an x-linked mental retardation syndrome with craniofacial abnormalities, microcephaly and club foot

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  • American Journal of Medical Genetics 17:375-382 (1984)


    Lewis B. Holmes, David L. Gang

    Embryology-Teratology Unit, Children's Service (L .B .H. ) ; Departments of Pathology (D .L .G. ) , Massachusetts General Hospital; Departments of Pediatrics (L.B.H.) and Pathology (D.L.G.), Harvard Medical School, Boston, MA 02114


    A male infant, who died of renal insufficiency at 6 months, had 2 similarly affected maternal uncles who died at 16 and 6 months respectively. Their manifestations include microcephaly, a large anterior fontanel, short nose with anteverted nostrils, club foot deformity, retarded psycho- motor development and, in the index case only, kidney hypoplasia and dysplasia. The 2 obligatory carriers of this evidently X-linked recessive syndrome had no physical abnormalities.

    Key words: X-linked, hypotonia, club foot, craniofacial abnormalities,


    Several X-linked mental retardation/multiple congenital anomalies (MR/MCA) syndromes not associated with an abnor- mality of the X chromosome are known. Among others, these include the FG syndrome [Opitz et al, 19821, a syndrome of growth retardation, deafness and genital anomalies [Mattei et al, 19831, a syndrome of vertebral anomalies, abducens

    Address reprint requests to Dr. L.B. Holmes , Embryology- Teratology Unit, Massachusetts General Hospital, Boston, MA 02114.

    0 1984 Alan R. Liss, Inc.

  • 376 Holmes and Gang

    palsy and hypoplastic sacrum [Christian et al, 19771, a syndrome of dwarfism, cerebral atrophy and generalized keratosis follicularis [Cantu'et al, 19741 and a syndrome of microcephaly, craniofacial anomalies, heart defects and brittle scalp hair [Golabi et al, 19811.

    Other authors have reported on brothers with MR/MCA syndromes which may represent X-linked traits. Among others, these include a syndrome of midface retraction, hypertrichosis and skeletal anomalies [Donnai and Harris, 19791 , a syndrome of cataracts, short stature and primary hypogonadism [Martsolf et al, 19781, and a syndrome of arachnodactyly, retinitis pigmentosa, cataract and microcephaly [Mirhosseini et al, 19721.

    We report on a family in which 3 affected males have had very similar manifestations that differ from those described in reports of other X-linked MR/MCA syndromes. All 3 affected individuals died in the first two years of life.


    The propositus (111-3; Fig. 1) was born in 1979 at 38 weeks. During her pregnancy the mother had a preswned viral illness at about 4 weeks of gestation; 2 weeks later was exposed to a child with a fever and a rash. She had a protective level of rubella antibody. Oligohydramnios was noted at delivery. Holmes, unpublished) , and his length was 49 cm (10th centile). At birth he was noted to have: microcephaly (occipito-frontal head circumference 29.5 cm; < 3rd centile; Fig. 2), large anterior fontanel (4.5 x 4.5 em; > 97th centile) epicanthal folds, short nose (2.0 em; 10th centile) with anteverted nostrils, short upper lip (0.6 cm;

  • Brief Clinical Report 377


    Fig. 1. Affected males are indicated by the black squares, carrier females by the bull's eye and the propositus with arrow.

  • 378 Holmes and Gang

    Fig. 2 . Shows f l a t br idge of nose, ep ican tha l f o l d s , antever ted n o s t r i l s and s m a l l head s i z e of t h e propos i tus a t b i r t h .

    Autopsy f ind ings : microcephaly wi th s m a l l b r a i n which weighed 453 g (normal 762 + 73 g , Schulz e t a l , 1962) , i n d i s t i n c t temporal g y r i on t h e r i g h t bu t not on t h e l e f t ; hypoplasia of t h e c e r e b r a l white mat te r ; t hy rog lossa l duct c y s t ; incomplete loba t ion o f both lungs ; severe r e n a l hypo- p l a s i a and dysp la s i a (combined weight 6 g , normal 62 + 1 4 g , Schulz e t a l , 1962) . were normal.

    The o the r organs, inc luding eyes ,

    Leukocytes and s k i n f i b r o b l a s t chromosomes were normal.

    The o l d e s t a f f e c t e d uncle (11-2) w a s born i n 1951 at term, a f t e r an uneventful pregnancy. I n r e t r o s p e c t , h i s mother concluded t h a t t h e f a c i a l appearance of t h i s boy (F ig . 4 ) and of h i s b r o t h e r (11-5) showed a s t r i k i n g

  • Brief Clinical Report 379

    F i g . 3. Shows the severe equinovarus foot deformity in the propositus at birth.

    F i g . 4. Similar facial appearance in 11-2 at 5 months.

  • 380 Holmes and Gang

    resemblance t o t h a t o f t h e p ropos i tu s . She r e c a l l s t h a t he had a c lub foot deformity, bu t not as severe as i n h i s nephew (111-2). t o hold up h i s head.

    By 3 months it w a s noted t h a t he made no e f f o r t

    A t 1 4 months he w a s noted t o have: extremely wide a n t e r i o r fon tane l , ep i can tha l f o l d s , abnormal t e e t h and chronic cons t ipa t ion . Radiographs showed no abnormal i t ies of t h e t h o r a c i c sp ine ; t h e s k u l l w a s considered t o be narrow. H i s dea th a t 1 6 months w a s a t t r i b u t e d t o e n c e p h a l i t i s . No autopsy w a s performed.

    The second a f f e c t e d uncle (11-5) w a s born i n 1957 a f t e r one uneventful pregnancy. He weighed 2900 g a t b i r t h and w a s noted t o have apparent ly low-set e a r s , ep i can tha l folds, a shor t neck and a calcaneovalgus foot deformity. A t 3% months of age h i s head circumference w a s 40 cm (25 th t o 50th c e n t i l e ) , t h e a n t e r i o r fon tane l w a s 4 em wide; he had a f l a t nasa l br idge and ep ican tha l f o l d s and h i s i n t e r - inne rcan tha l d i s t ance w a s 3.0 em ( > 3 r d c e n t i l e , Smith, 1982). hypotonic; he w a s not responsive t o h i s environment and had a harsh , g r a t i n g c r y .

    He w a s

    He d ied a t 6 months during a f e b r i l e i l l n e s s . The microscopic sec t ions obtained a t t h e t i m e of t h e autopsy were reviewed by one of u s ( D . L . G . ) . The only abnormality i d e n t i f i e d w a s hype rp la s i a and immaturity of t h e panc rea t i c i s l e t s . The kidneys weighed 45 .5 g (combined normal 62 + 1 4 g, Schulz e t a l , 1962). B r a i n weight w a s 550 g , which i s s m a l l f o r 6 months (normal 762 + 73 g , Schulz e t a l , 1962) ; t h e b r a i n w a s considered normal in appearance. abnormali t ies were i d e n t i f i e d i n t h e s p i n a l cord , t h e brainstem or t h e cerebellum.


    The 2 c a r r i e r s (1-2 and 11-4) have normal i n t e l l i g e n c e and none of t h e f a c i a l changes noted i n t h e 3 a f f e c t e d males. The in t e r - inne rcan tha l d i s t ance of 11-2 w a s 2.8 ern (25th c e n t i l e , Smith, 1982).


    The 3 a f f e c t e d males descr ibed have a s i m i l a r phenotype

    The s e v e r i t y of t h e MR i n t h i s d i so rde r i s t h a t i s d i s t i n c t from t h a t of any o the r known X-linked MR/MCA syndrome. underscored by t h e f a c t t h a t none of t h e s e 3 males had any

  • Brief Clinical Report 381

    meaningful response to his environment. While the renal insufficiency of the propositus undoubtedly lead to his demise in infancy, his 2 affected uncles did not have any life-threatening anomalies. At this time there is no realistic method for prenatal diagnosis, Serial measurements of head size might be employed to rule out the presence of microcephaly. However, one uncle had a normal head size at 3% months; the head circumference of the 2 uncles at birth is not known.


    We appreciate very much the assistance of the family in collecting medical information needed for this report, Dr. Leonard Atkins and his staff in carrying out the special chromosome studies and Miss Jane Pultinas in typing this report. This work was supported in part by NIH Grant No, HD15241 and a grant from Merrell Dow Pharmaceuticals, Inc -


    Cantu J-M, Hernandez A, Larracilla J, Trejo A, Macotela-Ruiz E (1974): A new X-linked recessive disorder with dwarfism, cerebral atrophy, and generalized keratosis follicularis. J Pediatr 84 : 564-567.

    Reed T (1977): X-linked skeletal dysplasia with mental retardat ion. Clin Genet 11 : 128-136.

    Donnai D, Harris R (1979): A further case of a new syndrome including midface retraction, hypertrichosis, and skeletal anomalies. J Med Genet 16 : 483-486.

    retardation/multiple congenital anomaly syndrome. Clin Res 29:131A, 1981.

    Martsolf JT, Hunter AGW, Haworth JC (1978): Severe mental retardation, cataracts, short stature, and primary hypogonadism in two brothers. Am J Med Genet 1:291-299.

    Mattei JF, Collignon P, Ayme S, Giraud F (1983): X-linked mental retardation, growth retardat ion, deafness and microgenitalism. A second family report. Clin Genet 23: 70-74.

    Christian JC, DeMeyer W, Franken EA, Huff JS, Khairi S,

    Golabi M, Ito M, Hall BD (1981): A new X-linked mental

  • 382 Holmes and Gang

    Mirhosseini SA, Holmes LB, Walton DS (1972) : Syndrome of pigmentary r e t i n a l degenerat ion, c a t a r a c t , microcephaly and severe mental r e t a r d a t i o n . J Med Genet 9:193-196.

    Opitz J M , Kaveggia EG, Adkins WN Jr, Gi lbe r t EF, Viseskul C , Pe t t e r sen J C , Blumberg B (1982): S tudies of malformation syndromes of humans, XXXIIIC. The FG syndrome-further s t u d i e s on t h r e e a f