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SKIN CREASES, CONGENITAL SYMMETRIC CIRCUMFERENTIAL, 2; CSCSC2

SKIN CREASES, CONGENITAL SYMMETRIC CIRCUMFERENTIAL, 2; CSCSC2

Congenital symmetric circumferential skin creases is characterized by the folding of excess skin, which leads to ringed creases, primarily of the limbs. Affected...

Congenital symmetric circumferential skin creases is characterized by the folding of excess skin, which leads to ringed creases, primarily of the limbs. Affected individuals also exhibit intellectual disability, cleft palate, and dysmorphic features (summary by Isrie et al., 2015).

For a discussion of genetic heterogeneity of congenital symmetric circumferential skin creases, see CSCSC1 (156610).

▼ Clinical Features

Tinsa et al. (2009) described a 9-year-old Tunisian boy, born of consanguineous parents, who had an increased number of deep skin creases of the limbs, mental retardation, seizures, and cleft palate. He exhibited dysmorphic features including elongated face, hypertelorism, epicanthal folds, upslanting palpebral fissures, microphthalmia, wide nasal bridge, absent maxillary incisors and decay of several teeth, and low-set posteriorly rotated ears with thick overfolded helices. He also had a short neck, mild pectus excavatum, widely spaced nipples, ventral penile curvature with hypospadias, hypoplastic scrotum, and undescended testes. Skeletal x-rays showed diffuse osteopenia, and brain MRI revealed hypoplastic vermis, hypoplastic corpus callosum, and atonic dilation of ventricles. Abdominal ultrasound and intravenous urography showed left ureterocele. Auditory brainstem-evoked response revealed bilateral mild deafness. The proband's mother stated that there had been spontaneous partial improvement of the excess folds of skin over the extremities. The proband had a healthy older sister, but another sister with circumferential ringed skin creases had died at 2 months of age.

Wouters et al. (2011) reported a 3.5-year-old Belgian girl and a 15-month-old Spanish boy with circumferential skin creases. Both exhibited a flat midface, broad nasal bridge, epicanthal folds, microphthalmia, low-set small dysplastic ears, microstomia, and cleft palate; both had moderate developmental delay with absence of expressive language, which was more severe in the boy, who was born of first-cousin parents. He also had hypoplastic scrotum and hypospadias, and brain imaging showed hypoplasia of the corpus callosum and mildly dilated lateral ventricles.

Isrie et al. (2015) studied an 8.75-year-old Belgian girl who was born with circumferential skin creases that disappeared by age 4 years. Dysmorphic features included flat face, broad nasal bridge, epicanthal folds, microphthalmia, low-set small posteriorly rotated ears with overfolded helices and upturned ear lobes, and microstomia. She did not have cleft palate, and she exhibited mild intellectual disability.

▼ Molecular Genetics

In 3 unrelated patients with congenital symmetric circumferential skin creases, Isrie et al. (2015) performed whole-exome sequencing and identified mutations in the MAPRE2 gene, including homozygosity for a Y87C mutation (605789.0001) in the Tunisian boy originally described by Tinsa et al. (2009) and homozygosity for an N68S mutation (605789.0002) in the Spanish boy reported by Wouters et al. (2011). DNA was unavailable from the Tunisian parents; however, the Spanish parents were each heterozygous carriers of the N68S mutation, and the father had a possible history of minor skin folds in infancy. In addition, an affected Belgian girl, previously reported by Wouters et al. (2011), was heterozygous for a maternally inherited nonsense mutation (Q152X; 605789.0003); her mother had mild cognitive impairment and exhibited similar facial dysmorphism. Subsequent sequencing of the MAPRE3 gene in an unrelated Belgian girl with CSCSC revealed heterozygosity for an R143C mutation (605789.0004).

Tags: 18q12.1, 18q12.2