Hernandez A, Padilla H, et al. Further delineation of the onychotrichodysplasia, chronic neutropenia and mild retardation syndrome (ONMRS) [Abstract]. Sixth International Congress on Human Genetics, Jerusalem, 1981:267. 37. Tay CR. Ichthyosiform erythroderma, hair shaft abnormalities, and mental and growth retardation. A new recessive disorder. Arch Dermatol 1971;104:4-13. 38. De Prost Y, Lemaistre R, Dupre A. Trichothiodystrophie associee Ii une ichthyose et un retard statural et psychomoteur (Syndrome de Tay). Ann Dermatol Venereol 1986;113:1016-7. 39. Lehmann AR, Arlett CF, Broughton BC, et al. Trichothiodystrophy, a human DNA repair disorder with heterogeneity in the cellular response to ultraviolet light. Cancer Res 1988;48:6090-6. 40. Chapman S. The trichothiodystrophy syndrome of Pollitt. Pediatr Radial 1988;18:154-6. 41. Crovato F, Borrone C, Rebora A. TrichothiodystrophyBIDS, IBIDS and PIBIDS? [Letter] Br J Dermatol 1983;108:247. 42. Stefanini M, Lagomarsini P, Arlett CF, et al. Xeroderma pigmentosum (complementation group D) mutation is present in patients affected by trichothiodystrophy with photosensitivity. Hum Genet 1986;74:107-12. 43. King MD, Gummer CL, Stephenson JBP. Trichothiodystrophy-neurotrichocutaneous syndrome of Pollitt: a report of two unrelated cases. J Med Genet 1984;21:286-9. 44. Rebora A, Guarrera M, Crovato F. Amino acid analysis in hair from PIBI(D)S syndrome [Letter]. J AM ACAD DERMATOL 1986;15:109-11. 45. Van Neste D, Caulier B, Thomas P, et aI. PIBIDS: Tay's syndrome and xeroderma pigmentosum [Letter]. J AM ACAD DERMATOL 1985;12:372-3. 46. Happle R, Traupe H, Grobe H, et al. The Tay syndrome (congenital ichthyosis with trichothiodystrophy). Eur J Pediatr 1984;141 :147-52. 47. Diaz-Perez JL, Vasquez JA. Flattened hair syndrome: a new disease [Letter]. Arch DermatoI1983;1l9:854-S. 48. Larregue M, Ottavy N, Bressieux JM, et a1.Bebe collodion. Trente-deux nouvelles observations. Ann Dermatol Venereol 1986;113:773-85. 49. Van Neste D, Degreef H, Van Haute N, et aI. TTD variante: une variante clinique de trichothiodystrophie: aspects

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cliniques Ii propos de deux cas non publies [Abstract]. Nouv DermatoI1988;7(supp 1):49. Blanchet-Bardon C, Sarrasin A, Renault G, et a1. Prenatal diagnosis of BIDS and IBIDS syndromes: trichothiodystrophies with DNA repair defect [Abstract]. Br J Dermatol 1989;123(supp 34):18. Fois A, Balestri P, Calvieri S, et al. Trichothiodystrophy without photosensitivity. Biochemical, ultrastructural and DNA repair studies. Eur J Pediatr 1988;147:439-41. Rebora A, Crovato F. PIBI(D)S syndrome--trichothiodystrophy with xeroderma pigrnentosurn (group D) mutation. JAM ACAD DERMATOL 1987;16:940-7. Van Neste DJ, Antoine JL, Vasseur F, et aI. Tay's syndrome and xeroderma pigmentosum [Abstract]. Seventeenth World Congress of Dermatology, Part 1. 1987:WS-18. Crovato F, Borrone C, Rebora A. The Tay syndrome (congenital ichthyosis with trichothiodystrophy) [Letter]. Eur J Pediatr 1984;142:233-4. Yong SL, Cleaver JE, Tullis G D, et al. Is trichothiodystrophy part of the xeroderma pigmentosum spectrum? [Abstract] Am J Hum Genet 1984;36:82S. Nuzzo F, Stefanini M. The association of xeroderma pigmentosum with trichothiodystrophy: a clue to a better understanding of XP-D? In: Castellani A, ed. DNA damage and repair. New York: Plenum Press, 1989:61-72. Lehmann AR, Norris PG. DNA repair and cancer: speculations based on studies with xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy. Carcinogenesis 1989;10:1353-6. Lehmann AR. Cockayne's syndrome and trichothiodystrophy:defective repair without cancer. Cancer Rev 1987;7:82103. Crovato F, Rebora A. PIBI (D) S syndrome; a new entity with defect of the deoxyribonucleic acid excision repair system [Letter]. JAM ACAD DERMATOL 1985;13:683-5. Stefanini M, Lagomarsini P, Giorgi R, et al. Complementation studies in cells from patients affected by trichothiodystrophy with normal or enhanced UV photosensitivity. Mutat Res 1987;191:117-9. Stefanini M, Lagomarsini P, Fois A, et a1. Sensitivity to sunlight in patients affected by trichothiodystrophy is related to the capacity to repair the UV-induced DNA damage [Abstract]. Br J Cancer 1986;54:355. Cantu JM, Arias J, Foncerrada M, et al. Syndrome of onychotrichodysplasia with chronic neutropenia in an infant from consanguineous parents. Birth Defects 1975;11:63-5. Poissonnier M, Blanc A, Bat P. Conseil genetique dans une neuro-ectodermose: la trichothiodystrophie (TID) de Vera Price. Cheveux cassants dont la teneur en soufre est reduite, J Genet Hum 1988;36:361-5. Brown AC. Congenital hair defects. Birth Defects 1971;7:52-68. Venencie PY, Dupre A, Gouttieres F, et al. Trichothiodystrophie. Soc Fr Dermatol Journees parisiennes, cas 78. 1982. Coulter DL, Beals TF, Allen RJ. Neurotrichosis: hair-shaft abnormalities associated with neurological diseases. Dev Med Child NeuroI1982;24:634-44. Arbisser AI, Scott CI Jr, Howell RR, et al. A syndrome manifested by brittle hair with morphologic and biochemical abnormalities, developmental delay and normal stature. Birth Defects 1976;12:219-28. Cahuzac p. Vanlerberghe 0, Morel P. Trichothiodystrophie. Soc Fr Dermatol Journees parisiennes, cas 80. 1984. Calvin H, Bedford JM. Formation of disulfide bonds in the

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79. Leonard IN, Gummer CL, Dawber RPR. Generalized trichorrhexis nodosa. Br J Dermatol 1980;103:85·90. 80. Morganti P, Muscardin L, AviceU, et al. Abnormal amino acid changesin human hair associated with rare congential syndromes. In: OrfanosCE,Montagna W, Sttlttgen G, eds, Hair research:status and future aspects. Berlin: SpringerVerlag; 1981 :442-5. 81. Gold RJM, Scriver CR. The characterization of hereditary abnormalities of keratin: Clouston's ectodermal dysplasia. Birth Defects 1971;7:91-5. 82. GillespieJM. The dietaryregulationof the synthesisof hair keratin. In: Crewther WG, ed. Symposium on fibrous proteins. London: Butterworths, 1968:362-3. 83. Miyazawa F, Tamura T, Nozaki F. Alteration of amino acid composition and keratinolysis of hair due to chemical damage. In: KoboriT, Montagna W, eds. Biology and diseaseofthehair. Baltimore: UniversityPark Press;1976:65967. 84. Whiting DA. Structural abnormalities of the hair shaft. JAM ACAD DERMATOL 1987;16:1-25. 85. Van Neste D. Dysplasies pilaires congenitales: conduite Ii tenir et interet de diverses methodes de diagnostic. Ann Dermatol VenereoI1989;116:251-63. 86. Opitz JM. Pathogeneticanalysis of certain developmental and geneticectodermal defects.Birth Defects 1988;24:75102. 87. McKusick V. Mendelianinheritance in man. Catalogs of autosomal dominant, autosomal recessive, and x-linked phenotypes. Baltimore: John Hopkins University Press, 1988. . 88. GillespieJM, Marshall RC, Rogers M. Trichothiodystrophy. Biochemical and clinicalstudies. Australas J Dermatol 1988;29:85-93.