An article by Constantine A. Stratakis, MD, D(med)Sci, PhD(hc)
Senior Investigator (ret) & Emeritus Scientific Director, NICHD, NIH, Bethesda, MD, USA
Chief Scientific Officer, ELPEN, Inc. & Executive Director, Athens Research Institute, Athens, Greece
Senior Investigator, FORTH, Heraklion, Crete, Greece
Giants (from the Greek “Γίγαντες”) are known from ancient times in all societies and cultures. In Greek mythology, the giants rebelled against the Olympian Gods in a supernatural fight that ended by their final defeat that resulted in Olympian sovereignty on earth. The battle is known as gigantomachy (1).
In Hebrew, the Nephilim were giants that existed before the flooding that occurred at Noah’s time. Goliath was a giant Philistine warrior that was defeated by David, the man who was to become king of Israel. It is said that Goliath’s height was 9 feet 6 ½ inches, almost 3 meters (2). Akhenaten, the reformer Egyptian pharaoh who moved Egypt’s capital and established a new religion around the sun, may also have had a form of gigantism that was passed on to his family.
Both gigantes and nephilim were related to the divine but seen as different, even vile; they had to be eliminated: in fact, one of the reasons for Noah’s flooding was to get rid of the nephilim. To this day, Enceladus (Ἐγκέλαδος), a giant who was buried under Aetna, is one of the Greek words for “earthquake”, adding to the connotation of large size as disastrous. Even at war, where one might think being larger might confer an advantage, giants were understood to be not effective soldiers (probably due to their comorbidities); that is why Frederic the Great disbanded the regiment of “Potsdam Giants” created by his father, Frederick William I of Prussia.
But there is no question that giants always attracted attention (1, 3, 4). The Irish giants in the 17th and 18th century made a living by participating in exhibitions throughout Europe (see picture); James Byrne, whose skeleton was kept at the Royal College of Surgeons of England was 7 feet 8 inches (2.34 m) tall. The Alton giant (Robert Pershing Wadlow, 1918-1940) was the tallest man of his time and of international fame, just like recently every move of a 2.51m-tall Turkish farmer, Sultan Kösen, was being recorded as “the world’s tallest living man”.
Overgrowth was recognized as an abnormality (although not necessarily a medical condition) as early as the 7th century C.E.: St. Isidore, Archbishop of Seville, included large size of the body in his list of growth defects. However, the credit for the first medical description of growth hormone (GH)-caused overgrowth as a disease should be given to Pierre Marie who also coined the term “acromegaly” in 1886. Today we know, as Prof. Wouter W. de Herder has told us, that others like the Dutch physician Johannes Wier had described the disease earlier (4). Minkowski and Cushing linked acromegaly to pituitary tumors, and the discoveries of radiation therapy and transsphenoidal surgery followed (3).
The last 30 years has produced amazing discoveries in the genetics of gigantism and acromegaly (5): GNAS defects (activating mutations of the G-protein stimulatory subunit alpha, Gsa) lead to gigantism in McCune-Albright syndrome (MAS), and in acromegaly when confined to sporadic GHPAs (6). PRKAR1A mutations that lead to increased cAMP signaling, just like GNAS mutations, are responsible for gigantism or acromegaly in the context of Carney complex (CNC) but have never been found in sporadic GH-producing adenomas (GHPAs) (7). MEN1 (menin) gene mutations lead to gigantism and/or acromegaly in the context of multiple endocrine neoplasia (MEN) type 1 (MEN 1) but only rarely in sporadic acromegaly (8). Mutations in the cyclin-dependent kinase (CDKN) 1B (CDKN1B) are found in MEN type 4 (MEN 4) (1); other CDKNs, all essential molecules in the regulation of cell cycle, growth and proliferation, are mutated, rarely, in MEN 1/MEN 4-like syndromic gigantism and/or acromegaly but not in sporadic GHPAs (1, 5, 8).
Most of the patients with gigantism before puberty have defects on the X-chromosome in the context of a condition that we named X-linked acromegaloidism or X-LAG at the NIH (9); their presentation is rather dramatic and does not mimic the usually insidious onset of sporadic acromegaly (10). Patients with familial isolated GHPAs (FIPA) also exist and may present with only gigantism or acromegaly; their genetic defect is in the aryl-hydrocarbon receptor-interacting protein or AIP (11).
Finally, syndromic gigantism or acromegaly can occur in the context of succinate dehydrogenase (SDH) mutations, where it is found in association with paragangliomas and pheochromocytomas (12) and/or other states, associated with multiple tumors and caused by yet unknown genetic defects (13).
Although genetics has unraveled the mysteries of gigantism and/or acromegaly in the last two decades, there have been fewer advances in the treatment of these two conditions.
In this article, we focus on the most recent discovery in the field: the description of X-LAG.
Gigantism, acromegaly and XLAG’s discovery
Pituitary gigantism is a rare growth disorder that is caused by excessive secretion of growth hormone, usually by a pituitary tumor, starting in childhood and adolescence. The cause of pituitary gigantism is often unknown, but genetic factors play an important role, as mentioned above. X-LAG was discovered in my laboratory in 2013-2014.
This disorder leads to dramatic GH-induced overgrowth beginning in infancy. We found that X-LAG is due to a microduplication (extra copy) of a region of chromosome Xq26.3 (MIM#300942). This microduplication includes a gene for the orphan G protein-coupled receptor (GPCR), GPR101, which regulates growth by a mechanism that is only just being explored.
We then collaborated with Professor Albert Beckers of the University of Liege and found out that X-LAG syndrome can occur both in families as a cause of familial isolated pituitary adenomas (FIPA) and as isolated cases.
We published this important advance in the understanding of the cause for gigantism in the New England Journal of Medicine (9). In this and other reports, we described the clinical and pathological characteristics of this newly recognized syndrome in several patients and families worldwide.
The primary genetic change in patients with X-LAG was detected by a method called array comparative genomic hybridization (aCGH) utilizing DNA extracted from patients’ white blood cells. This technique involves comparing the genetic material of an individual with a reference DNA and can identify when there are increased numbers of genetic regions (duplications) or losses of genetic material (deletions) as compared with normal.
The change identified in patients with X-LAG syndrome by this group of researchers was a small microduplication on the long arm of the X chromosome; the X chromosome is one of the two sex chromosomes in humans. The microduplication involved a region that has never been previously recognized as being important in growth disorders. It contains a gene called GPR101, and this extra copy of this gene in X-LAG syndrome appears to have a major disruptive effect on normal growth hormone secretion by the pituitary. This leads to overgrowth of the cells in the pituitary gland that produce GH and another hormone prolactin; this overgrowth (hyperplasia) eventually becomes a pituitary tumor called an adenoma. As the function of GPR101 is almost completely unknown, this discovery has opened a new chapter in our understanding of how growth is regulated.
How does X-LAG present?
Most patients are female and from normal-height families. Patients are usually born following unremarkable pregnancies and are generally normal sized at birth. Sometime in the first year of life X-LAG syndrome patients begin to show increased growth in both height/length and weight. This usually occurs by about 12 months of age, but it can be later and many patients are diagnosed between the ages of 3 and 4 years. Parents report rapid growth, accelerated changes in clothing and shoe size and in some cases this is accompanied by increased appetite and other food-seeking behavior. In some patients, the insulin level is increased and there is evidence of insulin resistance although none described so far have had frank diabetes. Some patients had headache and visual changes (9-11)
The hormonal changes consist primarily of very high levels of growth hormone (GH) and insulin-like growth factor type 1 (IGF-1). The growth hormone levels do not suppress during an oral glucose tolerance test. In most patients, prolactin levels are also increased (some markedly so), but none had galactorrhea. Diagnostic imaging showed pituitary tumors or enlargement that in nearly all cases were larger than 1 cm in diameter (macroadenomas) and most were much larger than this. These tumour sizes are notable when one considers the very young age of the X-LAG syndrome patients at diagnosis. Histopathology of resected tissue usually demonstrates mixed pituitary adenomas with cells positive for growth hormone and prolactin. Some cases have only overgrowth or hyperplasia of these pituitary cells and in other cases both adenoma and hyperplasia co-exist.
What are the therapeutic options?
X-LAG management is challenging like in most cases of gigantism and acromegaly. If neurosurgery occurs at an early stage, it may be curative in some younger patients (ie halting vertical growth before permanent adult gigantism can occur). Where a pituitary tumour is distinct and visible, the surgeons’ goal is to remove the tumour while leaving the normal pituitary gland intact.
In many instances, however, distinct pituitary tumors are not visible. In those cases, and in cases where the initial tumor removal was not successful in controlling the concentrations of hormones associated with growth (GH & IGF-1), a more radical surgery is considered. This involves surgical removal of the entire pituitary gland (complete hypophysectomy), with many patients requiring a fat graft from the abdomen and a lumbar drain to help prevent leakage of cerebrospinal fluid (CSF) just after surgery.
In other circumstances, medical therapy is warranted. Dopamine agonists such as cabergoline may suppress prolactin secretion but does not markedly affect GH levels or tumour volume alone. Somatostatin analogues including octreotide do not seem to have a potent effect on growth hormone either when administered prior to or after surgery when there is some remnant tumour tissue.
Pegvisomant, a GH receptor antagonist, has been used in some of these patients with good responses in terms of slowing growth and reducing IGF-1 concentrations over the medium term. It is not yet clear how effective or safe this medication is in the longer term and what is the optimal dose for children. So far, none of the children receiving pegvisomant had experienced tumour expansion, and re-growth of tumour post-surgical resection has not been seen. However even a small residual piece of tumour tissue in X-LAG syndrome can secrete enough growth hormone to require medical therapy for decades. The poor response to octreotide/lanreotide in this cohort is significant. While it is too early to be categorical, it is plausible that pegvisomant may be the more efficacious option and could be considered early in medical treatment of this condition. Some patients had repeated surgery and or radiotherapy. Multiple pituitary hormone deficiency is frequent following therapy particularly in those cured by radical surgery alone, and paradoxically, GH therapy may be needed for normal growth to adult height after surgical cure during childhood.
Gigantism and acromegaly today are not where they were a few years ago: for example, who would have thought two decades ago that, by 2021, most children with gigantism would have an identifiable genetic cause? Although molecularly unexplained cases remain, they account for a relatively small percentage of GH excess in pediatrics and young adults.
In addition to genetics, transsphenoidal surgery, molecule-targeting medical therapies, and novel modes of irradiation (14) make 2021 an exciting time to write this article, as we continue to work on improving the care of our patients and their families.
- Stratakis CA, 2015 A giant? Think of genetics: growth hormone-producing adenomas in the young are almost always the result of genetic defects. Endocrine 50(2): 272-275.
- Markantes GK, Theodoropoulou A, Armeni AK, Vasileiou V, Stratakis CA, Georgopoulos NA. Cyclopes and giants: from Homer’s Odyssey to contemporary genetic diagnosis. Hormones (Athens) 2016;15(3):459-463.
- Sheaves R. A history of acromegaly. Pituitary. 1999;2(1):7-28.
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- Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab. 2009;94(5):1826-34.
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- Xekouki P, Szarek E, Bullova P, Giubellino A, Quezado M, Mastroyannis SA, Mastorakos P, Wassif CA, Raygada M, Rentia N, Dye L, Cougnoux A, Koziol D, de La Luz Sierra M, Lyssikatos C, Belyavskaya E, Malchoff C, Moline J, Eng C, Maher LJ Third, Pacak K, Lodish M, Stratakis CA. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in human and mice. J Clin Endocrinol Metab. 2015;100(5):E10-9.
- Mai PL, Korde L, Kramer J, Peters J, Mueller CM, Pfeiffer S, Stratakis CA, Pinto PA, Bratslavsky G, Merino M, Choyke P, Linehan WM, Greene MH. A possible new syndrome with growth-hormone secreting pituitary adenoma, colonic polyposis, lipomatosis, lentigines and renal carcinoma in association with familial testicular germ cell malignancy: A case report. J Med Case Rep. 2007;1:9.
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