3mc Syndrome 1

A number sign (#) is used with this entry because of evidence that 3MC syndrome-1 is caused by homozygous mutation in the MASP1 gene (600521) on chromosome 3q27.

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).

Genetic Heterogeneity of 3MC Syndrome

Also see 3MC syndrome-2 (3MC2; 265050), caused by mutation in the COLEC11 gene (612502), and 3MC syndrome-3 (3MC3; 248340), caused by mutation in the COLEC1 gene (607620).

Clinical Features

Michels et al. (1978) described 3 brothers and a sister with the eyelid triad of blepharophimosis, blepharoptosis and epicanthus inversus, plus a developmental defect of the anterior segment of the eye leading to corneal stromal opacities, limitation of upward gaze, cleft lip-palate, and some minor skeletal abnormalities in the form of spina bifida occulta, cranial asymmetry, abnormality of the occipital bone, and radioulnar synostosis. The fifth finger was short. The family was Mexican-American. The parents were not known to be consanguineous and were unaffected. Cohen (1986) designated the disorder Michels syndrome. Cunniff and Jones (1990) reported an affected girl whose parents were unrelated.

Guion-Almeida and Rodini (1995) reported the case of 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. Al Kaissi et al. (2007) suggested that the patient reported by Guion-Almeida and Rodini (1995) had Carnevale syndrome (265050).

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, Malpuech syndrome (248340), and Carnevale syndrome (265050), 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); Mingarelli et al. (1996) had described 2 sisters with what the authors called ocular-skeletal-abdominal (OSA) syndrome (see 265050).

Leal and Baptista (2007) reported 3 additional Brazilian cases of Michels syndrome: 2 brothers, aged 23 and 17 years, respectively, born to first-cousin parents, and an unrelated 11-year-old girl. The younger affected brother had a normal twin brother, and a fourth brother, who had died at 2 years of age from diarrhea, was reported to have had the same facial appearance as the 2 affected brothers. The younger affected brother also had short stature and sexual infantilism and was found to have growth hormone deficiency and secondary hypogonadism; the authors questioned whether these were manifestations of Michels syndrome. Leal and Baptista (2007) also noted that the affected girl did not have epicanthus inversus, although she displayed other key features of Michels syndrome, including blepharoptosis, blepharophimosis, telecanthus, and cleft lip/palate. The authors stated that these 3 cases brought the total number of published cases of Michels syndrome to 10.

Leal et al. (2008) described a brother and sister with blepharoptosis, highly arched eyebrows, hearing loss, and caudal appendage. Blepharophimosis, periumbilical depression, and anterior chamber anomaly was present in the sister. Leal et al. (2008) noted that the sibs had features that overlap the Michels, Malpuech, Carnevale, and OSA syndromes. They concluded that the symptoms present in the sibs supported the suggestion of Titomanlio et al. (2005) that the disorders represent a single entity that might be termed the 3MC syndrome.

Mapping

In 2 families with 3MC syndrome, 1 of which was known to be consanguineous, Rooryck et al. (2011) performed homozygosity mapping and identified a 2.2-Mb shared region of identity by descent at chromosome 3q27.

Molecular Genetics

In 2 Turkish families with 3MC syndrome mapping to chromosome 3q27, Sirmaci et al. (2010) performed whole genome sequencing of candidate genes and identified homozygosity for a missense and a nonsense mutation in the MASP1 gene (600521.0004-600521.0005, respectively).

In 2 families with 3MC syndrome mapping to chromosome 3q27, Rooryck et al. (2011) analyzed candidate genes and identified 2 homozygous missense mutations in the MASP1 gene (600521.0001 and 600521.0002, respectively) that segregated with the disorder in each family. Analysis of the MASP1 gene in 2 additional Brazilian families with 3MC syndrome, originally reported by Leal and Baptista (2007) and Leal et al. (2008), respectively, revealed homozygosity for a third missense mutation in affected individuals (600521.0003).

Urquhart et al. (2016) ascertained an additional 13 patients from 12 families with 3MC syndrome, in whom they analyzed the MASP1 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 MASP1 and COLEC11 genes and identified homozygosity for a nonsense mutation in MASP1 in a Pakistani patient, as well as homozygosity for mutations in COLEC11 in 3 unrelated patients.