Exosc3 Pontocerebellar Hypoplasia
Summary
Clinical characteristics.
EXOSC3 pontocerebellar hypoplasia (EXOSC3-PCH) is characterized by abnormalities in the posterior fossa and degeneration of the anterior horn cells. At birth, skeletal muscle weakness manifests as hypotonia (sometimes with congenital joint contractures) and poor feeding. In persons with prolonged survival, spasticity, dystonia, and seizures become evident. Within the first year of life respiratory insufficiency and swallowing difficulties are common. Intellectual disability is severe. Life expectancy ranges from a few weeks to adolescence. To date, 82 individuals (from 58 families) with EXOSC3-PCH have been described.
Diagnosis/testing.
The diagnosis of EXOSC3-PCH is suspected in children with characteristic neuroradiologic and neurologic findings, and is confirmed by the presence of biallelic EXOSC3 pathogenic variants identified by molecular genetic testing.
Management.
Treatment of manifestations: No specific therapy is available. Treatment is symptomatic. Contractures and scoliosis are managed by passive or active movement and bracing as needed. Aspiration risk and seizures are managed in a routine manner. Education is adapted to the level of cognitive abilities.
Surveillance: Regular examinations to address: growth and nutritional status (including problems with feeding and risk of aspiration); respiratory function; joint contractures and scoliosis. Observation for and management of epileptic seizures.
Genetic counseling.
EXOSC3-PCH is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an EXOSC3 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an unaffected carrier, and a 25% chance of inheriting both normal alleles. Once the EXOSC3 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
Diagnosis of EXOSC3 pontocerebellar hypoplasia (EXOSC3-PCH) should be suspected in children with severe neurologic impairment and characteristic findings on brain imaging.
Neurologic Findings
Common
- Hypotonia (onset is usually at birth, but a later onset is possible)
- Signs of neurogenic muscle atrophy, such as muscle atrophy and decreased tendon reflexes
- Central motor neuron signs (spasticity, dystonia), especially in individuals with prolonged survival
- Lower motor neuron involvement, demonstrated by EMG (abnormal EMG potentials, increased motor unit potentials, fasciculations)
Less common
- Joint contractures (can be present at birth or develop later)
- Swallowing insufficiency
- Ophthalmologic findings of:
- Small or pale optic discs indicative of optic atrophy
- Nystagmus
- Strabismus
- Seizures
Brain MRI Findings Consistent with Pontocerebellar Hypoplasia Type 1 (PCH1) *
Common
- Hypoplasia and/or atrophy of the cerebellum in varying degrees
- Hypoplasia and/or atrophy of the pons in varying degrees
- Cerebellar vermis and cerebellar hemispheres equally affected
Less common
- Intracerebellar cysts [Eggens et al 2014]
- Supratentorial abnormalities, such as widened extracerebellar CSF spaces and widened lateral ventricles due to small basal ganglia
* See Nomenclature.
Family History
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of EXOSC3 pontocerebellar hypoplasia is established in a proband with suggestive findings and biallelic EXOSC3 pathogenic variants identified by molecular genetic testing (see Table 1).
Note: Identification of biallelic EXOSC3 variants of uncertain significance (or identification of one known EXOSC3 pathogenic variant and one EXOSC3 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain imaging findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of EXOSC3-PHC has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Single-gene testing. Sequence analysis of EXOSC3 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
A cerebellar hypoplasia multigene panel that includes EXOSC3 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. Of note, given the rarity of EXOSC3-PCH, some panels for cerebellar hypoplasia 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.
Option 2
Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in EXOSC3 Pontocerebellar Hypoplasia
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| EXOSC3 | Sequence analysis 3 | ~99% 4 |
| Deletion/duplication analysis 5 | Partial-gene deletion in 1 person 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.
Wan et al [2012], Rudnik-Schöneborn et al [2013], Zanni et al [2013], Eggens et al [2014]
- 5.
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
- 6.
Eggens et al [2014]
Clinical Characteristics
Differential Diagnosis
Key disorders to consider in the differential diagnosis of pontocerebellar hypoplasia type 1 (PCH1) include EXOSC8-, SLC25A46-, and VRK1-related PCH1, PCH2/4 (TSEN54-related PCH), spinal muscular atrophy type 1, PCH10, and PCH12 (see Table 2).
PCH1. About 50% of individuals with PCH1 have pathogenic variants in EXOSC3 (i.e., EXOSC3-PCH). In children with EXOSC3-PCH, neonatal death, delayed nerve conduction velocities, and congenital respiratory and feeding difficulties occur less frequently than in those without identifiable EXOSC3 pathogenic variants [Rudnik-Schöneborn et al 2014].
PCH2/4. Dyskinesias and seizures are common in PCH2, the most common type of PCH. PCH4 is a severe form of PCH2, often with congenital contractures and polyhydramnios. In children with EXOSC3-PCH, central motor findings (together with the typical brain MRI findings of cerebellar or pontocerebellar hypoplasia) may falsely suggest a diagnosis of PCH2. Compared to findings in EXOSC3-PCH, the findings in PCH2 are:
- No abnormalities of the spinal cord (whereas in PCH1 anterior horn cells are involved);
- Attenuation of the pons on brain MRI (whereas in PCH1 the pons can be unaffected).
Table 2.
Genes of Interest in the Differential Diagnosis of EXOSC3 Pontocerebellar Hypoplasia
| Gene(s) | Phenotype/ Disorder | MOI | Brain MRI Findings | Clinical Characteristics |
|---|---|---|---|---|
| Key differential diagnosis disorders (in order of relevance) | ||||
| EXOSC8 SLC25A46 VRK1 | PCH1 1, 2 | AR | Pontine atrophy may not be present in some individuals. |
|
| TSEN54 | TSEN54-PCH (PCH2, 4, & 5) | AR |
|
|
| SMN1 | Spinal muscular atrophy type 1 | AR | Normal |
|
| CLP1 | PCH10 (OMIM 615803) | AR | Mild cerebellar atrophy/hypoplasia | Very rare disorder characterized by DD, microcephaly, spasticity, axonal motor & sensory neuropathy, abnormal muscle tone, seizures, motor neuron degeneration |
| COASY | PCH12 (OMIM 618266) | AR | Prenatal-onset microcephaly; hypoplasia of cerebellum, brain stem, spinal cord | Severe prenatal-onset PCH, microcephaly, arthrogryposis w/hypoplasia of spinal cord & brain stem, multiple congenital contractures, polyhydramnios, motor neuron degeneration |
| Other disorders to consider (in alphabetic order by gene) | ||||
| B3GALNT2 B4GAT1 DAG1 FKRP FKTN GMPPB ISPD LARGE1 POMGNT1 POMGNT2 POMK POMT1 POMT2 RXYLT1 4 | Alpha-dystroglycanopathies | AR | Wide spectrum of brain malformations incl cobblestone lissencephaly & hydrocephalus | Muscle weakness & ophthalmologic abnormalities |
| CASK | ID & microcephaly w/pontine & cerebellar hypoplasia (See CASK Disorders.) | XL | Neocortical dysplasia (simplified gyral pattern, thin brain stem w/flattening of pons) & severe cerebellar hypoplasia (PCH) |
|
| CHMP1A | PCH8 1 | AR | MRI findings similar to PCH1B | Microcephaly, delayed walking, variable foot deformities, chorea, dystonic posturing, impaired cognition |
| PCLO | PCH3 1 | AR | ||
| >40 genes (e.g., PMM2 5) | Congenital disorders of glycosylation (CDG) (See also PMM2-CDG (CDG-Ia).) | AR (XL) | Pontocerebellar hypoplasia w/superimposed atrophy, delayed myelination | Dysmorphic features, ataxia; organ failure in neonatal period |
| RARS2 | PCH6 1 | AR |
| |
| RELN | Lissencephaly 2 (OMIM 257320) | AR | Classic lissencephaly w/coexistent cerebellar & pontine hypoplasia | |
| SEPSECS | PCH2 1 | AR | Progressive cerebello-cerebral atrophy closely resembles mild PCH. | Clinical findings closely resemble mild PCH2. |
| TOE1 | PCH7 1 | AR | PCH | Disorders of sex development |
| VLDLR | VLDLR cerebellar hypoplasia | AR | Gross cerebellar hypoplasia, flat ventral pons, simplified gyri | Ataxia & ID |
AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PCH = pontocerebellar hypoplasia; XL = X-linked
- 1.
van Dijk et al [2018]
- 2.
OMIM Phenotypic Series: Pontocerebellar hypoplasia
- 3.
Children with EXOSC3 pathogenic variants other than c.395A>C (p.Asp132Ala) have a more severe phenotype that includes severe pontine and cerebellar hypoplasia, joint contractures, and death in infancy.
- 4.
OMIM Phenotypic Series: Muscular dystrophy-dystroglycanopathy, type A
- 5.
PMM2-CDG (CDG-Ia) is the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides.
Other conditions to consider in the differential diagnosis
- Lissencephalies without known gene defects exhibiting two-layered cortex, extreme microcephaly, and cerebellar and pontine hypoplasia [Forman et al 2005]
- Pontocerebellar hypoplasia in extremely premature infants (gestational age <28 weeks); an acquired phenocopy to be considered [Volpe 2009, Pierson & Al Sufiani 2016]
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with EXOSC3 pontocerebellar hypoplasia (EXOSC3-PCH), 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 of EXOSC3 Pontocerebellar Hypoplasia
| System/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Measure length & weight. | See Gastrointestinal/Feeding if evidence of failure to thrive. |
| Gastrointestinal/ Feeding | Gastroenterology / nutrition / feeding team eval | Assess swallowing & feeding to determine safety of oral vs gastrostomy feeding. |
| Respiratory | Assess airway & pulmonary function & secretion management. | Consult pulmonologist. |
| Neurologic | Eval by pediatric neurologist | Assess for:
|
| Hearing loss | Eval by audiologist | |
| Vision | Eval by pediatric ophthalmologist |
|
| Musculoskeletal | Multidisciplinary neuromuscular clinic assessment by orthopedist, physical medicine, OT/PT | To incl assessment of:
|
| Palliative care | Refer to palliative care specialist. | When deemed appropriate by family & care providers |
| Genetic counseling | By genetics professionals 1 | To inform affected persons & their families re nature, MOI, & implications of EXOSC3-PCH to facilitate medical & personal decision making |
| Family support/ resources | Assess:
|
MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
- 1.
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations
No specific treatment for EXOSC3-PCH exists; the goals are to maximize function and reduce complications.
Ideally, each affected individual is managed by a multidisciplinary team of relevant specialists including developmental pediatricians, neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, pulmonologists, and psychologists depending on the clinical manifestations (see Table 4).
Table 4.
Treatment of Manifestations in Individuals with EXOSC3 Pontocerebellar Hypoplasia
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Seizures | Per standard practice | By neurologist experienced in epilepsy management |
| Irritability | None | Often related to chorea (involuntary movements) |
| Musculoskeletal | Multidisciplinary neuromuscular clinic physical medicine, OT/PT |
|
| Orthopedics | Manage contractures, clubfoot, scoliosis w/bracing &/or surgical intervention. | |
| Feeding/Dysphagia | Gastroenterology / nutrition / feeding team | Modify food consistency to ↓ aspiration risk &/or consider NG feeding & gastrostomy. |
| Speech | Speech/language eval | Consider involving speech therapist & OT to improve communication skills. |
| Respiratory |
| Per treating pulmonologist |
| Neurodevelopmental | Early intervention / individual education program based on needs | See Developmental Delay / Intellectual Disability Management Issues. |
NG = nasogastric; OT = occupational therapy, PT = physical therapy
Developmental Delay / 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:
- IEP services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Surveillance
Table 5.
Recommended Surveillance for Individuals with EXOSC3 Pontocerebellar Hypoplasia
| System/Concern |
|---|