Alternative titles; symbols
ORPHA: 474; DO: 0110089;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4p14 | Short-rib thoracic dysplasia 5 with or without polydactyly | 614376 | Autosomal recessive | 3 | WDR19 | 608151 |
A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-5 with or without polydactyly (SRTD5) is caused by homozygous or compound heterozygous mutation in the WDR19 gene (608151) on chromosome 4p14.
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013).
There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330).
For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
De Vries et al. (2010) described a 22-year-old Dutch woman with Jeune syndrome and mutation in the WDR19 gene, who was born to healthy, unrelated parents and had 1 healthy younger sib. At 1 year of age, she was evaluated for growth failure, abnormal chest shape, and short limbs. Skeletal radiographs showed a small, narrow thorax, brachydactyly of the fingers, short and broad diaphyses, wide metaphyses of the arms and legs, and short iliac bones with spiky protrusions. She had no history of respiratory difficulties, but was hospitalized at 3 years of age for a respiratory infection, at which time she was discovered to have elevated serum creatinine, proteinuria, and hypertension. At 4 years of age, she began peritoneal dialysis, and underwent renal transplantation at 5 years of age; rejection led to a second kidney transplant at 12 years of age. Histopathology of the native kidneys revealed that most glomeruli were totally sclerotic, and the remainder showed capillary collapse. Periglomerular fibrosis, tubular atrophy, and tubular dilation with interstitial lymphocyte infiltration were seen. At 22 years of age she was living independently, working as a nurse, and had mildly impaired exercise tolerance. Ophthalmoscopy showed cataracts, attenuated arteries, and macular abnormalities, which were under investigation. De Vries et al. (2010) studied 12 additional patients diagnosed with Jeune syndrome and noted that with age, the thoracic malformation in these patients tended to become less pronounced and respiratory problems decreased, and that the prognosis of ATD appeared to be better than previously described.
Montolio-Marzo et al. (2020) reported a 6-year-old Spanish boy with Mainzer-Saldino syndrome and mutation in the WDR19 gene. The proband exhibited trigonocephaly due to early closure of the metopic suture, growth retardation, dorsolumbar kyphoscoliosis, and cone-shaped phalangeal epiphyses. He developed early-onset progressive renal insufficiency, and ultrasound showed cystic nephropathy as well as dilated intrahepatic bile ducts. He required peritoneal dialysis from age 1 year, and underwent renal transplantation at age 2 years. In addition, he experienced night blindness and nystagmus by age 1 year, and ocular examination showed attenuated vessels and diffuse pigmentary changes in the peripheral retina. Autofluorescence imaging showed a bull's-eye pattern with increased signal surrounding the macula and central hypofluorescence, and mottled pattern in the peripheral retina. Optical coherence tomography showed an absence of outer retinal layers and thinning of the perimacular retina with central preservation.
Bredrup et al. (2011) analyzed the candidate gene WDR19 in 14 patients with Jeune syndrome. In a 22-year-old Dutch woman originally reported by de Vries et al. (2010), they identified homozygosity for a missense mutation in the WDR19 gene (L7P; 608151.0003). Her unaffected parents were heterozygous for the mutation, which was not detected in her unaffected sister.
In a 6-year-old Spanish boy with Mainzer-Saldino syndrome, who was negative for mutation in 10 NPHP-associated genes, Montolio-Marzo et al. (2020) analyzed 140 genes associated with cystic, glomerular, and congenital renal anomalies as well as urinary tract anomalies and identified compound heterozygosity for missense mutations in the WDR19 gene, H481R (608151.0018) and A914D (608151.0019). Sanger sequencing confirmed the mutations and their segregation with disease in the family.
Bredrup, C., Saunier, S., Oud, M. M., Fiskerstrand, T., Hoischen, A., Brackman, D., Leh, S. M., Midtbo, M., Filhol, E., Bole-Feysot, C., Nitschke, P., Gilissen, C., and 16 others. Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am. J. Hum. Genet. 89: 634-643, 2011. [PubMed: 22019273] [Full Text: https://doi.org/10.1016/j.ajhg.2011.10.001]
de Vries, J., Yntema, J. L., van Die, C. E., Crama, N., Cornelissen, E. A. M., Hamel, B. C. J. Jeune syndrome: description of 13 cases and a proposal for follow-up protocol. Europ. J. Pediat. 169: 77-88, 2010. [PubMed: 19430947] [Full Text: https://doi.org/10.1007/s00431-009-0991-3]
Huber, C., Cormier-Daire, V. Ciliary disorder of the skeleton. Am. J. Med. Genet. 160C: 165-174, 2012. [PubMed: 22791528] [Full Text: https://doi.org/10.1002/ajmg.c.31336]
Montolio-Marzo, S., Catala-Mora, J., Madrid-Aris, A., Armstrong, J., Diaz-Carcajosa, J., Carreras, E. IFT144 and mild retinitis pigmentosa in Mainzer-Saldino syndrome: a new association. Europ. J. Med. Genet. 63: 104073, 2020. [PubMed: 33002628] [Full Text: https://doi.org/10.1016/j.ejmg.2020.104073]
Schmidts, M., Vodopiutz, J., Christou-Savina, S., Cortes, C. R., McInerney-Leo, A. M., Emes, R. D., Arts, H. H., Tuysuz, B., D'Silva, J., Leo, P. J., Giles, T. C., Oud, M. M., and 23 others. Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy. Am. J. Hum. Genet. 93: 932-944, 2013. [PubMed: 24183451] [Full Text: https://doi.org/10.1016/j.ajhg.2013.10.003]