Clinical characteristics.

CSNK2B-related neurodevelopmental disorder (CSNK2B-NDD), reported in more than 80 individuals to date, is characterized in most individuals by developmental delay (DD) / intellectual disability (ID) and seizures. Most young children have delays in speech and motor development. The majority of individuals older than age five years at the time of evaluation have ID ranging from borderline/mild to severe/profound. Seizures, present in most individuals, range in type and severity. While many individuals have pharmaco-responsive epilepsy, others have severe epilepsy with recurrent episodes of refractory status epilepticus. Less consistent findings include ataxia or impaired coordination, generalized hypotonia of infancy, neurobehavioral/psychiatric manifestations, and digital anomalies.

Diagnosis/testing.

The diagnosis of CSNK2B-NDD is established in a proband with suggestive findings and a heterozygous CSNK2B pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This includes multidisciplinary care by specialists in pediatrics, developmental pediatrics, neurology, physical medicine and rehabilitation, physical therapy, occupational therapy, speech therapy, social work, and medical genetics / genetic counseling.

Surveillance: To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, routinely scheduled evaluations with multidisciplinary care providers are recommended.

Genetic counseling.

CSNK2B-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Almost all probands reported to date whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant. Rarely, individuals diagnosed with CSNK2B-NDD have an affected parent. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband is known to have the CSNK2B pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once the CSNK2B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

CSNK2B-NDD should be considered in probands with the following clinical findings and family history.

Clinical findings

• Mild-to-profound developmental delay (DD), intellectual disability (ID), or learning disability
• Epilepsy ranging from mild pharmaco-responsive epilepsy to severe intractable epilepsy with recurrent status epilepticus. Seizure types include the following:
  • Generalized tonic or tonic-clonic seizures
  • Absence seizures
  • Myoclonic seizures
  • Atonic or myoclonic-atonic seizures
  • Myoclonic-absence seizures
  • Focal-onset seizures

Less common and variable findings include the following:

• Ataxia or impaired coordination
• Generalized hypotonia of infancy
• Neurobehavioral/psychiatric manifestations
• Facial features
• Digital abnormalities
• Short stature

Family history. Because CSNK2B-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of CSNK2B-NDD is established in a proband with suggestive findings and a heterozygous CSNK2B pathogenic (or likely pathogenic) variant identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous CSNK2B variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with exome sequencing / genome sequencing [Manickam et al 2021, Smith et al 2023]. Other options include use of chromosomal microarray analysis (CMA) or a multigene panel. Note: Single-gene testing (sequence analysis of CSNK2B, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability or epilepsy multigene panel that includes CSNK2B 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 CSNK2B-NDD, some panels for intellectual disability or epilepsy 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. Genome sequencing is also possible. To date, the majority of reported CSNK2B pathogenic variants (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing. Of note, some CSNK2B pathogenic splicing variants beyond the canonical splice site have been identified [Zhang et al 2022].
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

CSNK2B-related neurodevelopmental disorder (CSNK2B-NDD) is characterized by seizures and variable degrees of developmental delay / intellectual disability. Less consistent findings include ataxia or impaired coordination, generalized hypotonia of infancy, neurobehavioral/psychiatric manifestations, digital abnormalities, and nonspecific facial features.

To date, more than 80 individuals have been identified with a CSNK2B pathogenic variant [Poirier et al 2017, Li et al 2019, Ernst et al 2021, Yang et al 2021, Asif et al 2022, Orsini et al 2022, Wilke et al 2022, Yang et al 2022, Zhang et al 2022, Trivisano et al 2023]. The following description is based on the well-documented phenotypic features of these individuals (see Table 2).

Developmental delay (DD) and intellectual disability (ID). While most individuals have developmental delays and/or intellectual disability, there is marked variability in developmental outcomes.

The following discussion is based on information reported on 48 individuals in publications with at least two individuals with CSNK2B-NDD on whom neurodevelopmental outcomes and age of evaluation are included [Poirier et al 2017, Ernst et al 2021, Yang et al 2021, Yang et al 2022, Trivisano et al 2023]. Ages at the time of evaluation of these individuals ranged from younger than five years (16 individuals), 5-17 years (25 individuals), and 18 years and older (7 individuals).

Of these individuals, the majority (45/48) had developmental delays in at least one domain. Most (39/45) had both speech and motor delays. Of the three individuals reported not to have developmental delay, two were younger than age five years and one (age nine years at the time of evaluation) had a learning disability [Ernst et al 2021, Yang et al 2022].

• Motor delay. Of the 93% (42/45) who had motor delay, the average age of independent walking was 24 months. Sixteen of 21 individuals achieved independent walking by age three years. Five individuals walked after age three years (range: 4-7 years).
  Two males older than age five years were unable to ambulate independently by the time of evaluation; both had severe epilepsy with recurrent refractory status epilepticus associated with regression. The 12-year-old male lost the ability to walk independently at age nine years; the 26-year-old male had started to walk independently at age seven years but was unable to walk without assistance by the time of evaluation [Ernst et al 2021].
• Speech delay. Of the 40 of 46 individuals who had speech delays, five were nonverbal or minimally verbal at the time of evaluation. Three of the five were ages 5 to 17 years; two were adults.

Of those older than age five years at the time of evaluation, 23 of 29 had ID. Twelve had borderline or mild ID; five had moderate ID; five had severe or profound ID; and one individual's level of ID was not reported. Of the six who did not have intellectual disability, four had a learning disability.

Trivisano et al [2023] also described two families with multiple affected individuals with intrafamilial variability regarding developmental outcomes.

One study noted a possible difference in neurodevelopment outcomes between males and females, with males having a more severe intellectual disability (see Figure 1b in Ernst et al [2021]).

Epilepsy. Age of seizure onset ranged from during the neonatal period to age 10 years. Some individuals had febrile seizures only or an isolated unprovoked seizure and did not meet criteria for epilepsy. Ninety percent of individuals who had developed epilepsy by the time they were reported had their first seizure at age three years or younger [Ernst et al 2021, Yang et al 2022, Trivisano et al 2023].

Epilepsy types included generalized epilepsy, focal epilepsy, and combined generalized and focal epilepsy [Ernst et al 2021]. Seizure types included tonic-clonic, myoclonic, atonic, myoclonic-atonic, absence, atypical absence, myoclonic-absence, and tonic. While the most common seizure type was generalized tonic-clonic, seizures seen initially in infants were often focal or myoclonic [Ernst et al 2021].

The severity of epilepsy was highly variable [Ernst et al 2021]. At least one individual had only a single seizure at age 1.5 months by the time of evaluation at age 12 years, whereas many individuals had multiple seizures daily. Seizures tended to cluster in many individuals. While many individuals had pharmaco-responsive epilepsy, others had severe epilepsy with recurrent episodes of refractory status epilepticus [Li et al 2019, Ernst et al 2021, Trivisano et al 2023]. No anti-seizure medication (ASM) has been demonstrated to have specific efficacy in CSNK2B-NDD, and different ASMs have been reported to be effective in different individuals.

Although the course of epilepsy tended to improve with age, several individuals experienced increased seizure frequency between ages 7 and 12 years [Ernst et al 2021].

EEG is often characterized by generalized epileptiform discharges, including generalized spike-and-wave and polyspikes [Ernst et al 2021]. Epileptiform abnormalities most often were high amplitude generalized or lateralized polyspikes occurring during sleep [Ernst et al 2021].

Multifocal epileptiform abnormalities were also described [Trivisano et al 2023].

Less commonly, some individuals with epilepsy had EEG studies that did not report epileptiform abnormalities (e.g., Patient 5 in Trivisano et al [2023]).

Slowing of the EEG background was observed in about 50% of individuals [Ernst et al 2021, Trivisano et al 2023].

Neuroimaging. Brain MRI abnormalities are variable with no identifiable persistent patterns. Nonspecific findings reported in a few or single individuals include the following:

• Delayed myelination (3 individual) [Li et al 2019, Ernst et al 2021, Orsini et al 2022]
• Enlargement of subarachnoid spaces (2 individuals) [Yang et al 2021], which resolved in one individual on later imaging [Li et al 2019]
• Ventriculomegaly that resolved on later imaging (1 individual) [Yang et al 2022]
• Cortical gyral simplification [Orsini et al 2022]
• Periventricular gliosis (1 individual) [Ernst et al 2021]
• Pineal gland abnormalities [Trivisano et al 2023]
• Scattered signal abnormalities identified in gray and white matter [Yang et al 2021, Zhang et al 2022]

Hindbrain abnormalities reported in one or more individuals include T₂ hyperintensity and restricted diffusion in the pontine central tegmental tracts, pontine hypoplasia, cerebellar vermis hypoplasia with a large cisterna magna, and Chiari malformation [Ernst et al 2021].

Microcephaly, seen in one individual, was associated with severe intellectual disability [Orsini et al 2022].

Neurobehavioral/psychiatric manifestations. Behavioral manifestations (including tantrums, aggression, and hyperactivity) were reported in 26/83 individuals in well-described cohorts. Eleven individuals had autism spectrum disorder or autistic features; eight had attention-deficit/hyperactivity disorder (ADHD); and one had anxiety, depression, and obsessive-compulsive disorder [Asif et al 2022].

Other reported findings include the following:

• Ataxia / poor coordination (10/81 individuals) [Ernst et al 2021, Trivisano et al 2023]
• Ectodermal anomalies [Poirier et al 2017, Ernst et al 2021, Asif et al 2022, Orsini et al 2022, Wilke et al 2022, Zhang et al 2022, Trivisano et al 2023]
  • Dental abnormalities (14 individuals), including widely spaced teeth, small teeth, large central or superior incisors, hyperdontia, hypodontia, diastema, delayed tooth eruption, and prominence of the upper dental arch
  • Skin findings (several individuals), including soft/translucent skin, intermittent rashes, congenital scalp nevus sebaceous, vascular skin abnormality, partial hypopigmentation, and hypopigmented and hyperpigmented macules
  • Hair findings (3 individuals), including thin hair, one of whom had sparse temporal hair and coarse posterior hair
• Endocrine/growth
  • All five individuals reported by Yang et al [2022] had short stature. Of the two who underwent growth hormone (GH) stimulation testing, one had complete GH deficiency and one had partial GH deficiency.
  • One individual reported by Ernst et al [2021] had partial GH deficiency, short stature, and hypoglycemia of childhood, and another individual had delayed bone age / puberty.
  • One individual was noted to have growth delay [Orsini et al 2022], one was reported to have short stature [Asif et al 2022], and one was reported to have growth stagnation in infancy [Trivisano et al 2023].
• Cardiovascular abnormalities. Since each of the following cardiac abnormalities (reported in one individual) can be seen in the general population, it is unclear whether they are manifestations of CSNK2B-NDD or incidentally identified: congenital heart disease (unspecified) [Ernst et al 2021], patent foramen ovale [Ernst et al 2021], Ebstein anomaly and atrial septal defect [Asif et al 2022], fenestrated atrial septal defect [Asif et al 2022], Wolff-Parkinson-White syndrome [Asif et al 2022], episodes of supraventricular tachycardia at birth [Ernst et al 2021], mitral and tricuspid valve insufficiency [Orsini et al 2022], episode of unspecified cardiac arrhythmia at birth [Trivisano et al 2023], and aortic root dilatation (z score = 2.4].
• Genital abnormalities. Undescended testes were reported in two individuals; hypospadias and uterine agenesis was reported in one individual [Ernst et al 2021, Zhang et al 2022]. It is unclear if these are incidental findings or manifestations of CSNK2B-NDD.
• Microcephaly and macrocephaly. Multiple individuals have had either microcephaly (15%) [Ernst et al 2021, Asif et al 2022, Orsini et al 2022, Wilke et al 2022] or macrocephaly (7%) [Ernst et al 2021].
• Digital abnormalities include clinodactyly of fingers and toes; syndactyly of fingers and toes; polydactyly; tapered fingers; hypoplasia of fingers and toes; broad thumb; protonation of feet; nail hypoplasia; and both long and short fingers [Ernst et al 2021, Asif et al 2022, Orsini et al 2022, Wilke et al 2022]. One individual with contractures of the first, fourth, and fifth fingers of one hand required surgery to release a trigger finger [Asif et al 2022].
• Facial features. In about half of individuals a facial gestalt can be seen, variably including a broad or narrow forehead; frontal bossing; wide-spaced and/or deep-set eyes; a wide and/or depressed nasal bridge; bulbous nose or broad nasal tip; underdeveloped ala nasi; smooth philtrum; thin vermilion of the upper lip; wide mouth; downturned corners of the mouth; prognathism; a pointed chin; and various ear abnormalities (e.g., overfolded helix, forward-facing ear lobes) [Asif et al 2022, Di Stazio et al 2023].

Intrafamilial variability. In one reported family, the proband had a history of neonatal hypoxia, hypotonia, moderate ID, epilepsy, and disruptive behavior disorder; the proband's father, who had the same CSNK2B pathogenic variant, had mild ID and febrile seizures that did not requirement treatment. In another family, the mother and proband had mild cognitive disability, whereas an affected sib with the same CSNK2B pathogenic variant had normal cognitive ability and ADHD [Trivisano et al 2023].

Prognosis. It is unknown whether life span in CSNK2B-NDD is abnormal. One individual is alive at age 36 years [Ernst et al 2021], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been established across all variant classes, given high phenotypic variability and the small total number of individuals reported to date, the small number of individuals with recurrent variants, and the inconsistent reporting of certain phenotypic features. Nonetheless, genotype-phenotype correlations have been proposed for missense variants affecting certain residues [Ernst et al 2021, Zhang et al 2022]:

• Substitutions at p.Asp32 (p.Asp32Asn or p.Asp32His), reported in individuals with intellectual disability and craniodigital anomalies [Asif et al 2022]
• Missense variants in the zinc finger domain (amino acids 105-140), associated with milder intellectual disability and more manageable seizures than CSNK2B missense variants in other domains [Zhang et al 2022]

Nomenclature

The term "intellectual disability-craniodigital syndrome (IDCS)" was proposed to refer to the phenotype observed in individuals with substitutions in CSNK2B at p.Asp32 [Asif et al 2022]. That these CSNK2B missense variants cause a distinct syndrome has been challenged, as individuals with other pathogenic CSNK2B variants have been reported with similar dysmorphisms and digital abnormalities [Di Stazio et al 2023] (see Genotype-Phenotype Correlations).

Prevalence

To date, more than 80 individuals have been identified with a CSNK2B pathogenic variant (see Clinical Description).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CSNK2B-NDD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for CSNK2B-NDD. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

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

CSNK2B-related neurodevelopmental disorder (CSNK2B-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Almost all probands reported to date with CSNK2B-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo CSNK2B pathogenic variant.
• Rarely, individuals diagnosed with CSNK2B-NDD have an affected parent. Transmission of a CSNK2B pathogenic variant from an affected parent to an affected child has been reported in two families to date [Trivisano et al 2023].
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• 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 CSNK2B pathogenic variant.
  • The proband inherited a CSNK2B pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a CSNK2B pathogenic variant that is present in the germ (gonadal) cells only.

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

• If a parent of the proband is known to have the CSNK2B pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Of note, significant intrafamilial clinical variability has been observed in the two families reported to date with recurrence [Trivisano et al 2023] (see Clinical Description, Intrafamilial variability).
• If the CSNK2B pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with CSNK2B-NDD has a 50% chance of inheriting the CSNK2B pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CSNK2B pathogenic variant, the parent's family members may be at risk.

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 young adults who are affected and parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the CSNK2B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

CSNK2B encodes casein kinase II subunit beta (CK2β), a regulatory subunit of casein kinase II (CK2), a serine/threonine kinase implicated in many diverse cellular functions. The holoenzyme is a heterotetramer comprised of two catalytic alpha subunits (combinations of α and α') flanking a beta subunit, the latter specifically encoded by CSNK2B [Niefind et al 2001]. Casein kinase is ubiquitously expressed with high levels of expression in the brain [Guerra et al 1999]. The alpha subunit is encoded by CSNK2A1, which has also been associated with neurodevelopmental disease [Okur et al 2016] (see Okur-Chung Neurodevelopmental Syndrome).

Mechanism of disease causation. The mechanism of disease causation in CSNK2B-related neurodevelopmental disorder is not fully understood. Because a subset of CSNK2B pathogenic variants is expected to result in reduced beta subunit expression, haploinsufficiency appears to be one important disease mechanism [Di Stazio et al 2023]. Indirect support for reduced CK2β expression as a cause of nervous system dysfunction comes from experimental evidence showing altered dendritic arborization and synaptic physiology because of CSNK2B knockdown in neural stem cells [Yang et al 2018]. Although reduced holoenzyme formation and activity is the presumed relevant consequence of CSNK2B haploinsufficiency, holoenzyme-independent mechanisms are also possible.

It is unclear whether some CSNK2B missense pathogenic variants might be hypomorphic alleles or have a dominant-negative effect in reducing activity of the heterotetramer in a more profound way (as proposed by Asif et al [2022]).

Author Notes

Natalie Lippa, MS, CGC, is Assistant Professor of Genetic Counseling in the Department of Medicine at Columbia University Vagelos College of Physicians and Surgeons.

Maureen Mulhern, MS, MAT, CGC, is a genetic counselor in the Inter-Departmental Genetic Counseling Program, Department of Neurology, and in the Precision Genomics Laboratory at the Columbia University Vagelos College of Physicians and Surgeons.

Michelle Ernst Florido, MS, CGC, is Assistant Program Director for the Genetic Counseling Graduate Program at the Columbia University Vagelos College of Physicians and Surgeons.

Chelsea Earley, MD, is a pediatric clinical epilepsy fellow at Columbia University Irving Medical Center.

Tristan T Sands, MD, PhD, is Assistant Professor of Neurology at the Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Morgan Stanley Children's Hospital. Dr Sands sees patients with genetic causes of epilepsy and neurodevelopmental disability, and his laboratory conducts translational research as part of the Center for Translational Research in Neurodevelopmental Disease (CTRND).

The CTRND at Columbia University is actively involved in ongoing clinical and translational research on CSNK2B-related neurodevelopmental disorder. Contact Dr Sands (ude.aibmuloc.cmuc@72stt) with clinical questions or research interests.

Acknowledgments

We would like to thank the CSNK2B Neurodevelopmental Syndrome Foundation and patients with CSNK2B-NDD and their families.

Revision History

• 5 September 2024 (bp) Review posted live
• 7 August 2023 (ts) Original submission

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