Cerebrocostomandibular Syndrome

A number sign (#) is used with this entry because of evidence that cerebrocostomandibular syndrome (CCMS) is caused by heterozygous mutation in the SNRPB gene (182282) on chromosome 20p13.

Description

Cerebrocostomandibular syndrome (CCMS) is characterized mainly by severe micrognathia, rib defects, and mental retardation. A spectrum of rib gap defects have been reported ranging from a few dorsal rib segments to complete absence of ossification. In about half of the 65 reported cases to date, there is cerebral involvement including mental retardation, microcephaly, and histologic anomalies. Both autosomal dominant and autosomal recessive forms of the disorder have been described (Zeevaert et al., 2009).

See CDG2G (611209) for a cerebrocostomandibular-like syndrome.

Clinical Features

In a female and 2 male sibs, McNicholl et al. (1970) described a syndrome of mental retardation, palatal defects (short hard palate with central hole, absent soft palate, absent uvula), micrognathia, glossoptosis, and severe costovertebral abnormalities. A barking cough in one suggested tracheal cartilage abnormality as in the case of Smith et al. (1966) which bore other similarities.

In the family reported by McNicholl et al. (1970), the normal father and mother were 40 and 33, respectively, at the birth of the first affected child. The condition has also been designated 'rib gap defects with micrognathia' (Miller et al., 1972). The 'gaps' occur in the posterior portion of the ribs and may lead to 'flail chest.'

Silverman et al. (1980) gave an extensive review of 22 cases. They pointed out that familial cases are seemingly unusual and stated that 'the possibility exists that some teratogenic agent has played a role in the clustering of cases since 1963...' Cleft palate and glossoptosis often contribute to the presenting sign, neonatal respiratory distress. Intrauterine and postnatal growth retardation are common. Deficiency in the posterior portion of affected ribs by roentgenography is a sine qua non for diagnosis.

Leroy et al. (1981) provided the first evidence of dominant inheritance; a mother and her son and daughter (by different fathers) were affected. The 3 patients were intellectually normal, but indistinct speech was commented on. The authors suggested that mental defect may not be inherent to CCMS but rather a frequent consequence of neonatal respiratory distress.

Schroer and Meyer (1985) reported an isolated case in a 15-year-old girl. Hennekam et al. (1985) reported 2 affected brothers who also had spina bifida.

Trautman et al. (1985) reported CCMS in the sib of a patient reported by Silverman et al. (1980). This observation lends support to autosomal recessive inheritance.

Drossou-Agakidou et al. (1991) described a sibship with 2 sets of dizygotic twins with CCMS. All 4 had Pierre-Robin anomalad and rib dysplasia. Cerebral involvement was evident in 2 who had had perinatal asphyxia.

Plotz et al. (1996) described 2 more sporadic cases of this syndrome in males, one of whom died at 12 hours, and the other at 10 months. A detailed review of 48 previously reported cases showed that respiratory distress, gaps of posterior ribs, and micrognathia were virtually constant manifestations. Males were affected in 28 of 47 cases. Approximately two-thirds of patients had cleft palate and glossoptosis. Microcephaly was found in 11 of 28 cases. Defects of the heart and kidneys were uncommon.

Merlob et al. (1987) described affected father and daughter. Prenatal diagnosis was made by ultrasonography in the case of the daughter. The most prominent ultrasonographic sign was the unusual shape of the ribs, which were very short and defective. The diagnosis can be confirmed in utero by ultrasound examination of the fetal mandible and head.

Hennekam and Goldschmeding (1998) described a newborn with complete absence of ossification of the ribs, extreme micrognathia, absence of external ear canals and the inner ears, and diminished mobility in the upper limbs. They suggested that this represents an unusually severe expression of the CCM syndrome. Myogenic factor-5 (MYF5; 159990), goosecoid (GSC; 138890), and CBFA1 (RUNX2; 600211) were discussed as candidate genes, on the basis of their role in bone formation and the phenotype of knockout mice.

Kirk et al. (1999) described a family in which 2 sibs had apparently absent ribs and severe micrognathia on prenatal ultrasonography. The pregnancies were terminated at 19 and 12 weeks' gestation, respectively. At autopsy, the first fetus showed severe micrognathia, a U-shaped defect of the soft palate, marked postnuchal edema, absent olfactory bulbs, and cribriform plate and rib abnormalities. The ribs consisted of cartilage anteriorly, with only a small amount of fibrous tissue present laterally and posteriorly. The second fetus, at 12 weeks' gestation, had agnathia, with a large U-shaped defect of the soft palate. There was moderate postnuchal edema. The ribs were unossified and there were gaps in the cartilage where primitive mesenchyme was present posteriorly and laterally. These findings were consistent with a severe form of cerebrocostomandibular syndrome. The early fetal histopathology in both cases suggested a possible mechanism by which the characteristic 'rib gaps' of cerebrocostomandibular syndrome may develop, with evidence for abnormal function of a gene or genes involved in regulation of rib chondrogenesis.

James and Aftimos (2003) reported an infant and her father with typical features of CCMS. The child was diagnosed on prenatal ultrasound and was found to have the previously unreported prenatal finding of an omphalocele. James and Aftimos (2003) reviewed 28 cases of familial CCMS and determined that families suggestive of autosomal recessive and autosomal dominant inheritance are not distinguishable on the basis of clinical manifestations.

Tooley et al. (2016) tabulated the clinical and radiologic findings in 16 patients with CCMS, of whom 8 had previously been reported, including 6 by Lynch et al. (2014), 1 by Watson et al. (2014), and 1 by Ramaswamy et al. (2016). Severe micrognathia and reduced numbers of ribs with gaps were consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis were common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defects were observed. Microcephaly and significant developmental delay were present in a small minority of patients. Key radiologic findings included narrow thorax, multiple posterior rib gaps, and abnormal costotransverse articulation. A novel finding in 2 patients was bilateral accessory ossicles arising from the hyoid bone.

Molecular Genetics

Using a combination of whole-exome and Sanger sequencing in 10 unrelated families with CCMS, Lynch et al. (2014) identified heterozygosity for 6 different regulatory mutations in the SNRPB gene (see, e.g., 182282.0001-182282.0004) in 9 of 10 probands. All patients had micrognathia and posterior rib gaps. The authors noted that although intellectual disability is reported to be a common feature of CCMS, it was not prevalent in this cohort: 2 of the 14 patients for whom this information was provided had mild learning disabilities and another patient was reported to have mild neurocognitive delay. One patient with 'classic CCMS' was negative for sequence or copy-number variants in the coding regions and UTRs of the SNRPB gene.

In 5 unrelated French patients with CCMS, who were negative for mutation in the NABP1 (OBFC2A; 612103) and NABP2 (OBFC2B; 612104) genes, Bacrot et al. (2015) identified heterozygosity for 4 missense mutations (see, e.g., 182282.0001 and 182282.0002) and 1 splice site mutation (182282.0004) in the SNRPB gene. All of the patients had Pierre-Robin sequence and posterior rib gaps, but no intellectual disability.

Tooley et al. (2016) studied 16 patients with CCMS, including 8 who were previously reported (Lynch et al., 2014; Watson et al., 2014; Ramaswamy et al., 2016). SNRPB mutations were identified in 8 of the 9 patients for whom DNA was available and in whom mutations had not previously been reported; mutations in 7 of these patients had previously been described (see, e.g., 182282.0001 and 182282.0002). The authors concluded that CCMS is caused by specific SNRPB mutations in the vast majority of cases.

Exclusion Studies

In a male Taiwanese infant with features consistent with CCMS, offspring of nonconsanguineous parents, Su et al. (2010) screened 3 candidate genes identified by Hennekam and Goldschmeding (1998) (MYF5, GSC, and RUNX2), as well as the TCOF1 (606847) gene for mutations. No mutations were found in the coding exons or splice sites of the 4 genes.