Short-Rib Thoracic Dysplasia 6 With Or Without Polydactyly

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-6 with or without polydactyly (SRTD6) is caused by homozygous mutation in the NEK1 gene (604588) on chromosome 4q33.

There is also evidence that SRTD can be caused by digenic biallelic mutation in the NEK1 and DYNC2H1 (603297) genes.

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, see SRTD1 (208500).

Clinical Features

Majewski et al. (1971) reported 4 cases with a syndrome characterized by short ribs and limbs, median cleft lip, pre- and postaxial polysyndactyly, genital abnormalities, and anomalies of epiglottis and viscera. Death occurred perinatally in all. Majewski et al. (1971) identified 32 nearly identical or similar cases from the literature.

Spranger et al. (1974) reported a similar patient (case 1) whose sib may have died of the same condition, which they referred to as Majewski type short rib-polydactyly (SRP) syndrome. They noted that polycystic kidneys occur with this condition as well as with Meckel syndrome (249000). Spranger et al. (1974) stated that the most distinctive finding in the Majewski type of SRP syndrome is disproportionate shortening of the tibia. The radiologic appearance of the pelvis is normal and the metaphyseal margins of the tubular bones are regular.

Motegi et al. (1979) appear to have reported the first confirmed instance of Majewski syndrome in sibs (2 brothers).

Chen et al. (1980) reported a case with consanguineous parents. Microscopically, cartilage showed markedly stunted and disorganized endochondral ossification. Extraskeletal manifestations were hydrops, cleft lip, malformed larynx with hypoplastic epiglottis, pulmonary hypoplasia, glomerular and renal tubular cysts, ambiguous genitalia, pachygyria, and small cerebellar vermis.

Cooper and Hall (1982) reported 3 cases and compared them with 5 other fully documented cases. Two were sibs and 2 previously born children in this family had been affected also; all 4 were male. One case was the offspring of first-cousin Pakistani parents. The authors knew of other cases of the Majewski type of SRPS in Pakistani immigrant families in England. Central harelip and cleft palate were consistent features. The striking oval configuration of the tibias was noted.

Silengo et al. (1987) presented 2 patients who they suggested lent support to the idea that the Mohr (252100) and the Majewski syndromes are mild and severe expressions, respectively, of the same autosomal recessive disorder. The 2 patients had features typical of Mohr syndrome but, in addition, had laryngeal anomalies and hallucal and postaxial polysyndactyly of the feet typical of Majewski syndrome. In the latter condition, the oral/facial findings are almost identical to those of the Mohr syndrome. Franceschini et al. (1995) reported on a patient with manifestations typical of Mohr syndrome and of the short rib-polydactyly syndromes. Neri et al. (1995) suggested that this group of disorders, which they referred to as oral-facial-skeletal syndromes, may turn out to be a family of disorders such as the achondroplasia/craniosynostosis syndromes which had shortly before been traced to mutations in the fibroblast growth factor receptor genes and the achondrogenesis/SED congenita/Stickler complex due to mutation in collagen type II and XI genes.

Thiel et al. (2011) investigated 3 probands, including 2 fetuses and an infant who died 1 hour after birth, with SRPS type II (Majewski) from 3 independent families: 2 consanguineous families of Turkish and Bedouin origin, respectively, and 1 nonconsanguineous family of German origin. All affected individuals had a narrow thorax with hypoplastic lungs, extreme polysyndactyly, disproportionate dwarfism, and median cleft lip and palate. One presented with a ventriculoseptal defect and cystic kidneys. The radiographic hallmarks of all probands included shortened and horizontal ribs, squared scapulae and elevated clavicles with lateral kinking, normal spine and pelvis configuration, and shortening of the bones of all 4 extremities, with extreme reduction of tibial bone length.

Clinical Variability

McInerney-Leo et al. (2015) reported a 3-year-old girl from the British Isles (patient SKDP-126.3) who exhibited short stature, hyperopia, microform cleft lip, pectus carinatum, narrow thorax with bifurcated ribs, mesomelic shortening of the limbs with significantly short tibiae, brachydactyly, and hypermobile joints. The child also showed gross motor and speech delays, and had macrocephaly that was believed to be secondary to hydrocephalus. She had no renal or cardiac anomalies. The tentative diagnosis was Jeune asphyxiating thoracic dystrophy versus Sensenbrenner syndrome.

Wang et al. (2017) reported a 12.5-year-old Caucasian boy who was considered healthy until age 7 years, when his vision deteriorated abruptly and he was diagnosed with hyperopia, astigmatism, and neuroretinal degeneration. Electroretinography (ERG) at age 11 years showed severe generalized retinal dystrophy. Skeletal dysplasia was diagnosed at age 8 years, when narrow thorax and hyperflexible finger joints were observed. Skeletal survey revealed narrow thorax with short ribs, mild platyspondyly with rounded vertebral bodies, underdeveloped lower pelvis, sclerotic proximal femoral metaphyses and mild metaphyseal broadening of the distal femora and proximal tibia. Echocardiography showed mild insufficiency of bicuspid and tricuspid valves. Laboratory tests including hepatic and renal evaluation were normal. The patient was given a clinical diagnosis of axial spondylometaphyseal dysplasia.

Cytogenetics

Urioste et al. (1994) described an apparently balanced pericentric inversion of chromosome 4 in a newborn infant with clinical and radiologic manifestations of a short rib-polydactyly syndrome. Central cleft upper lip and hamartomatous lesions of the tongue as well as the polydactyly were illustrated. Some manifestations were those of the Majewski type of SRPS, whereas others were those of the Beemer-Langer type (269860). The full clinical pattern was difficult to fit into any of the specific types of SRPS; the clinical findings underscored the considerable overlap of the several types. The mother, who was asymptomatic, had the same (or seemingly same) pericentric inversion of one chromosome 4. Maternal features included complete situs inversus, an anomaly that has been described in the Saldino-Noonan, Verma-Naumoff, and Beemer-Langer types of SRPS, but apparently not in the Majewski type. Urioste et al. (1994) raised the question of whether a gene for SRPS is located at either 4q13 or 4p16, the location of the breakpoints in creation of the pericentric inversion. They suspected 4q13, rather than 4p16, because rearrangements on 4p16 have been described rather frequently and the manifestations have been of a type not shared by the patient they described. In a later note, Urioste et al. (1994) raised the question of the syndrome being due to disruption of a gene in the 4p16 region where achondroplasia, hypochondroplasia, thanatophoric dysplasia, and Ellis-van Creveld syndrome map.

Mapping

By genomewide linkage and homozygosity mapping in 2 consanguineous families segregating SRPS type II, Thiel et al. (2011) mapped the disorder to chromosome 4q32.1-q34.3 (maximum hlod of 2.95).

Molecular Genetics

Thiel et al. (2011) considered the NEK1 gene, located within the SRPS type II locus region, as a likely candidate for the disorder because mutant mice homozygous for the orthologous gene show polycystic kidney disease, craniofacial anomalies, and growth reduction. By sequencing of the NEK1 gene in the probands from 2 consanguineous families, they identified homozygosity for different mutations in each (604588.0001-604588.0002). In the proband from a nonconsanguineous family, they identified heterozygosity for an insertion mutation in the NEK1 gene (604588.0003) and heterozygosity for a missense mutation in the DYNC2H1 gene (603297.0016); no second mutation was found in either gene, and each parent was heterozygous for one of the mutations. Thiel et al. (2011) found that absence of functional full-length NEK1 severely reduces cilia number and alters cilia morphology in vivo.

El Hokayem et al. (2012) analyzed the NEK1 gene in 11 unrelated cases of SRPS type II, all of which were either terminated pregnancies or cases of neonatal death, and identified 4 homozygous mutations in 4 cases (see, e.g., 604588.0001 and 604588.0004). Compound heterozygous mutations in the DYNC2H1 gene (see, e.g., 603297.0017-603297.0020) were identified in 4 cases (see SRTD3; 613091); in the remaining 3 cases, no mutations were found in either gene, suggesting further genetic heterogeneity.

In a 3-year-old British girl with SRTD, McInerney-Leo et al. (2015) performed whole-exome sequencing and identified compound heterozygosity for mutations in the NEK1 gene: a splice site mutation (604588.0009) and a missense mutation (P172S; 604588.0010), neither of which was found in internal or public variant databases. Heterozygosity for a missense mutation in another SRTD-associated gene was also detected in this patient, an H297Q substitution in the WDR60 gene (615462), and the authors noted that this variant might modify the SRTD phenotype.

In a 12.5-year-old boy with severe retinal dystrophy, narrow thorax, short ribs, mild platyspondyly, and mild metaphyseal changes in the long bones, who had been clinically diagnosed with axial spondylometaphyseal dysplasia (see 602271) but was negative for mutation in the C21ORF2 gene (603191), Wang et al. (2017) performed whole-exome sequencing and identified compound heterozygosity for a nonsense mutation (S1036X; 604588.0011) and a missense mutation (D1277A; 604588.0012) in the NEK1 gene. The authors suggested that the phenotypic variability exhibited in this patient might be explained by the location of mutations on the NEK1 protein, since most of the previously reported mutations were located in the N terminus whereas this patient's mutations were in the C terminus.

Genotype/Phenotype Correlations

El Hokayem et al. (2012) reviewed the clinical features of 11 unrelated cases of SRPS type II, 4 of which were due to mutations in the NEK1 gene (SRTD6) and 4 due to mutations in the DYNC2H1 gene (SRTD3); in 3 cases, no mutation was detected in either gene. Lingual and gingival hamartoma were frequently observed in the mutation-positive group, present in 60% of NEK1 cases and in 25% of DYNC2H1 cases, but were absent from the mutation-negative group, whereas lobulated tongue was mostly observed in the mutation-negative group. Kidney cysts, intestinal malrotation, and heart defects were observed in both groups, but holoprosencephaly and polymicrogyria were observed only in the mutation-negative group.