The diagnostic criteria for short rib-polydactyly type II (Majewski syndrome) include short and narrow thorax, horizontally oriented ribs, short tubular bones with smooth ends, ovoid tibiae that are shorter than the fibulae or tibial agenesis, and pre- and/or ... The diagnostic criteria for short rib-polydactyly type II (Majewski syndrome) include short and narrow thorax, horizontally oriented ribs, short tubular bones with smooth ends, ovoid tibiae that are shorter than the fibulae or tibial agenesis, and pre- and/or postaxial polysyndactyly (summary by El Hokayem et al., 2012). The short rib-polydactyly syndromes (SRPSs) are a group of autosomal recessive lethal skeletal dysplasias characterized by markedly short ribs, short limbs, polydactyly, and multiple anomalies of major organs, including heart, intestines, genitalia, kidney, liver, and pancreas. Five types have been distinguished: SRPS I (Saldino-Noonan type; 263530), SRPS II (Majewski type), SRPS III (Verma-Naumoff type; 263510), SRPS IV (Beemer-Langer type; 269860), and SRPS V (614091). - Genetic Heterogeneity of Short Rib Polydactyly Type II Another form of short rib-polydactyly syndrome type II (Majewski syndrome), here designated IIB (615087), is caused by mutation in the DYNC2H1 (603297) gene on chromosome 11q13. There is also evidence that short rib-polydactyly type II can be caused by digenic biallelic mutation in the NEK1 and DYNC2H1 genes.
Majewski et al. (1971) reported 4 personal cases of SRPS and 32 nearly identical or similar cases from the literature. Death occurred perinatally in all. Malformations included median cleft lip, pre- and postaxial polysyndactyly, short ribs and limbs, ... Majewski et al. (1971) reported 4 personal cases of SRPS and 32 nearly identical or similar cases from the literature. Death occurred perinatally in all. Malformations included median cleft lip, pre- and postaxial polysyndactyly, short ribs and limbs, genital abnormalities, and anomalies of epiglottis and viscera. Meckel syndrome (249000), Smith-Lemli-Opitz syndrome (270400), OFD syndrome (311200), Mohr syndrome (252100), Jeune syndrome (208500), and Ellis-van Creveld syndrome (225500) share some of these features but are distinguishable. Spranger et al. (1974) reported a patient whose sib may have died of the same condition. Polycystic kidneys occur with this condition as well as with Meckel syndrome. Spranger et al. (1974) referred to this condition as short-rib polydactyly (SRP) syndrome. The most distinctive finding in the Majewski 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 (Spranger et al., 1974). Motegi et al. (1979) appear to have reported the first instance of the confirmed 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 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 SRPS, Majewski type, 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 OFD II or 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. Martinez-Frias et al. (1993) described 2 patients, from unrelated Spanish families, with SRPS associated with anencephaly and other central nervous system anomalies. Both patients presented clinical and radiologic characteristics that overlapped those of the different established types of SRPS. Although these 2 patients could be considered to have a new type of SRPS, Martinez-Frias et al. (1993) believed that they represented a severe expression of SRPS. In 1 family, 2 affected brothers had different clinical and radiologic findings, illustrating intrafamilial variability within SRPS. Given the extensive overlap in all published cases of lethal SRPS, Martinez-Frias et al. (1993) suggested that all cases constitute variability of a single entity. Thiel et al. (2011) investigated 3 probands 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. Thiel et al. (2011) noted that in accordance with the classification of SRPS type II, 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.
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 and 4 due to mutations in the DYNC2H1 gene; in ... 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 and 4 due to mutations in the DYNC2H1 gene; 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.
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 ... 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 short rib-polydactyly syndrome 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 SRPS IIB, 615087); in the remaining 3 cases of SRPS type II, no mutations were found in either gene, suggesting further genetic heterogeneity.