Ogden Syndrome

A number sign (#) is used with this entry because of evidence that Ogden syndrome (OGDNS) is caused by mutation in the NAA10 gene (300013) on chromosome Xq28.

Description

Ogden syndrome is an X-linked neurodevelopmental disorder characterized by postnatal growth failure, severely delayed psychomotor development, variable dysmorphic features, and hypotonia. Most patients also have cardiac malformations or arrhythmias (summary by Popp et al., 2015).

Clinical Features

Rope et al. (2011) reported 2 families segregating an X-linked recessive condition characterized by postnatal growth failure with severe delays and dysmorphic features characterized by wrinkled forehead, prominent eyes, widely opened anterior and posterior fontanels, downsloping palpebral fissures, thickened lids, large ears, flared nares, hypoplastic alae, short columella, protruding upper lip, and microretrognathia. There were also delayed closing of fontanels and broad great toes. Skin was characterized by redundancy or laxity with minimal subcutaneous fat, cutaneous capillary malformations, and very fine hair and eyebrows. Death resulted from cardiogenic shock following arrhythmia, which was noted in all affected individuals, all males. Several of the boys had structural anomalies of their hearts including ventricular septal defect, atrial septal defect, and pulmonary artery stenosis. Arrhythmias included torsade de pointes, premature ventricular contraction (PVC), premature atrial contraction (PAC), supraventricular tachycardia (SVtach), and ventricular tachycardia (Vtach). Most of the children had inguinal hernia, and the majority had unilateral cryptorchidism. All had neonatal hypotonia progressing to hypertonia, and cerebral atrophy on MRI; several, but not all, had neurogenic scoliosis. Death occurred prior to 2 years in all cases and prior to 1 year in the majority.

Clinical Variability

Popp et al. (2015) reported 2 unrelated patients, a 10-year-old Swiss boy and a 4-year-old German girl, with a severe neurodevelopmental disorder with additional features reminiscent of those reported by Rope et al. (2011). Both had postnatal growth retardation, but the girl was more severely affected with significant short stature (-4.38 SD) and microcephaly (-3.04 SD). Psychomotor development was significantly delayed: the girl could not walk or speak and had poor eye contact with stereotypic behavior, whereas the boy learned to walk at age 6 years, never achieved continence, and had severe intellectual disability with autistic features. Both patients had variable dysmorphic facial features: the boy had prominent forehead, deep-set eyes, long eyelashes, downslanting palpebral fissures, large ears, and high-arched palate, whereas the girl had delayed closure of the fontanels, long eyelashes, thin arched eyebrows, broad nasal bridge, and thin upper lip. Both patients had truncal hypotonia and hypertonia of the extremities. The girl also had prolonged QT interval, atrial septal defect, pulmonary artery stenosis, delayed bone age, and pectus carinatum. The boy had hypoplastic scrotum, small hands and feet, and epileptiform activity on EEG; he did not have cardiac abnormalities. The boy had previously been reported in a large exome sequencing study of patients with nonspecific severe intellectual disability (Rauch et al., 2012).

Casey et al. (2015) reported 2 young adult Irish brothers with a complex neurodevelopmental disorder characterized by delayed psychomotor development, dysmorphic facial features, scoliosis, and cardiac dysfunction with long QT syndrome. The phenotype differed somewhat between the brothers: 1 was more intellectually impaired, whereas the other was more physically disabled. Both had failure to thrive and poor growth early in life, as well as delayed walking and speech acquisition and waddling gait. Dysmorphic features included coarse facies, low anterior hairline, hypertelorism, epicanthal folds, prominent forehead and philtrum, high cheek bones, depressed midface, flat nasal bridge, low-set and small crumpled ears, dental anomalies, and coarse hair. Additional features included recurrent infections, inguinal hernia, small hands and feet, and acetabular dysplasia; one had valgus foot deformities. EEG in 1 brother showed a diffusely slowed background, consistent with an encephalopathy. As young adults, both developed arrhythmias with long QT syndrome; 1 had 2 myocardial infarctions. The mother was mildly affected with intellectual disability, coarse facial features, small hands and feet, cardiac arrhythmia, prolonged QT, premature coronary artery disease, and ventricular tachycardia.

Inheritance

The transmission pattern of Ogden syndrome in the family reported by Rope et al. (2011) was consistent with X-linked recessive inheritance; the pattern in the family reported by Casey et al. (2015) suggested X-linked dominant inheritance as the carrier mother was mildly affected.

Molecular Genetics

Rope et al. (2011) used X chromosome exon sequencing to identify a missense mutation (S37P; 300013.0001) in the NAA10 gene, encoding the catalytic subunit of the major human N-terminal acetyltransferase. The ser37-to-pro mutation was not identified in any unaffected family members or in 401 participants in the ClinSeq project, 180 genomes in the 1000 Genomes Project, the 10Gen dataset, 184 Danish exomes, or 40 whole genomes from the Complete Genomics Diversity Panel. There was no evidence of identity by descent between the families, and Rope et al. (2011) concluded that the mutation arose independently in each family. Serine-37 and its surrounding residues are conserved among eukaryotes. Acetylation assays demonstrated significantly impaired biochemical activity of the mutant NAA10 protein.

Genotype/Phenotype Correlations

In 2 living unrelated children, a boy and a girl, with severe developmental delay and additional features reminiscent of Ogden syndrome, Popp et al. (2015) identified different de novo missense mutations in the NAA10 gene: a hemizygous A116W substitution (300013.0003) in the boy, and a heterozygous V107F substitution (300013.0004) in the girl. The mutations were identified by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the A116W protein had a small but significant reduction in catalytic activity (15% reduction compared to wildtype), whereas the V107F mutant had almost no catalytic activity (about 5% residual activity). Popp et al. (2015) noted that the residual NAA10 activity in their male Swiss patient was significantly higher than that reported by Rope et al. (2011) in the male patients with the S37P mutation (30-70% reduction), which correlated with the less severe phenotype in the Swiss boy.

In 2 young adult brothers, born of unrelated Irish parents, with a variant of Ogden syndrome, Casey et al. (2015) identified a hemizygous missense mutation in the NAA10 gene (Y43S; 300013.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the mildly affected mother. In vitro functional expression studies showed that the mutant protein had reduced stability and an 85% reduction in catalytic activity. Casey et al. (2015) noted that although the Y43S mutation resulted in a more severe impairment in catalytic activity compared to the S37P mutation, the Irish brothers had a less severe phenotype than the patients reported by Rope et al. (2011), indicating that in vitro NAA10 activity in itself may not be sufficient to explain the resulting phenotype.