Goldberg-Shprintzen Syndrome

A number sign (#) is used with this entry because of evidence that Goldberg-Shprintzen syndrome (GOSHS) is caused by homozygous mutation in the KIAA1279 (609367) gene on chromosome 10q21.1.

Description

Goldberg-Shprintzen syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by intellectual disability, microcephaly, and dysmorphic facial features. Most patients also have Hirschsprung disease and/or gyral abnormalities of the brain, consistent with defects in migration of neural crest cells and neurons. Other features, such as megalocornea or urogenital anomalies, may also be present. Goldberg-Shprintzen syndrome has some resemblance to Mowat-Wilson syndrome (MOWS; 235730) but is genetically distinct (summary by Drevillon et al., 2013).

Yomo et al. (1991) referred to this disorder as Goldberg-Shprintzen syndrome, which should not be confused with Shprintzen-Goldberg craniosynostosis syndrome (182212) or 2 other Shprintzen syndromes (192430, 182210).

Clinical Features

Goldberg and Shprintzen (1981) described a brother and sister with Hirschsprung megacolon, microcephaly, hypertelorism, submucous cleft palate, short stature, and learning problems. Hurst et al. (1988) described a consanguineous Pakistani pedigree in which 2 boys (cases 1 and 2) in separate sibships had Hirschsprung disease and microcephaly. One had iris coloboma and the other did not. One of the patients with Hirschsprung disease, microcephaly, and iris coloboma (case 3) described by Hurst et al. (1988) may have had Mowat-Wilson syndrome rather than Goldberg-Shprintzen syndrome. Halal and Morel (1990) reported a single case.

Yomo et al. (1991) described brother and sister with Hirschsprung disease, hypotonia, and ptosis, which they suggested might represent the same disorder as that reported by Goldberg and Shprintzen (1981).

Silengo et al. (2003) reported an Italian infant with GOSHS. Megacolon was suspected in the perinatal period, and surgery and histologic analysis confirmed short-segment Hirschsprung disease. The patient had mild but progressive microcephaly (-2 SD) and dysmorphic facial features, including sloping forehead, hypertelorism, sparse eyebrows, depressed nasal bridge, bulbous nose, and full lips. Other features included pale optic discs with poor fixation and abnormal EEG. Brain MRI showed pachygyria, hypoplasia of the corpus callosum, and cerebellar hypoplasia. She showed severely delayed psychomotor development at age 4 months. Silengo et al. (2003) postulated a defect in neuronal crest cell migration as well as in neuronal migration.

Brooks et al. (2005) described a family with Hirschsprung disease as a variable feature and bilateral generalized polymicrogyria malformation of the cerebral cortex characterized by an increased number of smaller convolutions or gyri and disruption of the normal 6-layered cerebral cortical structure as a constant feature. The diagnosis for this family was considered to be GOSHS, although bilateral generalized polymicrogyria had apparently not been reported as part of the syndrome.

Murphy et al. (2006) described 2 brothers from a nonconsanguineous family with classic features of Goldberg-Shprintzen syndrome, including Hirschsprung disease with microcephaly, developmental delay, and characteristic facies. Previously undescribed findings in the brothers were foot anomalies, including camptodactyly and clinodactyly of the second to fourth toes.

Drevillon et al. (2013) reported 5 patients from 3 unrelated consanguineous families with GOSHS. The families were of Moroccan, French, and Iraqi origin. All patients had moderate to severe psychomotor retardation, microcephaly, poor or absent language development, and hypotonia. Four patients had Hirschsprung disease, and 1 had constipation. Dysmorphic facial features included sparse hair, arched eyebrows, long eyelashes, ptosis, downslanting palpebral fissures, prominent ears, thick earlobes, prominent nasal bridge, thick philtrum, everted lower lip, and pointed chin. Variable brain anomalies, such as polymicrogyria, gyral anomalies, corpus callosum hypoplasia, and enlargement of the subarachnoid space, were also present. Additional developmental anomalies were inconsistently observed; these included congenital heart disease (2 patients), urogenital abnormalities (2 patients), oligodontia (1 patient), and scoliosis (1 patient). Drevillon et al. (2013) concluded that the phenotype results from defects in development of both the enteric and central nervous systems.

Clinical Variability

Valence et al. (2013) reported 2 fetuses, offspring of consanguineous Pakistani parents, who were found on prenatal ultrasound to have ventriculomegaly, microcephaly, abnormal cortical folding, hypoplastic brainstem, and hypoplastic corpus callosum. One fetus had dysmorphic facial features. Postmortem examination of 1 fetus excluded Hirschsprung disease; postmortem examination was not performed in the other fetus. A combination of linkage analysis and whole-exome sequencing identified a homozygous truncating mutation in the KIAA1279 gene (609367.0005) that segregated with the disorder in the family. Valence et al. (2013) noted that Hirschsprung disease is a variable feature of GOSHS and that polymicrogyria is a consistent finding in this disorder. The report expanded the phenotypic spectrum associated with KIAA1279 mutations, and Valence et al. (2013) suggested that the presence of polymicrogyria, microcephaly, and hypoplastic corpus callosum should suggest the clinical diagnosis of GOSHS, even in the absence of other cardinal signs of the disorder.

Inheritance

The Goldberg-Shprintzen megacolon syndrome appears to be inherited as an autosomal recessive trait, as indicated by the occurrence of the disease in consanguineous pedigrees and in affected sibs with unaffected parents (Hurst et al., 1988; Brooks et al., 1999).

Mapping

In the large consanguineous Moroccan family reported by Brooks et al. (1999), Brooks et al. (2005) performed a genome screen and identified by homozygosity mapping a novel locus at 10q21.3-q22.1.

Molecular Genetics

In affected members of 2 families segregating Goldberg-Shprintzen syndrome, the Moroccan family previously reported by Brooks et al. (1999) and a British Pakistani family, Brooks et al. (2005) identified homozygous nonsense mutations in the KIAA1279 gene (609367.0001-609367.0002). The finding established the importance of KIAA1279 in both enteric and central nervous system development.

In 5 patients from 3 unrelated consanguineous families with GOSHS, Drevillon et al. (2013) identified homozygous truncating mutations in the KIAA1279 gene (609367.0001; 609367.0003-609367.0004), consistent with a loss of function. In vitro cellular studies showed that KIAA1279 normally interacts with actin and microtubules, suggesting a role in neuronal development and migration.