Clinical characteristics.

CASK disorders include a spectrum of phenotypes in both females and males. Two main types of clinical presentation are seen:

• Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK
• X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants

MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting.

MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable.

In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features.

Diagnosis/testing.

The diagnosis of a CASK disorder is established in a female who is heterozygous for a CASK pathogenic variant and in a male who is hemizygous for a CASK pathogenic variant on molecular genetic testing. Rarely, affected males have a mosaic pathogenic variant.

Management.

Treatment of manifestations: Treatment is symptomatic and includes standard management of developmental delay and intellectual disability issues; medication for seizures; nutritional support; use of physiotherapy; and treatment of abnormal vision or hearing loss.

Genetic counseling.

CASK disorders are inherited in an X-linked manner. Risk to the family members of a proband with a CASK disorder depends on the phenotype (i.e., MICPCH or XLID ± nystagmus) in the proband.

• MICPCH. Most affected females and males represent simplex cases (i.e., the only affected family member) and have the disorder as the result of a de novo CASK pathogenic variant. Because heterozygous females manifest the phenotype, an asymptomatic mother is unlikely to be heterozygous for the CASK pathogenic variant. If a proband represents a simplex case, the recurrence risk to sibs appears to be low but greater than that of the general population because of the possibility of parental germline mosaicism.
• XLID ± nystagmus. The father of a male with a CASK disorder will not have the disorder nor will he be hemizygous for the CASK pathogenic variant. If a male is the only affected family member, the mother may be a heterozygote or the affected male may have a de novo pathogenic variant. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. If the mother of the proband has a CASK pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will typically be asymptomatic but may have a range of manifestations. If the CASK pathogenic variant cannot be detected in maternal leukocyte DNA, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism.

Once the CASK pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a CASK disorder are possible.

Suggestive Findings

CASK disorders should be considered in individuals with intellectual disability of any degree and any of the following additional findings:

• Progressive microcephaly up to -10 SD
• Pontine and cerebellar hypoplasia
• Hypotonia, hypertonia, or a combination of both (central hypotonia and hypertonia of extremities)
• Seizures (including early and intractable seizures comprising Ohtahara syndrome, West syndrome, or myoclonic epilepsy)
• Nystagmus, strabismus, optic nerve hypoplasia, and/or retinopathy
• Sensorineural hearing loss
• Short stature

Establishing the Diagnosis

The diagnosis of a CASK disorder is established in a female who is heterozygous for a CASK pathogenic variant and in a male who is hemizygous for a CASK pathogenic (or likely pathogenic) variant (see Table 1).

Note: (1) Rarely, affected males have a mosaic pathogenic variant. (2) Per ACMG 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. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Because the phenotype of CASK disorders is often indistinguishable from many other inherited disorders with intellectual disability, microcephaly, and/or pontine and cerebellar hypoplasia, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of CASK, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A multigene panel for intellectual disability or brain malformation or specialized for pontocerebellar hypoplasia that includes CASK and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition 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. (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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible.
  Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/ duplication analysis (which may include exome array or chromosomal microarray analysis to detect exon and whole-gene deletions or duplications).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: (1) In a few males, CASK rearrangements in the hemizygous state as well as CASK rearrangements and a deletion-insertion variant in the mosaic state have been reported [Saitsu et al 2012, Moog et al 2015, Hayashi et al 2017]. (2) Karyotype analysis may be appropriate when sequence analysis and deletion/duplication analysis do not identify a pathogenic variant and the suspicion of a CASK disorder is high. Two females with a balanced Xp inversion disrupting CASK have been observed [Najm et al 2008; K Kutsche, unpublished].

Clinical Description

CASK disorders are more commonly reported in females and include a spectrum of phenotypes that differs in females and males:

• Females typically have moderate-to-severe intellectual disability and in most individuals, progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH). Possible findings are ophthalmologic anomalies and sensorineural hearing loss. Females who are relatives of males with the X-linked intellectual disability (XLID) ± nystagmus phenotype may rarely present with a mild-to-severe intellectual disability phenotype.
• In males the spectrum is broad, ranging from severe (intellectual disability and MICPCH, or early-infantile epileptic encephalopathy [Ohtahara syndrome, West syndrome, or early myoclonic epilepsy]) to mild (XLID ± nystagmus and additional clinical features) [Moog et al 2015].

To date, 130 individuals (45 males and 85 females) have been identified with a pathogenic variant in CASK [Moog et al 2011, Burglen et al 2012, Hayashi et al 2012, Takanashi et al 2012, Moog et al 2015, Dunn et al 2017, Hayashi et al 2017, Muthusamy et al 2017, Cristofoli et al 2018, Rama Devi et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.

Females

A total of 85 females with MICPCH have been reported to date, the eldest of whom is age 25 years. The following information about the natural history is based on the recent reviews of Moog et al [2011], Burglen et al [2012], Hayashi et al [2012], and Takanashi et al [2012] unless otherwise noted.

Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH)

Head circumference. At birth the occipital frontal circumference (OFC) is in the normal or low-normal range in approximately two thirds of affected females; the others show microcephaly (OFC < -2 SD). Microcephaly invariably becomes severe (OFC -3.5 to -10 SD) during the first year, and usually during the first four months of life.

Developmental delay / intellectual disability (DD/ID). Affected females acquire head control and make eye contact in the range of two to 24 months. Most affected females are able to sit independently between seven and 36 months; only 20%-25% attain the ability to walk (between 18 and 72 months).

Language is nearly absent in most; some utter words. One individual could say two-word sentences. Intellectual development is severely impaired in nearly all affected females, with a few showing moderate ID.

The behavioral phenotype may include sleep disturbances, hand stereotypies, and self biting.

Neurologic features include (axial) hypotonia, hypertonia of the extremities (possibly progressing to spasticity), and dystonia or other movement disorders. Seizures of various types are observed in about 40%; onset is between birth and age ten years.

The severity of the pontocerebellar hypoplasia observed on MRI is not of prognostic value [Moog et al 2011].

MRI findings

• Pontine and cerebellar hypoplasia with diffuse mild-to-severe hypoplasia of the cerebellum affecting the hemispheres and vermis proportionally [Moog et al 2011, Burglen et al 2012, Hayashi et al 2012, Takanashi et al 2012] (Figure 1). Pons and cerebellum have been reported to have a normal appearance in two females with progressive microcephaly, ID, and a pathogenic variant in CASK [Cristofoli et al 2018].
  • Cerebellar hemispheres can be affected asymmetrically.
  • Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
• Normal- or low normal-sized corpus callosum with low cerebrum / corpus callosum ratio [Takanashi et al 2010]
• Associated MRI finding: mildly reduced number and complexity of gyri in the frontal region of the cerebral cortex and mild dilatation of the lateral ventricles [Moog et al 2011]

Figure 1.

MRI of the brain of a girl age 2.5 years with MICPCH and a heterozygous CASK pathogenic variant a. Sagittal image showing mild pontocerebellar hypoplasia with sparing of pontine bulging. The corpus callosum is normal.

Other findings

• Birth length is normal. Short stature is common by age four years [Moog et al 2011, Takanashi et al 2012].
• Scoliosis is frequently observed.
• Various ophthalmologic findings can be observed, in particular optic nerve hypoplasia, retinopathy, nystagmus, and strabismus [LaConte et al 2019].
• Approximately 28% of affected females have sensorineural hearing loss [Moog et al 2011, Burglen et al 2012, Takanashi et al 2012].
• Congenital visceral anomalies (e.g., renal/urologic or cardiac anomalies) are rarely seen; no particular anomaly occurs recurrently.
• Recent reviews suggest a facial phenotype consisting of well-drawn arched eyebrows, a broad nasal bridge and tip, small or short nose, long philtrum or protruding maxilla, small chin, and large ears.

Mortality in affected females has not been reported.

X-Linked Intellectual Disability (XLID) ± Nystagmus

Clinical findings in the majority of heterozygotes (typically identified as relatives of more severely affected males):

• Normal intelligence; mild-to-severe ID in some females only
• Normal-to-mild ocular findings including congenital nystagmus and strabismus
• No additional neurologic signs besides mild tremor or absence seizures
• MRI finding: normal or mainly unknown

Genotype-Phenotype Correlations

In females, microcephaly with pontine and cerebellar hypoplasia (MICPCH) is typically associated with heterozygous CASK pathogenic loss-of-function variants [Moog et al 2011, Burglen et al 2012, Hayashi et al 2012, Takanashi et al 2012, Hayashi et al 2017]. The X-linked intellectual disability (XLID) with or without nystagmus phenotype in females is typically associated with CASK hypomorphic pathogenic variants.

In males, the three clinically distinguishable groups are associated with different classes of pathogenic CASK variants [Moog et al 2015]:

• In males with MICPCH with severe epileptic encephalopathy, the most severe phenotype, the majority of CASK pathogenic variants are germline loss-of-function alterations.
• In the group with MICPCH, males are somatic mosaics of a CASK loss-of-function variant or carry partly penetrant variants in the hemizygous state.
• The largest group of males with XLID with or without nystagmus typically have CASK hypomorphic pathogenic variants, including missense and splice variants [Moog et al 2015].

Penetrance

Penetrance for the MICPCH phenotype (associated with the heterozygous CASK pathogenic loss-of-function variants) appears to be complete in the female individuals reported to date.

Penetrance of CASK pathogenic variants appears to be complete in males. In males with mosaic CASK pathogenic variants the level of somatic mosaicism may be one factor that determines clinical variability. In females heterozygous for a pathogenic hypomorphic CASK variant penetrance is incomplete with high clinical variability.

Nomenclature

An FG syndrome (FGS)-like phenotype has been suggested as a distinct CASK-related phenotype based on findings in affected males from two families [Piluso et al 2009, Dunn et al 2017]. However, with the exception of FGS1 caused by a recurrent MED12 pathogenic variant (see MED12-Related Disorders), FGS is not clearly defined and FGS4 is not discernible as phenotype. Thus, it seems more appropriate to subsume the phenotype described in these families under XLID with or without nystagmus.

Prevalence

The prevalence of CASK disorders is unknown. At least 130 individuals (45 males and 85 females) with a CASK pathogenic variant have been reported.

Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH)

X-Linked Intellectual Disability (XLID) ± Nystagmus

XLID with nystagmus may be seen in the X-linked disorder Allan-Herndon-Dudley syndrome caused by hemizygous pathogenic variants in SLC16A2. These individuals show severe ID, microcephaly, neurologic features (spasticity, dystonia, and ataxia), scoliosis, large ears, and other dysmorphisms. Nystagmus is reported in some individuals.

XLID without nystagmus has a broad differential diagnosis as a multitude of genes are known to cause nonsyndromic and syndromic XLID (see OMIM Phenotypic Series: Nonsyndromic XLID and Syndromic XLID).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a CASK disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the 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

Intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) and X-linked intellectual disability (XLID) with or without nystagmus are caused by pathogenic variants in CASK and are inherited in an X-linked manner.

Risk to the family members of a proband with a CASK disorder depends on the phenotype (i.e., MICPCH or XLID ± nystagmus) in the proband.

Risk to Family Members

Parents of a female proband

• MICPCH. Most females with MICPCH represent simplex cases (i.e., the only affected family member) and have the disorder as the result of a de novo CASK pathogenic variant. However, it is possible (though not likely) that a female with MICPCH inherited a CASK pathogenic variant from a mother or a father with somatic and/or germline mosaicism.
  If the parents of the proband are asymptomatic, they are unlikely to have the pathogenic variant because penetrance of the MICPCH phenotype appears to be complete. However, it is possible (though not likely) that a parent of the proband has somatic and/or germline mosaicism.
• XLID ± nystagmus. A female with XLID ± nystagmus may have the disorder as the result of a de novo pathogenic variant or a pathogenic variant inherited from her mother. (Because hemizygous males are affected, it is unlikely that a female with XLID ± nystagmus would have inherited a pathogenic variant from her father.)
• Molecular genetic testing of the mother (and possibly the father) may help to determine if the CASK pathogenic variant was inherited.
• Note: If the CASK pathogenic variant cannot be detected in either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.

Parents of a male proband

• The father of a male with a CASK disorder will not have the disorder nor will he be hemizygous for the CASK pathogenic variant; therefore, he does not require further evaluation/testing.
• MICPCH. Most males with MICPCH with or without severe epileptic encephalopathy represent simplex cases (i.e., the only affected family member) and have the disorder as the result of a de novo or somatic mosaic CASK pathogenic variant.
  If the mother of the proband is asymptomatic, she is unlikely to be heterozygous for the pathogenic variant because penetrance of the MICPCH phenotype appears to be complete. However, it is possible (though not likely) that the mother has somatic and/or germline mosaicism. (Mosaicism for a CASK deletion has been described in an asymptomatic other of an affected male [Saitsu et al 2012].)
• XLID ± nystagmus. If a male is the only affected family member, the mother may be a heterozygote* or the affected male may have a de novo pathogenic variant (as most males have been identified as the result of evaluating families with XLID, it is unknown how many affected males represent simplex cases). In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote.
  Molecular genetic testing of the mother is recommended to confirm her genetic status. (Note: If a woman has more than one affected child and no other affected relatives and if the CASK pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.)
  * Heterozygous females are typically asymptomatic but may display mild-to-severe ID with or without ocular features, absence seizures, and/or tremor.
• Note: If the CASK pathogenic variant cannot be detected in the mother, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a mother with germline (or somatic and germline) mosaicism. Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism.

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

• MICPCH. If the proband represents a simplex case, the recurrence risk to sibs appears to be low but greater than that of the general population because of the possibility of germline mosaicism in the mother (presenting a risk to male and female sibs) or the father (presenting a risk to female sibs).
• XLID ± nystagmus. If the mother of the proband has a CASK pathogenic variant, the chance of transmitting it in each pregnancy is 50% (males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will typically be asymptomatic but may display mild-to-severe ID with or without ocular features, absence seizures and/or tremor). If the CASK pathogenic variant cannot be detected in maternal leukocyte DNA, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism.

Sibs of a male proband. The risk to the sibs of a proband depends on the genetic status of the mother:

• MICPCH. If the proband represents a simplex case, the recurrence risk to sibs appears to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.
• XLID ± nystagmus. If the mother is heterozygous for the CASK pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%. (Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will typically be asymptomatic but may display mild-to-severe ID with or without ocular features, absence seizures, and/or tremor.) If the CASK pathogenic variant cannot be detected in maternal leukocyte DNA, the risk to sibs is greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of female proband

• MICPCH. To date, females with MICPCH are not known to reproduce.
• XLID ± nystagmus. A female with XLID ± nystagmus has a 50% chance of transmitting the CASK pathogenic variant to each child.

Offspring of a male proband. To date, males with a CASK disorder are not known to reproduce.

Other family members. A male proband's maternal aunts and maternal cousins may be at risk of having the pathogenic variant. Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

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 women who are heterozygous (asymptomatic or symptomatic) or are at risk of being heterozygous.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the CASK pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a CASK disorder are possible.

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 choice, discussion of these issues may be helpful.

Molecular Pathogenesis

CASK encodes the calcium-/calmodulin-dependent serine protein kinase (CASK), a multidomain protein of the membrane-associated guanylate kinase (MAGUK) family. Although expressed in different tissues, CASK is widely distributed in different regions of the brain.

CASK contains:

• An N-terminal calmodulin dependent protein kinase (CamK) domain
• Two L27 (L27.1 and L27.2) domains
• A PSD-95/discs large/ZO-1 (PDZ) domain
• An src homology 3 (SH3)
• A guanylate kinase (GK) domain at the C-terminus

CASK plays a critical role in brain development and function. It controls synapse formation and activity by (1) presynaptic organization and regulation of neurotransmitter release, (2) maintaining the morphology of dendritic spines and trafficking of glutamate receptors to postsynaptic sites, and (3) regulating the transcription of genes involved in cortical development [Hsueh 2006, Hsueh 2009].

Mechanism of disease causation. The majority of CASK pathogenic variants in females with MICPCH and males with MICPCH with or without severe epileptic encephalopathy are predicted null alleles and associated with a severe phenotype [Najm et al 2008, Moog et al 2011, Burglen et al 2012, Hayashi et al 2012, Moog et al 2015, Hayashi et al 2017]. Males with hemizygous pathogenic loss-of-function variants are more severely affected than females.

A few heterozygous missense variants identified in females with MICPCH specifically impair binding of CASK to the interaction partner Mint1 or neurexin. The question remains whether this impairment is sufficient to cause the severe phenotype in females [LaConte et al 2018, LaConte et al 2019].

The hypomorphic CASK pathogenic variants in males (and the rare females) with X-linked intellectual disability with or without nystagmus are mainly missense and splice variants. These variants may interfere with specific functions of the CASK protein, while leaving other functions of CASK intact [Moog et al 2015].

Author Notes

We are interested in determining the phenotypic spectrum and molecular pathogenesis of CASK disorders.

Acknowledgments

We thank the families with individuals affected by MICPCH who are participating in our research programs.

Author History

Kerstin Kutsche, PhD (2013-present)
Ute Moog, MD (2013-present)
Gökhan Uyanik, MD; Hanusch Hospital, Vienna (2013-2020)

Revision History

• 21 May 2020 (ha) Comprehensive update posted live
• 26 November 2013 (me) Review posted live
• 28 February 2013 (kk) Original submission

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