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Acrogigantism (X-Linked)

X-linked acrogigantism (XLAG) is a rare condition involving excessive growth in early childhood (typically beginning in the first two years of life), with associated coarsening of facial features, enlargement of the hands and feet, and increased appetite1. XLAG is caused by duplications of the GPR101 gene on the X chromosome resulting in increased growth hormone (GH) secretion from pituitary adenomas, which are noncancerous tumors (75% of cases), or diffuse pituitary hyperplasia, which is general overgrowth of the gland (25% of cases)2,3. The pituitary overgrowth that is characteristic of XLAG often results in the co-occurance of hyperprolactinemia (as the hormone prolactin is also secreted by pituitary cells), causing breast growth in males and irregular menstruation (periods) in females. Treatment can involve surgery and/or medications that reduce pituitary hormone secretion, depending on the presentation. If untreated, XLAG can lead to markedly increased stature and resulting physical and psychological sequelae.

Females with XLAG

Unlike in many X-linked conditions, most patients (80%) with XLAG are female, and females are affected with the same disease severity as males2. Most cases are simplex, meaning that the patient is the only person in their family to have XLAG because it was caused by a de novo (i.e. new) mutation. The GPR101 gene duplications that cause XLAG can be germline (meaning the genetic error existed in the parent’s reproductive cells, so the duplication is present in all of the child’s cells), or somatic (meaning the error occurred during replication of the child’s own cells during development, so only a fraction of their cells have the duplication, a phenomenon known as mosaicism). While less common, familial X-linked transmission can occur to pass down XLAG to children. Those cases are caused by germline duplications that are not de novo.

In XLAG, female patients usually have germline duplications while male patients usually have somatic duplications with mosaicism4. However, there is no difference in the severity of disease seen between females and males. This is likely because having even a small proportion of cells containing the GPR101 gene duplication will result in severely elevated GH secretion, causing the full phenotype of disease.

It is thought that males have XLAG less commonly than females because male fetuses with germline GPR101 duplications may sometimes not be viable (while females have one normal X chromosome to help improve viability), though this theory has not been proven. Notably, three cases of familial XLAG have been reported in males, with germline GPR101 duplications passed down from mother to son4. This proves that germline duplications in males are not entirely unviable, and importantly shows that females with germline XLAG can have affected male children (in addition to affected female children). However, unlike in females, no de novo germline mutations have been reported in male patients.

This page was last updated in July, 2026. Please note that research into this condition is limited and the number of reported cases is small. As a result, percentages and prevalence rates may not be accurate or widely applicable. Decisions regarding your own health should be made in consultation with your medical provider.

  1. Iacovazzo D, Korbonits M. X-Linked Acrogigantism. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, eds. GeneReviews®. University of Washington, Seattle; 1993. Accessed July 14, 2026. http://www.ncbi.nlm.nih.gov/books/NBK476671/ 

  2. Coopmans EC, Korbonits M. Molecular genetic testing in the management of pituitary disease. Clin Endocrinol (Oxf). 2022;97(4):424-435. doi:10.1111/cen.14706
  3. Trivellin G, Daly AF, Faucz FR, et al. Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation. N Engl J Med. 2014;371(25):2363-2374. doi:10.1056/NEJMoa1408028
  4. Daly AF, Yuan B, Fina F, et al. Somatic Mosaicism Underlies X-linked Acrogigantism (XLAG) Syndrome in Sporadic Male Subjects. Endocr Relat Cancer. 2016;23(4):221-233. doi:10.1530/ERC-16-0082