Hydrocephalus, Congenital, 2, With Or Without Brain Or Eye Anomalies

A number sign (#) is used with this entry because of evidence that congenital hydrocephalus-2 with or without brain or eye anomalies (HYC2) is caused by homozygous mutation in the MPDZ gene (603785) on chromosome 9p23.

Description

Congenital hydrocephalus-2 is a congenital disorder with onset in utero. Affected individuals have hydrocephalus with variably dilated ventricles and variable neurologic sequelae. Some individuals have other brain abnormalities, including lissencephaly, thinning of the corpus callosum, and neuronal heterotopia. Most patients have delayed motor development and some have delayed intellectual development and/or seizures. Additional congenital features, including cardiac septal defects, iris coloboma, and nonspecific dysmorphic features, may be observed. Some patients die in utero, in infancy, or in early childhood, whereas others have long-term survival (summary by Shaheen et al., 2017).

For a discussion of genetic heterogeneity of congenital hydrocephalus, see 233600.

Clinical Features

Al-Dosari et al. (2013) reported a consanguineous Saudi Arabian family in which several individuals had congenital communicating hydrocephalus. A 27-year-old unaffected pregnant woman presented at 30 weeks' gestation when ultrasound of the fetus showed extreme hydrocephalus with callosal dysgenesis or agenesis and thinning of the cerebral cortex. The findings were confirmed after birth. The cerebral aqueduct was not dilated. The infant soon developed seizures. Ventriculoperitoneal shunt was placed at 25 days, and follow-up at age 10 months showed that she had started to roll over and babble. Family history of the mother was significant for 2 affected sibs who had mildly decreased IQ, 2 brothers who died as young children due to complications of hydrocephalus, 2 affected stillbirths in her mother, and 1 abortion in her mother possibly affected by history. In another unrelated Saudi family, a fetus was found to have hydrocephalus on ultrasound and was stillborn. That family history was significant for 2 abortions possibly affected. Simplified gyral pattern was a common associated brain malformation in all cases.

Shaheen et al. (2017) reported 3 unrelated consanguineous Saudi families (families 4, 5, and 24) in which several members had congenital hydrocephalus. Severe hydrocephalus and variable brain abnormalities were detected on prenatal ultrasound. Features included lissencephaly, abnormal gyration, colpocephaly, thinning or absence of the corpus callosum, small cerebellum, and Dandy-Walker malformation. At least 1 patient had seizures. Most patients had additional congenital anomalies, including 2-vessel cord, congenital cardiac septal defects, coloboma, and cleft lip and palate. Most of the patients died in utero or in infancy. These families were part of a genetic study of 27 consanguineous Saudi families with congenital hydrocephalus.

Shaheen et al. (2017) also reported 3 unrelated patients, of Palestinian, European, and Kuwaiti origin, with HYC2. A 2.5.-year-old girl was noted to have had mild hydrocephalus, polyhydramnios, and a 2-vessel cord on prenatal imaging. After birth, brain imaging showed dilated ventricles, subependymal gray matter heterotopia. She had additional congenital abnormalities, including atrial septal defect, right-sided congenital diaphragmatic hernia, and macular hypoplasia. She had delayed motor development, but fine motor skills and language were nearly normal. Dysmorphic features include frontal bossing, facial asymmetry, bulbous nose, persistent fetal pads, and striking creases over her knees. The second child was an 8-year-old boy with multiple congenital anomalies, including foveal dysplasia with thin inner retina, lung hypoplasia, aberrant subclavian artery, malrotation of the gut, and sensorineural hearing loss. Brain imaging at age 5.5 years showed small olfactory bulbs, mildly enlarged ventricles, and subependymal nodular gray matter heterotopia. Dysmorphic features included relative macrocephaly, full anterior fontanel, iris coloboma, downslanting palpebral fissures, posteriorly rotated ears, microretrognathia, small teeth, and joint hypermobility. However, aside from hypotonia and decreased reflexes, neurologic examination was reported as normal. The third patient was a 15-month old boy with relative macrocephaly, large anterior fontanel, iris coloboma, prominent optic nerve, hypotonia, and decreased reflexes. He also had cholestasis and liver failure associated with a mutation in the TJP2 gene (607709), which was thought to be unrelated to the neurologic phenotype.

Inheritance

The transmission pattern of congenital hydrocephalus in the families reported by Al-Dosari et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

By linkage analysis of a consanguineous Saudi family with congenital hydrocephalus, Al-Dosari et al. (2013) found linkage to a 7-Mb interval on chromosome 9p24.1-p22.3 (lod score of 3.5).

Molecular Genetics

In affected members of a consanguineous Saudi family with autosomal recessive hydrocephalus, Al-Dosari et al. (2013) identified a homozygous truncating mutation in the MPDZ gene (Q210X; 603785.0001). The same homozygous mutation was identified in another Saudi patient with the disorder who was stillborn. Haplotype analysis suggested a founder effect, and the mutation age was estimated at 380 years.

In affected members of 3 consanguineous Saudi families with HYC2, Shaheen et al. (2017) identified a homozygous Q210X mutation in the MPDZ gene, consistent with a founder effect in this population. The patients were part of a large genetic study of 27 consanguineous Saudi families with congenital hydrocephalus. Shaheen et al. (2017) identified biallelic mutations in the MPDZ gene (603785.0002-603785.0005) in 3 additional unrelated patients of various ethnic descent (Palestinian, European, and Kuwaiti) with HYC2. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed.