Congenital hypopituitarism in two brothers with a duplication of the ‘acrogigantism gene’ GPR101: clinical findings and review of the literature

Melitza S.M. Elizabeth*, Annemieke J.M.H. Verkerk, Anita C.S. Hokken-Koelega, Joost A.M. Verlouw, Jesús Argente, Roland Pfaeffle, Sebastian J.C.M.M. Neggers, Jenny A. Visser, Laura C.G. de Graaff

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
22 Downloads (Pure)


Purpose: Congenital hypopituitarism (CH) can cause significant morbidity or even mortality. In the majority of patients, the etiology of CH is unknown. Understanding the etiology of CH is important for anticipation of clinical problems and for genetic counselling. Our previous studies showed that only a small proportion of cases have mutations in the known ‘CH genes’. In the current project, we present the results of SNP array based copy number variant analysis in a family with unexplained congenital hypopituitarism. Methods: DNA samples of two affected brothers with idiopathic CH and their mother were simultaneously analyzed by SNP arrays for copy number variant analysis and Whole Exome Sequencing (WES) for mutation screening. DNA of the father was not available. Results: We found a 6 Mb duplication including GPR101 and SOX3 on the X-chromosome (Xq26.2-q27.1) in the two siblings and their mother, leading to 2 copies of this region in the affected boys and 3 copies in the mother. Duplications of GPR101 are associated with X-linked acrogigantism (the phenotypic ‘opposite’ of the affected brothers), whereas alterations in SOX3 are associated with X-linked hypopituitarism. Conclusion: In our patients with hypopituitarism we found a 6 Mb duplication which includes GPR101, a gene associated with X- linked gigantism, and SOX3, a gene involved in early pituitary organogenesis that is associated with variable degrees of hypopituitarism. Our findings show that in duplications containing both GPR101 and SOX3, the growth hormone deficiency phenotype is dominant. This suggests that, if GPR101 is duplicated, it might not be expressed phenotypically when early patterning of the embryonic pituitary is affected due to SOX3 duplication. These results, together with the review of the literature, shed a new light on the role of GPR101 and SOX3 in pituitary function.

Original languageEnglish
Pages (from-to)229-241
Number of pages13
Issue number2
Early online date13 Nov 2020
Publication statusPublished - Apr 2021

Bibliographical note

Funding Information:
For this project, we received financial support from Pfizer Netherlands. Acknowledgements

Funding Information:
ME, AV, AHK, JV, JA, RP, SN and JV have nothing to declare. LdG received an Investigator Initiated Research Grant from Pfizer.

Publisher Copyright:
© 2020, The Author(s).


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