= Gigantism =

Artist/Title /Date

Charles Eisenmann Studio Photograph, 1880

Description of Disease & Etiology

Acromegaly and gigantism occur secondary to excessive growth hormone (GH) secretion. The predominant cause of over secretion is a pituitary adenoma. The process of linear growth is disrupted if this excess of GH occurs before closure of the epiphyseal plates.1 Approximately 50% of these cases have a genetic element. There are several genetic disorders that produce GH secreting tumors: 1) Multiple Endocrine Neoplasia- Type 1 (MEN1), Carney Complex, McCune-Albright Syndrome, Familial Isolated Pituitary Adenomas (FIPA) and X-linked Acrogigantic Syndrome (X-LAG). MEN-1Syndrome is an autosomal dominant trait which is an inactivating mutation in the MEN1 gene which codes for menin. This protein functions in cell cycle control and oxidative stress regulation. Pituitary lesions develop in about 40% of these cases but only account for 1% of the total cases of acromegaly/gigantism. The Carney Complex is another rare autosomal dominant disorder. This mutation disrupts the encoding of type1A regulatory subunit of protein kinase A. Approximately 13% of these cases will develop pituitary adenomas. The McCune-Albright Syndrome is the result of a postzygotic mutation that disrupts many endocrine cells. Hypersecretion of GH will occur in approximately 30% of these cases. The most frequent cause (29% of the total genomic cases) are the FIPAs with the most common mutation being the AIP mutation (Aryl hydrocarbon receptor interacting protein gene). The second most common cause is the X-LAG Syndrome. This is a microduplication and is more predominant in females.2

Pathology

Pituitary gigantism is caused by chronic GH and insulin-like growth factor -1 (IGF-1) secretion from a pituitary adenoma. Most soft and hard tissue grow excessively, thus increasing physical size and organ size.3 If GH excess occurs after the fusion of epiphyseal plates, the patients will have features of acromegaly in conjunction with gigantism which is referred to as acro-gigantism. The pathological effects cause systemic complications, primarily metabolic and cardiovascular malfunction.4

Signs/Signifiers of Illness

<span id="the-clinical-signs-of-acromegaly-gigantism-are-due-to-excess-ghigf-1-levels.-there-is-an-overgrowth-of-cartilage-bone-and-soft-tissues.-this-is-often-manifested-as-an-increase-in-size-of-hands-and-feet-facial-dysmorphism-thickened-skin-hyperhidrosis-seborrhea-and-enlargement-of-viscera.-the-subsequent-complications-can-involve-the-musculoskeletal-system-arthralgia-osteoarthritis-carpal-tunnel-syndrome-and-paresthesia-calcium-metabolism-malfunction-increased-density-in-cortical-bone-with-a-decrease-in-trabecular-bone-cardiovascular-involvement-including-hypertension-left-ventricular-septal-hypertrophy-diastolic-dysfunction-coronary-heart-disease-and-heart-failure.-the-respiratory-system-can-be-involved-with-snoring-and-sleep-apnea-and-associated-abnormal-glucose-and-lipid-metabolism.-5"> The clinical signs of acromegaly-gigantism are due to excess GH/IGF-1 levels. There is an overgrowth of cartilage, bone and soft tissues. This is often manifested as an increase in size of hands and feet, facial dysmorphism, thickened skin, hyperhidrosis, seborrhea and enlargement of viscera. The subsequent complications can involve the musculoskeletal system (arthralgia, osteoarthritis, carpal tunnel syndrome and paresthesia), calcium metabolism malfunction, increased density in cortical bone with a decrease in trabecular bone, cardiovascular involvement including hypertension, left ventricular septal hypertrophy, diastolic dysfunction, coronary heart disease and heart failure. The respiratory system can be involved with snoring and sleep apnea, and associated abnormal glucose and lipid metabolism. 5

Treatment

<span id="there-are-several-therapies-for-the-treatment-of-excess-gh.-surgical-removal-is-the-recommended-treatment-for-well-circumscribed-pituitary-adenomas-and-it-is-considered-curative.-however-lifelong-hormonal-replacement-will-be-necessary.-radiation-therapy-can-be-a-primary-or-adjunctive-treatment-modality.-this-treatment-has-been-successful-in-decreasing-gh-levels-to-the-normal-range.-however-the-treatment-timeframe-can-be-up-to-five-years-in-length-with-the-chance-of-inducing-hypopituitarism-post-treatment.-medical-treatment-involves-usage-of-a-somatotropin-analogue-or-a-gh-receptor-blocker.-the-somatotropin-analogue-has-suppressed-gh-and-igf-1-levels-in-50-70-of-the-patients.-the-usage-of-pegvisomant-which-is-a-gh-analog-that-binds-to-gh-receptors-has-been-effective-in-acromegalic-adults-who-do-not-respond-to-the-somatotropin-analogues.-it-is-being-considered-as-an-additional-treatment-option-for-children.6"> There are several therapies for the treatment of excess GH. Surgical removal is the recommended treatment for well-circumscribed pituitary adenomas and it is considered curative. However, lifelong hormonal replacement will be necessary. Radiation therapy can be a primary or adjunctive treatment modality. This treatment has been successful in decreasing GH levels to the normal range. However, the treatment timeframe can be up to five years in length with the chance of inducing hypopituitarism post treatment. Medical treatment involves usage of a somatotropin analogue or a GH receptor blocker. The somatotropin analogue has suppressed GH and IGF-1 levels in 50-70% of the patients. The usage of Pegvisomant which is a GH analog that binds to GH receptors has been effective in acromegalic adults who do not respond to the somatotropin analogues. It is being considered as an additional treatment option for children.6

Social Determinants of Illness

Gigantism-acromegaly is a rare disease with the symptoms and features of the disease developing slowly. Often there is a delay in the diagnosis which causes a decrease in the quality of life for the patients and increased treatment expenses which may not be as effective as treatments started in a timely diagnosis. An earlier diagnosis will have a great impact on morbidity and mortality.7 Author: Donna S. Johnson, DVM

Author: Donna S. Johnson, DVM

Citations:

Rostomyan, L., Daly, A. F., & Beckers, A. (2015). Pituitary gigantism: Causes and clinical characteristics. Annales d’Endocrinologie, 76(6), 643–649. https://doi.org/10.1016/j.ando.2015.10.002

Bogusławska, A., & Korbonits, M. (2021). Genetics of Acromegaly and Gigantism. Journal of Clinical Medicine, 10(7), 1377. https://doi.org/10.3390/jcm10071377

Beckers, A., Petrossians, P., Hanson, J., & Daly, A. F. (2018). The causes and consequences of pituitary gigantism. Nature Reviews Endocrinology, 14(12), 705–720. https://doi.org/10.1038/s41574-018-0114-1

Sada, V., Puliani, G., Feola, T., Pirchio, R., Pofi, R., Sesti, F., De Alcubierre, D., Amodeo, M. E., D’Aniello, F., Vincenzi, L., Gianfrilli, D., Isidori, A. M., Grossman, A. B., Sbardella, E., Savage, A. M., Foresta, C., Krausz, C., Durante, C., De Martino, M. C., … the TALENT group. (2024). Tall stature and gigantism in transition age: Clinical and genetic aspects—a literature review and recommendations. Journal of Endocrinological Investigation, 47(4), 777–793. https://doi.org/10.1007/s40618-023-02223-z

Rostomyan, L., Daly, A. F., & Beckers, A. (2015). Pituitary gigantism: Causes and clinical characteristics. Annales d’Endocrinologie, 76(6), 643–649. https://doi.org/10.1016/j.ando.2015.10.002

Tyrtova, L. V., Викторовна, Т. Л., Olenev, A. S., Сергеевич, О. А., Parshina, N. V., Васильевна, П. Н., Skobeleva, C. V., & Владимировна, С. К. (2019). Pituitary gigantism. The possibility of medical treatment. Pediatrician (St. Petersburg), 10(5), 93–99. https://doi.org/10.17816/PED10593-99

Sisco, J., & van der Lely, A. J. (2021). Towards an Earlier Diagnosis of Acromegaly and Gigantism. Journal of Clinical Medicine, 10(7), 1363. https://doi.org/10.3390/jcm10071363