Wolf-Hirschhorn Syndrome with Hyperparathyroidism: A Case Report and a Narrative Review of the Literature

Abstract

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion condition. The WHS core phenotype includes developmental delays, intellectual disabilities, seizures, and distinctive facial features. Various other comorbidities have also been reported, such as hearing loss, heart defects, as well as eye problems and kidney problems. In this report, we present a case of WHS accompanied by hyperparathyroidism and hypercalcemia, which has not been previously reported. A girl was born at 37 weeks of gestation by vaginal delivery. She was small for the gestational age (2,045 g) and admitted to neonatal intensive care unit. She had typical WHS facial features and was found to have bilateral small kidneys associated with transient metabolic acidosis and renal insufficiency. She had right-sided sensorineural hearing loss, a small atrial septal defect, and colpocephaly and hypoplasia of corpus callosum. She had a single seizure which was well controlled with an oral antiepileptic medication. Cytogenetic studies demonstrated a large terminal chromosome 4p deletion (21.4 Mb) and 4p duplication (2.1 Mb) adjacent to the deletion. A unique finding in this patient is her consistently elevated levels of parathyroid hormone and serum calcium, suggesting hyperparathyroidism. We present this rare case along with a review of the literature and hope to draw an attention to a potential relationship between WHS and hyperparathyroidism.

Keywords

Wolf-Hirschhorn syndrome - 4p deletion - 4p duplication - hyperparathyroidism

Authors' Contributions

C.X. designed the study, collected clinical data, performed literature review, and wrote the manuscript. D.K. performed the data analysis and assisted in figure preparation. B.Y. performed chromosome and CMA data analysis and manuscript editing. D.S. performed CMA data analysis and assisted in CMA figure preparation. J.D. CMA contributed in data analysis. J.G.J. supported in case discussion and manuscript editing. B.A.P. designed the study, collected clinical data, and edited the manuscript.

Publication History

Received: 26 November 2020

Accepted: 24 March 2021

Article published online:
26 June 2021

• References

• 1 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]
• 2 Battaglia A, Carey JC. Wolf-Hirschhorn syndrome and the 4p-related syndromes. Am J Med Genet C Semin Med Genet 2008; 148C [phone]
• 3 Alberto F. Genetics of parathyroids disorders: Overview. Best Pract Res Clin Endocrinol Metab 2018; 32 (06) 781-790
• 4 Cristina EV, Alberto F. Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-Jaw tumour, Familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism. Best Pract Res Clin Endocrinol Metab 2018; 32 (06) 861-875
• 5 Marx SJ, Sinaii N. Neonatal severe hyperparathyroidism: novel insights from calcium, PTH, and the CASR gene. J Clin Endocrinol Metab 2020; 105 (04) 105
• 6 Dershem R, Gorvin CM, Metpally RPR. et al; Regeneron Genetics Center. Familial hypocalciuric hypercalcemia type 1 and autosomal-dominant hypocalcemia type 1: prevalence in a large healthcare population. Am J Hum Genet 2020; 106 (06) 734-747
• 7 Kong J, Wang O, Nie M. et al. Familial isolated primary hyperparathyroidism/hyperparathyroidism-jaw tumour syndrome caused by germline gross deletion or point mutations of CDC73 gene in Chinese. Clin Endocrinol (Oxf) 2014; 81 (02) 222-230
• 8 Demirel N, Aydin M, Zenciroglu A. et al. Hyperparathyroidism secondary to maternal hypoparathyroidism and vitamin D deficiency: an uncommon cause of neonatal respiratory distress. Ann Trop Paediatr 2009; 29 (02) 149-154
• 9 Cole DE, Janicic N, Salisbury SR, Hendy GN. Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor gene. Am J Med Genet 1997; 71 (02) 202-210
• 10 Belcher R, Metrailer AM, Bodenner DL, Stack Jr BC. Characterization of hyperparathyroidism in youth and adolescents: a literature review. Int J Pediatr Otorhinolaryngol 2013; 77 (03) 318-322
• 11 Kollars J, Zarroug AE, van Heerden J. et al. Primary hyperparathyroidism in pediatric patients. Pediatrics 2005; 115 (04) 974-980
• 12 Hirschhorn K, Cooper HL. Chromosomal aberrations in human disease. A review of the status of cytogenetics in medicine. Am J Med 1961; 31: 442-470
• 13 Battaglia A, Carey JC, South ST. Wolf-Hirschhorn syndrome: a review and update. Am J Med Genet C Semin Med Genet 2015; 169 (03) 216-223
• 14 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
• 15 Nevado J, Ho KS, Zollino M. et al; Wolf-Hirschhorn Spain's Working Group. International meeting on Wolf-Hirschhorn syndrome: update on the nosology and new insights on the pathogenic mechanisms for seizures and growth delay. Am J Med Genet A 2020; 182 (01) 257-267
• 16 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
• 17 Sukarova-Angelovska E, Kocova M, Sabolich V, Palcevska S, Angelkova N. Phenotypic variations in wolf-hirschhorn syndrome. Balkan J Med Genet 2014; 17 (01) 23-30
• 18 Battaglia A, Carey JC, South ST. Wolf-Hirschhorn Syndrome; retired chapter, for historical reference only. In: Adam MP, Ardinger HH, Pagon RA. et al. (eds). Seattle, WA: GeneReviews((R)); 1993
• 19 Gatto A, Ferrara P, Leoni C. et al. Oligonephronia and Wolf-Hirschhorn syndrome: a further observation. Am J Med Genet A 2018; 176 (02) 409-414
• 20 Ferrara P, Del Bufalo F, Nicoletti A. et al. Wolf-Hirschhorn syndrome with improvement of renal function. Am J Med Genet A 2010; 152A [phone]
• 21 Battaglia A, Carey JC, Viskochil DH, Cederholm P, Opitz JM. Wolf-Hirschhorn syndrome (WHS): a history in pictures. Clin Dysmorphol 2000; 9 (01) 25-30
• 22 Karaman S, Hazan F, Erdem SB, Gülez N, Genel F. Do microdeletions lead to immune deficiency?. Cent Eur J Immunol 2020; 45 (01) 69-72
• 23 Campos-Sanchez E, Deleyto-Seldas N, Dominguez V. et al. Wolf-Hirschhorn syndrome candidate 1 is necessary for correct hematopoietic and B cell development. Cell Rep 2017; 19 (08) 1586-1601
• 24 Peng HH, Wang TH, Chao AS, Chang YL, Chang SD, Soong YK. Prenatal diagnosis of monosomy 4p14-->pter and trisomy 11q25-->qter: clinical presentations and outcomes. Prenat Diagn 2005; 25 (12) 1133-1137
• 25 Hanley-Lopez J, Estabrooks LL, Stiehm R. Antibody deficiency in Wolf-Hirschhorn syndrome. J Pediatr 1998; 133 (01) 141-143
• 26 Xing Y, Holder Jr JL, Liu Y. et al. Prenatal diagnosis of Wolf-Hirschhorn syndrome: from ultrasound findings, diagnostic technology to genetic counseling. Arch Gynecol Obstet 2018; 298 (02) 289-295
• 27 Zhen L, Fan SS, Huang LY. et al. Prenatal diagnosis of Wolf-Hirschhorn syndrome: ultrasonography and molecular karyotyping results. Eur J Obstet Gynecol Reprod Biol 2018; 225: 19-21
• 28 Debost-Legrand A, Goumy C, Laurichesse-Delmas H. et al. Prenatal ultrasound findings observed in the Wolf-Hirschhorn syndrome: data from the registry of congenital malformations in Auvergne. Birth Defects Res A Clin Mol Teratol 2013; 97 (12) 806-811
• 29 Chao A, Lee YS, Chao AS, Wang TH, Chang SD. Microarray-based comparative genomic hybridization analysis of Wolf-Hirschhorn syndrome in a fetus with deletion of 4p15.3 to 4pter. Birth Defects Res A Clin Mol Teratol 2006; 76 (10) 739-743
• 30 Basgul A, Kavak ZN, Akman I, Basgul A, Gokaslan H, Elcioglu N. Prenatal diagnosis of Wolf-Hirschhorn syndrome (4p-) in association with congenital diaphragmatic hernia, cystic hygroma and IUGR. Clin Exp Obstet Gynecol 2006; 33 (02) 105-106
• 31 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]
• 32 Battaglia A, Calhoun ARUL, Lortz A, Carey JC. Risk of hepatic neoplasms in Wolf-Hirschhorn syndrome (4p-): Four new cases and review of the literature. Am J Med Genet A 2018; 176 (11) 2389-2394
• 33 Rutter S, Morotti RA, Peterec S, Gallagher PG. Hepatic malignancy in an infant with Wolf-Hirschhorn syndrome. Fetal Pediatr Pathol 2017; 36 (03) 256-262
• 34 Roselló M, Monfort S, Orellana C. et al. Submicroscopic duplication of the Wolf-Hirschhorn critical region with a 4p terminal deletion. Cytogenet Genome Res 2009; 125 (02) 103-108
• 35 Zollino M, Wright TJ, Di Stefano C. et al. “Tandem” duplication of 4p16.1p16.3 chromosome region associated with 4p16.3pter molecular deletion resulting in Wolf-Hirschhorn syndrome phenotype. Am J Med Genet 1999; 82 (05) 371-375
• 36 Rowe LR, Lee JY, Rector L. et al. U-type exchange is the most frequent mechanism for inverted duplication with terminal deletion rearrangements. J Med Genet 2009; 46 (10) 694-702
• 37 Yu S, Graf WD. Telomere capture as a frequent mechanism for stabilization of the terminal chromosomal deletion associated with inverted duplication. Cytogenet Genome Res 2010; 129 (04) 265-274
• 38 Sireteanu A, Braha E, Popescu R, Gramescu M, Gorduza EV, Rusu C. Inverted duplication deletion of 8P: characterization by standard cytogenetic and SNP array analyses. Rev Med Chir Soc Med Nat Iasi 2013; 117 (03) 731-734
• 39 Østergaard E, Pedersen VF, Skriver EB, Brøndum-Nielsen K. Brothers with Chudley-McCullough syndrome: sensorineural deafness, agenesis of the corpus callosum, and other structural brain abnormalities. Am J Med Genet A 2004; 124A (01) 74-78
• 40 Edwards TJ, Sherr EH, Barkovich AJ, Richards LJ. Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. Brain 2014; 137 (Pt 6): 1579-1613
• 41 O'Driscoll MC, Black GC, Clayton-Smith J, Sherr EH, Dobyns WB. Identification of genomic loci contributing to agenesis of the corpus callosum. Am J Med Genet A 2010; 152A [phone]
• 42 Bushinsky DA, Sessler NE, Glena RE, Featherstone JD. Proton-induced physicochemical calcium release from ceramic apatite disks. J Bone Miner Res 1994; 9 (02) 213-220
• 43 Locatelli F, Cannata-Andía JB, Drüeke TB. et al. Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia. Nephrol Dial Transplant 2002; 17 (05) 723-731
• 44 Greenberg A, Piraino BM, Bruns FJ. Hypercalcemia in patients with advanced chronic renal failure not yet requiring dialysis. Am J Nephrol 1989; 9 (03) 205-210
• 45 Krause MW, Hedinger CE. Pathologic study of parathyroid glands in tertiary hyperparathyroidism. Hum Pathol 1985; 16 (08) 772-784
• 46 Marx SJ. New concepts about familial isolated hyperparathyroidism. J Clin Endocrinol Metab 2019; jc.2018-02789
• 47 Riccardi A, Aspir T, Shen L. et al. Analysis of activating GCM2 sequence variants in sporadic parathyroid adenomas. J Clin Endocrinol Metab 2019; 104 (06) 1948-1952
• 48 Marchiori E, Pelizzo MR, Herten M, Townsend DM, Rubello D, Boschin IM. Specifying the molecular pattern of sporadic parathyroid tumorigenesis-The Y282D variant of the GCM2 gene. Biomed Pharmacother 2017; 92: 843-848
• 49 Guan B, Welch JM, Sapp JC. et al. GCM2-activating mutations in familial isolated hyperparathyroidism. Am J Hum Genet 2016; 99 (05) 1034-1044