Crisponi/cold-Induced Sweating Syndrome 3

A number sign (#) is used with this entry because of evidence that Crisponi/cold-induced sweating syndrome-3 (CISS3) is caused by homozygous mutation in the KLHL7 gene (611119) on chromosome 7p15.

Heterozygous mutation in the KLHL7 gene can cause adult-onset retinitis pigmentosa-42 (RP42; 612943).

Description

Crisponi/cold-induced sweating syndrome-3 is an autosomal recessive disorder characterized by infantile-onset hyperthermia and abnormal paroxysmal contractions of the facial and oropharyngeal muscles, resulting in feeding and respiratory difficulties. Other features include joint contractures and camptodactyly. Death in infancy may occur, and those that survive may develop retinitis pigmentosa later in childhood. Individuals with some forms of Crisponi syndrome may develop paradoxical cold-induced sweating later in childhood, although this is a variable finding (summary by Angius et al., 2016).

For a discussion of genetic heterogeneity of Crisponi/cold-induced sweating syndrome, see CISS1 (272430).

Clinical Features

Angius et al. (2016) reported 5 patients from 4 unrelated consanguineous Turkish families with a phenotype reminiscent of Crisponi syndrome. The patients presented in infancy with hyperthermia and abnormal paroxysmal contractions of the oropharyngeal muscles, resulting in feeding and swallowing difficulties. Additional features included camptodactyly, joint contractures, full cheeks, high-arched palate, and depressed nasal bridge. Three patients died between 7 and 24 months of age. One of the deceased patients had no evidence of retinitis pigmentosa at age 12 months, but 2 surviving children developed retinitis pigmentosa at 4 and 6 years, respectively. Ophthalmologic examination of the parents of 1 of the patients with retinitis pigmentosa did not show signs of retinal anomalies; the parents of the other patient with retinitis pigmentosa were not available for study. None of the patients exhibited cold-induced sweating.

Inheritance

The transmission pattern of CISS3 in the family reported by Angius et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 4 unrelated consanguineous Turkish families with CISS3, Angius et al. (2016) identified 4 different homozygous mutations in the KLHL7 gene (611119.0004-611119.0007). The mutations were found by whole-exome sequencing and segregated with the disorder in the families. One of the mutations resulted in a truncated protein with loss of most of the KELCH domain, whereas 3 were missense mutations affecting the KELCH domain. In vitro expression studies of the missense mutations showed that they had subcellular localization similar to wildtype and colocalized with CUL3 (603136). Angius et al. (2016) hypothesized that the mutations interfered with recognition of and binding to substrates, leading to failure of ubiquitination of the substrates.