Trichothiodystrophy, mental retardation, short stature, ataxia, and gonadal dysfunction in three Moroccan siblings

American Journal of Medical Genetics 35566-573 (1990)

Trichothiodystrophy, Mental Retardation, Short Stature, Ataxia, and Gonadal Dysfunction in Three Moroccan Siblings Serge Przedborski, Alina Ferster, Sylvie Goldman, Renee Wolter, Micheline Song, Tonne Tonnesen, Rodney J. Pollitt, and Esther Vamos Service of Neurology, H6pital Universitaire Erasme (S.P.), H6pital Universitaire des Enfants Reine Fabwlia (AP. , R.W.), Departments of Child Psychiatry (S.G.) and Dermatology (M.S.), H6pital Universitaire Saint-Pierre, and Department of Medical Genetics, H6pital Universitaire Brugmann (E.V.), Uniuersitk Libre de Brml les , Brussels, Belgium; The John F. Kennedy Institute, Glostrup, Denmark (T.T.); The Childrens Hospital, Western Bank, Sheffield, England (R.J.P.).

Three sibs, a boy and two girls, born to Moroc- can consanguineous parents, were affected with a syndrome characterized by brittle hair, mental retardation, short stature, ataxia, and gonadal dysfunction. The hair in these three patients displayed the morphological and biochemical hallmarks of trichothiodystrophy (TTD). Gonadal function tests showed abnormal gonadotropic responses to LHRH, consistent with delayed puberty in the male and ovarian failure in both females. Comparison with previously reported cases of TTD associated with mental retardation suggests genetic heterogeneity, although specific biochemical markers are needed in order to answer this question.

KEY WORDS: gonadal function tests, hypogonadism, hair anomaly

INTRODUCTION The association of brittle hair and mental retardation

occurs in several inherited diseases. In some of these disorders, the metabolic defect has been identified [Danks, 1983; Walser, 1983; Wolf et al., 19831, whereas in others [Norwood, 1964; Pollitt et al., 1968; Tay, 1971; Jackson et al., 1974; Arbisser et al., 19761, it remains unknown. In these syndromes, brittle hair displays a consistent pattern of morphological [Coulter et al., 1982; Happle et al., 19841 and physicochemical [Pollitt and Stonier, 1971; Baden et al., 1976; Gillespie and Mar-

Received for publication August l, 1988; revision received July 6, 1989.

Address reprint requests to E. Vamos, M.D., Laboratoire de Genetique Mkdicale, Hapita1 Universitaire Brugmann, 4 place Van Gehuchten, 1020 Brussels, Belgium.

0 1990 Wiley-Liss, Inc.

shall, 19831 abnormalities due to a decrease in sulphur- rich proteins that can be used as markers for diagnostic purposes. Most of the cases reported so far present with moderate to severe mental retardation and short stature. Other clinical features including skin ichthyosis, photosensitivity, nail and enamel dystrophy, cataracts, hypogonadism, and ataxia are less consistently observed.

Here we report on three sibs with brittle hair, mental retardation, short stature, ataxia, and evidence of gonadal dysfunction, as demonstrated by abnormal gonadal function tests.

CLINICAL REPORT The family originates from Morocco. The parents are

first cousins and healthy. Of the nine children born to this couple, three (one boy, two girls) present with the syndrome. The six others are healthy, although one has a cleft palate. The three affected sibs were born by spon- taneous delivery, after uneventful full-term pregnan- cies. They were considered normal until age 8 months for sib 3 (1.E) and 18 months for sibs 1 (M.E) and 2 (K.E). No details could be provided by the parents concerning the children’s psychomotor development except that M.E started to walk and speak at age 4 years. There was no history of seizures.

The clinical results of the first examination are sum- marized in Table I. All three sibs had short stature, microcephaly, hypotelorism, epicanthal folds, high arched palate, normally set but poorly rimmed ears, and micrognathia (Fig. 1). In addition, K.E had a bilateral clinodactyly of the fifth finger and a single transverse palmar crease in the left hand, and 1.E had a partial syndactyly of the second and third toes and bilateral single transverse palmar creases. In all three sibs, the scalp hair was kinky, dry, and brittle with areas of alopecia. Eyebrows and eyelashes were short and sparse in M.E and K.E and absent in I.E. The remaining body surface presented no pilosity. Hair pigmentation, teeth, nails, and skin appeared normal. No photosensitivity

Tkichothiodystrophy 567

was noted. In both girls, the external genitalia were normal, whereas in the boy, they were infantile (Fig. 1A) with prepubertal size testes located in the scrotum. The three sibs had mild hypotonia of limbs, brisk tendon reflexes, and flexor plantar responses. Ataxia was ob-

TABLE I. Clinical Manifestations at First Examination

Age

Sex Height (cm) Weight (kg) Head circum-

ference (cm)

D ysmorphic features

Brittle hair Skin

Teeth and nails Genitalia Ataxia Intellectual

quotientb

Sib 1 (M.E) 16 years

M 135 (< P3) 31 (< P3) 51 (< P3)

+ + N

N

infantile

25 t

Sib 3 Sib 2 (K.E) (1.E)

4 years 13

F F 85 (< P3) 72 (P10) 11.5 (P3) 72 (< P3) 45.7 (< P3) 43.5 (P3)

months

+ t

t + N Transient

eczema N N

N N t + a

40 40

“First observed at age 4 years.

+ : present, N: normal. Evaluated by the Terman-Merill scale.

served during the first examination of M.E and K.E, but not until age 4 in I.E. M.E appeared inattentive, aggres- sive, and lacking social adjustment, whereas K.E and I.E. were more sociable. M.E pronounced only ten words and required help with washing and dressing, whereas K.E walked alone and handled a spoon well but pronounced repetitive consonant sounds and did not have nocturnal sphincter control. I.E. crawled, transferred objects from hand to hand, and pronounced polysyllabic vowel sounds.

After 2 years follow-up, height, weight, and head cir- cumference remained well below the third percentile in all three sibs. Hair growth improved, and the percent- age of anomalous hair shafts decreased spontaneously. On psychometric evaluation, M.E did not show any pro- gress. In contrast, K.E. pronounced ten words and acquired nocturnal sphincter control, and 1.E was able to walk and feed alone and jargonized.

Neurological Investigations In all three sibs, electromyography, nerve conduction

velocities, auditory- and somatosensory-evoked poten- tials, fundi, and visual fields were normal. EEG was normal in M.E and showed diffuse bursts of thetaldelta- waves for K.E and I.E. The photic stimulation disclosed a generalized epileptiform activity for K.E.

Imaging Investigations In all three sibs, skeletal surveys showed diffuse osteo-

penia and bone ages below 2 standard deviations for

Fig. 1. A: Patient 1 (M.E.) (aged 16 years): short stature, infantile genitalia. H: Patient 3 (1.E.I (aged 13 months): facial dysmorphism, sparse kinky hair.

60 -

50 -

40 -

30 -

20 i

30 -

20 -

50 -

40 -

30 -

20 -

10 -

0 -

30 -

20 -

10 -

LHRH

0 ' 1 I l l I I ' -30 0 30 60 90 120 -30 0 30 60 90 120

TIME ( m i d

LHRH

I I l l I I 1

-30 0 30 60 90 120

TIME(min1

C

70 4

60j LHRH

+

- E

E 40 -

J 301 I

20

0 -30 0 30 60 90 120

TIME (min)

LHRH

o J ~ 1 1 1 1 1 i

-30 0 30 60 90 120

TIMEhin)

LHRH 120

70

60

50

40

30

20

10

0 I I 1 1 1 1 I

-30 0 30 60 90 120

TIME(min) TIME(rnin1 Fig. 2. A-C.

D 120 -

110 -

100 -

90 -

80 -

70 -

60 -

50 -

' 4 0 -

3

5 LL

30 -

20 -

10 -

0 -

60 -

E 50 - 3

40 -

. I J

30 -

20 - 10 -

0 -

LHRH +

-30 0 30 60 90 120 TIME (mid

LHRH + 1

-30 0 ' 30 so 90 I20 TIME lmin)

Fig. 2. Gonadotropic responses to LHRH. P-.) patient's response; arrow: iv injection of LHRH (25 Fglml); shaded area = normal range (mean ? SDI. A Patient 1 (boy aged 16 years): insufficient gonadotropic responses to LHRH in comparison with the normal range (boys aged 16-18 years, n = 27). B: Patient 1 aged 18 years: slight improvement ofthe gonadotropic responses to LHRH. C: Patient 2 (girl aged 4 years): exaggerated gonadotropic responses to LHRH in comparison with the normal range (girls aged 2 to 8 years, n = 21). D Patient 3 (girl aged 13 months): exaggerated gonadotropic responses t o LHRH in comparison with the normal range (girls aged 6-24 months, n = 5).

TABLE 11. Amino Acid Composition of Hair Hydrolysates (Mol Percent)

Normals" Normals" Normals" Normals" EB.M EB.1 EB.K Norma@ ASP 6.3 5.9 5.9 6.0 8.2 8.5 8.1 5.7 THR 8.0 8.7 8.9 8.4 5.9 6.5 5.6 7.9 SER 12.1 12.5 12.9 13.5 9.9 9.2 9.5 12.7 GLU 14.2 14.0 13.8 14.2 15.1 16.1 15.4 12.8 PRO 7.1 7.8 7.7 7.9 5.6 4.7 5.4 9.7 GLY 6.4 6.5 6.4 6.6 6.6 6.6 6.6 6.7 ALA 5.3 4.9 5.0 5.0 6.6 6.8 6.8 5.0 VAL 6.2 5.6 5.8 5.7 6.2 6.2 6.4 5.8 CYS 8.4 8.5 9.1 8.0 4.6 3.9 4.4 9.5 MET .5 .2 .4 .4 .8 .8 .9 .5 ILE 2.8 2.8 2.8 2.7 3.8 3.9 3.9 2.9 LEU 7.5 7.1 7.0 7.0 9.8 9.5 9.7 6.7 TYR 2.2 2.1 2.2 2.3 2.7 2.7 2.7 2.2 PHE 2.0 1.9 2.0 1.8 2.5 2.5 2.5 1.9 HIS 1.1 1.1 1.0 1.0 1.0 1.1 1.1 .9 LYS 3.0 3.0 2.6 2.9 3.8 4.0 3.9 2.8 ARG 6.6 7.3 6.5 6.6 7.0 6.9 7.0 6.0 "Analyzed with the patients' hair. 'Ten normal hair samples analyzed in a different series [Pollitt and Stonier, 19713.

al., 1974; Baden et al., 19761, or hair-brain syndrome (McKusick no. 23405), or Pollitt syndrome [Pollitt et al., 19681 (McKusick no. 27555) refer to the patients without skin involvement.

3. IBIDS syndrome (I for ichthyosis) [Jorizzo et al.,

1980,1982) (McKusickno. 24217) or Tay syndrome [Tay, 1971; Happle et al., 19841 refer to patients with congenital ichthyosis and appearance of premature aging. 4. PIBIDS syndrome (P for photosensitivity) [Cal-

deron and Gonzalez-Cantu, 1979; Van Neste and Bore,

570 Przedborski et al.

normal children of comparable age and sex. Genital tract sonography was normal. Brain CT showed moderate cortical and subcortical atrophy in M.E and 1.E and was normal in K.E.

Laboratory Data Full blood counts, urinalysis, blood gases, pH, cre-

atinine, electrolytes, calcium, phosphorus, ALT, AST, CPK, iron, ammonia, lactate, pyruvate, plasma and urinary aminoacids, urinary organic acids, and karyotype were normal. Serum copper and zinc levels were assayed on three different occasions by atomic absorption spec-

His tological Studies On light microscopy, the hair shaft consistently had

irregular, slightly undulating contours (Fig. 3A) and, less frequently, clean transverse fractures (Fig. 3B). On polarizing microscopy, the hair shaft showed alternat- ing bright and dark bands. Scanning electron micro- graphs demonstrated that cuticle scales were abraded; ridging and fluting were present along the longitudinal axis, and, when viewed laterally, the hair shaft appeared flattened. Skin biopsies showed no abnormalities when analyzed with light and electron microscopy.

mgidl in K.E., and 25.4 ? 2.1 mgidl in 1.E: (N1 20-50 mgidl). Plasma biotin levels were 210 pgiml for M.E.,

limit, 350 pgiml). Plasma biotinidase activities were three sibs (Dr. R. Baumgartner, Baslery

Kinderspital, Basel, Switzerland).

DISCUSSION 3l8 Pdml forK.E.3 and447 Fdml for 1.E. (lower normal The three children described in this report present

with cystine-deficient brittle hair, mental short stature, ataxia, and gonadal dysfunction. Parental consanguinity and involvement of sibs of both sexes strongly support an autosomal recessive mode of inheritance for this syndrome.

shaft anomalies are associated with mental retardation,

deficiency, argininosuccinyluria, and Menkes disease are excluded in our patients, in view of the absence of specific biochemical changes associated with these in-

In the three sibs described here, the hair exhibited the morphological (irregular twisting, transverse fractures) and biochemical (cystine deficiency) hallmarks of tri-

in

Endocrine Studies

thyrotropin (TsH), Serum prolactin, cortisol, dehydro-

and growth hormone (GH) were normal as were the responses of GH, ACTH, and cortisol to iv insulin (0.1 IU/kg), o f G ~ to im glucagon (0.1 mg/kg), and o f ~ s H to iv thyrotropin-releasing hormone (200 kg). In the boy born disorders. (M.E) at ages 16 and 18 years, plasma testosterone levels were, respectively, 1.2 and 2.8 ng/ml (normal range for age and sex: 3-10 ng/ml), and the luteinizing

2A,B). In both girls (K.E, LE), estrone, estradiol, and condition from trauma

responses to iv LHRH were exaggerated ( ~ i ~ . ~c ,D) . a genetic trait associated withmental retardation. In all these cases, family histories were consistent with auto- soma1 recessive inheritance. In Table IV, the clinical

Analysis of Hair Amino Acids manifestations in our patients are compared with those Observed in PreviouslY reported cases With 'TTD and mental retardation. As shown in Table IV, most reported Datients present with short stature and impaired gona-

For all three sibs, thyroxine, triiodothyronine, and Among the various genetic syndromes where hair

epiandrosterone sulphate, adrenocorticotropin (ACTH) , the diagnoses ofbiotin-dependent carboxylase

hormone (LH) and the follicle-stimulating hormone (FSH) responses to iv LHRH Were insufficient (Fig.

progesterone were normal for age and the LH and FSH

chothiodystrophy (TTD) as definedby Price et al. [19801* TTD has been reported Once as an acquired

[Leonard et al.9 19801, it has most often been reported as

Amino acid analyses of hair hydrolysates (Table 11) showed a significant decrease in cystine contents.

Copper Metabolism in Cultured Fibroblasts Copper metabolism was investigated in cultured skin

fibroblasts from the three sibs and their parents. In two of the sibs (K.E., I.E.), these studies were performed on cultures initiated from two different biopsies. Table I11 shows the results of pulse and chase experiments with labeled copper; 64Cu uptake and retention after 24 h in unlabeled medium were normal in cells from the parents, patient M.E., and the second culture of patient K.E. Fibroblasts from the first culture of K.E. as well as from both cultures of I.E. showed increased copper uptake, but the percent retention was normal.

ha1 funciion. Additional findings, less often obs&ved, include ichthyosis, premature aging appehrance, skin photosensitivity, cataracts, and nail and enamel dystro-

A variety of eponyms and acronyms has been assigned to these genetic conditions with TTD and mental retardation:

phy.

1. Sabinas syndrome (McKusick no. 21139) refers to the patients with normal stature [Arbisser et al., 1976; Howell et al., 19811.

2. BIDS syndrome (brittle hair, impaired intelligence, decreased fertility, short stature) [Jackson et

Richothiodystrophy 571

TABLE 111. Labeled Copper Uptake and Retention in Fibroblasts

Uptake ng 64Cu per mg protein

per 20 h % retention Patient M.E. 20.5 22.3

Patient K.E., 2d culture 18.9 20.7 Patient I.E., 1st culture 39.8 24.0 Patient I.E., 2d culture 28.1 23.6 Father 15.8 22.4 Mother 18.0 15.6

Patient K.E., 1st culture 28.5 21.9

2.5-97.5 Mean (95% limits) Median percentiles

(n=20) (n=7)

(n = 21) b = 6 )

(n = 26) (n = 16)

Controls XX 18.9 11.1-26.7 20.9 11.3-24.0

Controls XY 21.1 9.0-33.3 15.9 13.1-21.3

Menkes 75.5 46.5-99.9 65.3 52.5-79.8

1983; Crovato et al., 1983; Kinget al., 1984; Luckyet al., 1984; Stefanini e t al., 1986; Rebora and Crovato, 1987, 19881 (McKusick no. 27872) refers to patients with ichthyosis vulgaris and photosensitivity.

Since TTD has been reported in patients with the Marinesco-Sjogren syndrome [Baden et al., 19761, Re- bora and Crovato [1987] have suggested that this syndrome [Norwood, 19641 (McKusick no. 24880) may also be included within this group of diseases, representing the most severe expression of the BIDS syndrome.

to Tabie Our patients are most to patients with the syndrome, particularly to the cases reported by Jackson et al. [1974] within a large

Fig, 3. A Light microscopy ( x 10): irregular and undulatingcontour of the hair shaft. B: Higher magnification ( x 20): transverse fracture (trichoschisis) of the hair shaft (arrow).

TABLE IV. Clinical Features in Patients With TTD and Mental Retardation

Gonadal Nail: Short dys- Photo- enamel

Syndromes References stature function Ichthyosis sensitivity Cataracts Ataxia F'rogeria dystrophy - - Sabinas Arbisser et al., 1976 - - - - -

IBIDS Tay, 1971 + * + ? * + * ?

Howell et al., 1981

Price et al., 1980 Jorizzo et a]., 1980, 1982 Happle et al., 1984 Fois et al., 1988

-

PIBIDS Calderon and Gonzalez- + * + + 2 & * & Cantu, 19'77

Van Neste and Bore, 1983 Crovato et al., 1983 King et al., 1984; Lucky et al., 1984 Rebora and Crovato, 1987

- - + + - - Marinesco- Norwood, 1964 + * BIDS Pollitt et al., 1968 + + Present + + -

+ , present; - , absent; ? , inconstant.

Sjogren Skre and Berg, 1979

Jackson et al., 1974 - & - - - -

+ - - - -

patients

572 Przedborski et al.

Amish kindred. The question of whether all syndromes with TTD represent phenotypic variants of the same mutation, or distinct mutations, remains a matter of debate. Although variations with respect t o the degree of mental deficiency, neurologic disturbances, and gonadal dysfunction are noted within each of these five groups of TTD patients, there is little intrafamilial vari- ability. Indeed, within sibships, major signs such as ichthyosis and photosensitivity, when present, are al- ways found in all affected sibs. Taken alone, the clinical data would therefore support genetic heterogeneity of the TTD-mental retardation syndrome(s1. Nevertheless, a definite answer t o this question must await the identi- fication of biochemical markerb), specific to each group of TTD patients.

In this respect, at least the PIBIDS syndrome might be distinguished from the other TTD conditions, since a defect in DNA repair has been demonstrated in several unrelated patients [Yong et al., 1984; Van Neste et al., 1985; King et al., 1986; Stefanini et al., 1986; Rebora and Crovato, 19871. Moreover, somatic cell hybridiza- tion studies have shown that PIBIDS cells are not com- plemented by xeroderma pigmentosum-group D (XPD) cell with respect to DNA repair. With the exception of one of the two patients reported by King et al. (1986), all cases with TTD and photosensitivity tested for DNA repair present with the defect. The DNA repair defect may be a rather specific marker for PIBIDS, since a patient with TTD and ichthyosis without photosensitivity had no DNA repair defect [Fois et al., 19881. DNA repair studies have not yet been performed in our patients. However, in view of the absence of ichthyosis and photosensitivity, normal DNA repair should be an- ticipated.

Rebora et al. [1986] suggested that subtle changes in amino acid composition of the hair may further help to delineate the syndromes associated with TTD. Indeed, they pointed out a two-fold increase in phenylalanine in hair from PIBIDS patients, whereas hair from TTD patients without photosensitivity had normal phenylalanine contents. However, the recently reported case of Fois et al. [1988], as well as our patients, all ofwhom are not photosensitive, had hair phenylalanine contents slightly above the normal range. More data on hair amino acids in TTD are therefore needed in order to assess the significance of phenylalanine contents of the hair with regard to the delineation of the TTD syndrome(s).

In order to account for the hair and brain defects, we have considered the possibility of a disorder in copper transport, as occurs in Menkes disease [Danks, 19831. Although copper uptake was increased in fibroblasts from the first cultures of our female patients, these data could only be confirmed in one (I.E.). Copper uptake was normal in the male patient as well as in his parents. Moreover, the rates of 64Cu retention were normal in all cell lines from this family. Normal fibroblast copper turnover was also reported in a patient with the PIBIDS syndrome [Rebora et al., 19861. Therefore, the few data obtained do not support the hypothesis of a disorder in copper metabolism in TTD syndrome(s1.

In most reported adolescent and adult patients with

TTD, impaired gonadal function was suggested by hypogonadism andlor decreased fertility. Hypogonadism was only rarely mentioned in prepubertal cases of TTD. Go- nadal function tests are lacking in most instances. The 16 year old male reported by Lucky et al. [19841 with TTD and photosensitivity had small testes and elevated basal levels of FSH. Gonadotropic responses to LHRH were previously evaluated in only one case of TTD with ichthyosis; normal LH and FSH responses were found for this 8 year old girl [Fois et al., 19881. In the three sibs reported here, there is evidence for impaired gonadal function. However, it is noteworthy that, within this single sibship, gonadal dysfunction is variable. Indeed, in the boy aged 16, the tests showed low testosterone levels and gonadotropic responses to LHRH in the prepubertal range (Fig. 2A). Two years later, similar tests showed gonadotropic responses in the early pubertal range (Fig. 2B). These data are consistent with delayed puberty [Styne and Grumbach, 19861. In contrast, both girls had hypergonadotropic hypogonadism with ovarian failure. No explanation can as yet be provided for such discrepant expression of gonadal dysfunction in these sibs.

Hypergonadotropic hypogonadism was also reported in some of the Norwegian cases of Marinesco-Sjogren syndrome [Skre and Berg, 19791. For these cases, genetic linkage between these two autosomal recessive traits was postulated. Considering the suggestion that the same gene loci are involved in the BIDS and the Marinesco-Sjogren syndromes, the findings of hypo- gonadotropic hypogonadism in our male patient and hypergonadotropic hypogonadism in both females do not support the hypothesis of genetic linkage between hypergonadotropic hypogonadism and the BIDS syndrome. It is otherwise possible that a single gene defect affects the hair and the central nervous system as well as the gonads, albeit in different ways for the latter. Baden et al. 119761 suggested that the presence of sulfur-rich keratin-like proteins in mammalian sperm might be the link between hypogonadism and TTD. The question of whether this explanation might be applied to ovarian failure in affected females cannot be answered at present, as the presence of sulfur-rich proteins in ovary is not documented. Genetic linkage between a putative TTD gene and the XP-D locus has also been postulated in order to account for the inconstant association of TTD with a DNA repair defect [Stefanini et al., 1986; Rebora and Crovato, 1987; Fois et al., 19881. Map- ping of the XP-D locus might provide a clue as to the chromosome localization of (one of) the TTD gene(s). Such studies at the DNA level are needed in order to settle the question of genetic heterogeneity of the TTD syndrome(s1.

ACKNOWLEDGMENTS The authors wish to thanks Drs. Gruter and Hanck

(Hoffman-La Roche & Cie, Basel) for biotin levels determination, Dr. R. Baumgartner (Basler Kinderspital, Basel) for biotinidase activity determination, and Dr. P. Tugendhadt for his insightful comments on the manu- script. Serge Przedborski is research assistant of the Belgian Fund for Scientific Research.

lkichothiodystrophy 573

REFERENCES Arbisser AI, Scott CI, Howell RR, Ong PS, Cox HL (1976): A syndrome

manifested by brittle hair with morphologic and biochemical abnormalities, developmental delay and normal stature. Birth Defects

Baden HP, Jackson CE, Weiss L, Jimbow K, Lee L, Kubilus J, Gold RJM (1976): The physicochemical properties of hair in the BIDS syndrome. Am J Hum Genet 28:514-521.

Coulter DL, Beals TF, Allen R J (1982): Neurotrichosis: Hair-shaft abnormalities associated with neurological diseases. Dev Med Child Neurol 24:634-644.

Calderon R, Gonzalez-Cantu N (1979): Kinky Hair, photosensitivity, broken eyebrows and eyelashes, and non progressive mental retardation. J Pediatr 95:1007-1008.

Crovato F, Borrone C, Rebora A (1983): Trichothiodystrophy-BIDS, IBIDS and PIBIDS? Br J Dermatol 108:247.

Danks DM (1983): Hereditary disorders of copper metabolism in Wilson’s disease and Menkes’ disease. In Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS (eds): “The Metabolic Basis of Inherited Disease,” Ed 5. New York: McGraw-Hill, pp

Fois A, Balestri P, Calvieri S, Zampetti M, Giustini S, Stefanini M, Lagomarsini P (1988): Trichothiodystrophy without photosensitivity biochemical, ultrastructural and DNA repair studies. Eur J Pediatr 147:439-441.

Gillespie JM, Marshall RC (1983): A comparison of the proteins of normal and trichothiodystrophic human hair. J Inv Dermatol 80:195-202.

Happle R, Traupe H, Grope H, Bonsmann G (1984): The Tay syndrome (congenital ichthyosis with trichothiodystrophy). Eur J Pediatr 141:147-152.

Howell RR, Arbisser AI, Parsons US, Scott CI, Fraustadt U, Collie WR, Marschall RN, Ibana OC (1981): The Sahinas syndrome. Am J Hum Genet 33:957-967.

Jackson CE, Weiss L, Watson J H (1974): “Brittle” hair with short stature, intellectual impairment and decreased fertility: An autoso- ma1 recessive syndrome in an Amish kindred. Pediatrics 54:201-207.

Jorizzo JL, Crounse RG, Wheeler CE (1980): Lamellar ichthyosis, dwarfism, mental retardation and hair shaft abnormalities. J Am Acad Dermatol 2:309-317.

Jorizzo JL, Atherton DJ, Crounse RG, Wells RS (1982): Ichthyosis, brittle hair, impaired intelligence, decreased fertility and short stature (IBIDS syndrome). Br J Dermatol 106:705-710.

King MD, Gummer CL, Stephenson JBP (1984): Trichothiodystrophy- neurotrichocutaneous syndrome of Pollitt: A report of two unrelated cases. J Med Genet 21:286-289.

King MD, Arlett CF, Lehmann AR, Hayne LV, Stephenson JBP (1986): Clinical and cellular studies in trichothiodystrophy. In “24th An- nual Symposium SSIEM, Amersfoort, September 9th-12th” (Ab- stract 158).

Leonard JN, Gummer CL, Dawber RPR (1980): Generalized trichorrhexis nodosa. Br J Dermatol 103:85-90.

12:219-228.

1251-1268.

Lucky PA, Kirsch N, Lucky AW, Carter DM (1984): Low-sulfur hair syndrome associated with UBV photosensitivity and testicular failure. J Am Acad Dermatol 11:340-346.

Norwood WF (1964): The Marinesco-Sjogren syndrome. J Pediatr 65:431-437.

Pollitt RJ, Jenner FA, Davies M (1968): Sibs with mental and physical retardation and trichorrhexis nodosa with abnormal amino acid composition of the hair. Arch Dis Child 433211-216.

Pollitt RJ , Stonier PD (1971): Proteins of normal hair and of cystine- deficient hair from mentally retarded siblings. Biochem J

Price VH, Odom RB, Ward WH, Jones FT (1980): Trichothiodystrophy. Sulfur-deficient brittle hair as a marker for a neuroectodermal symptom complex. Arch Dermatol 116:1375-1384.

Rebora A, Guarrera M, Crovato F (1986): Amino acid analysis in hair from PIBIDS syndrome. J Am Acad Dermatol 15:109-111.

Rebora A, Crovato F (1987): PIBIDS syndrome-Trichothiodystrophy with xeroderma pigmentosum (group D) mutation. J Am Acad Dermatol 16:940-947.

Rebora A, Crovato F (1988): Trichothiodystrophy, xeroderma pigmentosum and PIBIDS syndrome. Hum Genet 78:106-108.

Skre H, Berg K (1979): Linkage studies on the Marinesco-Sjogren syndrome and hypergonadotropic hypogonadism. Clin Genet

Stefanini M, Lagomarsini P, Arlett CF, Marinoni S, Borrone C, Crovato F, Trevisan G, Cordone G, Nuzzo F (1986): Xeroderma pigmentosum is present in patients affected by trichothiodystrophy with photosensitivity. Hum Genet 74:107-112.

Styne DM, Grumbach MM (1986): Delayed puberty and sexual infantil- ism. Puberty in male and female. Its physiology and disorders. In Yen SS, Jaffe RB (eds): “Reproductive Endocrinology,” Ed 2. Phila- delphia: W.B. Saunders, vol 12, pp 313-384.

Tay CH (1971): Ichthyosiform erythroderma, hair shaft abnormalities, and mental and growth retardation. A new recessive disorder. Arch Dermatol 104:4-13.

Van Neste D, Caulier B, Thomas P, Vasseur F (1985): PIBIDS: Tay’s syndrome and xeroderma pigmentosum. J Am Acad Dermatol 12:372-373.

Van Neste D, Bore P (1983): Trichothiodystrophie: Une Btude mor- phologique et biochimique. Ann Dermatol Venereol 110:409-417.

Walser M (1983): Argininossuccinate lyase deficiency (argininosuc- cinic aciduria). Urea cycle disorders and other hereditary hyperam- monemic syndromes. In Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS (eds): “The Metabolic Basis of Inher- ited Disease,” Ed 5 . New York: McGraw-Hill, pp 422-425.

Wolf B, Grier RF, Allen RJ, Goodman SI, Kien CL (1983): Biotinidase deficiency: The enzymatic defect in late-onset multiple carboxylase deficiency. Clin Chim Acta 131:273-281.

Yong SL, Cleaver JE , Tullis GD, Johnston MM (1984): Is trichothiodystrophy part of the xeroderma pigmentosum spectrum? Am J Hum Genet 362325.

122:433-444.

11:57-67.

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Trichothiodystrophy, mental retardation, short stature, ataxia, and gonadal dysfunction in three Moroccan siblings