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-
705
706
Journal of the American Academy of Derma tology
[tin and Pittelkow
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
Volume 22 Number 5, Part I May 1990
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-
708
Journal of the American Academy of Dermatology
[tin and Pittelkow
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
Volume 22 Number 5, Part I May 1990
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'
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-
705
706
Journal of the American Academy of Derma tology
[tin and Pittelkow
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
Volume 22 Number 5, Part I May 1990
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-
708
Journal of the American Academy of Dermatology
[tin and Pittelkow
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
Volume 22 Number 5, Part I May 1990
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'
