Short-Rib Thoracic Dysplasia 12

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

Beemer et al. (1983) reported a 'new' short rib syndrome in 2 unrelated infants who died shortly after birth. Features were hydrops, ascites, median cleft of the upper lip, narrow chest and short, bowed limbs. Evidence of autosomal recessive inheritance was occurrence in both sexes, consanguineous parents in 1 case, and a second affected sib in 1 case.

Passarge (1983) observed 2 brothers with a pattern of malformations similar to that reported by Beemer et al. (1983). Despite the absence of polydactyly, the question of whether this was the Majewski syndrome (see SRTD6, 263520) was raised. One brother had renal and pancreatic dysplasia as in Majewski syndrome. Winter (1988) also described a female infant with radiologic features of a lethal short rib syndrome but no polydactyly.

Balci et al. (1991) reported the disorder in Turkish brother and sister with affected first-cousin parents. Two earlier-born male infants had died 1 hour after birth with the same clinical appearance. Indeed, the third pregnancy ended in stillbirth of a female; in the fourth pregnancy, abnormality of the fetus, including fetal ascites and shortened lower limbs and narrow thorax, was identified, leading to termination at 24 weeks. Yang et al. (1991) reported the case of a male fetus aborted at 30 weeks' gestation because of abnormalities visualized on sonography. This was the first instance of polydactyly associated with this syndrome. Yang et al. (1991) pointed out that polydactyly must be rare in the Beemer type of short rib syndrome, whereas it is common in the Saldino-Noonan and the Verma-Naumoff types (see SRTD3, 613091) and a consistent feature in the Majewski type. Autosomal recessive inheritance was supported by the fact that the parents of one of the original cases were consanguineous and a subsequent sib was similarly affected (Beemer et al., 1983).

Lin et al. (1991) pointed out that the oral manifestations resemble those of an orofaciodigital syndrome with median cleft lip and accessory frenulum. Hennekam (1991) reported 2 affected female sibs, 1 having preaxial polydactyly of the feet. He stated that differentiation from the short rib syndrome of Majewski relies mainly on the radiologic appearance of the tibia.

Beighton et al. (1992) provided a new classification of the short rib syndromes designating the Beemer-Langer form as type IV. Referring to this as type IV short-rib syndrome, Cideciyan et al. (1993) reported the case of an infant who died of respiratory insufficiency during the first day of life. Findings evident on physical examination included bilateral anophthalmia, midline cleft lip and palate, bilateral single transverse palmar creases, and single umbilical artery. The external genitalia were normal female in type with a 46,XY karyotype. Autopsy showed pulmonary hypoplasia, bilateral renal cystic dysplasia, intrahepatic bile duct cysts with periportal fibrosis, pancreatic cysts, absent internal genitalia, and intracranial malformations.

The absence of polydactyly was originally considered one of the main discriminating factors between Beemer-Langer syndrome and Majewski syndrome. Lurie (1994) analyzed 6 reported cases of Beemer-Langer syndrome in sibs, in which at least 1 infant had classic manifestations (i.e., without polydactyly). Three of the 6 affected sibs had preaxial polydactyly. Two sibs with Beemer-Langer syndrome reported by Tsai et al. (1994) did not have polydactyly. Lurie (1994) therefore concluded that absence of this feature cannot be used to distinguish the 2 syndromes. Lurie (1994) showed a high frequency of brain defects (16 of 26 cases) and oral abnormalities, including cleft tongue, natal teeth, and oral frenula, (13 of 29 cases) in Beemer-Langer syndrome.

Elcioglu et al. (1996) described premature female twin fetuses concordantly affected with very short ribs, short limbs, macrocephaly, median cleft upper lip, and facial dysmorphism. Based on radiologic criteria and the pattern of associated abnormalities, the diagnosis of lethal short rib-polydactyly syndrome (Beemer-Langer type) was made. The twins were diamniotic and shared a single placenta. The parents were healthy but consanguineous. One twin died at day 10 as a consequence of respiratory distress; the second died 24 hours after birth of the same cause. Elcioglu et al. (1996) concluded that the disorder in these twins could be differentiated from the Saldino-Noonan and Verma-Naumoff types of SRPS by the absence of metaphyseal irregularity and spiking. The Majewski type was ruled out by the absence of hypoplastic, oval-shaped tibiae.

Kovacs et al. (2006) identified 9 patients with SRPS type IV from 7 different Hungarian Roma families. Each case was lethal, with death at 1 to 45 days after delivery. All had hypoplastic thorax, short limbs, short tubular bones, frontal bossing, non-ovoid and longer tibia than fibula, and smooth metaphyses, consistent with SRPS type IV. Most had polydactyly, syndactyly, and brain defects. Kovacs et al. (2006) noted that the Roma subpopulation is a geographically isolated community and estimated the annual incidence of SRPS type IV in this community at about 1 in 2,000 births.

Molecular Genetics

Exclusion Studies

In 7 patients with a clinical diagnosis of short rib-polydactyly syndrome type IV, El Hokayem et al. (2012) excluded mutations in the NEK1 (604588) and DYNC2H1 (603297) genes.