Macs Syndrome

A number sign (#) is used with this entry because MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis) is caused by homozygous mutation in the RIN2 gene (610222) on chromosome 20p11.

Clinical Features

Basel-Vanagaite et al. (2009) described 3 patients, members of 2 related consanguineous Israeli-Arab families, with macrocephaly, downward-slanting palpebral fissures, puffy eyelids, mild ichthyosis, sagging cheeks, everted lower lip, retrognathia, gingival hyperplasia, abnormal position of the teeth, severe hyperlaxity, flat feet, coarse and swollen facial appearance affecting the eyelids, lips, and cheeks, sparse scalp hair, and moderate to severe scoliosis with short stature. One of the patients also had mild dilatation of the aorta and another one had generalized osteoporosis, more severe in the spine. The cutaneous features were more apparent in the 2 older patients, suggesting that the disorder is progressive. No visceral involvement was noted. The abnormal appearance of the elastic tissue was restricted to the papillary dermis.

Syx et al. (2010) noted similarities between the patients reported by Basel-Vanagaite et al. (2009) and 3 Algerian sibs with an autosomal recessive genodermatosis previously reported by Verloes et al. (2005). The sibs, born to consanguineous parents, had progressive facial coarsening, gingival hypertrophy, severe scoliosis, sparse hair, and skin and joint laxity. Syx et al. (2010) suggested that the MACS acronym may not be the most appropriate to summarize the phenotypic spectrum of the disorder. True macrocephaly (OFC +3 SD) was initially observed in 2 of 5 patients (data not available in 1 patient reported by Basel-Vanagaite et al., 2009) and subsequently regressed to normal in 1 of them, meaning that final OFC was normal in 4 of 5 patients. The 3 patients described by Syx et al. (2010) had sparse hair, not alopecia, and they did not have cutis laxa. Syx et al. (2010) suggested that progressive scoliosis and buccofacial dysmorphism are the most consistent features of the syndrome, but sparse hair as well as joint and skin hyperextensibility also appear to be common to all 6 reported patients.

Albrecht et al. (2010) reported an 18-year-old Lebanese male, born to consanguineous parents, with MACS syndrome. He had mental retardation (IQ 62), short stature (156 cm), macrocephaly (OFC +3.5 SD), bitemporal narrowing, sagging chins, prominent lips, facial coarsening, cutis laxa of the hand, ankles, wrist and neck, gingival overgrowth, irregular teeth, sparse hair, thorax deformity without scoliosis, and brachydactyly of the first, second, and fourth digits of the hands and feet. He did not show signs of easy bruising, vascular abnormalities, hernias, or systemic involvement. Ultrastructural studies of the skin showed characteristic findings of cutis laxa with abnormal elastic fiber number and structure; in deeper layers, there were mild changes in the collagen fibril morphology. Patient fibroblasts showed abnormal morphology of the Golgi apparatus with swollen cisternae and vacuole accumulation.

Aslanger et al. (2014) described 2 sibs of Turkish descent, born to nonconsanguineous parents who came from the same village, with coarse facies and other dysmorphic features consistent with MACS syndrome. Soft, sagging skin, hyperextensibility, and bronchiectases were also present. The sister presented with hypergonadotropic hypogonadism. She had increased OFC (+2.7 SD) and her brother was normocephalic. Both sibs had progressive scoliosis, osteoporosis, and sparse scalp hair. Both had normal intelligence.

Inheritance

MACS syndrome is an autosomal recessive disorder based on the finding of causative homozygous mutations in the RIN2 gene (Basel-Vanagaite et al., 2009).

Mapping

Using Affymetrix Human Mapping NspI 250K arrays to genotype affected family members with MACS syndrome, Basel-Vanagaite et al. (2009) identified a shared continuous segment of homozygosity between markers rs6034837 and rs2092468 on chromosome 20p11.23-p11.21.

By homozygosity mapping in an Algerian family segregating an autosomal recessive genodermatosis with phenotypic similarities to MACS syndrome, Syx et al. (2010) identified a region on chromosome 20 delineated by SNPs rs6118558 and rs804605 that was homozygous among all affected patients, but not among the unaffected individuals. The RIN2 gene, which had been found to be mutated in the MACS syndrome by Basel-Vanagaite et al. (2009), was located within the candidate region.

Molecular Genetics

In 3 related patients with MACS syndrome, Basel-Vanagaite et al. (2009) identified homozygosity for a 1-bp deletion in the RIN2 gene (c.1878delC; 610222.0001). The mutation was not found in 182 ethnically matched control individuals. RIN2 protein was absent from fibroblasts from the patients, indicating a loss-of-function effect.

In 3 Algerian sibs from a consanguineous family with an autosomal recessive genodermatosis, previously described by Verloes et al. (2005), Syx et al. (2010) identified a homozygous 2-bp deletion in exon 8 of the RIN2 gene (c.2061_2062delGC; 610222.0002). The variant was not found in 94 control individuals. Ultrastructural studies of the skin revealed important abnormalities in the collagen fibril morphology, and fibroblasts exhibited a dilated endoplasmic reticulum and an abnormal Golgi apparatus with rarefied and dilated cisternae.

In a Lebanese man from a consanguineous family with MACS syndrome, Albrecht et al. (2010) identified homozygosity for the c.1878delC mutation in the RIN2 gene, previously identified by Basel-Vanagaite et al. (2009).

In 2 Turkish sibs with MACS syndrome, Aslanger et al. (2014) identified a homozygous insertion in exon 8 of the RIN2 gene (c.1878_1879insC; 610222.0003).