Unlike in acromegalic adults, in whom discreet pituitary adenomas are present in the overwhelming majority of patients (5), a number of different histopathologic mechanisms underlying childhood GH hypersecretion have been suggested or observed. These relate to the concept that childhood GH excess represents a distinct entity, with different characteristics in terms of pituitary morphology and function. Supporting this view have been reports of diffuse pituitary hyperplasia in the setting of early-onset gigantism, in which congenital growth hormone releasing-hormone (GHRH) excess has been proposed as the inciting cause(6;7). Additionally, the nearly ubiquitous finding of combined GH and prolactin over-secretion in nearly all cases of early childhood gigantism, a feature not universally present in acromegaly, suggests that a separate pathologic process may be involved. This dual hormonal secretion has been attributed to the presence of mammosomatotrophs (8;9), which are rare in adulthood but predominate in fetal life. Even in cases of apparent pituitary microadenomas or macroadenomas arising during early childhood, this unique biochemical feature has been present(10;11). In contrast, prolactin levels are usually normal in cases of pituitary GH-secreting adenomas originating during adolescence, which may be thought of as existing within the spectrum of adult GH hypersecretion. Interestingly, a reversible transformation of pituitary somatotrophs into bihormonal mammosomatotrophs under the influence of ectopic overproduction of GHRH has been observed, lending additional support to the concept that hypothalamic GHRH excess may play a pivotal role in the genesis of early-onset gigantism(12).

An additional cause of sporadic GH excess linked to CNS pathology is that which occurs in the setting of a hypothalamic gangliocytoma or neurocytoma. These rare tumors, comprised of large hypothalamic-like ganglion cells, have been demonstrated to produce GHRH(13;14) and to be found in close proximity to pituitary growth hormone-secreting adenomas(15). Normalization of serum growth hormone levels following resection of the hypothalamic tumor in some patients has further supported a central role for abnormal GHRH secretion in the development of gigantism or acromegaly in these cases(16).

Ectopic GH hypersecretion is a rare but important cause of acromegaly in adults, thought to represent less than 1% of all cases (17). Only approximately 50 cases have been described since 1959. In this condition, a paraneoplastic elaboration of GHRH or uncommonly GH (18) occurs within tumor cells. Specific lesions notorious for this capability include bronchial, carcinoid and pancreatic neoplasms (19). Extrapituitary GH excess has also been reported in the setting of a pituitary adenoma located within the sphenoid sinus (20), and in association with an empty sella (21). To our knowledge, an ectopic source of GHRH or GH leading to gigantism in a child has never been described.

Beginning in the 1970’s, several reports of gigantism occurring in young children with NF-1 have appeared in the medical literature(22). In these cases, excessive somatic growth has been noted as early as 6 months of life (23). Neuroimaging in these patients typically reveals an optic glioma (24), usually with infiltration into the medial temporal lobe. Growth hormone excess has been reported to resolve following chemotherapy for an optic nerve glioma, but whether this was a direct effect of the treatment is unknown (25). A number of investigations aimed at identifying the precise etiology of the gigantism in these children have been conducted. In all cases in which tumor tissue has been available, immunostaining for GH, GHRH and somatostatin has been uniformly negative (19(26;27). This, in conjunction with the known temporal lobe location of somatostatin-producing neurons, led to the hypothesis that GH excess in these patients was the result of a hypothalamic regulatory defect. Specifically, tumor infiltration of somatostatinergic pathways would presumably result in reduced somatostatin tone leading to overproduction of GHRH-mediated pituitary GH. Despite this plausible explanation, arginine-induced GH stimulation in a patient with gigantism in the setting of NF-1 was normal, contrary to the expected lack of response to arginine, which is believed to act through somatostatin inhibition (28). Thus, the precise pathogenesis of gigantism in NF-1 remains unclear. Moreover, little information is available regarding the overall incidence of GH hypersecretion in patients with NF-1 and optic gliomas, as systematic studies have not been performed. Figure 1 demonstrates the café-au-lait pigmentation and linear growth acceleration observed in a young boy with NF-1 and gigantism.

Figure 1. 

MAS is a complex and heterogenous disorder in which GH excess may arise in conjunction with additional endocrinopathies and other abnormalities. In the classic form, MAS results in the triad of precocious puberty, café-au-lait skin pigmentation, and fibrous dysplasia of bone. It has long been recognized, however, that individuals with MAS have a propensity to develop a number of endocrine problems, including gigantism or acromegaly from excessive growth hormone secretion (29). Elucidation of the molecular genetic defect in MAS in the early 1990’s (30) illuminated the underlying mechanism through which abnormal hormone secretion occurs in this condition. Activating mutations of Gsα, the stimulatory subunit of the heterotrimeric G-protein complex involved in intracellular signaling, have now been shown to form the basis for nearly all of the clinical manifestations of MAS(31;32). These mutations, which typically involve substitution of arginine at the 201 position with cysteine or histidine, result in unregulated signal transduction leading to increased intracellular cAMP accumulation and downstream gene transcription. The precise timing of the mutation during embryologic life, which occurs in a post-zygotic cell line, will ultimately determine the extent of abnormal cells and severity of the resultant clinical phenotype. The incidence of GH excess in classic MAS has generally been reported to be 15-20% (33). However, enhanced recognition of the frequency of atypical or forme fruste variants of MAS have the potential to result in an increase of this estimated frequency. Indeed, a number of historical reports of extreme gigantism where fibrous bone dysplasia was also present strongly suggest a diagnosis of MAS in these individuals, a hypothesis confirmed by molecular genetic analysis in at least one case (34;35). Subclinical growth hormone excess has also been reported in MAS, in which the only clinical manifestation may be the presence of normal stature (rather than short stature) in the context of a history of untreated precocious puberty. Additional phenotypic features in this subgroup of patients with MAS include a higher incidence of vision and hearing deficits, TRH responsiveness and hyperprolactinemia (36). A variety of pituitary morphologic abnormalities have been noted in MAS patients with GH hypersecretion, ranging from discrete pituitary adenomas (37;38) to diffuse pituitary hyperplasia (39), to no discernible radiographic abnormality (40). Of note is the fact that the identical Gsα mutation found in MAS has also been implicated in the pathogenesis of sporadic GH-secreting pituitary adenomas, where it results in formation of the gsp oncogene. Up to 40% of somatotroph adenomas in adults have been demonstrated to contain either an Arg201 activating mutation, or a related point substitution of glutamine at position 227 (41). Interestingly, these sporadic tumors as well as those from patients with MAS and acromegaly display the Gsα mutation exclusively from the maternal allele, providing evidence that the GNAS1 gene is subject to imprinting (42). Figure 2 demonstrates an area of classic café au lait skin pigmentation in a patient with MAS.

Figure 2. 

MEN-1 is one of a number of familial cancer syndromes characterized by autosomal dominant inheritance and multi-endocrine gland involvement. Although significant clinical heterogeneity exists in terms of specific tumor combinations, the most frequent manifestations of MEN-1 are parathyroid, pancreatic and pituitary adenomas (43). The gene for MEN-1, which had previously been mapped to chromosomal locus 11q13 (44), has now been cloned and demonstrated to encode for a 610 amino acid nuclear protein designated menin (45). Many different molecular genetic abnormalities within the menin gene have been identified in kindreds with MEN-1, including nonsense, missense, deletion, insertion and donor-splice mutations (46). Unfortunately, genotype/phenotype correlations have not been observed. In all cases of MEN-1, the development of neoplasia is thought to arise from a defect in normal tumor suppression via a 2-hit hypothesis. The first hit represents inheritance of a germline MEN-1 mutation, leading to a heterozygotic loss of the menin gene in every cell (47). As menin is believed to function as a tumor suppressor protein, the second hit involves a somatic MEN-1 mutation in one cell, with subsequent abnormal cellular transformation and clonal expansion. Indeed, somatic biallelic MEN-1 mutations have been demonstrated to be present in at least 15% of sporadic pituitary adenomas, including somatotroph tumors (48). Anterior pituitary adenomas in individuals with known MEN-1 have a reported prevalence of 10-60%, and are thought to represent the first clinical manifestation of the disease in up to 25% of sporadic cases (49). Of these, the majority are prolactinomas, with GH-secreting adenomas developing in approximately 10% of individuals with MEN-1 by age 40. The youngest reported case of gigantism in MEN-1 occurred in a 5-year-old boy, who presented with growth acceleration and a GH-secreting mammosomatotroph pituitary adenoma in the context of a known family history of MEN-1 (50). Molecular genetic analysis confirmed the germline and tumor tissue MEN-1 mutations, but failed to reveal an etiology for the accelerated presentation in this case. Nonetheless, current recommendations include screening for anterior pituitary hormone excess beginning at age 5 in all individuals with MEN-1, as well as ascertaining MEN-1 carrier status by germline mutation testing in a number of clinical situations (51).

Initially described in 1985 (52), CNC is a rare autosomal dominant disorder in which the cardinal features include multiple endocrine tumors, skin lentigines (spotty pigmentation), cardiac myxomas and neural sheath tumors. The condition shares characteristics with several other syndromes, including MEN-1 (multiple endocrine tumors), MAS (endocrine hyperfunction and skin pigmentation) and Peutz-Jeghers (mucosal lentiginoses and gonadal tumors). It has now been demonstrated, however, to have a unique clinical and molecular genetic identity. Two distinct genetic abnormalities have been implicated in the pathogenesis of CNC. The first consists of a locus on 2p16 (53), although a specific candidate gene within this region has not been identified. Additionally, mutations in the gene encoding for the protein kinase A regulatory subunit (1α) (PRKAR1A) at 17q22-24 have been demonstrated in 35-44% of both familial and sporadic cases of CNC (54). This protein, which is intricately involved in endocrine cell signaling pathways, is thought to function as a tumor suppressor gene. Supporting this theory has been the observation that tumors from patients with CNC (in which diminished levels of PRKAR1A are present) exhibit a 2-fold increase in cAMP responsiveness compared with control tumors (55). The identical mutation has also been found in some sporadic endocrine tumors (56). As is the case with MEN-1, a germline mutation is thought to be the inciting event for eventual development of the disease. The clinical presentation of CNC is extremely heterogenous, as is the age at diagnosis. The development of GH excess is rare, occurring usually during the 3rd and 4th decades of life, and typically found in only 10% of patients at the time of presentation (57). Thus, annual screening for GH hypersecretion is recommended only in postpubertal patients. As in cases of gigantism/acromegaly in the setting of MAS, diffuse pituitary hyperplasia (58) and concomitant hyperprolactinemia (59) are frequently seen in individuals with CNC and GH excess.

It has been recognized for several decades that isolated pituitary gigantism or acromegaly may occur in a familial pattern. This phenomenon, termed “Isolated Familial Somatotropinomas” (IFS), is defined as the development of GH hypersecretion in two or more members of a family that does not exhibit features of MEN-1 or CNC. At least 46 different affected kindreds have been reported (60). Unlike in MEN-1 and CC, GH excess tends to arise fairly early in life, with 70% of those with the disorder diagnosed before the 3rd decade. Early childhood gigantism in this setting has also occurred, involving sisters with abnormal linear growth since age 5 (61). Once assumed to represent a variant of MEN-1, mutations within the menin gene as the etiology for IFS have conclusively been excluded (62). However, the precise molecular genetic basis for the development of pituitary GH-secreting adenomas in these families has eluded detection. Thus far, both loss of heterozygosity and linkage to a 9.7 Mb region of 11q13 have been demonstrated in IFS, suggesting the presence of an additional putative tumor suppressor gene in this region, distinct from that involved in MEN-1 (63). Interestingly, a second potential locus has been mapped to 2p12-16, very close to the region implicated in a number of kindreds with CNC (64). Additional molecular genetic analysis performed in these patients has included a search for germline mutations within the GHRH receptor gene, Gsα and Gi2α genes, all of which were normal(65). Similar to observations in MEN-1, patients with IFS have discreet pituitary adenomas, the majority of which are comprised solely of somatotrophs (61).

As would be predicted, linear growth acceleration is the cardinal feature of excessive GH production in a child or adolescent. Based on numerous case reports, however, it is clear that the excessive linear growth observed in young children with gigantism may be accompanied or even preceded by macrocephaly (10), and or obesity (9;13; 22). Additional clinical features frequently encountered include frontal bossing, broad nasal bridge, prognathism, excessive sweating, voracious appetite, coarse facial features and enlargement of the hands and feet. Bone age radiographs in these patients have variably been reported to be normal or advanced, even in the complete absence of sex steroid production (10; 21; 22). Figure 3 demonstrates the prognathism, coarse facial features and typical tall stature seen in a 12-year-old boy with gigantism, and Figure 4 illustrates enlargement of the hands in this same patient.

Figure 3. 

Figure 4. 

The most consistent biochemical abnormality observed in patients with gigantism is an elevated IGF-1, which is known to exhibit an excellent correlation with 24 hour GH secretion (66). As previously mentioned, hyperprolactinemia is extremely common in early-onset GH hypersecretion. Depending on the individual situation, the additional pituitary screening evaluation may be normal, indicative of hypopituitarism or central precocious puberty. Concurrent endocrinopathies may also be present, particularly in patients with syndromes such as MAS or MEN-1. Rarely, alterations in glucose tolerance brought about by GH excess may result in the development of overt diabetes, leading to transient diabetic ketoacidosis in rare instances (67;68). An additional physiologic effect of GH excess that may have clinical significance is that of increased erythropoiesis, as demonstrated by a case of acromegaly-induced polycythemia vera that resolved following surgical resection of the GH-secreting adenoma (69). The importance of GH in the regulation of red blood cell production has further been supported by the observation that pre-treatment hemoglobin concentrations in children with idiopathic growth hormone deficiency are lower than controls (70).