Cask Disorders
Summary
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.
Diagnosis
CASK disorders are associated with a wide phenotypic spectrum ranging from mild-to-severe intellectual disability with or without nystagmus to moderate-to-profound intellectual disability and progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH), often associated with seizures. CASK disorders are X-linked and more commonly reported in females than in males. MICPCH in females is the most common phenotype to date.
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 variant (see Table 1).
Note: Rarely, affected males have a mosaic pathogenic variant.
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 at the most reasonable cost 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].
Table 1.
Molecular Genetic Testing Used in CASK Disorders
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| CASK | Sequence analysis 3, 4 | ~70% 5, 6 |
| Gene-targeted deletion/duplication analysis 7 | ~30% 5, 6, 7 | |
| CMA 8 | ~28% 5, 8 | |
| Karyotype | Rare 9 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
- 6.
Percentages are based on female probands. Surviving male probands are more likely to have a variant detected by sequence analysis (see Genotype-Phenotype Correlations.)
- 7.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Moog et al [2011], Burglen et al [2012], Hayashi et al [2012], Hayashi et al [2017]) may not be detected by these methods.
- 8.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including CASK) that cannot be detected by sequence analysis. Most reported deletions/duplications in CASK are large enough to be detected by CMA. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the Xp11.4 region. CMA designs in current clinical use target the Xp11.4 region.
- 9.
Two females with a balanced Xp inversion disrupting CASK have been observed [Najm et al 2008; K Kutsche, unpublished].
Clinical Characteristics
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
Males
A total of 45 males from birth to age 59 years with a pathogenic CASK variant have been described [Moog et al 2015, Dunn et al 2017, Hayashi et al 2017, Muthusamy et al 2017, Rama Devi et al 2019].
The phenotype in males represents a clinical continuum from the severe to the mild end of the spectrum and can be classified into three phenotypic groups [Moog et al 2015].
MICPCH with Severe Epileptic Encephalopathy
Head circumference. At birth, the OFC was (low) normal in half of the individuals. The other half had primary microcephaly (OFC <-2 SD). Mild-to-severe postnatal microcephaly evolved rapidly during the first months (OFC -2.7 to -9 SD).
DD/ID. All affected males had severe-to-profound DD or no development at all.
Neurologic features include early and intractable seizures (Ohtahara syndrome [Saitsu et al 2012], West syndrome [Takanashi et al 2012], myoclonic epilepsy [Nakamura et al 2014]), burst suppression and spasms [Moog et al 2015], and hyperkinesia [Rama Devi et al 2019].
MRI findings
- Typically severe diffuse pontocerebellar hypoplasia
- Simplified gyri, cortical atrophy, and hypomyelination may be also observed.
Other findings
- Multiple (minor) anomalies have been reported [Burglen et al 2012, Saitsu et al 2012, Moog et al 2015].
- Septal heart defects, tetralogy of Fallot and hydronephrosis can be observed [Nakamura et al 2014, Moog et al 2015].
Mortality. Males with this phenotype may have perinatal or early lethality. One affected male died at age two months [Rama Devi et al 2019], one at seven months, and another at 21 months [Moog et al 2015].
MICPCH with Severe Developmental Disorder
MICPCH in combination with a severe developmental disorder but without severe epilepsy has been reported in six males. The phenotype of male individuals in this group is comparable to MICPCH in females [Moog et al 2015, Hayashi et al 2017]:
- Head circumference. Postnatal microcephaly
- DD/ID. Severe
- Neurologic features. Mild ataxia reported in one male, dystonia/dyskinesia in another male. No seizures.
- MRI findings. Variable degree of diffuse pontocerebellar hypoplasia
- Other findings. Nystagmus
- Mortality. One affected male died at age two weeks.
X-Linked Intellectual Disability (XLID) ± Nystagmus
Mild-to-severe XLID with or without nystagmus and/or other anomalies have been reported in a total of 29 males [Moog et al 2015, Dunn et al 2017, Hayashi et al 2017].
- DD / mild-to-severe ID
- Seizures/epilepsy
- Congenital nystagmus and other eye findings including strabismus and mild pallor of the optic disc
Brain MRI has been reported in a minority of individuals only and did not show pontocerebellar hypoplasia.
Other findings include microcephaly, hypotonia, autism spectrum disorder, behavioral problems, tremor and unsteady gait, sensorineural hearing loss, feeding difficulties, constipation, short stature, cryptorchidism, and gastrointestinal and gastroesophageal complications.
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.
Differential Diagnosis
Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH)
Table 2.
Genes of Interest in the Differential Diagnosis of MICPCH
| Gene(s) | Disorder | MOI | Clinical Features | Brain MRI Findings |
|---|---|---|---|---|
| SEPSECS TSEN15 TSEN2 TSEN34 VPS53 TSEN54 | PCH2 | AR |
| In persons w/PCH2/PCH4:
|
| TSEN54 | PCH4 | AR | Polyhydramnios, contractures, severe generalized clonus, & central respiratory failure usually → neonatal death | |
| ARX STXBP1 (>80 genes) 1 | Ohtahara syndrome | XL AD | Early-infantile epileptic encephalopathy w/suppression burst | May or may not be assoc w/abnormalities on brain MRI |
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PCH = pontocerebellar hypoplasia; XL = X-linked
- 1.
See Phenotypic Series, Early Infantile Epileptic Encephalopathy for genes associated with this phenotype in OMIM.
- 2.
In CASK disorders, a "butterfly" pattern is visible that results from diffuse hypoplasia of the hemispheres and vermis.
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).
Management
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.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with CASK Disorders
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic | Neurologic eval | To incl brain MRI & EEG if not already done |
| Development | Developmental assessment |
|
| Psychiatric/ Behavioral | Neuropsychiatric eval | For individuals age >12 mos: screening for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD |
| Musculoskeletal | Orthopedics / physical medicine & rehabilitation / PT/OT eval | To incl assessment of:
|
| Gastrointestinal/ Feeding | Gastroenterology / nutrition / feeding team eval |
|
| Eyes | Ophthalmologic eval | Assess for nystagmus, optic nerve hypoplasia, retinopathy, & strabismus. |
| Hearing | Audiologic eval | Assess for hearing loss. |
| Cardiovascular | Echocardiogram | Assess for rare but possible cardiac anomaly. |
| Genitourinary | Ultrasound of the kidneys | Assess for rare but possible renal/urologic anomaly. |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling |
| Family support/resources | Assess:
|
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with CASK Disorders
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| DD/ID | See Developmental Delay / Intellectual Disability Management Issues. | |
| Epilepsy | Standardized treatment w/AEDs by experienced neurologist |
|
| Poor weight gain / Failure to thrive | Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. | Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia |
| Spasticity | Orthopedics / physical medicine & rehabilitation / PT/OT incl stretching to help avoid contractures & falls | Consider need for positioning & mobility devices, disability parking placard. |
| Abnormal vision &/or strabismus | Standard treatment(s) as recommended by ophthalmologist | Community vision services through early intervention or school district |
| Hearing | Hearing aids may be helpful as per otolaryngologist. | Community hearing services through early intervention or school district |
| Family/ Community |
|
|
AED = antiepileptic drug; DD = developmental dealy; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
- 1.
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit (pdf).
Developmental Disability / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
- Individualized education plan (IEP) services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine