J Med Genet: first published as 10.1136/jmg.18.2.129 on 1 April 1981. Downloaded from Journal of Medical Genetics, 1981, 18, 129-133 Syndromes of microcephaly, microphthalmia, cataracts, and joint contractures ROBIN M WINTER*, DIAN DONNAIt, AND MARTIN d'A CRAWFURD* From *the Kennedy Galton Centre, Harperbury Hospital, Harper Lane, Radlett, Hertfordshire WD7 9HQ; *the Division of Inherited Metabolic Diseases, Clinical Research Centre, Northwick Park Hospital, Watford Road, Harrow, Middlesex HAI 3UJ; and tthe Department of Medical Genetics, St Mary's Hospital, Hathersage Road, Manchester M13 OJH SUMMARY Three infants are described, one with the Neu-Laxova syndrome and two with the cerebro-oculo-facio-skeletal (COFS) syndrome. The relationship between these two syndromes is discussed in the light of the present cases and others in published reports. Pena and Shokeirl described ten infants with a syn- Case reports drome consisting of microcephaly, microphthalmia, cataracts, and joint contractures and in most cases CASE 1 characteristic facial appearance. They believed that This was a term female infant born to a 23-year-old autosomal recessive inheritance was involved in Caucasian primigravida. There was no family what they referred to as the cerebro-oculo-facio- history of similar abnormalities and no known skeletal syndrome (COFS) syndrome. A follow-up of parental consanguinity. Pregnancy was uneventful some of the original cases and details of several new and there was no history of drug ingestion. Birth- ones,2 together with other reports 3 4 which probably weight was 1-36kg (<3rd centile) and the head describe the same syndrome under different names, circumference was 24 cm (<3rd centile). The firmly established the existence of the COFS syn- forehead was sloping, the nasal bridge broad and http://jmg.bmj.com/ drome. However, details of other cases 5-8 have led prominent, and the eyes sunken and tightly closed Pena et a12 to suggest that other similar syndromes exist within the "same phenotypic syndrome com- munity". Infants described by Neu et a19 and Laxova et al 10 had microcephaly and joint contractures but were also characterised by oedema and bizarre facial on October 2, 2021 by guest. Protected copyright. features. Similar infants were described by Lazjuk et all' who drew attention to reports in the Czech literature,12 and following a review of all known cases they suggested that the constellation of signs be called the Neu-Laxova syndrome. However, the COFS syndrome, which may itself be heterogeneous, and the Neu-Laxova syndrome have sufficient features in common for some authors to consider them to be possibly part of the same entity.7 13 In the absence of a specific biochemical or other marker it is impossible to resolve this diagnostic hetero- AM geneity and in this report we describe three further cases, two of whom appear to conform most closely to the COFS group, and one of whom has features common to both the COFS and Neu-Laxova syndromes. Rece'ved for publication 29 May 1980 FIG 1 Case 1. 129 J Med Genet: first published as 10.1136/jmg.18.2.129 on 1 April 1981. Downloaded from 130 Robin M Winter, Dian Donnai, and Martin d'A Crawfurd with microphthalmia and cataracts (fig 1). There was and a large (1 5 cm) pilonidal sinus. A small um- micrognathia, with the upper lip overhanging the bilical hernia was present, but otherwise the abdomen lower, and malformed ears with abnormal antihelices. and external genitalia were normal. Tone of the The mouth and palate were normal. The neck was limbs was much increased and the tendon reflexes short and the chest broad, and there were flexion were very brisk. There were multiple flexion con- contractures of the elbows, wrists, fingers, hips, tractures of the elbow, wrists, fingers, hip, knees, and knees, and ankles with bilateral rocker-bottom feet. ankles. The skin of the soles of the feet manifested The skin of the trunk was yellow, shiny, cracked with some longitudinal folding although there was no peeling in places, and resembled the collodion skin rocker-bottom deformity. The skin was normal. of infants with congenital ichthyosis. The baby died Investigations for rubella, toxoplasma, and cyto- at 3 hours of age. A necropsy examination was re- megalovirus infection were negative. Urine analysis fused. Investigations for intrauterine infection were for amino-acids and reducing substances was nega- negative. The karyotype (G banded) was 46,XX. tive. Chromosome studies (G banded) showed a 46,XX karyotype. The patient failed to thrive and CASE 2 had severe feeding difficulties. Development was This was a female infant who was the product of a severely retarded. She died at the age of 5 years, term normal delivery to a 23-year-old Asian Indian probably of bronchopneumonia. Her weight at primigravida. Pregnancy was normal and there was death was 8 kg (<3rd centile). Necropsy examina- no history of drug ingestion or viral infections. The tion was not carried out. parents were first cousins. Birthweight was 2 2 kg (<3rd centile), head circumference was 29 5 cm CASE 3 (<3rd centile), and length was 53 cm (50th centile). This was a female infant, the second child born to At birth she was noted to have microcephaly, catar- healthy non-consanguineous Caucasian parents. acts, and multiplejoint contractures. On examination The first child, at the age of 8 years, is physically at 4 months of age her weight was 3 6 kg (<3rd and developmentally normal and there is no rele- centile), length 60 cm (25th centile), and head vant family history. There were no illnesses in the circumference 35-1 cm (<3rd centile). She was second pregnancy and no drugs, apart from iron microcephalic with a sloping forehead, prominent tablets, were taken. Delivery was by forceps and the root of the nose, bilateral cataracts, mild hypo- birthweight of the infant was 3 28 kg (25th centile). telorism, and convergent strabismus (fig 2). The neck The early neonatal period was uneventful but at the was short. There was marked scoliosis of the spine age of 4 months her weight was 5 67 kg and examina- http://jmg.bmj.com/ with a mongolian blue spot to the left of the sacrum tion revealed microcephaly (head circumference on October 2, 2021 by guest. Protected copyright. FIG 2 Case 2. FIG 3 J Med Genet: first published as 10.1136/jmg.18.2.129 on 1 April 1981. Downloaded from Syndromes of microcephaly, microphthalmia, cataracts, andjoint contractures 131 38-5 cm, <3rd centile), microphthalmia, and catar- (1) Those infants with relatively normal birthweight acts. Investigations for rubella, cytomegalovirus, but with progressive postnatal growth de- and toxoplasmosis were negative. Urine chromato- ficiency and progressive pathology of the central graphy was normal and chromosome studies (G nervous system, consisting of depletion of sub- banded) showed a 46,XX constitution. She had cortical white matter and myelin, compatible severe feeding difficulties, failed to thrive, and a with leucodystrophy. Examples of these patients developmental quotient on the Griffiths mental include the original patients described as having development scale was 24 at the age of 2 years. On the COFS syndrome by Pena and Shokeir,' some examination at the age of 4 years, her weight was of whom were later reinvestigated,2 the patients 7 25 kg (<3rd centile), length 74 cm (<3rd centile), described by Lowry et al,3 (the necropsy on one and head circumference 40 cm (<3rd centile). Her of those patients was reported by Dolman and eyes were small and deep set and cataracts were Wright14), and those described byScott-Emuakpor present (fig 3). The ears were large, the nasal bridge et al.4 These infants tend to have character- was prominent, and the upper lip overhung the lower istic facial features consisting of microcephaly, lip. The teeth were small and brittle. There was microphthalmia, blepharophimosis, cataracts, marked camptodactyly and a thoracic kyphosis was prominent root of the nose, upper lip overhang- present. ing the lower, micrognathia, and large ear She died at the age of 41 years from pneumonia pinnas. Musculoskeletal abnormalities include and acute cardiac failure. Permission for necropsy camptodactyly and flexion contractures, dis- was not granted. located hips with shallow acetabular angles, coxa valga, rocker-bottom feet, and a longi- Discussion tudinal groove on the soles. Pena et al2 suggested that the postnatal growth failure and cachexia Infants presenting with microcephaly, cataracts, were evidence of a primary growth deficiency. and joint contractures with associated anomalies In addition to the progressive neurological appear to fall into three groups (table). pathology, some members of this group have TABLE Comparison ofpresent cases with reported cases ofNeu Laxova and COFS syndromes Features Case I Case 2 Case 3 Neu-Laxova COFS COFS (early death) (classical) http://jmg.bmj.com/ General Small for dates + + - 9/9 4/5 8/14 Age at death±SD 3 h 5 yr 4 yr * 8 d 49 mth ±9-5 i 53 Failure to thrive + + + NA 5/5 17/17 Mental retardation NA + + NA NA 17/17 Head and neck Microcephaly + + + 8/9 4/4 16/17 Sloping forehead + + - 6/6 4/5 ? Prominent root of nose ± + + 1/7 5/5 8/8 on October 2, 2021 by guest. Protected copyright. Flat nose and nasal bridge - - - 6/7 0/5 0/8 Large ears + - + 2/3 4/5 9/9 Micrognathia + - - 3/6 3/5 8/9 Microphthalmia + - + 2/7 3/4 11/11 Cataracts + + + 1/7 3/4 11/15 Short neck + + - 6/6 2/4 0/10 Trunk Kyphosis - + + 0/7 2/5 13/14 Scoliosis - + - 0/7 0/2 13/14 Extremities Camptodactyly/finger deformity + + + 8/8 5/5 10/10 Syndactyly - - - 4/6 1/5 0/9 Flexion contractures + + + 8/8 5/5 14/16 Rocker-bottom feet + - - 6/6 3/5 7/12 Skin Ichthyosis/collodion skin + - - 5/7 0/5 0/14 Oedema of subcutis + - - 7/8 0/5 0/14 CNS Hypoplasia or agenesis of the corpus callosum ? ? ? 2/5 2/3 3/7 Cerebellar hypoplasia ? ? ? 4/5 1/3 3/7 Intracranial calcification ? ? ? 1/5 0/3 2/7 *Only one live born case (Neu et al9) died at 49 days.