Multinucleated Neurons, Anhydramnios, Renal Dysplasia, Cerebellar Hypoplasia, And Hydranencephaly

A number sign (#) is used with this entry because of evidence that multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly (MARCH) is caused by homozygous mutation in the CEP55 gene (610000) on chromosome 10q23.

Description

MARCH is an autosomal recessive lethal congenital disorder characterized by severe hydranencephaly with almost complete absence of the cerebral hemispheres, which are replaced by fluid, relative preservation of the posterior fossa structures, and renal dysplasia or agenesis. Affected fetuses either die in utero or shortly after birth, and show arthrogryposis and features consistent with anhydramnios. Histologic examination of residual brain tissue shows multinucleated neurons resulting from impaired cytokinesis (summary by Frosk et al., 2017).

Clinical Features

Strauss et al. (1984) reported a male stillborn infant with severe hydranencephaly and complete absence of the telencephalon, optic vesicle, tissues of the eyes, and olfactory bulb. The adrenal glands were hypoplastic, and there was bilateral renal, ureteral, and bladder agenesis.

Bendon et al. (1987) described 2 male infant sibs (family A) with a syndrome of multiple congenital anomalies, namely, hydranencephaly with multinucleated neurons, hypoplastic kidneys, and syndactyly of the second and third toes. In both sibs the cranial cavity was filled with fluid, with a rudimentary brain weighing only 14 or 15 grams present at the base of the skull. (The mean normal weight of the brain at 35 weeks of gestation is 280 grams.)

Gschwendtner et al. (1997) reported a female fetus aborted at 20 weeks' gestation due to anhydramnios, hydranencephaly, and dysplastic kidneys. Brain remnants showed multinucleated neurons.

Chu et al. (1998) reported 3 sibs, born of unrelated Hispanic parents, who were found to have hydranencephaly with small or absent kidneys and bladder on prenatal ultrasound. The pregnancies were complicated by oligohydramnios. One fetus had Potter facies, and 2 had pulmonary hypoplasia, arthrogryposis, and syndactyly of the toes. Fragments of brain tissue were nearly devoid of cerebral cortex and white matter, and binucleated neurons were found in nearly all gray matter regions. Chu et al. (1998) postulated that altered neuronal cytokinesis may be responsible for the abnormalities.

Bondeson et al. (2017) reported 2 Swedish fetuses with multiple anomalies on prenatal ultrasound, resulting in premature termination or intrauterine fetal death. They had fluid-filled skulls with absence of normal brain structures, cystic hygroma, clubfeet, and enlarged cystic kidneys. The authors suggested that the phenotype was reminiscent of Meckel syndrome (see, e.g., MKS1, 249000), but neither fetus had polydactyly.

Frosk et al. (2017) reported 3 sibs, born of Dutch-German Mennonites, with a pre- or perinatal lethal disorder: 2 were stillborn at 30 and 32 weeks' gestation, and 1 died within minutes of birth at 35 weeks' gestation. The pregnancies were complicated by anhydramnios or oligohydramnios, and the patients showed evidence of Potter sequence, including microretrognathia, limb contractures, single transverse palmar creases, fifth finger clinodactyly, talipes equinovarus, and pulmonary hypoplasia. Additional dysmorphic features included pinched nose with bulbous tip, choanal narrowing, redundant neck skin, cystic hygroma, broad hands with a short fifth digit, and toe syndactyly. Two infants with full autopsies had dysplastic aortic valves, dilated left ventricles, ureteral agenesis, and only vestigial remnants of renal tissue with a few glomeruli. All had a normal head size, but with severe hydranencephaly with almost complete absence of the cerebral cortex. There was hypoplasia of other neural tissues, such as cerebellum, brainstem, and basal portions of the temporal and frontal lobes. Microscopic examination showed disorganization of the temporal cortex, and about 5 to 10% of neurons and glial cells were multinucleated. Frosk et al. (2017) noted the phenotypic similarity to the patients reported by Strauss et al. (1984), Bendon et al. (1987), Gschwendtner et al. (1997), Chu et al. (1998), and possibly 2 patients reported by Hamby et al. (1950).

Inheritance

The transmission pattern of MARCH in the family reported by Frosk et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 male sibs, conceived of Mennonite parents, with MARCH, Frosk et al. (2017) identified a homozygous truncating mutation in the CEP55 gene (S425X; 610000.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the S425X mutant protein did not localize properly to the midbody on the intracellular bridge between 2 daughter cells during cytokinesis, consistent with a loss of function. In addition, the mutation was unable to rescue the abnormal jaw phenotype of zebrafish with knockdown of the CEP55 ortholog, indicating that the S425X mutant is functionally null. Haplotype analysis was consistent with a founder effect. Frosk et al. (2017) concluded that failed cytokinesis likely plays a role in the pathogenesis of this disorder, but also suggested a role for impaired signaling in the PI3K (see 601232)/AKT (see 164730) signaling pathway.

In 2 Swedish brothers with a phenotype consistent with MARCH, Bondeson et al. (2017) identified a homozygous nonsense mutation in the CEP55 gene (R86X; 610000.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; haplotype analysis suggested a founder effect. Degraded intestinal tissue from 1 of the fetuses appeared to show a lack of immunoreactivity for CEP55, suggesting a loss-of-function effect. Bondeson et al. (2017) concluded that the phenotype was consistent with an autosomal recessive lethal ciliopathy.

Animal Model

Frosk et al. (2017) found that morpholino or CRISR/Cas9-mediated disruption of the CEP55 ortholog in zebrafish embryos resulted in craniofacial abnormalities, micrognathia, cerebellar hypoplasia, and renal tubular atrophy. The changes were associated with increased apoptosis.