Webb-Dattani Syndrome

A number sign (#) is used with this entry because of evidence that Webb-Dattani syndrome (WEDAS) is caused by homozygous mutation in the ARNT2 gene (606036) on chromosome 15q25. One such family has been reported.

Description

Webb-Dattani syndrome is an autosomal recessive disorder characterized by frontotemporal hypoplasia, globally delayed development, and pituitary and hypothalamic insufficiency due to hypoplastic development of these brain regions. Patients present soon after birth with multiple pituitary hormonal deficiencies and subsequently develop microcephaly, seizures, and spasticity. Other features include postretinal blindness and renal abnormalities (summary by Webb et al., 2013).

Clinical Features

Webb et al. (2013) reported 6 children from a highly consanguineous Saudi Arabian kindred with a congenital brain malformation syndrome and other abnormalities. Features that became apparent in the first month of life included hypernatremia due to diabetes insipidus, central hypothyroidism due to thyroid-stimulating hormone deficiency, growth failure due to growth hormone deficiency, and adrenocorticotropic deficiency. None of the patients had hypoglycemia. Brain MRI showed an abnormal hypothalamo-pituitary axis with absent posterior pituitary bright spot, thin pituitary stalk, and hypoplastic anterior pituitary gland. The frontal and temporal lobes were hypoplastic, with a thin corpus callosum and global delay in brain myelination, particularly in the motor and occipital cortices. All children developed secondary microcephaly, severe global developmental delay, and seizures within the first year of life. Patients had total body spastic cerebral palsy, with abnormal hip posture and hip dislocation in 4. In addition, all patients showed no clinical response to light, with minimal pupil responses. Funduscopic and retinal examinations were normal, but 2 children showed evidence of postretinal pathway dysfunction. Other features included severe gastroesophageal reflux, hydronephrosis, vesicoureteral reflux, and a neurogenic bladder. Renal glomerular function was normal. All affected individuals had dysmorphic features, including prominent forehead, deep-set eyes, well-grooved philtrum, and retrognathia. Three patients died before 5 years of age. There was a history of multiple miscarriages in 1 branch of the family, suggestive of a degree of prenatal lethality.

Inheritance

The transmission pattern of Webb-Dattani syndrome in the family reported by Webb et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 children, born of consanguineous Saudi Arabian parents, with Webb-Dattani syndrome, Webb et al. (2013) identified a homozygous truncating mutation in the ARNT2 gene (606036.0001). The mutation was found by a combination of homozygosity mapping and whole-exome sequencing. Analysis of patient cells indicated that the mutation resulted in nonsense-mediated mRNA and complete loss of ARNT2 function.