Wolf-Hirschhorn Syndrome: Clinical and Genetic Data from a First Case Diagnosed in Central Africa

Abstract

Wolf-Hirschhorn syndrome (WHS) is a multiple congenital anomaly-intellectual disability syndrome caused by a deletion involving chromosome 4p16.3. We report clinical and genetic findings of the first WHS patient diagnosed in central Africa. This boy who presented with cleft palate, microcephaly, severe growth delay, and intellectual disability was 12 years old. Typical craniofacial features were present, though the characteristic “Greek helmet” appearance of the nose was less evident, probably reflecting a variable expression related to the genetic background. The clinical diagnosis of WHS was confirmed by array CGH, which revealed a terminal 4p16.3 deletion of 3.47 Mb, typically associated with a milder phenotype, contributing to the long survival of this child in a developing country.

Keywords

Wolf-Hirschhorn syndrome - cleft palate - severe growth delay - intellectual disability - sacral dimples

• References

• 1 Shimizu K, Wakui K, Kosho T. , et al. Microarray and FISH-based genotype-phenotype analysis of 22 Japanese patients with Wolf-Hirschhorn syndrome. Am J Med Genet A 2014; 164A [phone]
• 2 Lurie IW, Lazjuk GI, Ussova YI, Presman EB, Gurevich DB. The Wolf-Hirschhorn syndrome. I. Genetics. Clin Genet 1980; 17 (06) 375-384
• 3 Shannon NL, Maltby EL, Rigby AS, Quarrell OW. An epidemiological study of Wolf-Hirschhorn syndrome: life expectancy and cause of mortality. J Med Genet 2001; 38 (10) 674-679
• 4 Zollino M, Neri G. Genotype-phenotype correlations in Wolf-Hirschhorn syndrome. Eur J Hum Genet 2001; 9 (02) 150 . Doi: 10.1038/sj.ejhg.5200611
• 5 Zollino M, Lecce R, Fischetto R. , et al. Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet 2003; 72 (03) 590-597
• 6 Rodríguez L, Zollino M, Climent S. , et al. The new Wolf-Hirschhorn syndrome critical region (WHSCR-2): a description of a second case. Am J Med Genet A 2005; 136 (02) 175-178
• 7 Hannes F, Hammond P, Quarrell O, Fryns JP, Devriendt K, Vermeesch JR. A microdeletion proximal of the critical deletion region is associated with mild Wolf-Hirschhorn syndrome. Am J Med Genet A 2012; 158A [phone]
• 8 Zollino M, Orteschi D, Ruiter M. , et al. Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder. Epilepsia 2014; 55 (06) 849-857
• 9 Andersen EF, Carey JC, Earl DL. , et al. Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf-Hirschhorn syndrome. Eur J Hum Genet 2014; 22 (04) 464-470
• 10 Zollino M, Murdolo M, Marangi G. , et al. On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review. Am J Med Genet C Semin Med Genet 2008; 148C [phone]
• 11 Battaglia A, Filippi T, Carey JC. Update on the clinical features and natural history of Wolf-Hirschhorn (4p-) syndrome: experience with 87 patients and recommendations for routine health supervision. Am J Med Genet C Semin Med Genet 2008; 148C [phone]
• 12 Yang WX, Pan H, Li L. , et al. Analyses of genotypes and phenotypes of ten Chinese patients with Wolf-Hirschhorn syndrome by multiplex ligation-dependent probe amplification and array comparative genomic hybridization. Chin Med J (Engl) 2016; 129 (06) 672-678
• 13 Iype T, Alakbarzade V, Iype M. , et al. A large Indian family with rearrangement of chromosome 4p16 and 3p26.3 and divergent clinical presentations. BMC Med Genet 2015; 16: 104 . Doi: 10.1186/s12881-015-0251-5
• 14 Ho KS, South ST, Lortz A. , et al. Chromosomal microarray testing identifies a 4p terminal region associated with seizures in Wolf-Hirschhorn syndrome. J Med Genet 2016; 53 (04) 256-263
• 15 Bi W, Cheung SW, Breman AM, Bacino CA. 4p16.3 microdeletions and microduplications detected by chromosomal microarray analysis: new insights into mechanisms and critical regions. Am J Med Genet A 2016; 170 (10) 2540-2550
• 16 Rauch A, Schellmoser S, Kraus C. , et al. First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation. Am J Med Genet 2001; 99 (04) 338-342
• 17 Wright TJ, Costa JL, Naranjo C, Francis-West P, Altherr MR. Comparative analysis of a novel gene from the Wolf-Hirschhorn/Pitt-Rogers-Danks syndrome critical region. Genomics 1999; 59 (02) 203-212
• 18 Jugessur A, Shi M, Gjessing HK. , et al. Fetal genetic risk of isolated cleft lip only versus isolated cleft lip and palate: a subphenotype analysis using two population-based studies of orofacial clefts in Scandinavia. Birth Defects Res A Clin Mol Teratol 2011; 91 (02) 85-92
• 19 Battaglia A, Carey JC. Wolf-Hirschhorn syndrome and the 4p-related syndromes. Am J Med Genet C Semin Med Genet 2008; 148C [phone]
• 20 South ST, Whitby H, Battaglia A, Carey JC, Brothman AR. Comprehensive analysis of Wolf-Hirschhorn syndrome using array CGH indicates a high prevalence of translocations. Eur J Hum Genet 2008; 16 (01) 45-52
• 21 Zollino M, Di Stefano C, Zampino G. , et al. Genotype-phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome. Am J Med Genet 2000; 94 (03) 254-261
• 22 Van Buggenhout G, Melotte C, Dutta B. , 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 (09) 691-698
• 23 Maas NM, Van Buggenhout G, Hannes F. , 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 (02) 71-80
• 24 Ji TY, Chia D, Wang JM. , et al. Diagnosis and fine localization of deletion region in Wolf-Hirschhorn syndrome patients. Chin Med J (Engl) 2010; 123 (13) 1663-1667
• 25 Lumaka A, Cosemans N, Lulebo Mampasi A. , et al. Facial dysmorphism is influenced by ethnic background of the patient and of the evaluator. Clin Genet 2016;
• 26 Forae GD, Uchendu OJ, Igbe AP. ; GD. An audit of paediatric mortality patterns in a Nigerian teaching hospital. Niger Med J 2014; 55 (02) 130-133
• 27 Fotso JC, Ezeh AC, Madise NJ, Ciera J. Progress towards the child mortality millennium development goal in urban sub-Saharan Africa: the dynamics of population growth, immunization, and access to clean water. BMC Public Health 2007; 7: 218 . Doi: 10.1186/1471-2458-7-218
• 28 Modell B, Berry RJ, Boyle CA. , et al. Global regional and national causes of child mortality. Lancet 2012; 380 (9853): 1556 , author reply 1556–1557
• 29 Lumaka A, Mubungu G, Nsibu C, Tady BP, Lukusa T, Devriendt K. X-linked adrenal hypoplasia congenita: a novel DAX1 missense mutation and challenges for clinical diagnosis in Africa. Eur J Pediatr 2012; 171 (02) 267-270