Short-Rib Thoracic Dysplasia 9 With Or Without Polydactyly

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-9 with or without polydactyly (SRTD9) is caused by homozygous or compound heterozygous mutation in the IFT140 gene (614620) on chromosome 16p13.

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

The association of renal dysplasia, retinal pigmentary dystrophy, cerebellar ataxia, and skeletal dysplasia was reported in 2 patients by Mainzer et al. (1970) and in 1 patient by Popovic-Rolovic et al. (1976). Robins et al. (1976) observed similar skeletal changes and hepatic fibrosis with renal dysplasia.

Giedion (1979) summarized the cases of 8 patients under the age of 11 years with chronic renal failure and phalangeal cone-shaped epiphyses of the hands, coining the term 'conorenal syndrome.' Half of Giedion's patients had retinitis pigmentosa and 25% had ataxia. Giedion (1979) reported nephronophthisis in his patients; however, neither biopsy material nor clinical course was available to confirm that diagnosis.

Mendley et al. (1995) extended the delineation of the conorenal syndrome to include renal histopathologic and clinical features of a primarily glomerular disorder. They reported 2 sibs, aged 7 and 19 years, with cone-shaped phalangeal epiphyses and renal disease that was different in nature and rate of progression from cases previously described: the clinical features of nephronophthisis (medullary cystic kidney disease) were absent and, while the younger sib had reached end-stage renal disease, the older sib's renal function was only modestly impaired and had remained nearly unchanged for several years. The brother and sister were of Mexican extraction. The 7-year-old sister had prominent cone-shaped epiphyses in the distal phalanges and cone-shaped epiphyses in the middle phalanges of the index and fifth fingers. The 19-year-old brother had very short distal phalanges, some of which appeared flexed, and the middle phalanges of the second and fifth digits were markedly short. Both parents were phenotypically normal; hand radiographs in the mother were normal without signs of cone-shaped epiphyses. Percutaneous renal biopsy showed global scarring and acellularity of many glomeruli in both sibs.

Beals and Weleber (2007) provided follow-up on one of the patients originally described by Giedion (1979). The patient was then 40 years old. He had been found to have severe bilateral renal disease consistent with chronic pyelonephritis at age 2 years. He subsequently underwent multiple renal transplants, one of which lasted for over 30 years, and at the time of report was on dialysis. He was noted to have cataracts and exotropia at age 5 years. Electroretinography (ERG) at age 12 demonstrated decreased scotopic (rod-mediated) and moderate depression of the photopic (cone-mediated) b-wave response, suggesting an atypical, nonpigmented, primary retinal degeneration. Cataracts, thought to be the result of chronic steroid treatment, were removed in his twenties. By age 38, ERG revealed further progression of retinal degeneration. Fundal examination at age 40 showed early bone-spicula pigment deposits. Review of radiographs performed in childhood revealed cone-shaped epiphyses in the proximal and middle phalanges of the hands and feet. Hand radiographs at age 37 demonstrated mild shortening and deformity of the middle phalanges without evidence of cone-shaped epiphyses. A healthy 9-year-old son of the patient had normal hand radiographs and no history of kidney disease.

Perrault et al. (2012) reported 15 families in which affected individuals presented with 3 diagnostic criteria of Mainzer-Saldino syndrome (MZSDS), including early-onset retinal dystrophy with visual impairment, phalangeal cone-shaped epiphyses, and renal disease. Two additional families had similar features, but without overt renal disease. Other variable features included nystagmus, short stature, metaphyseal defects, and flattened femoral epiphyses. A minority of patients had hepatic involvement with cholestasis and fibrosis. Renal disease included end-stage renal failure with hyperechoic kidneys, and loss of corticomedullary differentiation and tubulointerstitial lesions on histology. Two patients from 1 family had craniosynostosis. In addition, 2 unrelated patients had a short thorax with short ribs, reminiscent of asphyxiating thoracic dystrophy (ATD), and a third patient carried a clinical diagnosis of ATD. Cognition was intact, except in 2 consanguineous families, which may have been due to other causes.

Schmidts et al. (2013) studied 7 unrelated patients with biallelic mutations in the IFT140 gene (see MOLECULAR GENETICS), including 5 with a clinical diagnosis of ATD and 2 who had been diagnosed with MZSDS. All exhibited brachymesophalangism, cone-shaped epiphyses, and small thoraces, although only 2 patients had experienced respiratory insufficiency. None had polydactyly. Renal ultrasound revealed increased echogenicity in all 7 patients, and 3 patients had cystic kidney disease; all developed end-stage renal disease in childhood. Short stature was present in 6 patients, possibly secondary to renal insufficiency in childhood. Two patients had enlarged livers, 1 of which showed increased echogenicity. Funduscopy revealed retinal disease in 4 patients during early childhood and in 1 at age 17 years; the 2 patients who underwent ERG evaluation showed no responses. Psychomotor delay was also present in 2 patients.

Clinical Variability

Bayat et al. (2017) described a 6.5-year-old British boy with short stature, brachydactyly, and facial dysmorphism, who experienced chronic lung infections from infancy with a persistent oxygen requirement until age 5 years. Facial features included frontal bossing, bitemporal narrowing, tall forehead, upswept anterior hairline, hypertelorism, bilateral epicanthal folds, depressed nasal bridge, wide mouth, and macroglossia. Radiography of torso and limbs showed narrowing of the thorax and 'coat-hanger' clavicles, with V-shaped metaphyses and cone-shaped epiphyses of the phalanges and metacarpals. In addition, there was brachydactyly involving all 3 phalanges as well as metacarpals and metatarsals. By age 9 months, significant developmental delay was apparent. At age 15 months, nystagmus was noted, and examination revealed small optic discs with abnormal pigmentation surrounding the macula. Full-field ERGs showed markedly reduced rod and cone responses, and the patient was diagnosed with retinal dystrophy. At age 20 months, he developed end-stage renal failure and became dialysis-dependent; he received a kidney transplant at age 4 years. Nephronophthisis was excluded by renal biopsy. The authors noted that the proband also exhibited ectodermal features, including sparse scalp hair, eyebrows, and eyelashes, delayed tooth eruption with small and widely spaced teeth, and an umbilical hernia, and stated that his clinical presentation was more characteristic of Sensenbrenner syndrome (see 218330) than MZSDS or ATD.

Pena-Padilla et al. (2017) reported a Mexican male infant who exhibited trigonocephaly (see 211750) as well as manifestations of ciliopathy, including asymmetric short ribs, mild chest narrowing, trident acetabular roofs, postaxial polydactyly, cone-shaped epiphyses, and dysplasia of renal, hepatic, and pancreatic tissues. Dysmorphic features included large anterior fontanel, prominent metopic ridge, bitemporal narrowing, frontal cowlick, low-set posteriorly rotated ears, upslanting palpebral fissures, broad nasal bridge, simple philtrum, high-arched palate, wide and irregular alveolar ridges, multiple oral frenula, macrostomia, micrognathia, and short neck with loose skin. Additional features seen on x-ray included short or absent middle phalanges of fingers 2 to 5, short proximal phalanges and absent middle phalanges of toes 2 to 5, undermodeling of metatarsals, and absence of tarsal bones. Brain CT showed large ventricles and hypoplasia of the corpus callosum. The proband died at age 1 month from complications of severe pneumonia, seizures, urinary tract infection, and acute renal failure. Autopsy showed renal and pancreatic cysts, and congenital hepatic fibrosis and cholangitis. The authors suggested that this patient broadened the spectrum of Opitz trigonocephaly C syndrome with features of ciliary dysfunction.

Molecular Genetics

In 10 patients from 6 unrelated families with a clinical diagnosis of Mainzer-Saldino syndrome, Perrault et al. (2012) identified homozygous or compound heterozygous mutations in the IFT140 gene (see, e.g., 614620.0001-614620.0006). Mutations in the first patient were identified by ciliome sequencing and confirmed by Sanger sequencing. In addition, compound heterozygosity for mutations in IFT40 was identified in a patient with a clinical diagnosis of Jeune syndrome/ATD (614620.0002; 614620.0005). Heterozygous mutations in the IFT140 gene were found in 4 additional patients with the disorder; a second pathogenic mutation was not detected in these patients. Clinical features of patients with biallelic mutations did not differ significantly from those in whom a heterozygous mutation or no mutation in the IFT140 gene was detected. In vitro functional expression studies in retinal pigment epithelial cells demonstrated that missense mutant IFT140 proteins had partial to complete loss of basal body localization and an increase of cytoplasm staining. Fibroblasts from 2 unrelated patients showed absent cilia in a high proportion of cells compared to controls, indicating a defect in ciliogenesis and/or cilia maintenance. Although mutant IFT140 was localized along the cilia axoneme, there appeared to be a defect in retrograde ciliary transport with an abnormal distribution of other ciliary proteins. IFT140 mutations were not found in 6 families with a similar phenotype, suggesting genetic heterogeneity. The findings indicated that IFT140 has a pivotal role in proper development and function of ciliated cells, and confirmed that Mainzer-Saldino syndrome is a skeletal ciliopathy.

Using whole-exome sequencing, sequencing of a ciliopathy gene panel, and Sanger sequencing, Schmidts et al. (2013) screened 64 probands clinically diagnosed with Jeune syndrome/ATD and 2 with MZSDS. They identified biallelic causative mutations in the IFT140 gene in 6 patients, including both MZSDS patients (see, e.g., 614620.0002 and 614620.0008-614620.0010). Patients with biallelic mutations presented with renal disease in early childhood and showed notable retinal involvement, but had a nonlethal thorax-related clinical course.

In a 6.5-year-old British boy with short stature, short ribs and narrow thorax, retinal dystrophy, and end-stage renal failure, who also exhibited brachydactyly and ectodermal features and received a clinical diagnosis of Sensenbrenner syndrome, Bayat et al. (2017) identified compound heterozygosity for a missense (G212R; 614620.0005) and a nonsense (R760X; 614620.0016) mutation in the IFT140 gene.

In a Mexican male infant with trigonocephaly, short ribs and narrow chest, cone-shaped epiphyses, postaxial polydactyly, cystic renal and pancreatic disease, and hepatic fibrosis, who died at age 1 month with severe pneumonia and acute renal failure, Pena-Padilla et al. (2017) identified compound heterozygosity for a splice site mutation in the IFT140 gene and a 17-bp deletion encompassing the IFT140 start codon. His unaffected parents and an unaffected brother were each heterozygous for 1 of the mutations. The deletion was not found in public variant databases, whereas the splice site mutation was found at an allele frequency of 0.000008515 in the ExAC database.

In a 10-year-old boy with features of MZSDS, who exhibited retinal dystrophy, acute-onset renal failure, and skeletal anomalies including bilateral coxa vara, broad femoral necks with mild bowing of the femoral diaphyses, and brachydactyly with shortened metacarpals and cone-shaped phalangeal epiphyses, Helm et al. (2017) identified homozygosity for the G212R substitution in the IFT140 gene (614620.0005). His unaffected mother was heterozygous for the variant, but his father did not carry the mutation. Analysis of exome data indicated that the proband had chromosome 16 maternal heteroisodisomy, with segmental isodisomy at 16p13, suggesting that an early error in meiosis occurred in the maternal gamete.