No abstract

Unknown syndrome: Hirschsprung's disease, microcephaly, and iris coloboma: a new syndrome of defective neuronal migration SUMMARY We describe three children with Hirschsprung's disease and microcephaly, two of whom also have an iris coloboma. Two of the children, one with a coloboma and one without, are from the same consanguineous pedigree. The third case is unrelated and was identified by the matching program of the London Dysmorphology Database. ' This is the first report of this combination of features which are considered to be secondary to defective neuronal migration. An autosomal recessive mode of inheritance is proposed. Case reports CASE 1 This male child was born to a consanguineous couple originally from Pakistan. The pedigree is shown in fig 1. The other affected member is case 2 in this report. Case I was the first child of the parents and was born by normal delivery at 39 weeks' gestation. Labour was induced because the ultrasound scan suggested intrauterine growth retardation. At birth, his weight was 2-25 kg (3rd centile) but his head circumference at 30 cm was 3 cm less than the II III IV I 1 2-Casel FIG 1 Pedigree to show the relationship of case 1 to case 2.

An apparently autosomal recessive syndrome of congenital renal tubular dysplasia and skull ossification defects is described in five infants from two separate, consanguineous, Pakistani Muslim kindreds. The clinical, pathological, and radiological features are similar to the phenotype associated with fetal exposure to angiotensin converting enzyme (ACE) inhibitors: intrauterine growth retardation, skull ossification defects, and fetal/ neonatal anuric renal failure associated with renal tubular dysplasia. There was no fetal exposure to ACE inhibitors in the affected infants. Phenotypic similarities between these familial cases and those associated with ACE inhibition suggest an abnormality of the "renin-angiotensinaldosterone" system (RAS). It is postulated that the molecular pathology in this uncommon autosomal recessive proximal renal tubular dysgenesis could be related to mutations of the gene systems governing the RAS.

Grebe syndrome is a rare autosomal recessive acromesomelic dysplasia. The syndrome was studied clinically, radiographically, and genetically in an Omani family with four affected children. The affected persons had normal axial skeletons, severely shortened, and deformed limbs with severity increasing in a proximo-distal gradient, and subluxated joints. The humeri and femora were hypoplastic with distal malformations. The radii/ulnae were shortened and deformed whereas carpal bones were invariably rudimentary or absent. The tibiae appeared rudimentary; fibulae were absent in two children, and some tarsal and metatarsal bones were absent. The proximal and middle phalanges were absent while the distal phalanges were present. The father and mother had short first metacarpal and middle phalynx of the fifth finger and hallux valgus respectively. Transition A1137G and deletion delG1144 mutations in the gene encoding the cartilage-derived morphogenetic protein-1 (CDMP-1) were identified in this family. The A1137G is a silent mutation coding for lysine, whereas the delG1144 predicts a frameshift mutation resulting in a presumable loss of the CDMP-1 biologically active carboxy-terminal domain. The affected siblings were homozygous for the delG1144 mutation while parents were heterozygous.