Okur-Chung Neurodevelopmental Syndrome

A number sign (#) is used with this entry because of evidence that Okur-Chung neurodevelopmental syndrome (OCNDS) is caused by heterozygous mutation in the CSNK2A1 gene (115440) on chromosome 20p13.

Description

Okur-Chung neurodevelopmental syndrome is an autosomal dominant disorder characterized by delayed psychomotor development, intellectual disability with poor speech, behavioral abnormalities, cortical malformations in some patients, and variable dysmorphic facial features. Additional features, including microcephaly, gastrointestinal problems, and low levels of immunoglobulins, may be observed in some patients (Okur et al., 2016).

Clinical Features

Okur et al. (2016) reported 5 unrelated girls, ranging in age from 2 to 13 years, with a syndromic neurodevelopmental disorder. Common features included developmental delay, intellectual disability with behavioral problems and delayed speech, hypotonia, and gastrointestinal problems such as dysphagia, gastric reflux, or constipation. Three had microcephaly and 3 had pachygyria on brain imaging. Three patients had variable dysmorphic features including low-set and folded ears, arched eyebrows, mild synophrys, ptosis, epicanthal folds, hypertelorism, broad nasal bridge, upturned nose, high palate, thin upper lip, protruding tongue, clinodactyly, and brachydactyly. All patients had behavioral problems such as tantrums, volatile mood, clapping, hand-flapping, and attention deficit-hyperactivity disorder features. Three patients had scoliosis and/or joint laxity. Three patients had immunologic findings of hypogammaglobulinemia and mild IgA or IgG deficiency. Two patients had ataxia. One patient had seizures.

Trinh et al. (2017) reported a 7-year-old German boy with features of OCNDS. At last examination at age 6.5 years, he had global developmental delay, impaired intellectual development, borderline microcephaly, brachycephaly, and dysmorphic features. Psychometric testing showed impaired social responsiveness. The patient had developmental delay in most areas, but average performance in articulation and receptive language. Sleeping difficulties and hyperactive behavior were also observed. EEG was unremarkable, and brain MRI showed a solid lesion of the pineal gland with minor cystic inclusions, which was not thought to be clinically significant.

Chiu et al. (2018) summarized findings in their 8 patients and 6 previously reported patients with OCNDS. Common facial features included microcephaly, hypertelorism, epicanthic folds, ptosis, arched eyebrows, low-set ears, ear-fold abnormalities, broad nasal bridge, and round face. Other clinical findings included neurodevelopmental delay in 93%, gastrointestinal issues in 57%, musculoskeletal issues in 57%, and immunologic abnormalities in 43%. None of the patients were reported to have a malignancy. The male:female ratio was 1:1.

Owen et al. (2018) described an additional 11 children with OCNDS from the DDD study, all of whom had impaired intellectual development and short stature. Other clinical features reported in at least 3 affected patients included neonatal hypotonia in 7, autistic spectrum traits in 4, swallowing difficulties in 3, and congenital heart disease in 3 (2 with septal defects and 1 with tetralogy of Fallot). Microcephaly was seen in only 1 patient. Shared facial features included malar flattening, depressed nasal bridge, short nose, thin upper vermilion, epicanthus, short philtrum, and widely spaced teeth, but the authors noted that there was not a recognizable facial gestalt. Recurrent infections were not reported in the patients. Brain MRI was normal in 5 of 6 patients, with delayed myelination in 1 patient.

Akahira-Azuma et al. (2018) reported an 8-year-old Japanese boy with OCNDS. He had an IQ of 21-35 at age 7 years 4 months (Tanaka-Binet scale), motor and speech delay, severe growth retardation with relative macrocephaly, behavioral problems, distinctive facial features, and abnormal MRI findings. His behavior was described as hyperactive and very friendly and interactive. Facial features included synophrys, hypertrichosis, downslanting palpebral fissures, and bulbous nose. The authors noted that some of these findings were suggestive of Kleefstra syndrome (610253), Coffin-Siris syndrome (135900), or Rubinstein-Taybi syndrome (180849). Brain MRI findings included a reduced anterior pituitary gland and delayed myelination.

Clinical Management

Chiu et al. (2018) made the following recommendations for the management of patients with OCNDS: (1) assessment by a clinical geneticist; (2) comprehensive neurodevelopmental assessment and multidisciplinary training; (3) serial measurement of growth, nutrition and skeletal malformation; (4) serial measurement of head circumference; and (5) immunologic evaluation if any suspicion of frequent or severe infections.

Molecular Genetics

In 5 unrelated girls with OCNDS, Okur et al. (2016) identified de novo heterozygous mutations in the CSNK2A1 gene (115440.0001-115440.0005), including 4 missense mutations and 1 splice site mutation. Functional studies of the variants and studies of patient cells were not performed, but Okur et al. (2016) noted that the CSNK2A1 gene is expressed in the brain and encodes the catalytic subunit of protein kinase CK2, which is involved in many biologic processes. The mutations were found by whole-exome sequencing of 4,102 patients with developmental delay/intellectual disability.

In a 7-year-old German boy with OCNDS, Trinh et al. (2017) identified a de novo heterozygous missense mutation (D156H; 115440.0006) in the CSNK2A1 gene. The variant was identified by trio exome sequencing and confirmed by Sanger sequencing.

Chiu et al. (2018) summarized data on 16 variants in the CSNK2A1 identified in 22 patients with OCNDS. All but 2 variants were located in the large protein kinase domain that spans exons 4 to 12. The most common area for variants was in exon 9, including the most frequently observed variant, K198R (115440.0002), which was found in 5 cases. Variants were believed to be disruptive by altering highly conserved amino acids with important roles in stabilization and substrate recognition.

Among 11 patients with OCNDS, Owen et al. (2018) identified 8 different de novo heterozygous missense mutations in the CSNK2A1 gene, including K198R, which was found in 4 unrelated individuals, suggesting a hotspot at this location.

Akahira-Azuma et al. (2018) identified de novo heterozygosity for the recurrent K198R mutation in the CSNK2A1 gene in an 8-year-old Japanese boy with OCNDS.