Short-Rib Thoracic Dysplasia 14 With Polydactyly

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-14 with polydactyly (SRTD14) is caused by homozygous mutation in the KIAA0586 gene (610178) on chromosome 14q23.

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).

For a discussion of genetic heterogeneity of short-rib thoracic dysplasia with or without polydactyly, see SRTD1 (208500).

Clinical Features

Alby et al. (2015) described 4 unrelated families with a lethal ciliopathy syndrome. In a consanguineous Lebanese family, the mother had 4 spontaneous abortions before 10 weeks' gestation, followed by a female infant born at term who died a few hours after birth. A subsequent pregnancy miscarried at 15 weeks, and examination of the fetus revealed severe hydrocephaly, cleft palate, postaxial polydactyly of all 4 limbs, right diaphragmatic hernia, and absence of clavicle bones; information about other skeletal abnormalities was not available. Another pregnancy was terminated at 15 weeks' gestation; prenatal ultrasound showed hydrops, and the fetus had hydrocephaly with occipital bone defect, cleft palate, preaxial polydactyly of all 4 limbs with polysyndactyly of the hands, and flat and wide iliac wings. In a Romanian family, in which the parents were distantly related, a first child was born healthy. However, the second pregnancy was terminated at 29 weeks' gestation after fetal ultrasound revealed hydramnios, micromelia, short ribs, small thorax, and hydrocephaly with vermis hypoplasia and agenesis of corpus callosum. Macroscopic examination showed cleft palate with multiple frenula and tongue hamartomas, narrow thorax with lung hypoplasia, preaxial polysyndactyly of the feet, and postaxial polydactyly of the hands. Neuropathologic examination showed olfactory bulb agenesis, vermian hypoplasia, and prerolandic polymicrogyria. A similarly affected third infant died 1 hour after birth. In a Hungarian family, an anencephalic fetus spontaneously aborted before 10 weeks' gestation. Their second child was a girl who required ventilatory support from birth and died at age 13 months. She had a small and narrow chest, short arms and legs, postaxial polydactyly of the hands, and duplication of the left hallux. Dysmorphic features included dysplastic and low-set ears, depressed nasal bridge, short upper lip that was bound down by multiple small frenula, hypoplastic gums, and short neck. She was unresponsive to visual stimuli and had small optic disc and retinal coloboma bilaterally. There was no response to acoustic stimuli and brainstem auditory evoked potential test showed no recognizable waves. She exhibited generalized hypotonia, lack of spontaneous movements, and reduced deep tendon reflexes. Brain MRI at 6 months showed a small brain with large ventricles and subarachnoid spaces, reduced white matter, cerebellar and medullary hypoplasia, large fourth ventricle, and the molar tooth sign on axial slices. X-rays showed narrow, elongated thorax with short ribs and short long bones. In a family from Kosovo, 2 affected males were born to distantly related parents. One patient died 1 day after birth, with a phenotype said to be identical to that of his brother. The second pregnancy was terminated at 26 weeks' gestation, and autopsy showed cleft palate, lingual hamartomas, occipital keyhole defect, narrow thorax with lung hypoplasia, postaxial polydactyly and brachyphalangy of the hands, preaxial polydactyly of the right foot, postaxial polydactyly of the left foot, and micropenis. X-rays revealed short ribs and micromelia, with round femoral ends and curved forearm bones. Neuropathologic examination showed corpus callosum agenesis with Probst bundles, vermis hypoplasia with the molar tooth sign, temporal polymicrogyria, and retinal coloboma.

Molecular Genetics

In a consanguineous Lebanese family in which 2 fetuses exhibited features similar to those of hydrolethalus syndrome (see 236680), including severe hydrocephaly, polydactyly, and skeletal abnormalities, Alby et al. (2015) sequenced the HYLS1 (610693) and KIF7 (611254) genes but found no mutations. Next-generation sequencing targeting 1,221 candidate ciliary genes identified homozygosity for a nonsense mutation in the KIAA0586 gene (S77X; 610178.0006) that segregated with disease and was not found in 300 Lebanese control chromosomes or in the dbSNP, Exome Variant Server, or ExAC databases. Additional next-generation sequencing of ciliary genes in 150 individuals with lethal ciliopathies and various combinations of brain and skeletal abnormalities identified 3 patients from 3 unrelated Eastern European families with cerebral anomalies, polydactyly, and long-bone shortening, including short ribs, who were all homozygous for the same splice variant in KIAA0586 (610178.0007). Haplotype analysis in the Romanian, Hungarian, and Kosovan families was consistent with a common ancestor, estimated to have lived 16 generations (480 years) earlier.