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Genetics of Pituitary Gigantism: Syndromic and Nonsyndromic Causes

  • Liliya Rostomyan
  • Iulia Potorac
  • Adrian F. Daly
  • Albert BeckersEmail author
Living reference work entry

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Part of the Endocrinology book series (ENDOCR)

Abstract

The last decades have seen an expansion of knowledge regarding GH-secreting pituitary adenomas in general and gigantism in particular. New conditions, such as familial isolated pituitary adenomas (FIPA) and X-linked acrogigantism (X-LAG), have been identified, as have some important underlying genetic and molecular factors that contribute to somatotropinoma tumorigenesis and behavior. These discoveries have prompted the study of large series of patients, which have revealed specific disease characteristics. Thorough assessment of each patient in order to correctly classify the disease is essential for optimal treatment and follow-up.

Keywords

Gigantism Pituitary adenoma Aryl hydrocarbon receptor interacting protein (AIP) gene Familial isolated pituitary adenoma (FIPA) Multiple endocrine neoplasia Carney complex McCune-Albright syndrome X-linked acrogigantism (X-LAG) GPR101 gene 

Introduction

Chronic, excessive growth hormone (GH) secretion that occurs in children or adolescents before growth plate fusion can lead to pituitary gigantism, if not recognized and controlled in a timely manner. The equivalent condition occurring in adults causes acromegaly. Rarely, ectopic GH or GH-releasing hormone (GHRH) hypersecretion can underlie the development of gigantism and acromegaly, but in the majority of these cases, excess GH is due to the presence of a GH-secreting pituitary adenoma (PA) (Borson-Chazot et al. 2012).

The prevalence of clinically relevant PA is about 1:1000 of the general population in developed countries (Daly et al. 2006b). Various subtypes develop from the different cell types of the anterior pituitary and include prolactinomas (50–55%), non-functioning PA (NFPA) (20–25%) that arise from gonadotrope cells, somatotropinomas that secrete GH (15–20%), ACTH-secreting PA (5%) and TSH-secreting PA (1%). The prevalence of somatotropinomas is estimated at 1:3000–14,000 with an incidence of 1 case per 125,000–323,000 population per year (Daly et al. 2006b; Fernandez et al. 2010; Gruppetta et al. 2013; Agustsson et al. 2015; Gatto et al. 2018; Caputo et al. 2018).

Most PA occur sporadically, but 5–10% have a hereditary or familial background. These familial PA can manifest either as part of syndromic conditions, such as Multiple Endocrine Neoplasia (MEN) type 1, MEN type 4, the paraganglioma/pheochromocytoma/PA association (3PAs), and Carney Complex (CNC), or develop as pituitary-specific diseases, as is the case for familial isolated PA (FIPA) and X-Linked Acrogigantism (X-LAG) (Beckers et al. 2016). Inherited forms of PA usually present specific characteristics, distinct from those of sporadic PA and these characteristics depend on the genetic background. Moreover, the clinical presentation of these syndromic forms can be variable not only between kindreds, but also within the same family (Beckers et al. 2013).

As pituitary gigantism is, by definition, a condition occurring at an early age, a genetic etiology is far more frequent than in cases of acromegaly. Indeed, half of patients with pituitary gigantism are found to carry genetic abnormalities (Rostomyan et al. 2015b). The genetic anomalies responsible for pituitary gigantism range from mutations in predisposing genes to pathological copy number variations (CNV). These can either be constitutional, present in and transmitted to every cell of the organism, or appear during the postzygotic development, due to somatic mosaicism.

The possibility that an apparently sporadic PA actually belongs to a familial form should always be kept in mind and prompt the detection of other manifestations that could indicate a PA-associated syndrome (Rostomyan and Beckers 2016). Identification of syndromic or nonsyndromic forms of familial PA is important as it allows a more appropriate management of index patients, as well as timely diagnosis in their relatives.

Nonsyndromic Pituitary Gigantism

Familial Isolated Pituitary Adenomas (FIPA)

PA occurring in a familial context have been described occasionally in the historic medical literature, for example, families with acromegaly. An inherited background was explored in this disorder (Verloes et al. 1999; Gadelha et al. 2000; De Menis and Prezant 2002).

Familial occurrence of all PA phenotypes (i.e., not only acromegaly) that were not part of a MEN1 or Carney Complex was investigated in a single-center study performed in Liège, Belgium, at the end of the 1990s (Valdes Socin et al. 2000). This distinct pituitary disease was defined as familial isolated pituitary adenomas (FIPA) and characterized in a large international cohort in 2006 (Daly et al. 2006a). FIPA is an inherited condition clinically characterized by the presence of PAs in two or more related members of a family in the absence of PA-associated syndromic diseases. Within the same family, patients may have the same PA phenotype (homogeneous FIPA) or different phenotypes (heterogeneous FIPA) (Daly et al. 2006a). Since the identification of FIPA, hundreds of kindreds have been reported by different international research groups (Beckers et al. 2013; Hernandez-Ramirez et al. 2015). Whereas in non-FIPA PA populations prolactinomas are by far the most common subtype of PA, in FIPA this predominance is not so clear. Combining data from two large international FIPA cohorts, prolactinomas constitute 27–38%, while GH/mixed GH-prolactin secreting adenomas account for about 41–47% (Beckers et al. 2013; Hernandez-Ramirez et al. 2015). Patients belonging to FIPA families are diagnosed with PA at younger ages (about 5 years earlier) and with larger tumors compared to patients with sporadic PA (Daly et al. 2006a).

In 2006, the aryl hydrocarbon receptor interacting protein (AIP) gene was identified as a predisposing gene in GH- and / or PRL-secreting PA in large kindreds from Finland and Italy (Vierimaa et al. 2006). The AIP gene, like MEN1, is located on chromosome 11q13. AIP is a tumor suppressor gene and inactivating germline mutations in this gene accompanied by loss of heterozygosity on the other normal allele lead to AIP-mutation associated pituitary tumor formation. AIP consists of 6 exons encoding a 330 amino acid protein. AIP is a ubiquitous, cytoplasmic protein, abundant in somatotrope, lactotrope, and mixed mammosomatotrope cells, with functional domains involved in various protein-protein interactions, including with the aryl hydrocarbon receptor (AHR) (Vierimaa et al. 2006). Decreased AIP immunostaining appears to be a characteristic of more aggressive PA (Jaffrain-Rea et al. 2009). AIP has been suggested to be a mediator of somatotropinoma growth and secretion (Chahal et al. 2012; Jaffrain-Rea et al. 2009; Kasuki et al. 2012; Formosa et al. 2013; Tuominen et al. 2015; Formosa and Vassallo 2017).

Germline AIP mutations are involved in approximately 20% of FIPA, particularly in homogeneous acromegaly (50%) (Daly et al. 2007). In AIP-positive FIPA cases, PA are larger and develop at younger ages. Most mutations lead to truncated proteins (nonsense, frameshift, splice-site), followed by missense mutations (20%), large deletions (≤10%), and other variants (Beckers et al. 2013). Truncated forms of AIP may be associated with a more frequent pediatric onset (60% vs. 33%) (Hernandez-Ramirez et al. 2015). In 80% of FIPA families, no AIP mutations are detected in particular in the absence of at least one case of GH- or prolactin-secreting PA and in familial microprolactinomas (Beckers et al. 2013).

Genetic screening should be performed in AIP-positive FIPA families so as to pinpoint the AIP mutation carriers. These individuals should undergo a complete clinical, biochemical (GH/IGF-1 and prolactin levels at a minimum, followed by relevant testing of other axes), and radiologic assessment (pituitary MRI) when their AIP positive status is revealed. Screening in young AIP mutation carriers is recommended and early clinical disease signs must be actively sought, particularly in the predisposed age groups – adolescents and young adults. If there is no evidence of a PA, regular annual clinical follow-up (clinical assessment and pituitary hormonal levels, and if necessary, imaging investigations) should be performed up to the age of 30 and less frequently in older patients. Only a minority of AIP mutation positive patients develop PA after the age of 30 (Beckers et al. 2013; Hernandez-Ramirez et al. 2015).

Codon 304 appears to be a mutational hotspot, with the most common change p.R304X initially being found in an Italian cohort and in large kindreds from Ireland (including a historical case of gigantism with a common ancestor living in the same geographical region) (Occhi et al. 2010; Chahal et al. 2011; Beckers et al. 2013; Hernandez-Ramirez et al. 2015; Radian et al. 2017). Another founder AIP mutation p.Q14X was found in the initial Finnish FIPA cohort and is specific to that population (Vierimaa et al. 2006). The increased carrier frequency for particular AIP mutation in a population with common origin explains the higher prevalence of AIP-related PA in the geographical area of their location (Chahal et al. 2011; Radian et al. 2017). Germline AIP mutations have incomplete penetrance, which is approximately 20% as observed in some large mutigenerational FIPA kindreds (Naves et al. 2007; Jennings et al. 2009; Igreja et al. 2010). Thus, AIP-related PA can develop only in a single patient in a family in which all other mutation carriers remain unaffected. These latter AIP mutation–associated PA are termed simplex cases.

AIP-related PA are frequently diagnosed at a young age (80% are diagnosed before the age of 30 years) (Beckers et al. 2013; Daly and Beckers 2015). Pediatric patients and young patients with large PA are considered to be significant at-risk populations. In patients younger than 30 years with large aggressive macroadenomas, the prevalence of AIP mutations is 12% and it increases to 20% in pediatric patients (Stratakis et al. 2010; Tichomirowa et al. 2011). Patients with AIP mutations mainly develop somatotropinomas (75%) either pure or mixed GH/prolactin, more rarely prolactinomas (15%), although all types of secreting and nonfunctioning PA related to AIP mutations can occur (Beckers et al. 2013). Patients with AIP-related somatotropinomas have a younger age of disease onset and are predominantly male and the tumors exhibit more aggressive features in terms of size and local growth and higher hormonal activity at diagnosis. Moreover, they are relatively more resistant to somatostatin analogs (SSA) therapy in terms of hormonal control and tumor shrinkage than AIP-negative acromegaly cases (Daly et al. 2010; Joshi et al. 2018). Some patients with AIP mutations that were resistant to first generation SSA can have a dramatic tumor shrinkage response and hormonal control with the multi somatostatin receptor specific agent, pasireotide during treatment for 8–10 years (Daly et al. 2019a). Finally, as a consequence of the excessive GH secretion by these usually large, aggressive somatotropinomas that develop at young ages, cases with gigantism occur significantly more frequently in AIP-positive patients than in AIP-negative acromegaly (32% vs. 6.5%, respectively) (Daly et al. 2010).

Germline AIP mutations are most prevalent in pituitary gigantism patients (Beckers et al. 2018). In an international cohort of 208 pituitary gigantism patients, AIP mutations were found in nearly one third of cases and represent the most frequent known genetic cause (Fig. 1). Other causes of pituitary gigantism include X-LAG syndrome (10%), MAS (5%), MEN1 (1%), and Carney complex (1%) (Rostomyan et al. 2015b).
Fig. 1

Genetic causes of pituitary gigantism; 46% of cases of pituitary gigantism can be explained by a genetic abnormality. The two main genetic causes of pituitary gigantism are AIP gene mutations and X-LAG syndrome. AIP+, AIP mutation affected; Genetically –, genetically negative testing; MAS, McCune-Albright Syndrome; X-LAG, X-linked acrogigantism syndrome (Rostomyan et al. 2015b)

Some AIP variants are considered most certainly pathogenic, but there are also variants of unknown significance encountered in some patients with PA. One such situation was found in a historical gigantism case from Mexico with p.A299V variant (Ramirez-Renteria et al. 2016). The role of these variants of unknown significance in pituitary tumorigenesis is difficult to affirm. However, their contribution, alongside other factors, to the disease phenotype, particularly in severe cases such as pituitary gigantism, cannot be excluded (Daly and Beckers 2017).

X-Linked Acrogigantism (X-LAG)

In 2014, a new pediatric syndrome defined by a very early onset and a particularly severe form of pituitary gigantism was identified and termed X-linked acrogigantism (X-LAG) (Trivellin et al. 2014). Children with X-LAG are usually born at full term with normal body size and proportions. The onset of abnormally accelerated growth usually occurs before the age of 12 months and children are generally diagnosed by the age of three with very severe overgrowth (Trivellin et al. 2014; Beckers et al. 2015). X-LAG represents the second most frequent genetic cause of pituitary gigantism so far (10%) and accounts for a majority of genetically confirmed pediatric onset gigantism cases (Rostomyan et al. 2015b). Despite the young age of onset, X-LAG patients frequently present some GH/IGF-1 driven clinical signs of acromegaly, such as coarse facial features, prominent mandible, acral enlargement, and soft tissue swelling. Furthermore, increased appetite (25%) and signs of insulin resistance (such as acanthosis nigricans) were reported in some cases. The clinical presentation of X-LAG patients, particularly in terms of the early pediatric onset of marked overgrowth, corresponds to that of historical cases of gigantism, such as those of Robert Wadlow (Fig. 2) and Zeng Jinlian, and suggests that X-LAG might explain many of the tallest recorded human heights (Trivellin et al. 2014; Beckers et al. 2015).
Fig. 2

The tallest man recorded in the history was Robert Pershing Wadlow (1918–1940). He died at the age of 22 from a lower limb infection, when he measured 2 m72. He presented with a phenotype similar to X-LAG syndrome with acceleration of linear growth as young as the age of 6 months. (Images courtesy of Dr. WW De Herder (Private Collection) (Rostomyan et al. 2015a))

X-LAG predominantly affects females (71%). The majority of pituitary lesions in X-LAG are GH/prolactin-secreting PA, though in some cases isolated diffuse pituitary hyperplasia was detected (Fig. 3). These tumors have high hormonal secretory potential with markedly elevated GH/IGF-1 levels and prolactin co-secretion in nearly all X-LAG patients. In resected pituitary tumors from X-LAG patients, pituitary hyperplasia can be found with or without adenomas. These tumors showed mixed (GH/ prolactin) hormonal staining and positive GHRH-receptor (GHRH-R) staining (Trivellin et al. 2014; Beckers et al. 2015; Naves et al. 2016). Moreover, elevated circulating GHRH levels were observed in some X-LAG patients. These findings point towards a form of GHRH dysregulation at the hypothalamic level, which is possibly involved in the development of PA and/or hyperplasia. This hypothesis was supported by in vitro studies in cell culture from an X-LAG pituitary tumor demonstrating that GHRH-R antagonist inhibited GH and prolactin secretion (Daly et al. 2016a).
Fig. 3

T1-weighted sagittal MRI revealed a pituitary tumor in a female patient with X-LAG syndrome. At diagnosis at the age of 3 years she had a large “bean shaped” pituitary lesion, producing extremely elevated amounts of growth hormone (Beckers et al. 2015)

Genetically, X-LAG was found to be associated with a microduplication on the X chromosome (Xq26.3), in a region that includes the GPR101 gene (Trivellin et al. 2014). This latter encodes an orphan G-protein coupled receptor. In the initial X-LAG cohort, Xq26 microduplications included four genes that were common to all patients; among those candidate genes, the expression of GPR101 was selectively increased in the pituitary tissue of two patients with Xq26.3 microduplications, suggesting its causative pathogenic role in X-LAG (Trivellin et al. 2014). These findings were then supported by a duplication that only included the GPR101 gene in an X-LAG patient (Iacovazzo et al. 2016).

Although it seems that the GPR101 gene function is intimately involved in the physiopathology of X-LAG, not much is known about this receptor, such as its precise biological functions. Its expression under physiological circumstances is high in mouse hypothalamus and macaque and rat pituitary. In adult human pituitary tissue, mRNA expression for GPR101 is low if not absent, although in human pituitary tissue it is expressed starting from 19 weeks of gestational age and the expression increases towards the end of gestation (Trivellin et al. 2014, 2016). These findings suggest a role for GPR101 in physiologic pituitary ontogenesis. In a pathological context, while GPR101 duplication is associated with GH hypersecretion, dysfunction of the receptor does not seem to play an important role in the condition of GH deficiency as shown in a series of patients with congenital isolated GH deficiency (Castinetti et al. 2016).

Most X-LAG cases are sporadic, although the condition can also occur in a FIPA context and thereby represents the second known genetic cause of FIPA in some AIP-negative kindreds with familial acrogigantism. Transmission of a family-specific Xq26.3 microduplication from the affected mother to her affected son with complete penetrance has been described to date in three homogeneous FIPA kindreds with acrogigantism (Trivellin et al. 2014; Gordon et al. 2016)

Aside from the constitutional Xq26.3 duplication, variable levels of somatic mosaicism (16–50%) for this CNV, occurring specifically in sporadic males, seem to be responsible for the clinical manifestations of X-LAG (Daly et al. 2016b; Rodd et al. 2016; Iacovazzo et al. 2016). These somatic mosaicism cases have a similar presentation to sporadic female patients or familial cases. As few as 16% of cells including the GPR101 duplication were found to be enough for the development of severe pituitary disease and dramatic overgrowth (Daly et al. 2016b).

The digital droplet PCR (ddPCR) technique allows screening of large patient groups for CNV of the GPR101 gene in comparison to the ZIC3 gene, a standard reference gene, which is the closest protein-coding gene that is never duplicated in X-LAG. (Daly et al. 2016b). Use of this specific method revealed a likely GPR101 duplication in a historical case of extreme gigantism: the Giant Constantin who died in 1902, and measured 2.59 m (Fig. 4). He started growing abnormally at a very young age and became one of the tallest men recorded in history. His >100-year-old DNA sample was extracted from bone powder by a specific paleontological technique from the skeleton (Beckers et al. 2017).
Fig. 4

Julius Koch (2 m59) travelled internationally, appearing as “The Giant Constantin.” He died in Mons, Belgium, in the early 1900s due to the effects of lower limb gangrene. His case was reported as with acro-gigantism due to pituitary lesion over 100 years ago. In 2017 paleogenetic studies in DNA derived from skeleton of Julius Koch revealed a duplicated copy number of GPR101, suggesting the X-LAG syndrome as a genetic cause of pituitary gigantism in this subject. Thus, he is the tallest human in history with a genetic diagnosis of gigantism (Beckers et al. 2017)

Treatment of X-LAG patients is challenging in the majority of cases due to large and aggressive tumors with the accompanying pituitary hyperplasia, which are resistant to the standard medical treatment used in acromegaly, namely SSAs (Trivellin et al. 2014; Beckers et al. 2015). What renders the management of the condition even more challenging is the need for rapid hormonal and tumor control. This is required on one hand in order to block the excessive linear growth before patients reach significantly elevated adult level stature (Rostomyan et al. 2015b) and on the other hand, to control the aggressive tumor growth (Naves et al. 2016). Pituitary GH hypersecretion in X-LAG patients often is poorly controlled by surgery and SSAs and multimodal treatment is usually required (Fig. 5) (Beckers et al. 2015). Whereas aggressive surgery and/or pegvisomant can be successful treatment, SSA therapy alone has a poor effect in XLAG, despite of the presence of somatostatin receptors subtype 2 (SSTR2) at moderate and high levels on immunostaining of tumor specimens (Trivellin et al. 2014; Beckers et al. 2015; Rostomyan et al. 2015b; Naves et al. 2016; Joshi et al. 2018).
Fig. 5

GH, IGF-1, and prolactin levels during treatment in a sporadic male patient with X-LAG syndrome. He was diagnosed at the age of 56 months with large pituitary lesion which was grossly resected. GH and prolactin decreased following this pituitary surgery, but IGF-1 remained above the normal range. Postoperative SSA (octreotide LAR 30 mg/month) and later dopamin agonist (cabergoline 0.25 mg 5 × week) treatment led to the reduction of the IGF-1 but it remained elevated and overgrowth continued. Pegvisomant (10 mg/day) administration rapidly decreased IGF-1 levels and allowed the SSA withdrawal. PRL, prolactin; DA, dopamin agonist; PegV, pegvisomant; grey zone indicates the normal IGF-1 range (Beckers et al. 2015)

Genetically Negative Nonsyndromic Pituitary Gigantism

Female predominance, very early-onset linear growth acceleration, and an already marked overgrowth at diagnosis associated with very elevated GH/IGF-1 and prolactin levels are important features that distinguish X-LAG from other forms of pituitary gigantism. In contrast to X-LAG, almost all gigantism patients with AIP mutations are males (95%), in whom the first symptoms appear at the age of adolescence or in young adulthood. These patients also present with an aggressive pituitary disease in terms of tumor size, local growth, and elevated hormonal levels (Beckers et al. 2013; Rostomyan et al. 2015b; Hernandez-Ramirez et al. 2015).

In half of the pituitary gigantism cases, the genetic causes remain unknown for the moment (Rostomyan et al. 2015b). Unlike adult acromegaly, in which case sporadic AIP-negative patients usually have milder manifestations than those with AIP-positive somatotropinomas, among pituitary gigantism patients, AIP mutations do not render the phenotype particularly more aggressive than that of genetically negative ones. Pituitary gigantism cases negative for all known genetic causes of somatotropinomas were found to exhibit similarly aggressive clinical presentations (Fig. 6), with highly elevated GH/IGF-1, resistance to treatment, and a frequent requirement for the use of multimodal treatment (Rostomyan et al. 2015b; Beckers et al. 2018). These genetically negative cases were mostly male. Although these patients were older at diagnosis, the longer periods of disease latency compared to X-LAG and AIP-positive patients suggest the disease had its onset in childhood or adolescence. The development of these particularly aggressive somatotropinomas is due to as yet unknown molecular etiologies (Rostomyan et al. 2015b; Iacovazzo et al. 2016).
Fig. 6

Panel A shows physical changes in an AIP mutation negative 24-year-old patient with sporadic nonsyndromic gigantism standing next to his mother. T1-weighted coronal MRI revealed an invasive GH-secreting macroadenoma (Panel B) (Mangupli et al. 2016)

Syndromic Pituitary Gigantism

Multiple Endocrine Neoplasia Type 1 (MEN1) and MEN1-Like Syndromes

MEN1 is a multiorgan tumor predisposition syndrome mainly affecting three endocrine targets: parathyroid, endocrine pancreas and digestive tract and anterior pituitary. Other endocrine or nonendocrine lesions are less frequent and can include adrenal cortical tumors, neuroendocrine tumors of the bronchi and thymus, cutaneous tumors (lipomas, angiofibromas, collagenomas), and meningiomas (Thakker et al. 2012; Thakker 2014). MEN1 is a rare genetic disease that affects about one in 10,000 to 100,000 individuals (Chandrasekharappa et al. 1997). It can occur in a sporadic or familial form with autosomal dominant transmission and almost complete penetrance (more than 95% of patients develop at least one manifestation of the disease by the age of 50). The MEN1 gene, mutations in which are responsible for this syndrome, is located on chromosome 11q13 (Chandrasekharappa et al. 1997). MEN1 is a tumor suppressor gene, which encodes a 610 amino acid protein called menin. The latter is expressed ubiquitously in many cell types with a mainly nuclear localization and a role in transcriptional regulation (differentiation, proliferation, cell cycle control, apoptosis) and stabilization of the genome (replication, DNA repair) (Agarwal et al. 2004; Scacheri et al. 2006; Thakker 2014). To date more than 700 mutations in MEN1 have been described (Lemos and Thakker 2008; Thakker 2014). Most of these mutations are detected by direct sequencing and represent frameshift mutations (42%), missense (25.5%), nonsense mutations (14%), splice-site alterations (10.5%), and in-frame anomalies (5.5%) (Concolino et al. 2016). In less than 10% of cases with normal sequencing, large genomic rearrangements can be found by multiple ligation-dependent probe amplification (MLPA). Inactivation of the second MEN1 allele occurs by loss of heterozygosity (LOH) and is detected in more than 90% of MEN1 lesions. A clear genotype-phenotype correlation has not been established for MEN1 (Thakker 2014). However, in a French MEN1 mutation database a higher risk of death from MEN1-related cancers has been noted in cases with mutations in the JunD interacting domain (Thevenon et al. 2013) and a recent study in French population demonstrated an association between large rearrangements in MEN1 and an earlier onset of the disease (Romanet et al. 2018).

Primary hyperparathyroidism is the most frequent (>90% of cases) and often the first MEN1 manifestation, occurring as early as in adolescence or in young adulthood (Verges et al. 2002). Gastroenteropancreatic neuroendocrine tumors (NETs) (30–70% of cases) associated with MEN1 mostly arise as gastrinomas, insulinomas, and nonfunctioning tumors (Thakker 2014). Some of these lesions can be malignant and contribute to the higher mortality of patients with MEN1, which in over 70% of patients is directly related to MEN1 manifestations (Goudet et al. 2010).

Pituitary adenomas are diagnosed in 30–40% of MEN1 cases, whereas about 2.7% of all PA develop in a MEN1 context (Marx et al. 1998; Wick 1997). Most frequently pituitary tumors are prolactinomas (50–60%), that are generally large (85% are macroadenomas), invasive, and relatively dopamine agonist resistant. They develop at a younger age when compared to sporadic PA (Verges et al. 2002; Beckers et al. 2003). Less frequent PA phenotypes include somatotropinomas (10%), corticotropinomas (5%), and NFPA (5–15%) (Thakker 2014). Pituitary carcinomas have also been reported in some MEN1 patients, as prolactinomas (Vroonen et al. 2012), gonadotropinomas (Benito et al. 2005), or thyrotropinomas (Scheithauer et al. 2009). Although in 17% of MEN1 patients PA is the first clinical manifestation of disease, isolated PA associated with MEN1 are very rare (Burgess et al. 1996; Verges et al. 2002). In young patients with apparently sporadic PA genetic screening besides initial AIP gene analysis, should include MEN1 gene testing (Cuny et al. 2013); screening efforts for AIP/MEN1 in sporadic PA should probably focus on large/aggressive tumors with early disease onset in childhood to young adulthood (Daly et al. 2019b).

MEN1 mutations are rarely associated with GH-secreting pituitary lesions. Infrequent cases of MEN1-associated somatotropinomas or mixed GH/prolactin-secreting PA have also been described in young patients that could cause somatic growth abnormalities leading to excessive final height and tall stature (O’Brien et al. 1996; Stratakis et al. 2000). MEN1 gene abnormalities were found in 1% of pituitary gigantism patients in a large international cohort (Rostomyan et al. 2015).

Patients with at least two MEN1 manifestations should be referred for MEN1 genetic screening, as should first-degree relatives of MEN1 mutation carriers as their risk of developing the disease is 50%. Once a MEN1 mutation is confirmed, patients then need to enter a regular clinical, biochemical and imaging screening protocol. Pituitary disease can develop at very young ages, with the youngest patient reported to have a MEN1-associated mixed GH/prolactin PA presenting at 5 years of age (Stratakis et al. 2000). Therefore, current guidelines recommend PA screening by yearly IGF-1 and prolactin measurement as well as pituitary MRI every 3 years starting as early as 5 years of age (Thakker et al. 2012). Furthermore, acromegaly-gigantism in MEN1 could be caused by ectopic GHRH hypersecretion from an ectopic NET.

In 2006 another multiple endocrine neoplasia syndrome was defined, referred to as MEN4 in humans and MENX in rats (Pellegata et al. 2006; Lee and Pellegata 2013). Similar to MEN1, MEN4 predominantly affects the parathyroid glands and the pituitary (Lee and Pellegata 2013). MEN4 is a much rarer condition than MEN1 and is encountered both in sporadic and familial cases. The transmission is autosomal dominant, due to mutations of the CDKN1B gene (Pellegata et al. 2006). The product of this gene is a 196 amino acid cyclin-dependent kinase inhibitor (p27Kip1). The few reported cases presenting with PA associated with MEN4 exhibited several secretory types of adenomas, including somatotropinomas (Lee and Pellegata 2013). Furthermore, a variant in the promoter region of the CDKN1B gene has been reported in a case of gigantism (Sambugaro et al. 2015). However, in AIP-negative FIPA families as well as in young patients, CDKN1B mutations were very rare (Stratakis et al. 2010; Tichomirowa et al. 2012) and their contribution to pituitary gigantism cases is very limited.

Carney Complex (CNC)

Carney complex is another rare, complex, multiorgan syndrome encompassing a wide variety of manifestations, affecting both endocrine and nonendocrine targets (Carney et al. 1986). The disease is usually diagnosed around the age of 20, but rare cases diagnosed at birth have also been reported (Stratakis et al. 2001). In over 70% of cases, CNC patients carry mutations in the PRKAR1A gene, situated on chromosome 17q24. The PRKAR1A gene encodes the 1A regulatory subunit of protein kinase A (PKA) (Kirschner et al. 2000; Correa et al. 2015). Transmission of the disease is autosomal dominant with a nearly complete penetrance (Correa et al. 2015). Among PRKAR1A-negative patients, other genetic anomalies have been reported, either in relation to another possible CNC locus situated at 2p16 (Stratakis et al. 1996) which leads to a less severe phenotype with a later disease onset (Bertherat et al. 2009) or to anomalies affecting the PRKACB gene (Forlino et al. 2014).

In terms of endocrine manifestations, the most frequent are primary pigmented nodular adrenal disease (PPNAD) leading to Cushing’s syndrome, testicular (60%) and ovarian (30%) tumors, pituitary GH/prolactin hypersecretion, and thyroid tumors (Stratakis et al. 2001). Although pituitary hyperplasia and mild GH hypersecretion are frequent, clinical forms of acromegaly as well as PA are rarely encountered. Acromegaly is usually diagnosed in younger patients than the sporadic forms and has a slow evolution (Boikos and Stratakis 2006).

Nonendocrine manifestations include cutaneous ones (lentigines, blue nevi, myxomas), cardiac myxomas, breast myxomas, psammommatous melanotic schwannomas mostly of the gastrointestinal tract and paraspinal sympathetic chain, and other rarer lesions (Correa et al. 2015).

In families, genetic screening should be offered to first-degree relatives of affected patients. Clinical evaluation in mutation carriers should target all the manifestations and performed regularly starting from infancy. GH abnormalities and gigantism prior to puberty are rare, and annual hormonal analysis should include serum GH, prolactin, and IGF-1 measurements; MR imaging of pituitary should be undertaken in cases of abnormal hormonal secretion (Kaltsas et al. 2000; Correa et al. 2015).

3P Association – Pituitary Adenomas, Paragangliomas, and Pheochromocytomas (3PAs)

Recently, a new endocrine neoplasia syndrome consisting of pituitary adenomas and paragangliomas/pheochromocytomas was described (Xekouki et al. 2012) and termed the 3P association (3PAs) (Xekouki et al. 2015). The first genetic anomaly reported to be associated with the 3PAs syndrome was found to involve the genes coding for subunits of the succinate-dehydrogenase enzyme complex (SDHx). These are established pheochromocytoma/paraganglioma predisposing genes. 3PAs due to mutations in the SDHx genes has an incomplete penetrance and cases can be sporadic or appear in a familial context (Xekouki et al. 2012; Dwight et al. 2013; Denes et al. 2015).

Pituitary adenomas occurring in the context of SDHx gene mutations seem to present a particular histologic aspect with intracytoplasmic vacuoles (Denes et al. 2015), the significance of which is still unclear. Several cases of somatotropinomas have been described in association with SDHx gene mutations (Xekouki et al. 2012, 2015 Denes et al. 2015). So far, cases of gigantism in relation of SDHx gene mutations have not been reported.

Recently, another pheochromocytoma/paraganglioma predisposition gene, the Myc-associated factor X (MAX), was found to also be associated with PA, representing a second potential genetic cause for the 3PAs syndrome. Importantly, intragenic MAX deletions are involved in some cases and these need to be screened for specifically using MLPA as they can be missed on Sanger sequencing (Daly et al. 2018). Among the five cases described so far (Roszko et al. 2017; Daly et al. 2018; Kobza et al. 2018), two were early onset somatotropinomas. These patients had aggressive features of their pheochromocytomas (large bilateral lesions, recurrent and metastatic disease) (Daly et al. 2018). In these cases, pituitary lesions were already macroadenomas at the time of diagnosis, thereby indicating a potentially aggressive behavior.

McCune-Albright Syndrome (MAS)

The McCune-Albright syndrome is due to postzygotic mosaicism for activating mutations of the GNAS1 gene, leading to constitutive activation of the cAMP signaling pathway. Depending on the moment in embryogenesis when the mutation occurs, a variable number of tissues can be affected from one patient to another (Dumitrescu and Collins 2008). Generally, the syndrome manifests as the triad consisting of irregular “café au lait” skin spots with a coast of Maine appearance, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies, most frequently gonadal leading to precocious puberty, thyroid, or pituitary with GH and prolactin hypersecretion (Dumitrescu and Collins 2008).

Up to 30% of patients with MAS suffer from acromegaly, which usually manifests at early ages (Salenave et al. 2014). Analysis of the pituitary tissue in some MAS cases has shown that the adenoma may develop within an area of diffuse pituitary hyperplasia (Vasilev et al. 2014).

When GH hypersecretion begins before growth plate fusion, it can lead to gigantism, in MAS which was found in 5% of a large series of patients with pituitary gigantism (Rostomyan et al. 2015) and in 7% of patients with MAS and acromegaly (Salenave et al. 2014). Treatment of acromegaly and gigantism is more complex than in sporadic cases as surgery is rendered difficult by the cranial fibrous dysplasia and radiotherapy raises concerns over the risk of sarcoma development in the areas of craniofacial bone disease. Moreover, MAS-associated cases of acromegaly-gigantism are frequently characterized by a poor response to SSA treatment. Some case series have reported pegvisomant to be effective for IGF-1 control in these individuals (Akintoye et al. 2006; Galland et al. 2006; Salenave et al. 2014).

Conclusion

Pituitary gigantism is a rare, yet etiologically heterogeneous disease. It can occur in the context of inherited or genetic conditions due to GH-producing PA that can be the sole disease manifestation or can be accompanied by various endocrine and nonendocrine abnormalities. Depending on the underlying hereditary condition and particular genetic abnormality, the clinical presentation will vary. However, most cases of genetically predisposed somatotropinomas leading to pituitary gigantism exhibit an aggressive behavior that translates into an early disease onset, highly increased hormonal secretion, large, extensive and invasive adenomas, and resistance to treatment. These features can lead to dramatic presentations with markedly abnormal growth velocity and extremely tall stature, especially when the disease is diagnosed late and control is not obtained. Earlier diagnosis and prompt treatment initiation and a younger age at hormonal control are associated with a lower final height. Hence, the guiding principle for the appropriate management of pituitary gigantism is early GH/IGF-1 status evaluation in patients with abnormally accelerated growth and effective hormonal and growth control as soon as possible.

Theoretically, any genetic anomaly leading to acromegaly can also cause gigantism, but there are currently two notable etiologies: AIP mutation positive cases and X-LAG. However, the other potential causes must be kept in mind and the clinical, biochemical and imaging exploration of any case of tall stature should be extensive enough to reveal other potential manifestations of syndromic conditions and orient the management towards adequate genetic studies. This will allow for appropriate, patient-tailored management and the timely diagnosis of potentially affected family members.

Cross-References

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Liliya Rostomyan
    • 1
  • Iulia Potorac
    • 1
  • Adrian F. Daly
    • 1
  • Albert Beckers
    • 1
    Email author
  1. 1.Department of Endocrinology, Centre Hospitalier Universitaire de LiègeUniversity of Liège, Domaine Universitaire du Sart-TilmanLiègeBelgium

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