Short-Rib Thoracic Dysplasia 20 With Polydactyly

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-20 with polydactyly (SRTD20) is caused by compound heterozygous mutation in the INTU gene (610621) on chromosome 4q28. One such patient has been reported.

Digenic inheritance has been reported in 1 patient.

Description

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).

Clinical Features

Toriyama et al. (2016) studied 2 patients with SRPS phenotypes, who both died in the neonatal period. The first was a female infant (R09-459A) born at 30 weeks' gestation with multiple congenital anomalies, including wide-open anterior-to-posterior fontanel, low-set small dysplastic ears, microphthalmia, cleft lip and palate, tongue hamartomas, natal teeth, esophageal diverticulum, short neck with hypoplastic larynx and trachea, hypoplastic lungs, atrioventricular canal, tetralogy of Fallot, uterine didelphys with double vagina, and imperforate anus. Radiographic analysis showed multiple skeletal anomalies, including short horizontal ribs, shortened long bones with smooth edges, and pre- and postaxial polydactyly. The second patient was a male infant (R04-176A) born at 35 weeks' gestation with open anterior fontanel, significant brachycephaly with frontal bossing, very low posterior hairline, low-set malformed ears, hypertelorism, absent nasal bridge, absent vermilion of upper lip, significant micrognathia, constricted chest and lungs, imperforate anus, and superiorly placed micropenis. Radiographs showed skeletal anomalies similar to those of the female infant, and the male infant also exhibited pre- and postaxial polydactyly. The authors stated that the most striking similarity between the 2 patients was the severity of polydactyly, noting that most SRPS patients have 6 or 7 digits per extremity, whereas both infants had 9 or 10.

Molecular Genetics

Toriyama et al. (2016) examined the exomes of individuals diagnosed with SRPS and identified a female infant (R09-459A) who was compound heterozygous for mutations in the INTU gene: a truncating mutation (E355X; 610621.0001) and a missense mutation (E500A; 610621.0002). In addition, they identified a male infant (R04-176A) who showed apparent digenic inheritance, exhibiting double heterozygosity for a truncating mutation in the INTU gene (Q276X; 610621.0003), inherited from his unaffected father, and a missense mutation in the WDR35 gene (W311L; 613602.0013), inherited from his unaffected mother.