Congenital Contractures Of The Limbs And Face, Hypotonia, And Developmental Delay

A number sign (#) is used with this entry because of evidence that congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) is caused by heterozygous mutation in the NALCN gene (611549) on chromosome 13q33.

Description

CLIFAHDD is a congenital disorder characterized by congenital contractures of the limbs and face, resulting in characteristic facial features, hypotonia, and variable degrees of developmental delay. All reported cases have occurred de novo (summary by Chong et al., 2015).

Clinical Features

Chong et al. (2015) reported 14 unrelated children with a similar congenital disorder characterized by severe contractures of the limbs, abnormal facial features, hypotonia, and variable degrees of developmental delay. Characteristic facial features included downslanting palpebral fissures, broad nasal bridge, anteverted nasal tip, large nares, short columella, long philtrum, micrognathia, pursed lips, H-shaped chin dimpling, deep nasolabial folds, and full cheeks. Limb deformities included camptodactyly, adducted thumbs, ulnar deviation, positional foot deformities ranging from varus deformity to severe clubfoot, and contractures of the elbows and knees. Patients also had short neck, scoliosis, and hip contractures. Many patients had neonatal respiratory distress and abnormal breathing patterns. All patients had global developmental delay with poor speech, and some had seizure-like activity. Brain MRI in some patients was normal, whereas others had cerebellar and/or cerebral atrophy. More variable features included gastroesophageal reflux and inguinal or umbilical hernia.

Molecular Genetics

In 14 unrelated patients with CLIFAHDD, Chong et al. (2015) identified 14 different de novo heterozygous missense mutations in the NALCN gene (see, e.g., 611549.0004-611549.0008). The first 6 mutations were found by exome sequencing, and subsequent mutations were found by sequencing the NALCN gene in 202 samples from patients with a similar disorder. All of the mutations were located in or near the predicted S5 and S6 segments of the protein, which are part of the pore-forming domain. In vitro functional cellular expression studies in HEK293T cells were performed for 2 of the mutations, both of which eliminated expression of the wildtype protein. Chong et al. (2015) postulated a dominant-negative effect.