A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities (NEDHFS) is caused by homozygous or compound heterozygous mutation in the PGM2L1 gene (611610) on chromosome 11q13.

Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities (NEDHFS) is an autosomal recessive disorder characterized by severe global developmental delay with impaired intellectual development and poor or absent speech. Affected individuals have dysmorphic facies, including large abnormally shaped ears and strabismus, hypotonia, and dry skin with keratosis pilaris. Some patients develop seizures. Metabolic studies are unremarkable (Morava et al., 2021).

Morava et al. (2021) reported 4 unrelated children (PT1-4) with a similar neurodevelopmental disorder who were identified through the GeneMatcher program after exome sequencing identified biallelic mutations in the PGM2L1 gene. Three patients were around 7 years of age; 1 was 30 months. The patients had severe global developmental delay with hypotonia, delayed walking or inability to walk, and impaired intellectual development with poor or absent speech. Two patients had ataxia and 1 had pyramidal signs. Three patients had seizures, including tonic-clonic and absence seizures. PT1 developed status epilepticus and afterwards showed severe developmental regression with a complete loss of motor skills. Brain imaging was normal in 2 patients and showed nonspecific abnormalities (frontal atrophy, signal abnormalities) in the other 2. All patients had facial dysmorphism, although the features were somewhat variable. These included large prominent ears with overfolded helices, downslanting palpebral fissures, epicanthal folds, high-arched and narrow palate, flat nasal bridge with prominent nasal tip, thin upper lip, pointy chin, long philtrum, and dental caries. All patients had exotropia or strabismus; 1 had hypermetropia (PT3) and another (PT1) had visual loss. Other features included feeding difficulties (in 2), dry skin with keratosis pilaris or eczema, joint hypermobility, and small hands and feet. Three patients developed early obesity. Laboratory studies, including transferrin glycoform analysis and metabolic studies, were unremarkable in all patients.

The transmission pattern of NEDHFS in the families reported by Morava et al. (2021) was consistent with autosomal recessive inheritance.

In 4 unrelated patients with NEDHFS, Morava et al. (2021) identified homozygous or compound heterozygous mutations in the PGM2L1 gene (611610.0001-611610.0005). The patients were ascertained through the GeneMatcher program after exome sequencing identified the mutations. Patient fibroblasts showed significantly reduced (90% decrease) glucose-1,6-bisphosphate levels compared to controls. Despite the decrease of hexose/pentose-bisphosphates, levels of nucleoside diphosphate (NDP) sugars were not affected, suggesting that protein glycosylation was not affected. The findings were consistent with a loss-of-function effect of the mutations. The authors postulated that PGM2L1 may have a regulatory role in sugar metabolism in the brain, which may explain the clinical features observed in these patients.