Microcephaly, Facial Dysmorphism, Renal Agenesis, And Ambiguous Genitalia Syndrome

A number sign (#) is used with this entry because of evidence that microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG) is caused by homozygous mutation in the CTU2 gene (617057) on chromosome 16q24.

Description

MFRG is an autosomal recessive syndrome in which microcephaly, unilateral renal agenesis, ambiguous genitalia, and facial dysmorphisms, including severe micrognathia, are observed in most patients. Variable brain, cardiac, and skeletal anomalies are present, including corpus callosum agenesis or dysgenesis, lissencephaly, atrial and ventricular septal defects, patent ductus arteriosus, hypoplastic right ventricle, and joint contractures (Shaheen et al., 2016).

Clinical Features

From a cohort of 31 consanguineous Saudi families with apparently novel dysmorphic syndromes, Shaheen et al. (2016) identified 3 probands with similar features who were homozygous for the same mutation in the CTU2 gene. In the first family (family 13), the stillborn proband (patient 14DG0993) and his deceased brother and sister exhibited intrauterine growth retardation (IUGR), severe primary microcephaly with agenesis of the corpus callosum, micrognathia, unilateral renal agenesis, congenital heart disease, and abnormal genitalia. In the second family (family 14), the proband (14DG1883) had IUGR with severe microcephaly, micrognathia, and hypoplastic maxilla, as well as hypoplastic right ventricle, unilateral left renal agenesis, and ambiguous genitalia. He died at 1 month of age from sepsis. In the third family (family 15), the deceased male proband (12DG0529) exhibited microcephaly, micrognathia, and retrognathia, and brain MRI showed lissencephaly, diffuse white matter hyperintensity, hypoplasia of the corpus callosum, and prominent subarachnoid spaces and ventricular system. Skeletal anomalies included 13 ribs on the left side and 11 on the right, and preaxial polydactyly of the right hand; he also had unilateral left renal agenesis and ambiguous genitalia. An older deceased brother was reported to have been similarly affected, with lissencephaly, crossed fused ectopic left kidney, ambiguous genitalia, and polydactyly.

Shaheen et al. (2016) ascertained 2 male cousins with MFRG, aged 4 and 17 months, from a consanguineous family from the United Arab Emirates. One cousin had an older sister with severe microcephaly who died at age 2 years. Both cousins developed joint contractures, and 1 exhibited postaxial polydactyly of the feet. The 4-month-old boy was hypotonic and was tube fed due to lack of suck/swallow reflex. The 17-month-old boy was in a long-term facility on ventilatory support and feeding by gastrostomy tube, and had shown no developmental progress. The authors designated the syndrome 'DREAM-PL,' for dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly.

Mapping

In affected individuals from 3 consanguineous Saudi families (families 13, 14, and 15) with microcephaly, facial dysmorphism, renal agenesis, ambiguous genitalia, and other congenital anomalies, Shaheen et al. (2016) found a single autozygous shared region (chr16:88,155,503-89,588,896; GRCh37) for which they obtained a lod score of 4.5.

Molecular Genetics

From a cohort of 31 consanguineous Saudi families with apparently novel dysmorphic syndromes, Shaheen et al. (2016) identified 3 probands (families 13, 14, and 15) with microcephaly, facial dysmorphism, renal dysgenesis, ambiguous genitalia, and other congenital anomalies who were all homozygous for a synonymous variant in the CTU2 gene (T247T; 617057.0001). RT-PCR revealed that the mutation impairs normal splicing, causing a frameshift resulting in a premature termination codon.

In 2 male cousins from the United Arab Emirates with MFRG, Shaheen et al. (2016) performed targeted mutation analysis and identified the previously detected T247T CTU2 mutation on the same haplotypic background. The authors stated that the carrier frequency of this founder mutation was 1 in 769 individuals in Saudi Arabia, and noted that the apparently synonymous nature of the causal variant might play a role in underdiagnosis of this syndrome.