Clinical characteristics.

Individuals with Okur-Chung neurodevelopmental syndrome (OCNDS) frequently have nonspecific clinical features, delayed language development, motor delay, intellectual disability (typically in the mild-to-moderate range), generalized hypotonia starting in infancy, difficulty feeding, and nonspecific dysmorphic facial features. Developmental delay affects all areas of development, but language is more impaired than gross motor skills in most individuals. Intellectual disability has been reported in about three quarters of individuals. Less common findings may include kyphoscoliosis, postnatal short stature, disrupted circadian rhythm leading to sleep disturbance, seizures, and poor coordination.

Diagnosis/testing.

The diagnosis of OCNDS is established in a proband with suggestive findings and a heterozygous pathogenic variant in CSNK2A1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding therapy and consideration of gastrostomy tube placement in those with persistent feeding issues; consideration of growth hormone therapy (as directed by an endocrinologist) in those with short stature and evidence of partial growth hormone deficiency; standard treatment of epilepsy (as directed by a neurologist) with anti-seizure medication; consideration of intravenous immune globulin treatment (as directed by an immunologist) for demonstrated hypogammaglobulinemia; physical therapy / occupational therapy / rehabilitation medicine for those with hypotonia and/or motor coordination issues; standard supportive developmental therapies; standard treatment of scoliosis, constipation, congenital heart defects, renal anomalies / pelviectasis, and sleep disorders.

Surveillance: At each visit: measure growth parameters, growth velocity, and nutritional status; monitor for signs of ongoing feeding issues / safety of oral intake and constipation; assess new neurologic manifestations (seizures, changes in tone, movement disorders, poor coordination); monitor developmental progress, behavior, and educational needs; monitor for evidence of frequent or unusual infections and for signs and symptoms of sleep disturbance. Every one to three years: ophthalmology evaluation.

Genetic counseling.

OCNDS disorder is expressed in an autosomal dominant manner and typically caused by a de novo CSNK2A1 pathogenic variant. Therefore, the risk to other family members is presumed to be low. Rarely, individuals diagnosed with OCNDS have the disorder as the result of a CSNK2A1 pathogenic variant inherited from an affected parent or an unaffected parent with low-level mosaicism in the blood. Once a CSNK2A1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Suggestive Findings

OCNDS should be considered in individuals with the following clinical findings.

Clinical findings

• Mild-to-moderate developmental delay (DD) or intellectual disability (ID)
• Generalized hypotonia in infancy and/or childhood
• Speech delay

AND

• Any of the following features presenting in infancy or childhood:
  • Infant feeding difficulties
  • Seizures, ranging from a single seizure event to intractable epilepsy
  • Behavioral findings including stereotypic movements, autism spectrum disorder, aggressiveness and tantrums, and attention-deficit/hyperactivity disorder
  • Slow growth, failure to thrive, or difficulty gaining weight
  • Nonspecific dysmorphic features (See Clinical Characteristics.)

Family history. Because OCNDS is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

The diagnosis of OCNDS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in CSNK2A1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous CSNK2A1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with DD or an older individual with ID may begin with chromosomal microarray analysis (CMA). Other options include use of a multigene panel or exome or genome sequencing. Note: Single-gene testing (sequence analysis of CSNK2A1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An ID multigene panel that includes CSNK2A1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of OCNDS, some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an ID multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing ID, whereas some multigene panels may not.
  Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Individuals with Okur-Chung neurodevelopmental syndrome (OCNDS) frequently have nonspecific clinical features, delayed language development, motor delay, intellectual disability, generalized hypotonia starting in infancy, difficulty feeding, and nonspecific dysmorphic facial features.

To date, 51 individuals have been identified with a pathogenic variant in CSNK2A1 [Okur et al 2016, Trinh et al 2017, Akahira-Azuma et al 2018, Chiu et al 2018, Colavito et al 2018, Owen et al 2018, Angione et al 2019, Duan et al 2019, Nakashima et al 2019, Martinez-Monseny et al 2020, Wu et al 2020, Seo et al 2020, Wu et al 2021]. The following description of the phenotypic features associated with this condition is based on 36 individuals with clinical data from these reports.

Developmental delay (DD) and intellectual disability (ID). The majority of affected individuals have DD affecting all areas of development. However, language development is more impaired than gross motor skills in most individuals. ID has also been reported in about three quarters of individuals. The average age of acquisition of selected early developmental milestones is as follows (Figure 1):

Figure 1.

Average age at which affected individuals achieved three developmental milestones: unsupported sitting, walking, and first words. The n values below the bar plots indicate the number of individuals for whom data were available for a given milestone. Data (more...)

• Sitting: 11 months (n=20)
• Walking: 28.8 months (n=25)
• First meaningful words: 38.3 months (n=18)

Behavioral findings. Affected individuals have been reported to be affectionate and happy when they are able to communicate. The most common behavior issues reported:

• Stereotypic movements (~1/3 of affected individuals)
• Autism spectrum disorder (~1/4)
• Aggressiveness and tantrums in part related to inability to communicate needs (~1/4)
• Attention-deficit/hyperactivity disorder (~1/5)

Seizures/epilepsy. About one third of affected individuals have been reported to have had a seizure at least once. Some individuals with only a single seizure have not been treated with anti-seizure medication; those with multiple unprovoked seizures have been treated (see Management).

• Intractable seizures reported in some individuals
• Status epilepticus reported in one individual

Other neurologic features

• Mild hypotonia noted from infancy was reported in about two thirds of affected individuals.
• Gait abnormalities and poor motor coordination were reported in about one sixth of individuals. Ataxia has also been reported in a few individuals [Okur et al 2016, Colavito et al 2018].

Gastrointestinal

• Infant feeding difficulties are common and manifest as poor suck in early infancy or difficulty transitioning to solid foods later in infancy.
• Feeding and swallowing difficulties may require gastrostomy tube placement.
• Constipation is common.

Growth. Some affected individuals are smaller at birth, although true intrauterine growth restriction is rare. About one third of affected individuals have been reported to have short stature (14/36; 38%) or failure to thrive (13/36; 36%), with height and weight usually measuring between 2 and 3 SD below the mean for either growth domain in those individuals.

Only one reported individual had congenital microcephaly. Outside of the newborn period, most affected individuals have an occipitofrontal circumference that is below the mean but still within the normal range for age and sex.

Musculoskeletal features. The most common musculoskeletal issues are scoliosis/kyphosis and loose/hyperextensible joints associated with hypotonia. Umbilical and inguinal hernias have also been reported.

Sleep. Sleep issues mainly stemming from circadian rhythm disturbance in early childhood may pose challenges for families. Rarely, individuals may also experience sleep apnea [Chiu et al 2018, Nakashima et al 2019].

Neuroimaging. More than half of the individuals for whom brain MRI results were reported had nonspecific abnormalities. Abnormalities reported in more than one individual include delayed myelination (n=3), smaller anterior pituitary gland (n=2), and thin corpus callosum (n=2). Other reported abnormal brain findings are simple gyral pattern, cerebellar vermis hypoplasia, cerebral atrophy, mega cisterna magna, solid lesion of the pineal gland with minor cystic inclusions, duplication of the pituitary gland, Rathke cleft cysts, and absent olfactory bulbs.

Other associated features (rare)

• Ophthalmologic involvement is nonspecific (e.g., strabismus) and infrequent.
• Endocrinologic. Partial growth hormone deficiency has been reported in two individuals [Chiu et al 2018, Wu et al 2021].
• Immunologic. Individuals with OCNDS tend to have frequent minor infections, and a few individuals have documented IgG deficiency (hypogammaglobulinemia) and/or IgA deficiency.
• Genitourinary abnormalities. Pelvicaliectasia, duplicated renal collection system, ectopic kidney, and labial adhesions have rarely been reported.
• Cardiovascular findings. Atrial septal defect has been reported in three unrelated individuals; pulmonary valve abnormality and tetralogy of Fallot have each been reported in one individual.
• Skin. Dry skin, eczema, palmar erythema, and cutis marmorata have each been reported in one individual.
• Facial features. No specific dysmorphic features have been observed. If present, dysmorphic features include round facies and short, broad nasal tip.

Prognosis. OCNDS is typically not a progressive disease, and individuals achieve many developmental milestones; however, speech difficulties may persist long term. It is unknown whether life span in OCNDS is abnormal; based on current data, life span is not limited by this condition. Data on possible progression are still limited.

Genotype-Phenotype Correlations

The majority of CSNK2A1 pathogenic variants are located in functional domains (Figure 2) of the protein; however, current data are insufficient to support genotype-phenotype correlations.

Figure 2.

Lollipop plot of reported pathogenic CSNK2A1 variants in the literature (n=51) and two-dimensional representation of their locations in the CSNK2A1 protein (x-axis). Blue-filled circles are missense pathogenic variants and red-filled circles are loss-of-function (more...)

Prevalence

OCNDS is rare and the exact prevalence is unknown. Only 51 individuals have been reported in the literature; others have been diagnosed but are not yet included in publications.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with OCNDS, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Okur-Chung neurodevelopmental syndrome (OCNDS) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with OCNDS whose parents have undergone molecular genetic testing have the disorder as a result of a de novo CSNK2A1 pathogenic variant.
• Rarely, individuals diagnosed with OCNDS have the disorder as the result of a CSNK2A1 pathogenic variant inherited from an affected parent or an unaffected parent with low-level mosaicism in the blood [Author, unpublished data].
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Author, unpublished data]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the proband's parents:

• If the CSNK2A1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Author, unpublished data].
• If a parent of the proband is known to have the CSNK2A1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.

Offspring of a proband. Each child of an individual with OCNDS has a 50% chance of inheriting the CSNK2A1 pathogenic variant.

Other family members. Given that most probands with OCNDS reported to date have the disorder as a result of a de novo CSNK2A1 pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo CSNK2A1 pathogenic variant. There is, however, a recurrence risk to sibs based on the possibility of parental germline mosaicism. Given this risk, prenatal and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CSNK2A1 regulates the downstream expression of more than 500 genes as a member of the serine/threonine kinase family of proteins [Borgo et al 2021]. It is postulated that pathogenic variants in CSNK2A1 disrupt the expression levels of genes that regulate neurologic development [Dominguez et al 2021].

Mechanism of disease causation. Loss of function that leads to reduced kinase activity or abnormal localization of the CK2α protein [Dominguez et al 2021]

Author Notes

Simons Searchlight: CSNK2A1

Acknowledgments

We would like to thank the families of individuals with Okur-Chung neurodevelopmental syndrome for their participation in research studies.

Revision History

• 9 June 2022 (ma) Review posted live
• 14 February 2022 (wc) Original submission

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