J Med Genet 1999;36:481–484 481 Two sibs with microcephaly, hygroma colli, renal dysplasia, and cutaneous syndactyly: a new lethal J Med Genet: first published as 10.1136/jmg.36.6.481 on 1 June 1999. Downloaded from MCA syndrome? HCJPJanssen, C Schaap, N Vandevijver, P Moerman, CEMdeDie-Smulders, J-P Fryns Abstract of this couple resulted at 38 weeks’ gestation in We report two sibs of Turkish descent with a dysmature but healthy girl. The second preg- multiple congenital anomalies including nancy is reported below as case 1. The third severe microcephaly, hygroma colli, cystic pregnancy ended at 27 2/7 weeks with a renal dysplasia, and bilateral cutaneous caesarean section because of maternal pre- syndactyly of toes IV-V. In addition, the eclampsia and fetal bradycardia. A dysmature/ second sib presented with bilateral fusion immature girl was born, who died 14 days later of the eyelids, a bicornuate uterus, and of complications related to prematurity (necro- clitoromegaly. The parents are first cous- tising enterocolitis). The fourth pregnancy is ins, which suggests autosomal recessive presented below as case 2. inheritance. In reviewing previously pub- lished reports, several cases were found with cerebral, renal, and digital anomalies CASE 1 as the main features. Several of the One day before delivery the mother reported additional symptoms present in the sec- absent fetal movements. Ultrasound examina- ond sib were suggestive of Fraser syn- tion showed oligohydramnios and fetal death. drome, but the severe microcephaly in Spontaneous labour ensued and a stillborn girl both sibs is unusual. The diVerential diag- was delivered at 29 5/7 weeks’ gestation. Birth nosis is discussed, including the possi- weight was 1050 g (50th centile), crown-rump bility of an entirely new entity in the broad length was 23 cm (3rd centile), and head spectrum of syndromes with cerebral, circumference was 21 cm (3 cm below the 3rd renal, and digital anomalies. centile). Examination showed a macerated (J Med Genet 1999;36:481–484) female fetus with severe microcephaly and a sloping forehead (fig 1). Hypertelorism, up- Keywords: lethal MCA syndrome; microcephaly; cystic ward slanting palpebral fissures, a broad nose renal dysplasia; cutaneous syndactyly with a depressed bridge, micrognathia, and a http://jmg.bmj.com/ high arched palate were present. The ears were normally implanted, but had an abnormal In the past, several syndromes have been appearance partly because of oedema of the described with cystic renal dysplasia and helices. The neck was short and a large anteri- cerebral and digital malformations as the main orly placed hygroma colli was present. In gen- features.12 In most of them the expression is eral there was diVuse hirsutism and cutis laxa, highly variable, resulting in a significant overlap Department of the latter probably related to the oligohydram- between the diVerent phenotypes. In this on October 2, 2021 by guest. Protected copyright. Molecular Cell Biology nios. Limb anomalies included joint contrac- and Genetics, report we present two sibs with severe micro- tures of the elbows, ulnar deviation of the University of Limburg, cephaly, hygroma colli, cystic renal dysplasia, hands, and bilaterally broad, low set thumbs. PO Box 1475, 6201 BL cutaneous syndactyly, and an oligohydramnios Maastricht, The Dermatoglyphics were atypical. There was tal- sequence. In one of them, additional abnor- Netherlands ipes equinovarus on the right side and bilateral, malities of the internal female genitalia and HCJPJanssen nearly complete cutaneous syndactyly of toes C Schaap fused eyelids were present. Despite a thorough IV-V. CEMdeDie-Smulders review of published reports, a satisfactory diag- nosis could not be made. Fusion of the eyelids, On the back there was a sacral dimple, but x Department of cutaneous syndactyly, abnormalities of the ray showed no vertebral defects. The genitalia Pathology, University were normal female. At necropsy, both kidneys Hospital Maastricht, internal genitalia, and cystic renal dysplasia initially suggested Fraser syndrome.3 However, were small and cystic. Microscopically multiple The Netherlands cysts, rare intact glomeruli, and primitive N Vandevijver severe microcephaly in Fraser syndrome is very P Moerman uncommon and it seems most appropriate to tubules with peritubular concentric fibrosis consider these two sibs as representing a new were seen. There was no metaplastic cartilage. Centre for Human entity in the spectrum of syndromes with The ureters were filiform, but the bladder Genetics, University cerebral, renal, and digital anomalies. appeared normal. The lungs were hypoplastic. Hospital Leuven, The liver and spleen were congested with foci Belgium of extramedullary haematopoesis. There was J-P Fryns Case reports no congenital hepatic fibrosis. Macroscopic Correspondence to: We report on two children of a consanguineous examination of the brain showed no structural Dr de Die-Smulders. Turkish couple (first cousins). Both parents are abnormalities. Unfortunately, microscopy was healthy and, more specifically, ultrasound not performed. Microbiological examination of Received 9 April 1998 Revised version accepted for examination of the kidneys in both parents the lungs, spleen, and liver showed excessive publication 22 October 1998 showed no abnormalities. The first pregnancy growth of E coli and Enterococcus faecalis. Chro- 482 Janssen, Schaap, Vandevijver, et al J Med Genet: first published as 10.1136/jmg.36.6.481 on 1 June 1999. Downloaded from Figure 3 Symmetrically enlarged kidneys with multicystic renal dysplasia. sloping forehead, hypertelorism with a broad, flat nose, a long philtrum, micrognathia, and relative macrostomia with macroglossia were present. The ears appeared large and were oedematous. There was bilateral fusion of the eyelids. The neck was short with a large Figure 1 (A) Full body view of sib 1: note the severe microcephaly, hygroma colli, contractures of the elbows, ulnar deviation of the hands, and talipes equinovarus. (B) Detail circumferential hygroma colli. The palate was of sib 1: severe microcephaly with sloping forehead, hygroma colli, and abnormal ears. closed. Both hands showed a simian crease, camptodactyly of digits II and III, and a short mosomal analysis of cultured skin fibroblasts fifth digit with only two phalanges. Both feet showed a normal 46,XX karyotype. had almost complete cutaneous syndactyly of toes II-III and IV-V and partial cutaneous syn- CASE 2 dactyly of toes III-IV. There were contractures During the fourth pregnancy, a structural of all the large joints, which was probably ultrasound at 20 weeks’ gestation again showed related to the anhydramnios. Genitalia were anhydramnios, microcephaly, and multicystic female with a large clitoris; the anus was open kidneys. The pregnancy was terminated at 20 and normally positioned. 6/7 weeks and a female fetus was delivered with Necropsy showed that the eyeballs were of a striking resemblance to case 1 (fig 2). Birth normal size and microscopically normal. Both weight was 210 g (below the 3rd centile), kidneys (weight 2.3 g) were symmetrically crown-rump length was 19 cm (50th centile), enlarged and showed multicystic renal dyspla- and head circumference was 15 cm (2 cm sia (fig 3). The bladder was hypoplastic. The below the 3rd centile). Microcephaly with a lungs (weight 2 g) were extremely hypoplastic, http://jmg.bmj.com/ but had normal lobulation. There was no laryngeal atresia. The heart displayed a situs solitus with a patent oval foramen, endocardial fibrosis of the right ventricle with a stenotic, dysplastic pulmonary valve, and a dysplastic aortic valve. There was no hepatic fibrosis. The brain weight was 5.5 g (normal weight for 21 weeks is 48 g). Microscopy of the brain showed on October 2, 2021 by guest. Protected copyright. normal development of the cortex, basal ganglia, ventricles, and cerebellum. There was a bicornuate uterus. The umbilical cord contained three vessels and was normally inserted. Chromosomal analysis on cultured skin fibroblasts showed a normal 46,XX karyotype and metabolic investigation to ex- clude Smith-Lemli-Opitz syndrome showed a normal 7- and 8-dehydrocholesterol and chol- esterol concentration in the umbilical cord plasma. Discussion We report on two sibs with multiple congenital anomalies including severe microcephaly, hy- groma colli, nearly complete cutaneous syn- dactyly of toes IV-V, and renal dysplasia. In addition, the second sib showed bilateral fusion of the eyelids, dysplastic valves of the aorta and pulmonary artery, a bicornuate uterus, and clitoromegaly. It is questionable whether fusion Figure 2 Full body view of sib 2 showing severe microcephaly, hygroma colli, hypertelorism, and fused of the eyelids, as present in the second sib, is a eyelids. true abnormality or related to gestational age. A new lethal MCA syndrome? 483 Table 1 Syndromes with cerebral, renal, and digital malformations as the main features This This J Med Genet: first published as 10.1136/jmg.36.6.481 on 1 June 1999. Downloaded from Smith-Lemli-Opitz Cerebro-reno-digital report, report, Fraser type II Winter-Tsukuhara spectrum1 sib 1 sib 2 Craniofacial anomalies Microcephaly ± ++±++ ++ Pachygyria − − + ± −− Cryptophthalmos + −−−−± Ptosis of eyelids − +−−−− Cleft palate + +−+−− High arched palate ± +−−+− Abnormal nose + ++−++ Abnormal ears + − + ± +− Micrognathia ±± − ± ++ Hands Skin syndactyly + −+−−− Camptodactyly − −+−−+ Polydactyly (postaxial) − +−+−− Oedema−−+−++ Contractures − −−−++ Low set thumb