Gigantism

Artist/ Title/ Date

Osmar Schindler. David und Goliath. 1888. Colour lithograph. 78 x 58 cm

Description of Disease & Etiology

The somatotropic axis regulates growth during childhood and adolescence, and abnormalities in growth hormone (GH) and insulin-like growth factor 1 (IGF1) cause growth disorders.1 The first description of acromegaly (adult disorder of GH excess) by Pierre Marie in 1886 stimulated a rise in interest in acromegaly and pituitary gigantism.2 Pituitary gigantism is a rare disorder of overgrowth caused by excessive secretion of GH or IGF1 from a somatotrope adenoma or hyperplasia that occurs before the epiphyseal plate closes.1,3 It is characterized by height overgrowth and presents in childhood and adolescence, and can be difficult to diagnose during puberty due to overlap with normal growth.

Patients with pituitary gigantism almost always have macroadenomas (pituitary adenoma ≥10 mm diameter) at diagnosis.1 Research over the past decade has uncovered multiple genetic etiologies, with ~50% of cases having known genetic causes associated with increased risk of pituitary tumorigenesis.4 These include aryl hydrocarbon receptor interacting protein (AIP) mutations, multiple endocrine neoplasia type 1, Carney complex, McCune-Albright syndrome (MAS), and X-linked acrogigantism (X-LAG) syndrome.1,3 The most frequent genetic mutation are AIP mutations or deletions.5 Patients with the AIP gene mutation have greater male predominance and a younger age of disease onset and diagnosis compared to those with genetically negative pituitary gigantism.1 Genes encoding proteins involved in pituitary gigantism can drive tumorigenesis in other patient groups and can lead to inherited or familial forms of pituitary adenomas.6 Patients with AIP mutations most commonly present with familial isolated pituitary adenomas (FIPA). These mutation-related pituitary adenomas are aggressive GH-secreting tumors in children or adolescents, with gigantism seen in about 1/3 of cases.5 X-LAG syndrome is implicated in many of the tallest humans in history; these patients have a younger age onset of disease and significant overgrowth typical of X-LAG syndrome.7

Signs/Signifiers of Illness

The primary clinical presentation of pituitary gigantism is excessive height. The pathological effects of excess GH and IGF1 are systemic and affect multiple organ systems, and patients are often diagnosed as children or in adolescence.1 Symptoms from the disease include acral enlargement, coarsening of facial features, headaches, excessive sweating, visual field defects, hypogonadism, skin disorders, joint disorders, sleep apnea, hypertension, carpal tunnel, and diabetes insipidus. Longterm disease can lead to complications from chronic GH excess, including impaired glucose tolerance and cardiovascular disease.4

Pathology

Pituitary adenomas are highly secretory in addition to their typically large size, leading to elevated levels of GH and IGF1.1 The disruption of certain genes alters the pituitary somatotropic function. This leads to hyperplasia and aggressive tumor formation causing GH hypersecretion.4 Large pituitary adenomas can disrupt normal gonadotrope function, while marked hyperprolactinemia (seen in cases involving AIP mutations or X-LAG syndrome) further contributes to hypogonadism. In growing individuals, reduced sex steroid levels in the setting of excess GH delay closure of the epiphyseal growth plates, prolonging the period of linear bone growth and ultimately resulting in more pronounced GH- and IGF1–mediated increases in height.1 The aggressive disease type causes a high symptom burden due to the early-onset resistant pituitary somatotropic tumorigenesis and difficult-to-control hypersection of GH and IGF1. Higher GH levels in females with pituitary gigantism are largely explained by X-LAG syndrome, a predominantly female condition characterized by marked GH hypersecretion. In the general population of patients with pituitary gigantism, excessive GH and IGF1 levels are often coupled with prolactin hypersection, especially in those with X-LAG syndrome.4

Treatment

Treatment for gigantism focuses on managing GH and IGF1 hypersecretion, controlling pituitary tumor growth, addressing the tumor effects on local structures, and reducing systemic hormonal hypersecretion pathologies.1 The mean maximal tumor diameter is 22mm and more than 75% of patients have extrasellar extension with most tumors being invasive at the time of diagnosis. The aggressive nature of the tumors results in limited hormonal control from pharmacotherapy alone.4 Almost one-third of patients need three or more interventions or modalities.1 Neurosurgery is a valid first-line option, but access to the pituitary is complicated in children.8,9 Multiple surgeries and radiotherapy are associated with hypopituitarism during long-term follow-up for pituitary gigantism.4 Treating pituitary gigantism is difficult, particularly because some genetic causes (AIP mutations, GPR101 duplications, and X-LAG syndrome) can lead to somatotrope tumors resistant to standard medical therapies, including somatostatin analogues.1,5 For those with somatostatin analogue-resistant pituitary gigantism from X-LAG syndrome or AIP mutations, pegvisomant, a GH receptor antagonist, can reduce levels of IGF1.7 Control of hormonal excess at an earlier age is associated with significantly lower final height, making this a key target for management to stabilize GH and IGF1 secretion.4 Combination medical therapy with somatostatin receptor analogues and pegvisomant can be used as a primary treatment or following pituitary surgery and radiotherapy, offering an effective way to control effects of hormonal hypersecretion.3

Social Determinants of Illness

Many medications used to treat acromegaly have not been adequately studied in pediatric populations and are not indicated for use in children, which creates barriers to access prescriptions for effective medical therapies for pituitary gigantism.1 Some studies indicated that environmental pollutants with certain endocrine disrupting activity can impact pituitary function and biology.10 The role of specific environmental pollutants interacting with the aryl hydrocarbon receptor pathway as it relates to the development of human GH-secreting pituitary tumors is still being studied. Multimodal treatment is often a costly endeavor, and therapy may be limited due to local cost limitations.11

Author(s): Maria Burdjalov, BS

Citations:

* 1) Beckers, A., Petrossians, P., Hanson, J., & Daly, A. (2018). The causes and consequences of pituitary gigantism. Nature Reviews. Endocrinology, 14. https://doi.org/10.1038/s41574-018-0114-1 * 2) de Herder, W. W. (2009). Acromegaly and gigantism in the medical literature. Case descriptions in the era before and the early years after the initial publication of Pierre Marie (1886). Pituitary, 12(3), 236–244. https://doi.org/10.1007/s11102-008-0138-y * 3) Mangupli, R., Rostomyan, L., Castermans, E., Caberg, J.-H., Camperos, P., Krivoy, J., Cuauro, E., Bours, V., Daly, A. F., & Beckers, A. (2016). Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: Clinical evaluation and genetic screening. Pituitary, 19(5), 507–514. https://doi.org/10.1007/s11102-016-0732-3 * 4) Rostomyan, L., Daly, A. F., Petrossians, P., Nachev, E., Lila, A. R., Lecoq, A.-L., Lecumberri, B., Trivellin, G., Salvatori, R., Moraitis, A. G., Holdaway, I., Klaveren, D. J. K., Zatelli, M. C., Palacios, N., Nozieres, C., Zacharin, M., Ebeling, T., Ojaniemi, M., Rozhinskaya, L., … Beckers, A. (2015). Clinical and genetic characterization of pituitary gigantism: An international collaborative study in 208 patients. https://doi.org/10.1530/ERC-15-0320 * 5) Daly, A., Tichomirowa, M. A., Petrossians, P., Heliövaara, E., Jaffrain-Rea, M.-L., Barlier, A., Naves, L. A., Ebeling, T., Karhu, A., Raapana, A., Cazabat, L., De Menis, E., Montanana, C. F., Raverot, G., Weil, R. J., Sane, T., Maiter, D., Neggers, S., Yaneva, M., … Beckers, A. (2010). Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas: An international collaborative study. Journal of Clinical Endocrinology and Metabolism, 95(11). https://doi.org/10.1210/jc.2009-2556 * 6) Martucci, F., Trivellin, G., & Korbonits, M. (2012). Familial isolated pituitary adenomas: An emerging clinical entity. Journal of Endocrinological Investigation, 35(11), 1003–1014. https://doi.org/10.1007/BF03346742 * 7) Beckers, A., Lodish, M. B., Trivellin, G., Rostomyan, L., Lee, M., Faucz, F. R., Yuan, B., Choong, C. S., Caberg, J.-H., Verrua, E., Naves, L. A., Cheetham, T. D., Young, J., Lysy, P. A., Petrossians, P., Cotterill, A., Shah, N. S., Metzger, D., Castermans, E., … Stratakis, C. A. (2015). X-linked acrogigantism syndrome: Clinical profile and therapeutic responses. Endocrine-Related Cancer, 22(3), 353–367. https://doi.org/10.1530/ERC-15-0038 * 8) Hindmarsh, P. C., Pringle, P. J., Di Silvio, L., & Brook, C. G. D. (1990). A Preliminary Report on the Role of Somatostatin Analogue (sms 201-995) in the Management of Children with Tall Stature. Clinical Endocrinology, 32(1), 83–91. https://doi.org/10.1111/j.1365-2265.1990.tb03753.x * 9) Hindmarsh, P. C., Pringle, P. J., Stanhope, R., & Brook, C. G. D. (1995). The effect of a continuous infusion of a somatostatin analogue (octreotide) for two years on growth hormone secretion and height prediction in tall children. Clinical Endocrinology, 42(5), 509–515. https://doi.org/10.1111/j.1365-2265.1995.tb02670.x * 10) Gore, A. C. (2010). Neuroendocrine targets of endocrine disruptors. Hormones, 9(1), 16–27. https://doi.org/10.14310/horm.2002.1249 * 11) Cannavo, S., Trimarchi, F., & Ferraù, F. (2017). Acromegaly, genetic variants of the aryl hydrocarbon receptor pathway and environmental burden. Molecular and Cellular Endocrinology, Hormone-Related Cancers and Endocrine Disruptors: New Aspects of an Old Question, 457, 81–88. https://doi.org/10.1016/j.mce.2016.12.019