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.

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).

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.

Yoshikawa et al. (2017) reported 2 Japanese girls with Sensenbrenner syndrome and mutation in the WDR19 gene. Both girls had growth failure, dolichocephaly, retinal dystrophy, narrow thorax, brachydactyly, psychomotor retardation, and hyperechogenic kidneys with poor corticomedullary differentiation. They exhibited severe hypertension in the neonatal period, and both progressed to end-stage renal disease within the first year of life. In patient 1, the kidneys were normal-sized with several small cysts, and renal biopsy showed findings consistent with infantile nephronophthisis, including glomerular cysts, dilation of tubules, tubulointerstitial fibrosis, and partially attenuated tubular basement membrane in nondilated tubules. In patient 2, the kidneys were enlarged with diffuse microcysts, and renal histology showed lobar disorganization with poor differentiation of normal nephron structures. Immunohistochemistry suggested poor differentiation of the metanephric mesenchyme for proximal tubules, and the histopathologic diagnosis was dysplastic kidney with diffuse glomerular cysts. Patient 1 received peritoneal dialysis, whereas patient 2 underwent renal transplantation at age 3 years. Additional findings in the patients included subdural hygroma, hydrocephalus, pancreatic cysts, and dilation of the intrahepatic bile ducts; patient 2 also exhibited polydactyly of the toes. The authors noted the different histopathologic findings between the 2 girls, and stated that patient 2 was the first reported patient to show dysplastic kidney caused by mutation in WDR19.

The transmission pattern of CED4 in the family reported by Bredrup et al. (2011) was consistent with autosomal recessive inheritance.

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.

In 2 unrelated Japanese girls with Sensenbrenner syndrome, Yoshikawa et al. (2017) performed next-generation sequencing and identified compound heterozygosity for mutations in the WDR19 gene. Both carried the recurrent R1178Q variant (608151.0010) on one allele, with patient 1 carrying a 1-bp deletion (608151.0016) and patient 2 carrying a splice site mutation (608151.0017) on the second allele. Sanger sequencing confirmed the mutations and their segregation with disease in both families. Noting that patient 2 exhibited dysplastic kidneys rather than the typical nephronophthisis histopathology, the authors suggested that WDR19-associated renal phenotypes may be more diverse than previously reported.