Chand Syndrome

A number sign (#) is used with this entry because of evidence that CHAND syndrome (CHANDS) is caused by homozygous mutation in the RIPK4 gene (605706) on chromosome 21q22.

Biallelic mutation in the RIPK4 gene can also cause Bartsocas-Papas syndrome (BPS; 263650), a more severe disorder with overlapping features.

Description

CHAND syndrome is characterized by ankyloblepharon, sparse, curly, and woolly hair, nail dysplasia, and oral frenula (summary by Busa et al., 2017).

Clinical Features

Baughman (1971) described a seemingly distinct syndrome characterized by curly hair and hypoplastic nails with congenital ankyloblepharon (fusion of eyelids).

Toriello (1994) suggested that the disorder reported by Ohishi et al. (1991) as a possibly new autosomal recessive ectodermal dysplasia was an example of CHANDS. Ohishi et al. (1991) reported a patient with alveolar synechia, ankyloblepharon, bilateral commissural lip pits, and inferiorly attached frenulum, hypoplastic nails, and woolly scalp hair. The parents were consanguineous, and the mother had congenital absence of the right upper second incisor and the left upper canine. The proband's older sister also had a congenital defect of the left upper deciduous canine, as well as a right inguinal hernia.

Gripp et al. (2013) reported a 5-year-old proband who presented at birth with bilateral cleft lip and palate with associated nasal deformity, ankyloblepharon of her left lid, dysplastic nails, and hypohidrosis. Her sparse hair grew slowly. She had no webbing or lip pits. Intellect was normal. Because the child was found to be homozygous for mutation in the RIPk4 gene, the authors considered the phenotype to be an attenuated from of Bartsocas-Papas syndrome.

Gollasch et al. (2015) reported 3 children in a consanguineous Kuwaiti kindred with CHANDS. All 3 showed ankyloblepharon, sparse, curly and woolly hair, and hypoplastic nails. Additional features included hypertelorism, flat nasal bridge, bilateral minimal adhesions (synechia) between lower and upper lips, and small pits on the upper lips. One patient had an imperforate vagina.

Busa et al. (2017) reported a 3-year-old boy (patient 2), born to consanguineous parents of Tunisian origin, who presented at birth with ankyloblepharon. Abdominal ultrasound revealed ureteral dilatation. Clinical examination at 1 month of age showed nail dysplasia, dry skin, bifid tongue, and multiple oral frenula. At age 3 years, his deciduous teeth were normal and his hair was curly, woolly, and sparse. Motor development was normal. He had slight speech delay.

Inheritance

Baughman (1971) suggested that this disorder is autosomal dominant; however, based on additional pedigree data obtained after the original report, Valdmanis et al. (1977) and Toriello et al. (1979) concluded that autosomal recessive inheritance is more likely, with an instance of pseudodominance as a result of multiple consanguineous matings in the family.

Molecular Genetics

In a 5-year-old girl with a presumed diagnosis of ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC; 106260) but who did not have a mutation in the TP63 gene (603273), Gripp et al. (2013) screened for mutations in the RIPK4 gene and identified homozygosity for a missense mutation (G163D; 605706.0005). The child's parents were heterozygous for the mutation. The authors considered the disorder to be an attenuated form of Bartsocas-Papas syndrome, but noted that unlike previously reported patients with BPS, their patient did not have pterygia or syndactyly. The authors also noted that TP63 is a direct transcriptional activator of RIPK4.

In 3 children in a consanguineous Kuwaiti kindred with a diagnosis of AEC or CHAND syndrome, Gollasch et al. (2015) excluded mutation in the TP63 gene and identified homozygosity for a missense mutation in the RIPK4 gene (E284K; 605706.0006) that segregated with the disorder in the family. Molecular modeling indicated that the mutation might lead to reduced stability of the homodimer structure of the protein.

In a 3-year-old boy (patient 2), born of consanguineous parents of Tunisian origin, with CHAND syndrome, Busa et al. (2017) identified homozygosity for the same E284K mutation in the RIPK4 gene that was identified in the patients reported by Gollasch et al. (2015). The authors of both articles noted that this mutation occurs outside the serine/threonine kinase and the ankyrin domains, contrasting with reported mutations in patients with BPS.