Goldberg-Shprintzen syndrome (GOSHS) is a rare autosomal recessive disorder characterized by microcephaly with polymicrogyria, mental retardation, Hirschprung's disease, and distinctive dysmorphic features, as yet incompletely delineated. In 2005 Brooks demonstrated by homozygosity mapping a novel locus at 10q21.3-q22.1 and found homozygous nonsense mutations in KIAA1279 at 10q22.1 encoding a highly conserved protein expressed in the central and peripheral nervous system (Am J Hum Genet 77:120-126). We report a consanguineous Pakistani family with GOSHS. Their first male child had a VSD, “meconium plug syndrome,” microcephaly, and severe feeding problems. He developed intractable diarrhea in Pakistan and died at 3 months of age, without autopsy. The second child had a generous cisterna magna noted on prenatal ultrasonography. At birth her head circumference was < 3%. She failed to pass meconium and rectal biopsy confirmed long segment Hirschprung's disease. MRI revealed abnormal gyral patterning and hypoplasia of the corpus callosum. She has moderate developmental delay. Distinctive features include arched eyebrows, prominent nasal tip, micrognathia, and long fingers and toes. During the mother's third pregnancy, molecular analysis in the Netherlands of KIAA1279 in the child and both parents revealed a homozygous deletion of exons 5 and 6 in the child, carried in heterozygous form by each parent. This permitted prenatal diagnosis in the United States. DNA was isolated and subjected to PCR amplification of six polymorphic STR loci. Amplicons from maternal peripheral blood and amniocytes were sized by capillary electrophoresis and compared, ruling out maternal cell contamination. PCR analysis indicated that exons 5 and 6 were present from at least one KIAA1279 allele, predicting a normal result. A phenotypically normal boy has since been born. This is the first prenatal diagnosis of GOSHS to our knowledge. This family is unusual in that the mechanism of GOSHS is deletion, not mutation, which may account for the somewhat more severe phenotype compared with some of the cases reported in the literature. GOSHS is a rare disorder, but we suspect it is underdiagnosed as its dysmorphic features may be difficult to recognize or Hirschprung's disease may obscure the overall clinical picture.
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