Abstract
Pseudohypoparathyroidism type 1B (PHP1B) is characterized by renal tubular resistance to parathyroid hormone (PTH) leading to hyperphosphatemia, hypocalcemia, elevated PTH, and hyperparathyroid bone changes. PHP1B is an imprinting disorder that results from loss of methylation at the maternal GNAS gene, which suppresses transcription of the alpha subunit of the stimulatory G protein of the PTH receptor. Emerging evidence supports an association between assisted reproductive technologies (ART) and imprinting disorders; however, there is currently little evidence linking PHP1B and ART. We present a twin boy conceived by ART to parents with no history of subfertility who presented at age 12 with bilateral slipped capital femoral epiphysis and bilateral genu valgum deformity. Clinical and laboratory investigation revealed markedly elevated PTH, low ionized calcium, elevated phosphorus, TSH resistance, and skeletal evidence of hyperparathyroidism, leading to the diagnosis of PHP1B. A partial loss of methylation at the GNAS exon A/B locus was observed. The patient’s dizygotic twin sibling was asymptomatic and had normal laboratory evaluation. This is the second reported case of a child with PHP1B conceived by ART, further supporting the possibility that ART may lead to an increased risk for imprinting defects.
Similar content being viewed by others
References
Thakker RV. Hypocalcaemic disorders, hypoparathyroidism, and pseudohypoparathyroidism. In: JAH W, Stewart PM, Amiel SA, Davies MJ, editors. Oxford textbook of endocrinology and diabetes. 2nd ed. Oxford: Oxford University Press; 2011. p. 675–86.
Mantovani G, Spada A, Elli FM. Pseudohypoparathyroidism and Gsα-cAMP-linked disorders: current view and open issues. Nat Rev Endocrinol. 2016;12:347–56.
Turan S, Bastepe M. The GNAS complex locus and human diseases associated with loss-of-function mutations or epimutations within this imprinted gene. Horm Res Paediatr. 2013;80:229–41.
Kinard RE, Walton JE, Buckwalter JA. Pseudohypoparathyroidism. Arch Intern Med. 1979;139:204–7.
Mantovani G, Spada A. Mutations in the Gs alpha gene causing hormone resistance. Best Pract Res Clin Endocr Metab. 2006;20:501–13.
de Nanclares GP, Fernández-Rebollo E, Santin I, García-Cuartero B, Gaztambide S, Menéndez E, et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab. 2007;92:2370–3.
Bastepe M, Fröhlich LF, Hendy GN, Indridason OS, Josse RG, Koshiyama H, et al. Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J Clin Invest. 2003;112:1255–63.
Jüppner H, Schipani E, Bastepe M, Cole DE, Lawson ML, Mannstadt M, et al. The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Natl Acad Sci U S A. 1998;95:11798–803.
Bastepe M, Lane AH, Jüppner H. Paternal uniparental isodisomy of chromosome 20q-and the resulting changes in GNAS1 methylation-as plausible cause of pseudohypoparathyroidism. Am J Hum Genet. 2001;68:1283–9.
Mussa A, Molinatto C, Cerrato F, Palumbo O, Carella M, Baldassarre G, et al. Assisted reproductive techniques and risks of Beckwith-Wiedemann syndrome. Pediatrics. 2017;140:e20164311.
Manipalviratn S, DeCherney A, Segars J. Imprinting disorders and assisted reproductive technology. Fertil Steril. 2009;91:305–15.
Amor DJ, Halliday J. A review of known imprinting syndromes and their association with assisted reproduction technologies. Hum Reprod. 2008;23:2826–34.
Fernandez M, Zambrano MJ, Riquelme J, Castiglioni C, Kottler ML, Jüppner H, et al. Pseudohypoparathyroidism type 1B associated with assisted reproductive technology. J Pediatr Endocrinol Metab. 2017;30:1125–32.
Hall FM, Segall-Blank M, Genant HK, Kolb FO, Hawes LE. Pseudohypoparathyroidism presenting as renal osteodystrophy. Skelet Radiol. 1981;6:43–6.
Dabbagh S, Chesney RW, Langer LO, DeLuca HF, Gilbert EF, DeWeerd JH. Renal-nonresponsive, bone-responsive pseudohypoparathyroidism. A case with normal vitamin D metabolite levels and clinical features of rickets. Am J Dis Child. 1984;138:1030–3.
Burnstein MI, Kottamasu SR, Pettifor JM, Sochett E, Ellis BI, Frame B. Metabolic bone disease in pseudohypoparathyroidism: radiologic features. Radiology. 1985;155:351–6.
Agarwal C, Siegle R, Agarwal S, Bilezikian JP, Hyman JE, Oberfield SE. Pseudohypoparathyroidism: a rare cause of bilateral slipped capital femoral epiphysis. J Pediatr. 2006;149:406–8.
Somasundaram KR, Sankararaman S, Siddiqui A, Zadeh H. Pseudohypoparathyroidsim as a rare cause of bilateral slipped capital femoral epiphysis. Indian J Orthop. 2012;46:705–9.
De Waal E, Vrooman LA, Fischer E, Ord T, Mainigi MA, Coutifaris C, et al. The cumulative effect of assisted reproduction procedures on placental development and epigenetic perturbations in a mouse model. Hum Mol Genet. 2015;24:6975–85.
Young LE, Sinclair KD, Wilmut I. Large offspring syndrome in cattle and sheep. Rev Reprod. 1998;3:155–63.
Young LE, Fernandes K, McEvoy TG, Butterwith SC, Gutierrez CG, Carolan C, et al. Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nat Genet. 2001;27:153–4.
Hiendler S, Wirtz M, Mund C, Klempt M, Reichenbach HD, Stojkovic M, et al. Tissue-specific effects of in vitro fertilization procedures on genomic cytosine methylation levels in overgrown and normal sized bovine fetuses. Biol Reprod. 2006;75:17–23.
Hiura H, Okae H, Miyauchi N, Sato F, Sato A, Van De Pette M, et al. Characterization of DNA methylation errors in patients with imprinting disorders conceived by assisted reproduction technologies. Hum Reprod. 2012;27:2541–8.
Marques CJ, Carvalho F, Sousa M, Barros A. Genomic imprinting in disruptive spermatogenesis. Lancet. 2004;363:1700–2.
Marques CJ, Costa P, Vaz B, Carvalho F, Fernandes S, Barros A, et al. Abnormal methylation of imprinted genes in human sperm is associated with oligozoospermia. Mol Hum Reprod. 2008;14:67–74.
Kobayashi H, Sato A, Otsu E, Hiura H, Tomatsu C, Utsunomiya T, et al. Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Hum Mol Genet. 2007;16:2542–51.
Doornbos ME, Maas SM, McDonnell J, Vermeiden JP, Hennekam RC. Infertility, assisted reproduction technologies and imprinting disturbances: a Dutch study. Hum Reprod. 2007;22:2476–80.
Hiura H, Okae H, Chiba H, Miyauchi N, Sato F, Sato A, et al. Imprinting methylation errors in ART. Reprod Med Biol. 2014;13:193–202.
Financial support
None
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Status
New submission. This work has not been previously published in any language anywhere and is not under simultaneous consideration or in press by another journal.
Rights and permissions
About this article
Cite this article
Goel, N.J., Meyers, L.L. & Frangos, M. Pseudohypoparathyroidism type 1B in a patient conceived by in vitro fertilization: another imprinting disorder reported with assisted reproductive technology. J Assist Reprod Genet 35, 975–979 (2018). https://doi.org/10.1007/s10815-018-1129-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-018-1129-1