Weiss-Kruszka Syndrome
Summary
Clinical characteristics.
Weiss-Kruszka syndrome is characterized by metopic ridging or synostosis, ptosis, nonspecific dysmorphic features, developmental delay, and autistic features. Brain imaging may identify abnormalities of the corpus callosum. Developmental delay can present as global delay, motor delay, or speech delay. Affected individuals may also have ear anomalies, feeding difficulties (sometimes requiring placement of a gastrostomy tube), and congenital heart defects. There is significant variability in the clinical features, even between affected members of the same family.
Diagnosis/testing.
The diagnosis of Weiss-Kruszka syndrome is established in a proband with suggestive features and by identification of a heterozygous pathogenic variant in ZNF462 or deletion of 9p31.2 involving ZNF462; rarely chromosome rearrangements that disrupt ZNF462 have been reported.
Management.
Treatment of manifestations: Referral to a craniofacial team and/or neurosurgeon for those with craniosynostosis; feeding therapy for those with feeding difficulties; gastrostomy tube placement for those with persistent feeding issues and/or dysphagia. Standard treatment for ptosis, developmental delay, autism, hearing loss, and congenital heart defects.
Surveillance: Assessment of head circumference and shape at each evaluation in infancy and early childhood. Measurement of growth parameters, evaluation of nutrition status and safety of oral intake, and assessment of developmental progress and educational needs at each visit. Ophthalmology and audiology evaluations based on degree of clinical suspicion.
Genetic counseling.
Weiss-Kruszka syndrome is inherited in an autosomal dominant manner. Approximately 95% of affected individuals have Weiss-Kruszka syndrome as the result of an apparently de novo pathogenic variant. Each child of an individual with Weiss-Kruszka syndrome has a 50% chance of inheriting the ZNF462 pathogenic variant. Children who inherit a ZNF462 pathogenic variant may be more or less severely affected than the affected parent because of intrafamilial clinical variability. Prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible if the ZNF462 pathogenic variant in the family has been identified.
Diagnosis
Formal diagnostic criteria for Weiss-Kruszka syndrome have not been established.
Suggestive Findings
Weiss-Kruszka syndrome should be suspected in individuals presenting with the following clinical and brain MRI findings.
Clinical findings
- Metopic ridging or synostosis
- Ptosis
- Nonspecific dysmorphic features (see Clinical Description, Craniofacial features)
- Developmental delay and/or autistic features
Brain MRI findings. Corpus callosum abnormalities
Establishing the Diagnosis
The diagnosis of Weiss-Kruszka syndrome is established in a proband with suggestive features and by the identification of one of the following on molecular genetic testing [Weiss et al 2017] (see Table 1):
- A heterozygous pathogenic variant involving ZNF462
- A heterozygous deletion of 9q31.2 involving ZNF462
Note: Chromosome rearrangements that disrupt ZNF462 have been rarely reported [Ramocki et al 2003, Talisetti et al 2003, Cosemans et al 2018].
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, 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. Because the phenotype of Weiss-Kruszka syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with intellectual disability and/or nonspecific dysmorphic features are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic findings suggest the diagnosis of Weiss-Kruszka syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
Single-gene testing. Sequence analysis of ZNF462 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ZNF462) that cannot be detected by sequence analysis.
An intellectual disability multigene panel that includes ZNF462 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a non-diagnostic CMA 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 Weiss-Kruszka syndrome some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For 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.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability and nonspecific dysmorphic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – 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.
Karyotype. Conventional cytogenetic analysis can be considered to exclude other large cytogenetic abnormalities or rare chromosome rearrangements that involve ZNF462 if the phenotype is consistent with Weiss-Kruszka syndrome but the above-mentioned studies do not detect a pathogenic variant involving ZNF462 [Ramocki et al 2003, Talisetti et al 2003, Cosemans et al 2018].
Table 1.
Molecular Genetic Testing Used in Weiss-Kruszka Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| ZNF462 | Sequence analysis 3 | 17/21 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 | |
| CMA 7 | 2/8 8 | |
| Karyotype | 2/8 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.
Kruszka et al [2019]
- 5.
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 may not be detected by these methods.
- 6.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
- 7.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ZNF462) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 9q31.2 region. CMA designs in current clinical use target the 9q31.2 region.
- 8.
Weiss et al [2017]
- 9.
Ramocki et al [2003], Talisetti et al [2003], Cosemans et al [2018]
Clinical Characteristics
Clinical Description
To date, 24 individuals from 21 families are have been identified with a pathogenic variant in ZNF462 [Ramocki et al 2003, Talisetti et al 2003, Weiss et al 2017, Cosemans et al 2018, Kruszka et al 2019]. The following description of the phenotypic features associated with this condition is based on these reported cases.
Note: The reports by Ramocki et al [2003] and Talisetti et al [2003] describe the same individual; the authors speculated that this individual’s features may have resulted from a fusion protein created by a balanced translocation that disrupted ZNF462.
Craniofacial features. The most common facial features (Figure 1):
syndrome including ptosis, downslanted palpebral fissures, exaggerated Cupid’s bow, and arched eyebrows.">Figure 1.
These four individuals demonstrate the most common facial characteristics of Weiss-Kruszka syndrome including ptosis, downslanted palpebral fissures, exaggerated Cupid’s bow, and arched eyebrows. Images published with permission
- Ptosis (20/24; 83%)
- Downslanted palpebral fissures (13/24; 54%)
- Exaggerated Cupid’s Bow (13/24; 54%)
- Arched eyebrows (12/24; 50%)
- Epicanthal folds (11/24; 46%)
- Short upturned nose with bulbous tip (11/24; 46%)
Fewer than half of affected individuals have metopic ridging or craniosynostosis involving the metopic or lambdoid suture (9/24; 38%).
Developmental delay. A vast majority (>75% of the known 24 affected individuals) have some type of developmental delay including global delay, motor delay, speech delay, or a combination of these.
- Speech delay is the most common finding, occurring in 42%.
- Motor delay is the second most common, occurring in 38%.Hypotonia is a contributor to motor delay, with 50% of individuals having decreased muscle tone.
A third (8 of the known 24 affected individuals) have an autism spectrum disorder.
Ears/hearing. 45% of probands had hearing loss or anomalies affecting the external ear configuration:
- Low-set ears in six (25%) of the 24 affected individuals
- Ear malformations in 12/24 affected individuals, including horizontal crux helix, prominent ears, ear pits, cupped ears, and overfolded ears
- Hearing loss of varying severity in three of the 24 affected individuals
Gastrointestinal. Feeding issues are prevalent, with half (12/24) of all affected individuals reporting difficulties and some requiring G-tube placement. Causes of feeding issues include the following:
- Gastroesophageal reflux requiring Nissen fundoplication
- Laryngomalacia leading to respiratory difficulty during oral feeding attempts
- Dysphagia
- Eosinophilic esophagitis
- Problems chewing
Heart malformations. A minority of affected individuals (5/24; 21%) have congenital heart malformations including ventricular septal defects, bicuspid aortic valve, transposition of the great arteries, and patent ductus arteriosus.
Limb anomalies. Roughly 25% of affected individuals have minor limb anomalies.
- Three have single palmar creases (13%)
- Three have fifth-finger clinodactyly (13%)
- One individual was reported to have proximally implanted thumbs, although this individual has a balanced translocation involving ZNF462 and KLF12 [Cosemans et al 2018].
Corpus callosum dysgenesis was initially thought to be a major characteristic of those with loss of function in ZNF462 [Weiss et al 2017]; however, as more cases are ascertained, the fraction of affected individuals with corpus callosum dysgenesis may be closer to 25% (6/24). Seizures have not been described in any affected individuals to date.
Prognosis. It is unknown if life span in Weiss-Kruszka syndrome is reduced. One reported individual is alive at age 67 years [Weiss et al 2017]. 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 genotype-phenotype correlations have been identified.
Prevalence
This disorder is rare and the prevalence is unknown. Only 24 affected individuals from 21 families are known [Ramocki et al 2003, Talisetti et al 2003, Weiss et al 2017, Cosemans et al 2018, Kruszka et al 2019].
Differential Diagnosis
Table 2.
Disorders with Intellectual Disability to Consider in the Differential Diagnosis of Weiss-Kruszka Syndrome
| Differential Diagnosis Disorder | Gene(s) | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/Weiss-Kruszka syndrome | Distinguishing from Weiss-Kruszka Syndrome | |||
| Blepharophimosis, ptosis, and epicanthus inversus | FOXL2 | AD |
|
|
| Noonan syndrome | BRAF KRAS LZTR1 1 MAP2K1 NRAS PTPN11 RIT1 SOS1 | AD (AR) 1 |
|
|
| Hereditary congenital ptosis 1 (OMIM 178300) | Unknown | AD | Ptosis | Brain, craniofacial, & heart malformations absent |
| Hereditary congenital ptosis 2 (OMIM 300245) | Unknown | XL | Ptosis |
|
| Trigonocephaly I (OMIM 190440) | FGFR1 | AD | Trigonocephaly | Mild synophrys |
| Trigonocephaly 2 (OMIM 614485) | FREM1 | AD | Trigonocephaly | Microcephaly in some individuals |
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; XL = X-linked
- 1.
Autosomal recessive inheritance of LZTR1-related Noonan syndrome has been reported [Johnston et al 2018].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Weiss-Kruszka syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Weiss-Kruszka Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Craniofacial | Physical examination to identify face shape & suture ridging | |
| Eyes | Ophthalmologic evaluation | To address ptosis |
| Development | Developmental assessment | To incl:
|
| Psychiatric/ Behavioral | Neuropsychiatric evaluation | Individuals age >12 mos: screening for behavior concerns incl traits suggestive of ASD |
| Ears/hearing | Audiology evaluation | To assess for hearing loss |
| Gastrointestinal/ Feeding | Gastroenterology / nutrition / feeding team evaluation |
|
| Cardiovascular | Cardiology consultation | Baseline echocardiogram recommended |
| Neurologic | Neurologic evaluation | |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | |
| Family supports/resources | Assess:
|
ASD = autism spectrum disorder
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with Weiss-Kruszka Syndrome
| Manifestation/Concern | Treatment | Considerations/Other |
| Craniosynostosis | Referral to a craniofacial team &/or neurosurgeon | For discussion of surgical correction |
| Ptosis | Standard treatment per ophthalmologist | |
| DD/ID | See Developmental Delay / Intellectual Disability Management Issues. | |
| Hearing loss | Hearing aids may be helpful; as per otolaryngologist | Community hearing services through early intervention or school district |
| Feeding difficulties / dysphagia / poor weight gain | Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues | Low threshold for clinical feeding evaluation &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia |
| Congenital heart defects | Standard treatment per cardiologist | |
| Family/Community |
|
|
DD = delvelopmental delay; ID = intellectual disability
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.
Developmental Disability / Intellectual Disability Management Issues
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.
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.
Ages 5-21 years
- In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a 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.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility.
- Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child’s behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Surveillance
Table 5.
Recommended Surveillance for Individuals with Weiss-Kruszka Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Head | Assessment of head circumference & head shape | Each evaluation in infancy & early childhood |
| Eyes | Ophthalmology evaluation | Frequency to be determined by the degree of ptosis |
| Development | Monitor developmental progress & educational needs | Each visit |
| Ears | Audiology evaluation | Based on clinical suspicion |
| Feeding | Measurement of growth parameters | Each visit |
| Evaluation of nutritional status & safety of oral intake | ||
| Miscellaneous/ Other | Assess family need for social work support (e.g., respite care, other local resources) & care coordination. | Each visit |
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.