Skin Creases, Congenital Symmetric Circumferential, 1

A number sign (#) is used with this entry because of evidence that congenital symmetric circumferential skin creases-1 (CSCSC1) is caused by heterozygous mutation in the TUBB gene (191130) on chromosome 6p21.

Description

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).

Genetic Heterogeneity of Congenital Symmetric Circumferential Skin Creases

CSCSC2 (616734) is caused by mutation in the MAPRE2 gene (605789) on chromosome 18q12.

Clinical Features

Kunze and Riehm (1982) reported 3 families segregating multiple benign ring-shaped skin creases as an autosomal dominant trait. In the first family, a boy had circumferential deep skin creases on the extremities and fingers with no signs of amputation or strangulation. He also exhibited facial dysmorphism, including epicanthal folds, upslanting palpebral fissures, hypertelorism, and median cleft palate. In addition, he had neuroblastoma in the right retroperitoneal space that was resected at age 6 months. His father had a history of ring-shaped creases on both arms during his first year of life, which later disappeared completely. In the second family, a father and 2 daughters were affected. The proband was born with multiple benign ring-shaped deep creases on all extremities, fingers, toes, and trunk, with no symptoms of strangulation. Dysmorphic features included micrognathia, malformed ears, and median cleft palate, as well as bilateral ureteroceles. Her older sister also had some circular skin alterations noted in the first months of life, although less prominent, and no rings were evident at age 2 years. Their healthy father had ring-shaped skin creases in the first year of life, and at 30 years of age only a few circular skin alterations persisted, typically seen in the summer when the ring-shaped creases were less pigmented. In the third family, the proband was a 4.8-year-old girl with mild mental retardation and slight circular creases. She was first seen at 4 months of age, at which time she had multiple circular deep rings around her extremities. Mild motor retardation was noted at 14 months, and she had recurrent febrile seizures beginning at 21 months. There was no family history of ring-shaped skin alterations.

Niikawa et al. (1985) reported 2 families with this syndrome. In the first family the trait occurred in 3 generations. The proband, a 3-year-old girl, had deep skin folds, gyrus-like on the back and circumferential in the limbs bilaterally. Her father and maternal grandmother had several skin creases around the wrists and forearms which they claimed were remnants of deep skin folds in infancy. In the second family a 5-year-old boy and his 10-month-old brother were affected. The parents were normal; it was unknown whether they had excessive skin folds in infancy.

Ross (1969) concluded that in his patient a diffuse underlying lipomatous nevus was present.

Wiedemann (1987) pictured an infant with multiple benign circumferential skin creases in association with a congenital heart defect. He also called attention to the demonstration of this feature in a representation of Eve nursing her son in a detail of a bronze door at the cathedral of Hildesheim in northwestern Germany.

Bass et al. (1993) described the disorder in 7 individuals in 4 generations with 3 instances of male-to-male transmission. The constricting bands were distributed symmetrically and circumferentially over the neck, forearms, and lower legs. Spontaneous resolution took place during childhood.

In a karyotypically abnormal child with multiple anomalies, mental retardation, hypertrichosis, and circumferential ringed creases, Schnur et al. (1993) found an underlying smooth muscle hamartoma in a skin biopsy of 1 of the creases. The same histologic pattern was documented in 4 other children with circumferential skin creases described in 4 separate reports, e.g., Oku et al. (1993). Schnur and Zackai (1997) pointed out that the developmentally delayed, although cytogenetically normal child reported by Pivnick et al. (1996) showed ringed creases of the extremities in published photographs and had demonstrated smooth muscle hamartoma described histologically. Schnur and Zackai (1997) suggested that both karyotype and skin biopsy be performed in children with ringed skin creases, with and without other anomalies.

In describing a 15-month-old girl with this syndrome, Sato et al. (1997) raised the question of a congenital disorder of elastic fiber formation in this condition. Histologic examination showed fragmented elastic fibers, in addition to smooth muscle hamartoma. On electron microscopy, decreased deposition of elastin (130160) was observed.

Elliott et al. (1996) suggested that the patient reported with circumferential skin creases by Cohen et al. (1993) may have had a distinct syndrome because of an unusual pattern of associated congenital anomalies and severe psychomotor retardation. The 4-year-old male had craniofacial anomalies, cleft palate, hypoplastic scrotum, inguinal and umbilical hernias, and other abnormalities.

Leonard (2002) reported a case similar to that reported by Cohen et al. (1993) and Elliott et al. (1996). The patient was a 29-month-old boy with symmetrical circumferential skin creases on the arms, legs, and digits, and other features, including epicanthal folds, microphthalmia, microcornea, microcephaly, small and low-set posteriorly angulated ears with thick overfolded helices, cleft palate, and moderate to severe psychomotor developmental delay. CT scan of the head in the newborn period was normal.

Kondoh et al. (2004) described a 3-year-old boy with circumferential skin creases as seen in this disorder, hearing impairment, undescended testes, short stature, and mental handicap. Skin biopsy from the inguinal region showed 'degenerative collagen.' Kondoh et al. (2004) suggested that the patient of Elliott et al. (1996) and their patient had a distinct disorder which they suggested be called HITCH syndrome for 'hearing impairment, undescended testis, circumferential skin creases, and mental handicap.'

Ulucan et al. (2013) reported a 1.5-year-old Turkish girl with deep skin creases of the limbs and a dysmorphic facial appearance. In addition to transverse symmetric circumferential skin creases on all limbs, she exhibited microcephaly and brachycephaly, flat face, epicanthal folds, broad and depressed nasal bridge, low-set posteriorly rotated ears with thick overfolded helices, microstomia, and high palate. She had mild speech delay, and 3D CT scan and MRI of the brain showed early closure of the superior sagittal and coronal sutures, hypoplastic corpus callosum, atrophic cerebellar vermis, and Dandy-Walker malformation.

Isrie et al. (2015) studied a 5.5-year-old Norwegian boy who was born with circumferential creases on his limbs and neck that disappeared by age 4 years, except for creases at the wrists. He also had microcephaly and dysmorphic features including flat face, epicanthal folds, short palpebral fissures, blepharophimosis, broad nasal bridge, small mouth, cleft palate, low-set posteriorly rotated ears, short neck, and long fingers. He had mild to moderate intellectual disability, but brain imaging was normal.

Cytogenetics

Devriendt et al. (2004) described their experience on long-term follow-up of a child presenting at birth with multiple circumferential skin creases, and suggested that these may be a sign of genetic mosaicism. The patient had mixoploidy with diploidy/triploidy mosaicism. The patient also had linear skin hyperpigmentation and limb asymmetry as well as nevus flammeus on one leg and grade IV hypospadias.

Molecular Genetics

In a Canadian boy with circumferential skin creases who was originally described by Leonard (2002), Isrie et al. (2015) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the TUBB gene (Q15K; 191130.0004). Sequencing of TUBB in 2 more patients with circumferential skin creases, 1 of whom was a Turkish girl previously reported by Ulucan et al. (2013), Isrie et al. (2015) identified the same Q15K mutation in the Turkish girl and a different missense mutation (Y222F; 191130.0005) in an affected Norwegian boy.