3mc Syndrome 3

A number sign (#) is used with this entry because of evidence that 3MC syndrome-3 (3MC3) is caused by compound heterozygous mutation in the COLEC10 gene (607620) on chromosome 8q24.

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

In France, Malpuech et al. (1983) studied 4 of at least 15 persons in a Gypsy family afflicted with mental and physical growth retardation, hypertelorism, facial clefting, and urogenital anomalies including micropenis, penoscrotal hypospadias, ectopic testis, and, judging from the published photograph, bifid scrotum. The kindred was highly inbred. The authors suggested that this was a 'new' autosomal recessive syndrome.

Guion-Almeida (1995) reported 3 unrelated Brazilian patients with short stature, hypertelorism, eye anomalies, facial clefting, hearing loss, urogenital abnormalities, omphalocele, caudal appendage, and mental retardation. The parents were normal in all cases; the parents in 1 of the 3 cases were first cousins. The facies was distinctive and similar in the 3 cases. The caudal appendage, which was illustrated with a photograph in each case, was associated with a prominent coccyx on radiographs.

Chinen and Naritomi (1995) reported this disorder in the sixth child of healthy parents. The first child, a male, had died at age 2 months of congenital heart disease. At birth, the proband, a male, had cardiac failure due to patent ductus arteriosus and ventricular septal defect. The first was ligated at 38 days of age. In addition to the facial features observed in the other cases and cryptorchidism and hypoplastic scrotum, periarticular skin dimples were noticed at the right elbow and knees. The right fourth and eighth ribs were fused and there was sagittal clefting of the vertebrae, wormian bones at the lambdoid suture, and short left fifth middle phalanx. He had moderate mental retardation. Although the parents denied consanguinity, they and their grandparents were natives of a small area in the northern part of Okinawa Island.

Crisponi et al. (1999) reported the cases of 2 Italian brothers with facial clefting, hypertelorism, urogenital anomalies including micropenis and shawl scrotum, hearing loss, caudal appendage, and umbilical hernia. The parents were not related.

Reardon et al. (2001) reported a 9-year-old boy whose clinical presentation resembled Malpuech syndrome, but who had radiologic features similar to those seen in patients with Juberg-Hayward syndrome (216100). At birth, the patient was noted to have left-sided cleft lip/palate, hypertelorism, micrognathia, right diaphragmatic hernia, left renal agenesis with an enlarged and downwardly displaced right kidney, bilateral undescended testes, and bilateral talipes. At age 2 he had surgery to repair a large umbilical hernia. The parents were nonconsanguineous; a second pregnancy ended in miscarriage of a fetus with a large abdominal herniation. Examination of the proband at age 9 revealed short stature, shawl scrotum, and limitation of flexion and extension at both elbows. Radiologic examination and review of earlier films showed features consistent with Juberg-Hayward syndrome, including mesomelic shortening, elbow dislocation, carpal bone abnormalities, mild scoliosis, and vertebral endplate irregularity, as well as generalized epiphyseal dysplasia. Reardon et al. (2001) suggested that the Malpuech and Juberg-Hayward syndromes may be allelic.

Galan-Gomez et al. (2004) described a brother and sister with a constellation of anomalies, some of which suggested Kabuki syndrome (147920) and others Malpuech syndrome. The boy had a caudal appendage.

Kerstjens-Frederikse et al. (2005) reported 3 patients with Malpuech syndrome from 2 families. A boy adopted from Brazil had severe clefting and growth retardation, hypoplastic scrotum, micropenis, cryptorchidism, a renal anomaly and urethral valve; the authors noted that his facial features showed a striking resemblance to the pictures in the reports from Malpuech et al. (1983) and Guion-Almeida (1995). Kerstjens-Frederikse et al. (2005) also described 2 brothers who had fetal hydrops, cardiac defects, cleft lip and palate, and micropenis.

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, 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).

Molecular Genetics

Using DNA samples from 6 patients with 3MC from a cohort known to be negative for mutation in the MASP1 (600521) and COLEC11 (612502) genes, Munye et al. (2017) performed whole-exome sequencing and identified compound heterozygosity for a nonsense mutation (R9X; 607620.0001) and a 1-bp deletion (607620.0002) in the COLEC10 gene in a 21-year-old Pakistani man. His affected 17-year-old sister was also compound heterozygous for the mutations, and their unaffected parents were each heterozygous for 1 of the mutations. Sanger sequencing of the COLEC10 in the remainder of the 3MC cohort revealed a Pakistani female patient who was compound heterozygous for R9X and a missense mutation (C176W; 607620.0003).