Cranioectodermal Dysplasia 4

A number sign (#) is used with this entry because of evidence that cranioectodermal dysplasia-4 (CED4) is caused by compound heterozygous mutation in the WDR19 gene (608151) on chromosome 4p14. One such family has been reported.

Description

Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a rare autosomal recessive heterogeneous ciliopathy that is primarily characterized by skeletal abnormalities, including craniosynostosis, narrow rib cage, short limbs, and brachydactyly, and ectodermal defects. Nephronophthisis leading to progressive renal failure, hepatic fibrosis, heart defects, and retinitis pigmentosa have also been described (summary by Arts et al., 2011).

For a discussion of genetic heterogeneity of cranioectodermal dysplasia, see CED1 (218330).

Clinical Features

Bredrup et al. (2011) described a 21-year-old Norwegian woman who was the second child of unrelated, healthy parents. At birth, she had developmental dysplasia of both hips and general hypotonia. At age 11 years, ophthalmoscopy revealed attenuated arteries and bone-spicule-shaped deposits in the periphery of the retina; electroretinogram (ERG) showed completely extinguished signals, indicative of tapetoretinal dystrophy. She had recurrent pneumonia and asthma, consistent with respiratory function tests that indicated reduced lung capacity. Short stature was treated with growth hormone therapy, after which her height attained the 10th centile. A renal ultrasound to investigate hypertension and a moderately increased serum creatinine revealed hyperechoic kidneys, and a biopsy showed nonspecific changes consistent with a nephronophthisis-like disease. The nephropathy progressed rapidly, and she underwent renal transplantation at 14 years of age. She also had idiopathic bone marrow hypoplasia. Her 16-year-old brother had developmental dysplasia of both hips and craniosynostosis of the sagittal suture. Routine ophthalmoscopy at 7 years of age revealed attenuated retinal vessels, and an ERG showed extinguished rod signals and severely reduced cone signals, consistent with a rod-cone dystrophy. Renal ultrasound showed hyperechoic kidneys, but there were no other signs of renal disease. Both sibs had multiple dental anomalies. A diagnosis of Sensenbrenner syndrome was made based on the combination of clinical findings in both sibs.

Molecular Genetics

In a sister and brother with clinical findings compatible with Sensenbrenner syndrome, from a Norwegian family in which haplotype analysis had excluded the 3 genes previously found to be mutated in Sensenbrenner syndrome, Bredrup et al. (2011) performed exome sequencing and identified variations in 7 candidate genes. Only 1 gene, WDR19 (608151), had variants that cosegregated with disease in the family: both affected sibs were compound heterozygous for a missense (L710S; 608151.0001) and a nonsense (R1103X; 608151.0002) mutation in WDR19. Each unaffected parent was heterozygous for 1 of the mutations, neither of which was found in 422 Norwegian controls.