Facial Dysmorphism, Hypertrichosis, Epilepsy, Intellectual/developmental Delay, And Gingival Overgrowth Syndrome

A number sign (#) is used with this entry because of evidence that facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome (FHEIG) is caused by heterozygous mutation in the KCNK4 gene (605720) on chromosome 11q13.

Clinical Features

Bauer et al. (2018) reported 3 unrelated children, aged 11 months, 5 years, and 8 years, with a similar neurodevelopmental syndrome identified through genetic research programs and GeneMatcher. Two patients were of Italian descent and 1 was European. Overall developmental progress was highly variable: patient 1 met essentially no developmental milestones at age 11 months, patient 2 met major milestones by age 5, but had a delay in motor skills and language, and patient 3 had mildly delayed milestones with walking at 3 years and single words at age 8. All had significant generalized hypertrichosis and a similar facial gestalt, including hypotonic facies, bitemporal narrowing, micrognathia, deep-set eyes, bushy eyebrows and long eyelashes, low-set ears, short deep philtrum, gingival overgrowth, prominent upper and lower vermilion, and everted upper lip. Other more variable features included nystagmus with optic hypoplasia, hypotonia, and hyperreflexia. Patients 2 and 3 had early-onset focal and generalized seizures that could be controlled with medication. Patient 1 did not have overt seizures, but he had an abnormal EEG with a disorganized pattern, some high voltage activity, and diffuse slow wave activity. Brain imaging in this patient showed a thin corpus callosum and enlarged ventricles. Patient 2 had a developmental index of 85 on the Griffiths scale. Patient 3 also had brachydactyly and congenital hip dysplasia.

Molecular Genetics

In 3 unrelated children with FHEIG, Bauer et al. (2018) identified de novo heterozygous missense mutations in the KCNK4 gene (A172E, 605720.0001 and A244P, 605720.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. In vitro functional expression studies using patch-clamp recording in CHO cells showed that the mutations caused a significant increase in basal K+ membrane conductance compared to wildtype. The mutant channels were insensitive to voltage, mechanical, and lipid stimulation, likely reflecting their maximum activation basally. Coexpression experiments indicated a dominant gain-of-function behavior of the mutations. Molecular modeling predicted that the lateral fenestrations of the channel were significantly less open in the mutant channels compared to wildtype, suggesting that the gating of the channel is affected, favoring channel opening and thus resulting in increased basal activation in the mutants.