3MC syndrome

What is 3MC syndrome?

This rare disease is a genetic syndrome, the exact prevalence of which is unknown.

The syndrome as named combines four previously separately identified and named disorders, Mingarelli, Malpuech, Michels and Carnevale, which are now known collectively as 3MC.

Main symptoms of the syndrome include developmental delay, and unique facial features, including features affecting the eyes.

This syndrome is also known as:
3MC Craniosynostosis With Lid Anomalies; Michels Syndrome; Formerly Oculopalatoskeletal Syndrome

What gene change causes 3MC syndrome?

Mutations to the COLEC11, COLEC10 and MASP1 genes are responsible for the syndrome which is inherited in an autosomal recessive pattern.

Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.

what are the main symptoms of 3MC syndrome?

Unique facial features of the syndrome include widely spaced eyes, narrowing of the eye opening, droopy eyelids, high arched eyebrows and a short stature. A cleft lip and palate are also potential syndromes.

Other associated symptoms include developmental delay, intellectual delay, hearing loss and slow growth in childhood.

Possible clinical traits/features:
Wide anterior fontanel, Omphalocele, Autosomal recessive inheritance, Sacral dimple, Clinodactyly of the 5th finger, Conjunctival telangiectasia, Cleft upper lip, Conductive hearing impairment, Coronal craniosynostosis, Dental crowding, Epicanthus inversus, Single interphalangeal crease of fifth finger, Intellectual disability, mild, Abnormality of eye movement, Lambdoidal craniosynostosis, Broad foot, Abnormal anterior chamber morphology, Cleft palate, Blepharophimosis, Postnatal growth retardation, Growth delay, Glaucoma, Short 5th finger, Short foot, Underdeveloped supraorbital ridges, Hydronephrosis, Highly arched eyebrow, Hypertelorism, Radioulnar synostosis, Skull asymmetry, Spina bifida occulta, Supernumerary nipple, Ptosis, Microcephaly

How does someone get tested for 3MC syndrome?

The initial testing for 3MC syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on 3MC syndrome

Michels et al., (1978) described three brothers and a sister, the offspring of Mexican-American parents, with cleft lip and palate, anterior chamber anomalies with corneal clouding, ptosis, blepharophimosis and epicanthus inversus. There was also spina bifida occulta, radioulnar synostosis and cranial asymmetry. Two of the sibs had lambdoidal craniosynostosis. Many patients have paraumbilical depressions (Leal and Baptista, 2007 - who review the clinical features).

Cunniff and Jones (1990) and Guion-Almeida and Rodini (1995) reported cases with features of the condition, but without anterior chamber abnormalities. De La Paz et al., (1991) reported three brothers and a sister with apparently the same condition. Two had cleft lip and palate and one a small omphalocele. Additional features were conjunctival telangiectasia, short stature and clinodactyly. There are some similarity to Peters' plus syndrome (qv).

Titomanilo et al., (2005) reported a case and noted the striking overlap with Carnevale (1989) syndrome - see elsewhere, the ocular-skeletal-abdominal syndrome (OSA) - described by Mingarelli et al., (1996) - but referenced under Carnevale syndrome, and Malpuech syndrome -see elsewhere. They suggest that they be joined under the eponym, 3MC (Malpuech, Michels, Mingarelli and Carnevale). BUT, see under Carnevale syndrome. Leal and Baptista (2007) agree. These authors reported two further sibs and a singleton. Without mutational confirmation the diagnosis is difficult. Adio et al., (2014) reported a case born to cousin parents with blepharophimosis, blepharoptosis, epicanthus inversus and cleft lip and palate. Her orbits were shallow, her hands were short and stubby and her feet were broad.

The two sibs reported by Leal et al., (2008) and the discussion that followed again raised questions about whether the reports by Michels, Malpuech and Carnevale and Al Kaissi ie., 3MC syndrome and OSA (Mingarelli et al., (1996), are not all the same condition. Two Turkish patients with similarities to these conditions was found by Sirmaci et al., (2010) to have MASP1 mutations. MASP1 encodes mannan-binding lectin serine protease 1.

Two genes in the lectin complement pathway (COLEC11 and MASP1) have been shown to be causitive (Rooryk et al., 2011). Eleven families were utilized.

Munye et al., (2017) described four patients from a 3MC cohort with Carnevale syndrome. Three of them carried novel homozygous mutations in the COLEC11 gene and the fourth patient carried a novel homozygous truncating mutation in the MASP1/3 gene. All patients presented with dysmorphic features including arched eyebrows, blepharoptosis, epicanthus inversus, hypertelorism, dysplastic ears and bilateral cleft lip and palate. Additional features varied between patients and included developmental delay, feeding difficulties, corneal clouding, deep set nails, diastasis recti or umbilical hernia (in three patients), radio-ulnar synostosis, sacral dimple, hypotonia, patent ductus arteriosus, horseshoe kidney and micropenis and undescended testes. The authors also described two patients with Michels syndrome and one patient with Malpuech syndrome mutations in the COLEC10 gene. Clinical features included characteristic dysmorphic features (blepharoptosis and epicanthus inversus in all patients, cleft lip and palate in two patients and dysplastic ears and ear pit in one patient), short stature in two patients and preaxial polydactyly, clinodactyly, and sacral dimple - each in one patient.

Graul-Neumann et al., (2018) described an adult female patient, followed from birth to 21 years, with a novel homozygous deletion in MASP1. Clinical features included characteristic facial features, hearing loss, and multiple congenital anomalies. This patient lacked intellectual disability, short stature, and cleft lip and palate typically associated with the mutation.

* This information is courtesy of the L M D.

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