3mc Syndrome 2

A number sign (#) is used with this entry because of evidence that 3MC syndrome-2 (3MC2) is caused by homozygous mutation in the COLEC11 gene (612502) on chromosome 2p25.

Description

The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (summary by Rooryck et al., 2011).

For a discussion of genetic heterogeneity of 3MC syndrome, see 3MC1 (257920).

Clinical Features

Carnevale et al. (1989) described 2 sons of consanguineous parents with an apparently distinct syndrome manifested by eyelid ptosis, convergent strabismus, partial agenesis of the abdominal muscles, hip dislocation, cryptorchidism, and developmental delay. The elbows showed an ability to extend fully with limitation of pronation and supination. In addition to blepharoptosis, the brothers had blepharophimosis and epicanthus inversus as in the autosomal dominant disorder of blepharophimosis (110100).

Guion-Almeida and Rodini (1995) reported a Brazilian girl born of first-cousin parents and presenting with craniosynostosis, telecanthus, blepharophimosis, blepharoptosis, epicanthus inversus, cleft lip and palate, skeletal defects, and hearing loss. She did not have mental retardation.

Mingarelli et al. (1996) reported 2 sisters with facial, ocular, and skeletal defects, and abdominal muscle hypoplasia. The authors referred to the disorder as the 'oculo-skeletal-abdominal (OSA) syndrome.' Autosomal recessive inheritance was suggested.

Titomanlio et al. (2005) reported a female infant of healthy nonconsanguineous Chinese parents who exhibited facial dysmorphism including blepharophimosis, blepharoptosis, epicanthus inversus, telecanthus, bilateral cleft lip and palate, and micrognathia. Her anterior fontanel was extremely large. She also had low-set ears, 2 accessory nipples, a tuberous angioma on the thorax, a supraumbilical depression, small hands with bilateral short fifth fingers, broad feet, and severe axial hypotonia. When last seen at 2 years, 10 months of age, she had mild psychomotor retardation and no speech, and a moderate bilateral conductive hearing loss was noted. Titomanlio et al. (2005) reviewed the phenotypic similarities between Michels syndrome (257920), Malpuech syndrome (248340), Carnevale syndrome and OSA syndrome, and suggested that they may represent a single recessive spectrum rather than separate disorders. Titomanlio et al. (2005) proposed that the combined entity could be referred to as the '3MC syndrome' (Malpuech-Michels-Mingarelli-Carnevale syndrome).

Al Kaissi et al. (2007) reported a 4.5-year-old boy with cleft lip and palate, broad forehead, asymmetric occiput, highly arched and fine eyebrows, ptosis, hypertelorism, downward slanting palpebral fissure, ectropion of the lateral third of the lower eyelids, broad nasal bridge, broad philtrum, and prominent ears. He had progressive torticollis, and limited elbow mobility, but otherwise had generalized joint hypermotility. All fingers and toes were mildly shortened. Radiographic examination showed craniosynostosis of the lambdoid suture, cervical scoliosis secondary to incomplete development of the anterior neural arch of C1 and fusion of C2 and C3. The left elbow showed radio-ulnar synostosis. Diastasis recti and umbilical depression were also present. The patient's elder sister had similar facial features, diastasis recti, and normal umbilicus. Neither patient had mental retardation. In a review of the literature of similar syndromes, Al Kaissi et al. (2007) concluded that their patients were most similar to those described by Carnevale et al. (1989), Guion-Almeida and Rodini (1995), and Mingarelli et al. (1996), and suggested the designation 'Carnevale syndrome.' The authors noted the similarities to both Michels syndrome and Malpuech syndrome, but considered them to be separate entities.

Mapping

In 4 consanguineous families with 3MC syndrome, Rooryck et al. (2011) performed homozygosity mapping and identified a greater than 2.2-Mb common region of homozygosity at chromosome 2p25.

Molecular Genetics

In 4 consanguineous families with 3MC syndrome mapping to chromosome 2p25, Rooryck et al. (2011) analyzed candidate genes and identified 3 homozygous missense mutations and 1 in-frame deletion in the COLEC11 gene (612502.0001-612502.0004). Analysis of COLEC11 in additional 3MC patients revealed homozygous mutations in probands from 3 families, including the family originally described by Carnevale et al. (1989) (612502.0005) and the family originally described by Mingarelli et al. (1996) (612502.0006).

Urquhart et al. (2016) ascertained an additional 13 patients from 12 families with 3MC syndrome, in whom they analyzed the MASP1 (600521) and COLEC11 genes. Two Israeli sibs were homozygous for a frameshift mutation in MASP1, and 5 unrelated patients were homozygous for 2 missense and 3 nonsense mutations in COLEC11, respectively. The remaining 6 patients, including 4 who were 'less typical' of 3MC syndrome, were negative for mutation in MASP1 and COLEC11. Urquhart et al. (2016) tabulated the clinical features of these patients and noted that all of the mutation-positive individuals had distinctive highly arched eyebrows with ptosis as well as more striking hypertelorism than mutation-negative individuals. The authors considered this facial phenotype to be a key diagnostic feature for the condition. They also found that a caudal appendage, usually taking the form of a cystic lesion over the sacrum, was a good indicator for mutation-positive individuals.

Using DNA samples from 36 patients in 34 families with 3MC syndrome, Munye et al. (2017) screened for mutations in the COLEC11 and MASP1 genes and identified homozygosity for mutations in COLEC11 in 3 unrelated patients from Pakistan, Somalia, and Lebanon, as well as homozygosity for a MASP1 mutation in 1 patient.