A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-15 with polydactyly (SRTD15) is caused by compound heterozygous mutation in the DYNC2LI1 gene (617083) on chromosome 2p21.

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).

SRTD15 is characterized by narrow thorax, oral and cardiovascular anomalies, short long bones, and postaxial polydactyly, in addition to other congenital anomalies. Considerable variability in features and in severity has been reported, with some affected individuals succumbing shortly after birth and others living to adulthood, even within the same family.

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

Taylor et al. (2015) studied 3 fetuses from 3 unrelated Caucasian families that were identified by prenatal ultrasound, with elective terminations performed at 14, 19, and 22 weeks, respectively. Prenatal ultrasound findings included shortened long bones, diminished chest circumference for gestational age, and polydactyly. No other obvious organ system anomalies were detected. Radiography showed polydactyly of the upper and lower extremities, a long narrow thorax with very short horizontal ribs, lack of ossification of some skeletal elements, and irregular metaphyseal borders with lateral spikes. Taylor et al. (2015) noted that these findings were similar to those observed in cases of SRTD due to mutation in the DYNC2H1 gene (603297; SRTD3, 613091) or WDR34 gene (613363; SRTD11, 615633).

Kessler et al. (2015) reported a family in which 3 sibs had polyhydramnios, narrow thorax, postaxial hexadactyly, and facial dysmorphism. The first affected sib was a female infant who exhibited agenesis of the epiglottis, postaxial hexadactyly of the hands and right foot, hypoplastic nails, atrioventricular septal defect, and hepatosplenomegaly. Distinctive facial features included epicanthal folds and downslanting palpebral fissures, low-set ears, medial cleft lip, asymmetric tongue, and hyperplastic gingivae. She also had a hypoplastic thorax causing respiratory distress, and she died 2 days after birth. After the next 3 pregnancies ended as missed abortions, a second affected girl was born, who showed similar facial features as well as hypoplastic epiglottis, postaxial hexadactyly of the left hand, and brachydactyly. She also had a narrow thorax and respiratory distress syndrome, but recovered after 2 months; she survived to adulthood and gave birth to an unaffected son. The third affected sib was a fetus terminated at 19 weeks' gestation, after postaxial hexadactyly and pronounced narrow thorax were noted; the fetus also exhibited medial cleft lip. The mother's next pregnancy resulted in an unaffected boy. Radiography of the first 2 affected sibs revealed cone-shaped epiphyses of the phalangeal bones, metaphyseal dysplasia, and narrow thorax with short ribs. Kessler et al. (2015) stated that the affected sibs' phenotypes were classified between EVC and Jeune syndrome.

Niceta et al. (2018) reevaluated 2 Italian sisters, originally reported by Digilio et al. (1997), who had short-limbed skeletal dysplasia, oral anomalies, and postaxial polydactyly. One sister also had an atrioventricular canal defect, and the other exhibited hydrometrocolpos and vaginal atresia, suggesting phenotypic overlap of EVC and Kaufman-McKusick syndrome (MKKS; 236700); however, Digilio et al. (2004) excluded linkage in the 2 sisters to the chromosomal regions where EVC and MKKS had been mapped. Niceta et al. (2018) reported that the sisters were then 42 years and 31 years old, and that an affected second cousin once removed had been identified. The older sister (SC742D1) had postaxial polydactyly of the hands and left foot, brachydactyly, nail dysplasia, narrow thorax, midline cleft of upper lip, oral frenula, and absence of 2 lower molars; hydrometrocolpos had been corrected shortly after birth. The younger sister (SC741D1) showed signs of skeletal dysplasia, including elongated and narrow thorax, short ribs, high and short clavicles, congenital spinal canal stenosis with short pedicles, wedging of thoracolumbar vertebral bodies, and bilateral postaxial polydactyly of hands and feet; in addition, she had midline notch of the upper lip, oral frenula, and absence of 1 molar, as well as partial atrioventricular canal defect that had been surgically corrected. She was in good health except for spinal problems, with multiple disc herniations and mild scoliosis, and she had given birth to a healthy child. The 4-year-old male relative (BL1304-12) showed macrocephaly, central cleft lip, gingival frenula, hypodontia, narrow elongated thorax, mesomelic shortening of limbs, postaxial polydactyly of both hands, complete cutaneous syndactyly between the second and third toes, nail dysplasia, and horseshoe kidneys. The stature of all 3 affected individuals was within the 25th to 50th centiles.

Niceta et al. (2018) reported a brother (MGM03-0553) and sister (MGM03-0552), aged 23 and 16 years, respectively, who had short ribs, narrow thorax, bilateral polydactyly of the hands and feet, and short limbs, with stature in the 25th to 50th centiles. The brother had supernumerary teeth and oral frenula, whereas his sister had midline cleft lip and hypodontia; both exhibited cardiac defects, with aortic coarctation in the brother and patent ductus arteriosus in the sister. Niceta et al. (2018) also reported a female infant (MGM14-1183) with short limbs, bilateral postaxial polydactyly of all extremities, severely narrowed thorax, and hypoplastic left ventricle who died in the first month of life due to cardiorespiratory problems.

Bryson et al. (2021) reported a 3-year-old girl with SRTD and congenital short gut. At birth, she was noted to have 4-limb postaxial polydactyly, short limbs, and a long narrow chest. Within 24 hours, she developed bilious vomiting and was found to have duodenal malrotation. At laparotomy, short small bowel was observed, measuring 45 cm from pylorus to ileocecal valve, with a normal colon. Skeletal survey at age 4 months revealed frontal bossing, small thorax with shortened horizontal ribs, horizontal acetabular roofs, flaring of iliac wings, and narrow sacroiliac notches with spikes. Postaxial polydactyly was accompanied by clefting of the fifth right metatarsal and ossified proximal bony phalanges of the fifth and sixth digits. At 39 months of age, she had significant short stature and low weight for age, and was gradually being weaned off parenteral nutrition, tolerating approximately one-third of her calories as an oral diet with enteral feeding via gastrostomy tube.

In 3 fetuses from 3 unrelated families with SRTD, Taylor et al. (2015) performed exome sequencing and identified compound heterozygosity for missense, nonsense, and splice site mutations in the DYNC2LI1 gene (617083.0001-617083.0005) that segregated with disease in the 2 families for which parental DNA was available.

By whole-exome sequencing in 1 of 3 sibs with SRTD, Kessler et al. (2015) identified compound heterozygosity for a nonsense (R208X; 617083.0006) and a missense (T221I; 617083.0007) mutation in the DYNC2LI1 gene. The missense mutation was present in heterozygosity in the unaffected mother, brother, and son of the patient; DNA from her healthy father and the 2 other affected sibs was unavailable. Neither mutation was present in 858 control chromosomes or in the ExAC database.

Niceta et al. (2018) studied a cohort of 25 unrelated patients with features consistent with or suggestive of EVC, who were negative for mutation in the EVC (604831), EVC2 (607261), and WDR35 (613602) genes. Whole-exome sequencing in a 4-year-old male proband (BL1304-12) revealed compound heterozygosity for mutations in the DYNC2LI1 gene, including the previously reported T211I missense mutation and a M1? mutation (617083.0008). His affected second cousins once removed, the 2 Italian sisters who had originally been reported by Digilio et al. (1997), were also compound heterozygous for the mutations, neither of which was found in approximately 800 in-house population-matched exomes. Screening of the remaining 24 patients for mutations in DYNC2LI1 and 67 other EVC candidate genes revealed 2 sibs (MGM03-0553 and MGM03-0552) who were compound heterozygous for T221I and a nonsense mutation (V141X; 617083.0009), and a female infant (MGM14-1183) who died in the first month of life and who was compound heterozygous for a frameshift (617083.0010) and a splice site (617083.0011) mutation. Niceta et al. (2018) concluded that DYNC2LI1 mutations are associated with a wide clinical spectrum, and suggested that the severity of the phenotype might depend on the extent of defective DYNC2LI1 function.

In a 3-year-old girl with SRTD and congenital short gut, who was negative for mutation in 22 skeletal ciliopathy-associated genes, Bryson et al. (2021) performed whole-genome sequencing and identified compound heterozygosity for a previously reported missense mutation in the DYNC1LI1 gene (L117V; 617083.0001) and a frameshift mutation (617083.0012). Familial segregation was not reported.