Medicine:Schaaf–Yang syndrome

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Short description: Human genetic disorder
Schaaf–Yang syndrome
Other namesPrader–Willi–like syndrome (PWLS), Chitayat–Hall syndrome[1]
File:Person with Schaaf-Yang syndrome.webp
Person showing facial features of SYS, such as: Trigonocephaly and tooth malposition. Also limb contractures can be seen.
SpecialtyNeurology, Medical genetics, Endocrinology
SymptomsFacial shape abnormality, undescended testes, feeding problems, hypotonia, flexion contracture, global developmental delay
CausesGenetic mutations
Diagnostic methodGenetic testing
PrognosisReduced life expectancy. Fetuses are demised due to fetal akinesia

Schaaf–Yang syndrome (SYS) is a rare genetic disorder that is caused by a heterozygous mutation in a paternal-expressed gene MAGEL2.[2] Main signs of this disorder are: intellectual disability/developmental delay, autism spectrum disorder, hypogonadism, hypotonia in infancy with feeding problems, and distal arthrogryposis.[3] Facial features are included short noses, dense eyebrows, and protruding jaw.[4]

Signs and symptoms

Symptoms of this disease are:[5]

Very frequent

Frequent

Occasional

  • Almond-shaped eyes
  • Atrial septal defect
  • Hypothyroidism
  • Central sleep apnea
  • Downturned corners of mouth
  • Thin nasal bridge
  • Thin upper lip
  • Seizure
  • Abnormal dryness of the mouth
  • Type 2 diabetes

Cause

The cause of this disease are mutation in a gene MAGEL2 which is located on chromosome 15 (15q11.2) and that gene is expressed from paternal chromosome 15 and methylated on maternal chromosome 15.[6][7] The MAGEL2 is a part of regulatory complex MUST, which consist of MAGEL2-USP7-TRIM27.[8][9] This complex regulates WASH complex which function is to promotes endosomal actin polymerization.[10] 50% of people with SYS inherited mutation from their father and remainder are de novo mutation (which means that mutation is new and none of the parents have it).[7][11]

MAGEL2-regulated WASH complex is important for the regulated secretion in the hypothalamus.[12] MAGEL2 mutation causes decreased secretion of hormones, such as: oxytocin, AVP, somatostatin, thyrotropin-releasing hormone, growth hormone, and luteinizing hormone.[13][14] Loss of that protein also showed neuronal activity loss in the hypothalamus and hippocampus of mice by disruptions of neuronal activity and changes in the synaptic excitation/inhibition balance through AMPA receptor trafficking defects.[15][16]

Diagnosis

SYS can be suspected by symptoms and subsequently can be diagnosed by genetic testing.[17]

Treatment

SYS doesn't have a cure.[7] Although symptomatic management is available, It might be effective but it still doesn't alleviate overall impact of SYS, which leaves caregivers unsatisfied.[18]

Prognosis

Life expectancy of person with SYS can be reduced due to fatal complication.[7] Survival into adulthood is possible and oldest patient with SYS is 36 years olds (at the time of article's publication).[19]

History

The first mention of SYS-like symptoms was described by Chitayat et al. (1990).[20] Although the name was coined by Christian P Schaaf and Yaping Yang, who described SYS in details in 2013.[21]

Prevalence

The prevalence of SYS is < 1/1,000,000.[22][19] Currently, it is estimated that about 250 people are diagnosed with SYS.[23]

References

  1. ↑ "Entry – #615547 – SCHAAF–YANG SYNDROME; SHFYNG – OMIM". https://www.omim.org/entry/615547. 
  2. ↑ Schaaf, Christian P.; Gonzalez-Garay, Manuel L.; Xia, Fan; Potocki, Lorraine; Gripp, Karen W.; Zhang, Baili; Peters, Brock A.; McElwain, Mark A. et al. (November 2013). "Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism" (in en). Nature Genetics 45 (11): 1405–1408. doi:10.1038/ng.2776. ISSN 1546-1718. PMID 24076603. 
  3. ↑ McCarthy, John; Lupo, Philip J.; Kovar, Erin; Rech, Megan; Bostwick, Bret; Scott, Daryl; Kraft, Katerina; Roscioli, Tony et al. (2018). "Schaaf–Yang syndrome overview: Report of 78 individuals" (in en). American Journal of Medical Genetics Part A 176 (12): 2564–2574. doi:10.1002/ajmg.a.40650. ISSN 1552-4833. PMID 30302899. 
  4. ↑ Fountain, Michael D.; Aten, Emmelien; Cho, Megan T.; Juusola, Jane; Walkiewicz, Magdalena A.; Ray, Joseph W.; Xia, Fan; Yang, Yaping et al. (2017-01-01). "The phenotypic spectrum of Schaaf–Yang syndrome: 18 new affected individuals from 14 families" (in English). Genetics in Medicine 19 (1): 45–52. doi:10.1038/gim.2016.53. ISSN 1098-3600. PMID 27195816. PMC 5116288. https://www.gimjournal.org/article/S1098-3600(21)01530-6/fulltext. 
  5. ↑ "Orphanet: Clinical signs and symptoms". https://www.orpha.net/en/disease/sign/398069. 
  6. ↑ GeneCards Human Gene Database. "MAGEL2 Gene – GeneCards | MAGL2 Protein | MAGL2 Antibody" (in en). https://www.genecards.org/cgi-bin/carddisp.pl?gene=MAGEL2. 
  7. ↑ 7.0 7.1 7.2 7.3 Schaaf, Christian P.; Marbach, Felix (1993), Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda M. et al., eds., "Schaaf–Yang Syndrome", GeneReviews® (Seattle (WA): University of Washington, Seattle), PMID 33570896, https://www.ncbi.nlm.nih.gov/books/NBK567492/, retrieved 2025-03-01 
  8. ↑ Gee, Rebecca R. Florke; Chen, Helen; Lee, Anna K.; Daly, Christina A.; Wilander, Benjamin A.; Tacer, Klementina Fon; Potts, Patrick Ryan (2020-11-20). "Emerging roles of the MAGE protein family in stress response pathways" (in English). Journal of Biological Chemistry 295 (47): 16121–16155. doi:10.1074/jbc.REV120.008029. ISSN 0021-9258. PMID 32921631. 
  9. ↑ Hao, Yi-Heng; Doyle, Jennifer M.; Ramanathan, Saumya; Gomez, Timothy S.; Jia, Da; Xu, Ming; Chen, Zhijian J.; Billadeau, Daniel D. et al. (2013-02-28). "Regulation of WASH-Dependent Actin Polymerization and Protein Trafficking by Ubiquitination" (in English). Cell 152 (5): 1051–1064. doi:10.1016/j.cell.2013.01.051. ISSN 0092-8674. PMID 23452853. 
  10. ↑ Schubert, Tim; Schaaf, Christian P. (2025). "MAGEL2 (patho-)physiology and Schaaf–Yang syndrome" (in en). Developmental Medicine & Child Neurology 67 (1): 35–48. doi:10.1111/dmcn.16018. ISSN 1469-8749. PMID 38950199. 
  11. ↑ "De novo mutation" (in en). 2011-02-02. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/de-novo-mutation. 
  12. ↑ Hoyos Sanchez, Maria Camila; Bayat, Tara; Gee, Rebecca R. Florke; Fon Tacer, Klementina (January 2023). "Hormonal Imbalances in Prader–Willi and Schaaf–Yang Syndromes Imply the Evolution of Specific Regulation of Hypothalamic Neuroendocrine Function in Mammals" (in en). International Journal of Molecular Sciences 24 (17). doi:10.3390/ijms241713109. ISSN 1422-0067. PMID 37685915. 
  13. ↑ Schubert, Tim; Schaaf, Christian P. (2025). "MAGEL2 (patho-)physiology and Schaaf–Yang syndrome" (in en). Developmental Medicine & Child Neurology 67 (1): 35–48. doi:10.1111/dmcn.16018. ISSN 1469-8749. PMID 38950199. 
  14. ↑ Chen, Helen; Victor, A. Kaitlyn; Klein, Jonathon; Tacer, Klementina Fon; Tai, Derek J. C.; Esch, Celine de; Nuttle, Alexander; Temirov, Jamshid et al. (2020-09-03). "Loss of MAGEL2 in Prader-Willi syndrome leads to decreased secretory granule and neuropeptide production" (in en). JCI Insight 5 (17). doi:10.1172/jci.insight.138576. ISSN 0021-9738. PMID 32879135. 
  15. ↑ Temkin, Paul; Morishita, Wade; Goswami, Debanjan; Arendt, Kristin; Chen, Lu; Malenka, Robert (2017-04-05). "The Retromer Supports AMPA Receptor Trafficking During LTP". Neuron 94 (1): 74–82.e5. doi:10.1016/j.neuron.2017.03.020. ISSN 0896-6273. PMID 28384478. 
  16. ↑ Ates, Tayfun; Oncul, Merve; Dilsiz, Pelin; Topcu, Iskalen Cansu; Civas, Cihan Civan; Alp, Muhammed Ikbal; Aklan, Iltan; Ates Oz, Edanur et al. (2019-01-01). "Inactivation of Magel2 suppresses oxytocin neurons through synaptic excitation-inhibition imbalance". Neurobiology of Disease 121: 58–64. doi:10.1016/j.nbd.2018.09.017. ISSN 0969-9961. PMID 30240706. https://www.sciencedirect.com/science/article/abs/pii/S0969996118303954. 
  17. ↑ "About SYS" (in en). https://www.fpwr.org/sys-about. 
  18. ↑ Dötsch, Laura; Matesevac, Lisa; Strong, Theresa V.; Schaaf, Christian P. (2023). "Caregiver-based perception of disease burden in Schaaf–Yang syndrome" (in en). Molecular Genetics & Genomic Medicine 11 (12). doi:10.1002/mgg3.2262. ISSN 2324-9269. PMID 37533374. 
  19. ↑ 19.0 19.1 Marbach, Felix; Elgizouli, Magdeldin; Rech, Megan; Beygo, Jasmin; Erger, Florian; Velmans, Clara; Stumpel, Constance T. R. M.; Stegmann, Alexander P. A. et al. (2020-10-19). "The adult phenotype of Schaaf–Yang syndrome". Orphanet Journal of Rare Diseases 15 (1): 294. doi:10.1186/s13023-020-01557-8. ISSN 1750-1172. PMID 33076953. 
  20. ↑ Chitayat, David; Hall, Judith G.; Couch, Robert M.; Phang, Min S.; Baldwin, Virginia J. (1990). "Syndrome of mental retardation, facial anomalies, hypopituitarism, and distal arthrogryposis in sibs" (in en). American Journal of Medical Genetics 37 (1): 65–70. doi:10.1002/ajmg.1320370116. ISSN 1096-8628. PMID 2240046. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320370116. 
  21. ↑ Schaaf, Christian P.; Gonzalez-Garay, Manuel L.; Xia, Fan; Potocki, Lorraine; Gripp, Karen W.; Zhang, Baili; Peters, Brock A.; McElwain, Mark A. et al. (November 2013). "Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism" (in en). Nature Genetics 45 (11): 1405–1408. doi:10.1038/ng.2776. ISSN 1546-1718. PMID 24076603. 
  22. ↑ "Orphanet: Schaaf–Yang syndrome". https://www.orpha.net/en/disease/detail/398069. 
  23. ↑ "Advancing research into Schaaf–Yang syndrome, a rare disease that causes intellectual disability and congenital malformations" (in en-US). https://web.ub.edu/en/web/actualitat/w/schaaf-yang-syndrome. 



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