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The causes and consequences of pituitary gigantism

Abstract

In the general population, height is determined by a complex interplay between genetic and environmental factors. Pituitary gigantism is a rare but very important subgroup of patients with excessive height, as it has an identifiable and clinically treatable cause. The disease is caused by chronic growth hormone and insulin-like growth factor 1 secretion from a pituitary somatotrope adenoma that forms before the closure of the epiphyses. If not controlled effectively, this hormonal hypersecretion could lead to extremely elevated final adult height. The past 10 years have seen marked advances in the understanding of pituitary gigantism, including the identification of genetic causes in ~50% of cases, such as mutations in the AIP gene or chromosome Xq26.3 duplications in X-linked acrogigantism syndrome. Pituitary gigantism has a male preponderance, and patients usually have large pituitary adenomas. The large tumour size, together with the young age of patients and frequent resistance to medical therapy, makes the management of pituitary gigantism complex. Early diagnosis and rapid referral for effective therapy appear to improve outcomes in patients with pituitary gigantism; therefore, a high level of clinical suspicion and efficient use of diagnostic resources is key to controlling overgrowth and preventing patients from reaching very elevated final adult heights.

Key points

  • Nearly 50% of patients with pituitary gigantism have a known underlying genetic cause; therefore, these patients should be strongly considered for genetic counselling and screening.

  • Once growth hormone (GH) hypersecretion has been established, efforts should be made to avoid delays in instigating treatment to control levels of GH and insulin-like growth factor 1.

  • A shorter time between diagnosis and the commencement of treatment is associated with a decreased final height in pituitary gigantism.

  • Pituitary gigantism is a disease that predominantly affects males, but males also have a longer delay in time to diagnosis than females, leading to a low proportion of male patients who have disease control by 18 years of age.

  • Somatotropinomas in pituitary gigantism are usually large (macroadenomas) and might be difficult to cure with surgery or medical therapy alone; therefore, multimodal approaches are common in pituitary gigantism.

  • The effect of large tumour size and multiple surgeries and radiotherapy is that patients with pituitary gigantism often have hypopituitarism at long-term follow-up.

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Fig. 1: An historical patient with pituitary gigantism.
Fig. 2: Signs and symptoms in pituitary gigantism at diagnosis.
Fig. 3: Evolution of the severity of signs and symptoms of pituitary gigantism before and after treatment.
Fig. 4: Schematic for performing genetic investigations in patients with pituitary gigantism.

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Acknowledgements

The authors acknowledge the support of an Actions de Recherche Concertées 2017 grant for the GOLIATHS project from Liège Université, a Fonds d’Investissement pour la Recherche Scientifique grant from the Centre Hospitalier Universitaire de Liège and a grant from the Jabbs Foundation, UK.

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Nature Reviews Endocrinology thanks K. Kovacs, S. Cannavò and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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A.B. and A.F.D. researched the data for the article, contributed to the discussion of content, wrote the article and reviewed and edited the manuscript before submission. P.P. and J.H. researched data for the article and reviewed and/or edited the article before submission.

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Correspondence to Albert Beckers.

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Glossary

Somatotropic axis

The hormonal system, including the hypothalamus, pituitary and peripheral tissues, that controls growth hormone secretion from the anterior pituitary gland and insulin-like growth factor 1 mainly from the liver.

Somatotrope adenoma

A benign tumour of the growth hormone-producing cells of the anterior pituitary gland.

Epiphyses

Proximal and distal end portions of long bones that contain cartilaginous growth plates at which longitudinal bone growth occurs until growth plate closure and epiphyseal fusion with the rest of the bone.

Extrasellar extension

Growth of a pituitary adenoma outside of the borders of the sella turcica.

Haploblock

Also known as haplotype block. A set of neighbouring genetic alleles or markers that tend to be inherited together over generations.

Pneumatization

Development of an air space within a sinus, such as the sphenoid sinus, that gradually takes place over childhood and has an influence on the neurosurgical access to the anterior pituitary gland.

Transsphenoidal

Neurosurgical approach to access the pituitary gland in the sella turcica via the sphenoid sinus.

Sellar floor

The base of the sella turcica in which the pituitary gland lies.

Transfrontal approach

A neurosurgical approach to the pituitary gland via the frontal bone of the skull.

Tumour debulking

Removal of tumour tissue to reduce overall tumour size and related symptoms when full tumour resection cannot be performed.

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Beckers, A., Petrossians, P., Hanson, J. et al. The causes and consequences of pituitary gigantism. Nat Rev Endocrinol 14, 705–720 (2018). https://doi.org/10.1038/s41574-018-0114-1

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