From neonatal signs to developmental delay: An infant with Wolf-Hirschhorn syndrome – a case study

  • Received 20.11.2024
  • Revised 06.03.2025
  • Accepted 27.05.2025
  • 636 Views
  • Retrieved from Vol. 11, No. 1, 2025
  • Pages 85-94

Wolf-Hirschhorn syndrome (WHS) is a rare genetic disorder with significant developmental, metabolic and craniofacial manifestations, highlighting the importance of continued research due to these challenges. This case report presents an 8-month-old female infant, born at term but classified as small for gestational age, who exhibited developmental delays, metabolic abnormalities and craniofacial dysmorphology characteristic of WHS. This report aimed to emphasise the clinical progression and diagnostic difficulties encountered in cases of WHS. Comprehensive genetic analyses and clinical evaluations were conducted, confirming the diagnosis. Key findings included recurrent respiratory distress with multiple failed weaning attempts, severe failure to thrive, seizures, sensorineural hearing loss, central hypotonia and feeding difficulties. Early neonatal complications and a prolonged, challenging stay in the neonatal intensive care unit were also noted, following which the infant was lost to follow-up until re-presenting at 8 months of age. This report underscores the necessity of early genetic screening and continuous follow-up for infants with congenital anomalies such as WHS. The findings may support paediatricians and neonatologists in the early identification and management of similar cases, thereby improving long-term outcomes

4p16.3 deletion; microcephaly; hypotonia; seizures; failure to thrive; Greek warrior helmet syndrome

https://doi.org/10.63341/ijmmr/1.2025.85
  1. Paprocka J, Kaminiów K, Yetkin O, Tekturk P, Baykan B, Leiz S, et al. Clinical and epilepsy characteristics in Wolf-Hirschhorn syndrome (4p-): A review. Seizure. 2024;116:14–23. DOI: 10.1016/j.seizure.2022.12.001
  2. Corrêa T, Mayndra M, Santos-Rebouças CB. Distinct epileptogenic mechanisms associated with seizures in Wolf-Hirschhorn syndrome. Mol Neurobiol. 2022;59(5):3159–69. DOI: 10.1007/s12035-022-02792-9
  3. Gavril EC, Luca AC, Curpan AS, Popescu R, Resmerita I, Panzaru MC, et al. Wolf-Hirschhorn xyndrome: Clinical and genetic study of 7 new cases, and mini review. Children. 2021;8(9):751. DOI: 10.3390/children8090751
  4. Mills A, Bearce E, Cella R, Kim SW, Selig M, Lee S, et al. Corrigendum: Wolf-Hirschhorn syndrome-associated genes are enriched in motile neural crest cells and affect craniofacial development in Xenopus laevis. Front Physiol. 2020;11:644596. DOI: 10.3389/fphys.2020.644596
  5. Shannon NL, Maltby EL, Rigby AS, Quarrell OWJ. An epidemiological study of Wolf-Hirschhorn syndrome: Life expectancy and cause of mortality. J Med Genet. 2001;38(10):674–9. DOI: 10.1136/jmg.38.10.674
  6. Battaglia A, Carey JC. The delineation of the Wolf-Hirschhorn syndrome over six decades: Illustration of the ongoing advances in phenotype analysis and cytogenomic technology. Am J Med Genet A. 2021;185(9):2748–55. DOI: 10.1002/ajmg.a.62341
  7. Berrocoso S, Amayra I, Lázaro E, Martínez O, López-Paz JF, García M, et al. Coping with Wolf-Hirschhorn syndrome: Quality of life and psychosocial features of family carers. Orphanet J Rare Dis. 2020;15(1):293. DOI: 10.1186/s13023-020-01476-8
  8. The World Medical Association. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects [Internet]. [cited 2024 November 3]. Available from: https://www.wma.net/what-we-do/medical-ethics/declaration-of-helsinki/
  9. World Health Organization. WHO child growth standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height, and body mass index-for-age: Methods and development. Geneva: World Health Organization; 2006. 312 P.
  10. Bergemann AD, Cole F, Hirschhorn K. The etiology of Wolf-Hirschhorn syndrome. Trends Genet. 2005;21(3):188–95. DOI: 10.1016/j.tig.2005.01.008
  11. Maas NMC, Van Buggenhout G, Hannes F, Thienpont B, Sanlaville D, Kok K, et al. Genotype-phenotype correlation in 21 patients with Wolf-Hirschhorn syndrome using high-resolution array comparative genome hybridisation (CGH). J Med Genet. 2008;45:71–80. DOI: 10.1136/jmg.2007.052910
  12. Zollino M, Di Stefano C, Zampino G, Mastroiacovo P, Wright TJ, Sorge G, et al. Genotype-phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome. Am J Med Genet. 2000;94(3):254–61. DOI: 10.1002/1096-8628(20000918)94:3%3C254::AID-AJMG13%3E3.0.CO;2-7
  13. Van Buggenhout G, Melotte C, Dutta B, Froyen G, Van Hummelen P, Marynen P, et al. Mild Wolf-Hirschhorn syndrome: Micro-array CGH analysis of atypical 4p16.3 deletions enables refinement of the genotype-phenotype map. J Med Genet. 2004;41(9):691–8. DOI: 10.1136/jmg.2003.016865
  14. Blanco-Lago R, Málaga-Diéguez I, García-Peñas JJ, García-Ron A. Wolf-Hirschhorn syndrome. A series of 27 patients: Their epidemiological and clinical characteristics. The current situation of the patients and the opinions of their caregivers regarding the diagnostic process. Rev Neurol. 2013;57(2):49. DOI: 10.33588/rn.5702.2013175
  15. Battaglia A, Carey JC, South ST. Wolf-Hirschhorn syndrome: A review and update. Am J Med Genet C Semin Med Genet. 2015;169(3):216–23. DOI: 10.1002/ajmg.c.31449
  16. Ho KS, Markhama LM, Twedea H, Lortzc A, Olson LM, Sheng X, et al. A survey of antiepileptic drug responses identifies drugs with potential efficacy for seizure control in Wolf-Hirschhorn syndrome. Epilepsy Behav. 2018;81:55–61. DOI: 10.1016/j.yebeh.2017.12.008
  17. Karalok ZS, Arhan EP, Erdogan KM, Gurkas E. Excellent response to levetiracetam in epilepsy with Wolf-Hirschhorn syndrome. Childs Nerv Syst. 2016;32(1):9–11. DOI: 10.1007/s00381-015-2908-1
  18. Lesperance MM, Grundfast KM, Rosenbaum KN. Otologic manifestations of Wolf-Hirschhorn syndrome. Arch Otolaryngol Head Neck Surg. 1998;124(2):193–6. DOI: 10.1001/archotol.124.2.193
  19. Ali MJ, Paulsen F. Syndromic and nonsyndromic systemic associations of congenital lacrimal drainage anomalies: A major review. Ophthalmic Plast Reconstr Surg. 2017;33(6):399–407. DOI: 10.1097/IOP.0000000000000923
  20. Boczek NJ, Lahner CA, Nguyen TM, Ferber MJ, Hasadsri L, Thorland EC, et al. Developmental delay and failure to thrive associated with a loss-of-function variant in WHSC1 (NSD2). Am J Med Genet A. 2018;176(12):2798–802. DOI: 10.1002/ajmg.a.40498
  21. Antonius T, Draaisma J, Levtchenko E, Knoers N, Renier W, van Ravenswaaij C. Growth charts for Wolf-Hirschhorn syndrome (0-4 years of age). Eur J Pediatr. 2008;167(8):807–10. DOI: 10.1007/s00431-007-0595-8