Weiss-Kruszka Syndrome

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 testing are possible if the ZNF462 pathogenic variant in the family has been identified.

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).

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):

• 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].

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.

Treatment of Manifestations

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.

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

Weiss-Kruszka syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• 95% of individuals diagnosed with Weiss-Kruszka syndrome have the disorder as the result of a de novo ZNF462 pathogenic variant.
• 5% of individuals diagnosed with Weiss-Kruszka syndrome have an affected parent. Clinical variability is reported in families; the phenotype in affected family members can range from isolated ptosis to agenesis of the corpus callosum and metopic craniosynostosis [Weiss et al 2017, Kruszka et al 2019].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Parental germline mosaicism has been reported in one family [Kruszka et al 2019].
• The family history of some individuals diagnosed with Weiss-Kruszka syndrome may appear to be negative because of failure to recognize the disorder in more mildly affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

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

• If a parent of the proband has the ZNF462 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Sibs who inherit a ZNF462 pathogenic variant may be more or less severely affected than the proband because of intrafamilial clinical variability.
• If the ZNF462 pathogenic variant cannot be detected in the leukocyte DNA of either parent and/or the parents are clinically unaffected, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Kruszka et al 2019].

Offspring of a proband. Each child of an individual with Weiss-Kruszka syndrome has a 50% chance of inheriting the ZNF462 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the ZNF462 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are mildly affected.

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). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the ZNF462 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. However, because of the intrafamilial clinical variability observed in Weiss-Kruszka syndrome, molecular genetic test results cannot predict clinical findings.

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 decision, discussion of these issues may be helpful.

Literature Cited

• Chang YS, Stoykova A, Chowdhury K, Gruss P. Graded expression of Zfp462 in the embryonic mouse cerebral cortex. Gene Expr Patterns. 2007;7:405–12. [PubMed: 17207666]
• Cosemans N, Vandenhove L, Maljaars J, Van Esch H, Devriendt K, Baldwin A, Fryns JP, Noens I, Peeters H. ZNF462 and KLF12 are disrupted by a de novo translocation in a patient with syndromic intellectual disability and autism spectrum disorder. Eur J Med Genet. 2018;61:376–83. [PubMed: 29427787]
• Eberl HC, Spruijt CG, Kelstrup CD, Vermeulen M, Mann M. A map of general and specialized chromatin readers in mouse tissues generated by label-free interaction proteomics. Mol Cell. 2013;49:368–78. [PubMed: 23201125]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schäffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C, Zenker M, Lee B, Biesecker LG, et al. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med. 2018;20:1175–85. [PMC free article: PMC6105555] [PubMed: 29469822]
• Kruszka P, Hu T, Hong S, Signer R, Cogné B, Isidor B, Mazzola SE, Giltay JC, Van Gassen KLI, England EM, Pais L, Ockeloen CW, Sanchez-Lara PA, Kinning E, Adams DJ, Treat K, Torres-Martinez W, Bedeschi MF, Iascone M, Blaney S, Bell O, Tan TY, Delrue MA, Jurgens J, Barry BJ, Engle EC, Savage SK, Fleischer N, Martinez-Agosto JA, Boycott K, Zackai EH, Muenke M. Phenotype delineation of ZNF462 related syndrome. Am J Med Genet A. 2019;179:2075–82. [PMC free article: PMC6935050] [PubMed: 31361404]
• Laurent A, Massé J, Omilli F, Deschamps S, Richard-Parpaillon L, Chartrain I, Pellerin I. ZFPIP/Zfp462 is maternally required for proper early Xenopus laevis development. Dev Biol. 2009;327:169–76. [PubMed: 19111535]
• Massé J, Laurent A, Nicol B, Guerrier D, Pellerin I, Deschamps S. Involvement of ZFPIP/Zfp462 in chromatin integrity and survival of P19 pluripotent cells. Exp Cell Res. 2010;316:1190–201. [PubMed: 20219459]
• Ramocki MB, Dowling J, Grinberg I, Kimonis VE, Cardoso C, Gross A, Chung J, Martin CL, Ledbetter DH, Dobyns WB, Millen KJ. Reciprocal fusion transcripts of two novel Zn-finger genes in a female with absence of the corpus callosum, ocular colobomas and a balanced translocation between chromosomes 2p24 and 9q32. Eur J Hum Genet. 2003;11:527–34. [PubMed: 12825074]
• Talisetti A, Forrester SR, Gregory D, Johnson L, Schneider MC, Kimonis VE. Temtamy-like syndrome associated with translocation of 2p24 and 9q32. Clin Dysmorphol. 2003;12:175–7. [PubMed: 14564155]
• Weiss K, Wigby K, Fannemel M, Henderson LB, Beck N, Ghali N, Anderlid BM, Lundin J, Hamosh A, Jones MC, Ghedia S, Muenke M, Kruszka P, et al. Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay. Eur J Hum Genet. 2017;25:946–51. [PMC free article: PMC5567153] [PubMed: 28513610]

Revision History

• 31 October 2019 (ma) Review posted live
• 27 February 2019 (pk) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Weiss-Kruszka Syndrome" is in the public domain in the United States of America.