Pituitary gigantism

INTRODUCTION — Pituitary gigantism refers to growth hormone (GH) excess that occurs before fusion of the epiphyseal growth plates. Therefore, by definition, the condition is only seen in growing children. In this setting, elevated levels of serum GH and insulin-like growth factor 1 (IGF-1) cause rapid, excessive linear growth and, if unchecked, extremely tall adult stature. In contrast, GH excess that begins in adulthood, after complete epiphyseal fusion, has no effect on stature and is called acromegaly.

Although many historical claims of gigantism have been exaggerated, case reports of true pituitary giants with heights of up to 8 feet 11 inches (272 cm) are documented in the medical literature [1]. The first known case of gigantism is alleged to be that of King Sa-Nakht, who ruled in Egypt in the 3^rd dynasty [2]. Familial gigantism has also been alleged to have been present in the family of Roman Emperor Maximinus Thrax [3]. (See "Causes and clinical manifestations of acromegaly".)

EPIDEMIOLOGY — Pituitary gigantism is a rare disorder. Most pediatric endocrinologists may see at most one or two patients with the condition during their careers. In one large series of 2367 children and adolescents with pituitary adenomas, only 15 (0.6 percent) had pituitary gigantism [4]. Although much of our understanding of this disease has been derived from isolated case reports and extrapolation from the adult literature [5], a retrospective review of 208 cases of pituitary gigantism from around the globe provides important insights [6]. These include male predominance and a lack of identifiable genetic etiology in approximately 50 percent of cases [7]. Gigantism may occur at any age and has been observed as early as the first two to three months of life.

ASSOCIATED CONDITIONS — Pituitary gigantism typically is a sporadic and isolated condition. However, it may occur within the context of a coexisting disorder or arise according to a pattern of familial inheritance.

Gigantism is a well-recognized feature of the following syndromes:

●McCune-Albright syndrome (MAS) – Approximately 20 percent of patients with MAS are thought to have growth hormone (GH) hypersecretion [8], although few large case series are available [9]. In one review of 112 patients with MAS and acromegaly, the mean age at diagnosis of acromegaly was just over 24 years [10]. However, GH excess has been reported in the setting of MAS in a child as young as 8.9 months of age [11]. Subclinical GH excess also has been reported in MAS, where it results in unexpected normal (rather than short) stature in the setting of untreated precocious puberty [12]. (See "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)

●Multiple endocrine neoplasia types 1 (MEN1) and 4 (MEN4) – GH excess eventually develops in up to 60 percent of patients affected with MEN1, usually with onset in the fourth and fifth decades of life [13]. GH excess in MEN1 is extremely rare in individuals younger than 40 years, although it has been reported in a child as young as age five years [14]. GH hypersecretion has also been reported as a feature of MEN4 [15], although the frequency of gigantism in this condition is unknown. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

●Carney complex – GH-secreting pituitary tumors are reported in approximately 15 percent of cases of the Carney complex and typically begin during the third and fourth decades of life [16]. However, childhood onset with gigantism has also been reported [17]. (See "Cushing syndrome due to primary pigmented nodular adrenocortical disease", section on 'Carney complex (CNC)'.)

●Neurofibromatosis – Gigantism is reported in up to 10 percent of patients with neurofibromatosis and optic nerve tumors and is often associated with tumors involving the optic chiasm [18]. However, pituitary tumors and hyperplasia with or without a concomitant optic pathway glioma have also been reported in children with neurofibromatosis and GH excess [19]. In this setting, gigantism is thought to be under-recognized and may be transient [20]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

●Paraganglioma, pheochromocytoma, and pituitary adenoma association (3PA) – Gigantism has been observed in adolescents as young as 15 years with 3PA, although the exact incidence in patients with this constellation has not been determined [21,22].

●Familial isolated pituitary adenomas – Among kindreds with familial isolated pituitary adenomas, isolated GH excess may be transmitted in an autosomal dominant fashion. Affected individuals in these families have been as young as nine years of age at diagnosis [23].

PATHOPHYSIOLOGY

Sources of growth hormone excess — Excess growth hormone (GH) can originate from a variety of sources including a pituitary GH-secreting adenoma, excessive production of GH-releasing hormone (GHRH) from the hypothalamus, or, rarely, an ectopic source of GH or GHRH (figure 1) [24,25]. In addition, dysregulation of neuroendocrine control mechanisms has been inferred from cases in which somatostatin-rich pathways have been disrupted, likely resulting in a diminished inhibitory constraint on GH secretion [26]. Upregulation of STAT3 (signal transducer and activator of transcription 3), resulting in GH hypersecretion, has been implicated in the development of pituitary somatotroph adenomas [27].

Distinct biochemical and pathologic features differentiate GH overproduction in children and adults, suggesting that the disease behaves differently depending upon the age at which it begins. In adults, most cases are caused by a pituitary GH-secreting adenoma [28]. Although pituitary adenomas can occur in children [29,30], early childhood-onset GH hypersecretion is thought to be more often caused by hypothalamic GHRH excess, which in several cases appears to have been present from, or even prior to, birth [31,32]. When pituitary tumors are identified as the source of GH excess in children, they may be a manifestation of a genetic condition, whereas in adults, they are usually an isolated abnormality [33]. (See 'Associated conditions' above.)

Etiologic mechanisms — A number of genetic abnormalities have been elucidated that are involved in the genesis of GH excess in certain settings [34]. The list of genes implicated in the development of gigantism continues to grow. However, all of the ones discovered thus far may be categorized as being either oncogenes or tumor-suppressor genes.

●A significant percentage of sporadic GH-secreting pituitary adenomas as well as those associated with McCune-Albright syndrome (MAS, MIM #174800) result from activation of the GNAS gene [35]. (See "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)

●GH excess in the setting of multiple endocrine neoplasia type 1 (MEN1; MIM #131100) is attributed to variants in the MEN1 gene encoding menin, a nuclear protein that is expressed in multiple tissues. MEN4 (MIM #610755) is caused by germline variants in CDKN1B (cyclin-dependent kinase inhibitor 1B) [36]. (See "Multiple endocrine neoplasia type 1: Genetics".)

●Up to 44 percent of cases of Carney complex are caused by variants in the PRKAR1A gene (protein kinase A regulatory subunit) on chromosome 17 [37]. (See "Cushing syndrome due to primary pigmented nodular adrenocortical disease", section on 'Carney complex (CNC)' and "Cushing syndrome due to primary pigmented nodular adrenocortical disease", section on 'Genetics'.)

●A variety of germline variants in genes encoding the enzyme succinate dehydrogenase are found in patients with the paraganglioma, pheochromocytoma, and pituitary adenoma association (3PA), some of whom have GH-secreting pituitary adenomas [22].

●The most frequently identified genetic abnormality in families with familial isolated pituitary adenomas (MIM #102200) is a loss-of-function variant in the AIP gene [38], encoding aryl hydrocarbon receptor-interacting protein. Sporadic variants in AIP have also been described [39]. A somatotropinoma has been reported in up to 35 percent of young patients with pituitary adenomas and germline variants in AIP [40]. Concomitant germline and somatic AIP variants have also been described, resulting in the development of a GH-secreting adenoma with particularly aggressive features [41]. An AIP founder variant has been identified in Northern Ireland that predisposes to the development of gigantism and is consistent with folklore accounts of Irish giants originating in this area [42].

●X-linked acrogigantism (XLAG; MIM #300942) refers to gigantism due to microduplications in the Xq26.3 region that includes GPR101 (G protein-coupled receptor 101 gene) and has emerged as an important cause of early-onset disease that is notoriously resistant to treatment. In a study of 43 patients with gigantism, microduplications in this region were identified in 13 patients, all of whom had disease onset before five years of age [43]. Both familial (autosomal dominant) and sporadic cases have been described [44]. Of note, XLAG in sporadic cases in boys may be caused by somatic mosaicism, and thus failure to identify Xq26.3 microduplications in peripheral blood does not rule out the condition [45]. Although the exact physiologic function and natural ligand of the GPR101 product remain unknown, it is thought to have some role in development of the GHRH-GH axis [46]. Molecular genetic studies have demonstrated that microduplications in Xq26.3 result in marked upregulation of GPR101 through disruption of the local chromatin architecture, resulting in enhanced promoter activity [47]. Pituitary adenomas in patients with XLAG typically secrete both GH and prolactin [48], as is generally the case in very early-onset pituitary gigantism. (See "Sex chromosome abnormalities", section on 'Xq26.3 microduplication' and "Causes and clinical manifestations of acromegaly", section on 'Causes'.)

Despite significant progress in understanding the molecular basis of GH hypersecretion in the conditions mentioned above, the precise pathophysiologic mechanisms in many patients with familial and sporadic somatotropinomas are unknown [6,49].

CLINICAL PRESENTATION

Growth — Excessive growth hormone (GH) secretion in adults typically is insidious in nature. In contrast, dramatic linear growth acceleration usually prompts initial investigation in children. Other growth parameters are affected as well. Mild to moderate obesity commonly accompanies tall stature in these patients.

In children with GH excess, the abnormal height growth typically precedes or is concurrent with rapid weight gain. In contrast, children with exogenous obesity typically have increases in their weight percentile before changes in height [50]. The mean onset of rapid growth in children with pituitary gigantism has been reported to be age 13 and occurs earlier in girls than in boys [6]. In addition to linear growth acceleration, progressive macrocephaly also is seen in children with gigantism and may constitute the presenting complaint, particularly during infancy [30]. (See "Macrocephaly in infants and children: Etiology and evaluation", section on 'Etiology'.)

Other signs and symptoms — The frequency of specific clinical features in children with gigantism is impossible to determine because the disorder is so rare. However, individual case reports and small series indicate common characteristics including large hands and feet, coarsening of the facial features with frontal bossing and prognathism (projection of the jaw), headaches, and excessive sweating [51-53]. GH-secreting pituitary adenomas are often associated with amenorrhea with or without galactorrhea in adolescent females and may cause symptoms of tumor compression such as headaches in both males and females [54].

Coexisting endocrinopathies, common in adults, are not typically seen in children with GH excess, although cardiac morphologic and functional changes are felt to be similar [55]. Oral glucose tolerance tests usually are normal. However, diabetic ketoacidosis as well as type 2 diabetes have been reported in adolescents with pituitary gigantism [56-58].

DIAGNOSIS — Most children who present with tall stature do not have pituitary gigantism [59,60]. Other etiologies of rapid linear growth (although not necessarily tall adult height), such as genetic tall stature, precocious puberty, or hyperthyroidism, should be carefully excluded. Dysmorphic facial features and/or neurocognitive problems may suggest a syndromic or chromosomal cause of tall stature (eg, Sotos, Weaver, Marshall-Smith, Klinefelter, or XYY syndrome). Coexisting disorders (eg, neurofibromatosis or McCune-Albright syndrome [MAS]) also must be considered. (See "The child with tall stature and/or abnormally rapid growth".)

Depending upon the clinical findings, initial evaluation may include radiographic determination of bone age, thyroid function tests, sex steroid hormone concentrations, karyotype, and growth hormone (GH)-related studies [61]. If initial biochemical testing suggests GH excess, a GH suppression test is used to make the definitive diagnosis of pituitary gigantism.

Biochemical studies — Serum insulin-like growth factor 1 (IGF-1) concentration is a valuable screening test in the evaluation for GH excess. Serum concentration of IGF-1 is an indicator of endogenous GH secretion because synthesis of IGF-1 is dependent upon GH [62]. In addition, the concentration of IGF-1 is constant, unlike the concentration of circulating GH, which varies widely throughout the day. Age-referenced norms for IGF-1 concentration must be used because IGF-1 concentrations rise gradually throughout childhood and are substantially higher during puberty than during the pre- or postpubertal years [63]. (See "Physiology of growth hormone".)

Other GH-related peptides, such as insulin-like growth factor-binding protein 3 (IGFBP-3), are elevated in patients with GH hypersecretion [64]. Prolactin usually is elevated in children with GH excess. This clinical feature is consistent with the pituitary histology in children with gigantism. The predominant pituitary cell type in children with gigantism is the mammosomatotroph, which secretes prolactin as well as GH, whereas the predominant cell type in acromegaly is the somatotroph, which secretes GH alone. A single case of co-secretion of GH and thyroid-stimulating hormone (TSH) has been reported in a 13-year-old boy with a gigantism and a pituitary macroadenoma [65].

A GH suppression test, the gold standard for making a definitive diagnosis, should be performed if screening tests suggest GH excess. The GH suppression test measures the serum GH response to an oral glucose load. In normal individuals, GH concentration using immunoradiometric assays typically falls below 1 ng/mL within two hours of the glucose load [66]. However, the significant variability in GH immunoassays represents a challenge to the establishment of definitive consensus guidelines for diagnosis and treatment of GH disorders in the clinical setting [67]. While some countries have standardized GH and IGF-1 measurements, no universal harmonization of the assays used to obtain these values exists [68].

The GH suppression test may yield false-positive results for some tall adolescents without GH hypersecretion. In one prospective study of 126 tall adolescents (height 3.1±0.8 standard deviation score [SDS]), 31 percent of normal subjects failed to suppress GH concentrations in response to oral glucose load, even when the test was prolonged beyond 120 minutes [69]. Sex and pubertal status also affect the degree of GH suppression following an oral glucose load. Nadir GH was found to be higher in girls than boys and highest during Tanner stage 2 to 3 in both genders [70]. Despite these variations, the vast majority of healthy pubertal children have a normal response to GH suppression test, with GH concentrations suppressing to less than 1 ng/mL after the glucose load.

Additional biochemical testing, although rarely necessary, includes stimulation tests using thyrotropin-releasing hormone (TRH; which is no longer available in the United States) or corticotropin-releasing hormone (CRH). Administration of TRH or CRH typically induces a paradoxical response in the setting of GH hypersecretion [71]. Measurement of peripheral GH-releasing hormone (GHRH) also may be useful because its elevation is suggestive of ectopic GHRH secretion.

Enhanced recognition of genetic causes of GH excess has led to the development of screening protocols for specific variants in patients with gigantism based on clinical features and family history [72].

Radiographic imaging — Radiographic imaging of the hypothalamus and pituitary gland is undertaken once biochemical evidence of pituitary gigantism is confirmed. Magnetic resonance imaging (MRI) with contrast is the study of choice because it has the ability to detect subtle abnormalities in the size and structure of the hypothalamic-pituitary region. In addition, MRI may reveal hypothalamic and/or optic pathway gliomas in patients with GH excess associated with neurofibromatosis [26].

Children with pituitary gigantism may have a variety of morphologic abnormalities that have important therapeutic implications. The abnormalities range from discrete well-circumscribed pituitary micro- or macroadenomas to diffuse pituitary hyperplasia or pituitary hyperplasia with adenomatous transformation [31,73].

TREATMENT — The three treatment modalities used to treat pituitary gigantism are surgery, radiation, and pharmacologic therapy. The therapy is individualized, depending upon the particular characteristics of the growth hormone (GH) excess [74]. More than one treatment modality may be used concurrently.

Surgery — Transsphenoidal surgery is the treatment of choice for discrete pituitary microadenomas or macroadenomas and may be curative [52,75]. This technique is safe in children, although complication and recurrence rates tend to be higher than in adults [4,76,77].

●A retrospective review of 41 children who underwent transseptal transsphenoidal pituitary surgery described the following complications: transient arginine vasopressin deficiency (49 percent), recurrent or residual disease (17 percent), nasal obstruction (12 percent), recurrent sinus infections (10 percent), and external nasal deformity (10 percent) [76].

●In one retrospective review of patients with GH-secreting pituitary adenomas who were followed for a mean of 73.5 months, recurrence was more common among patients younger than 20 years of age than in older patients (2 of 15 [13 percent] versus 2 of 198 [1 percent]) [4]. The mean follow-up period was 73.5 months (range 4 to 190 months). Another retrospective study reported surgical remission rates of 55.6 percent in patients with gigantism, compared with 61 percent in those with acromegaly. Recurrences occurred in 40 percent of children with GH-secreting adenomas, compared with 5.3 percent in adults [78]. These observations are consistent with reports suggesting increased biologic aggressiveness in GH-secreting tumors arising during childhood and adolescence compared with those occurring in adulthood [79].

●Anterior pituitary hormone deficiencies occur as a complication of transsphenoidal surgery more commonly in children than in adults (50 versus 20 percent) [4,80].

●The major surgical morbidity regardless of age is permanent arginine vasopressin deficiency (previously called central diabetes insipidus). (See "Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation".)

Radiation — Cranial radiation may provide useful adjunctive therapy in some settings, but its use in children has major disadvantages. These include delayed efficacy and the almost universal sequelae of panhypopituitarism [81]. Cranial radiotherapy causes GH, gonadotropin, and thyroid-stimulating hormone (TSH) deficiency and often leads to late growth failure. In addition, learning disabilities, emotional changes, and obesity may occur after cranial irradiation. (See "Specific learning disorders in children: Clinical features", section on 'Risk factors' and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)

Some practitioners question whether the dangers of radiation therapy in children with pituitary tumors outweigh the benefits. As a general rule, radiation therapy for pituitary gigantism should be avoided if possible.

Pharmacologic treatment — The development of new pharmacologic agents has contributed to the progress in treatment of GH excess (table 1). Medical therapy is indicated in patients whose GH excess is incompletely controlled by surgery or in whom surgery is not an option.

●Bromocriptine, a dopamine analog, used to be the agent used most commonly. This ergot derivative was used with variable efficacy in reducing serum GH levels [51].

●Octreotide, a somatostatin analog, is highly effective in the treatment of both adults and children with GH excess, and it has replaced bromocriptine as the most common agent. Octreotide typically is administered by subcutaneous injection, but it also may be delivered through continuous subcutaneous infusion. Continuous infusion may result in improved efficacy when adequate suppression is not achieved with intermittent administration [82].

●Combination therapy, consisting of bromocriptine and octreotide, also has been used successfully in some children with pituitary gigantism [83,84].

●Lanreotide, a sustained-release formulation of a somatostatin analog, is another available agent. This medication, administered intramuscularly every two to four weeks, is safe and effective in treating adults with acromegaly [85]. Although experience in children is limited, preliminary evidence suggests it is effective in treating childhood-onset GH hypersecretion [86,87]. The broader somatostatin analog pasireotide has demonstrated great promise in adults with acromegaly [88], but very limited experience with its use in children exists [89].

●Pegvisomant is a genetically engineered competitive GH receptor antagonist. It has selective high affinity for the GH receptor and acts by preventing the receptor dimerization and subsequent intracellular signaling that normally occur after ligand binding [90]. Studies in adults with acromegaly indicate that pegvisomant reduces insulin-like growth factor 1 (IGF-1) levels and improves clinical symptoms of GH excess [91-93]. Information regarding the use of pegvisomant for the treatment of GH excess in pediatric patients is accumulating. Pegvisomant appeared to be effective long term in several cases of sporadic GH-secreting pituitary adenomas in children that were unresponsive to other pharmacologic agents [94-97]. Pegvisomant was also found to be as effective as other medical therapies in reducing circulating levels of IGF-1 and insulin-like growth factor-binding protein 3 (IGFBP-3) in five patients with GH excess in the setting of McCune-Albright syndrome (MAS), three of whom were younger than 20 years of age [94]. Combination therapy consisting of pegvisomant and a long-acting octreotide analog was successful in normalizing IGF-1 levels in eight children with aggressive pituitary gigantism [98]. (See "Treatment of acromegaly".)

●Novel synthetic analogs of somatostatin, which inhibit both GH and prolactin, are in development and may prove more beneficial than existing therapies for the treatment of pituitary gigantism [99]. The combination of a ghrelin receptor inverse agonist and a somatostatin analog has also yielded intriguing results in the in vitro setting [100].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of acromegaly" and "Society guideline links: Growth hormone deficiency and other growth disorders".)

SUMMARY AND RECOMMENDATIONS

●Definition – Pituitary gigantism refers to growth hormone (GH) excess that occurs during the period of active linear growth. It is characterized by elevated levels of serum GH and insulin-like growth factor 1 (IGF-1), causing extreme growth acceleration and tall stature. In contrast, GH excess that begins in adulthood does not affect height and is called acromegaly. (See 'Introduction' above.)

●Associated conditions – Pituitary gigantism is usually a sporadic and isolated abnormality. However, it may occur as one manifestation of a genetic syndrome such as McCune-Albright syndrome (MAS), multiple endocrine neoplasia types 1 and 4 (MEN1 and MEN4), the paraganglioma-pheochromocytoma-pituitary adenoma association (3PA), and Carney complex. An inherited form of pituitary gigantism (familial somatotropinoma) also exists. Detection of genetic variants as the basis for GH excess can lead to earlier diagnosis and appropriate referrals for genetic counseling. (See 'Associated conditions' above.)

●Clinical presentation – Children with pituitary gigantism have extraordinarily rapid linear growth and frequently have obesity. However, the rapid growth in height typically precedes the development of obesity in children with GH excess. Other characteristics may include large hands and feet, coarsening of the facial features with frontal bossing and prognathism (projection of the jaw), headaches, and excessive sweating. GH-secreting pituitary adenomas are often associated with amenorrhea with or without galactorrhea in adolescent females. (See 'Clinical presentation' above.)

●Evaluation and diagnosis – Pituitary gigantism is extremely rare, and other causes of rapid linear growth such as precocious puberty or hyperthyroidism should be excluded.

•Initial tests in a child with suspected GH excess include serum concentrations of IGF-1, insulin-like growth factor-binding protein 3 (IGFBP-3), and prolactin. Age-referenced norms for correct interpretation of IGF-1 and IGFBP-3 levels must be used. Depending upon the clinical findings, initial studies may include a bone age radiograph, thyroid function tests, sex steroid hormone concentrations, and a karyotype. If the results suggest GH excess, a GH suppression test is used to make the definitive diagnosis of pituitary gigantism. (See 'Biochemical studies' above.)

•If a GH suppression test confirms GH hypersecretion, MRI (with contrast) of the hypothalamus and pituitary should be performed to look for a pituitary adenoma or diffuse pituitary hyperplasia. (See 'Radiographic imaging' above.)

●Treatment – The three therapeutic modalities for pituitary gigantism are surgery, radiation, and pharmacologic therapy. Transsphenoidal surgery is the treatment of choice for discrete pituitary microadenomas or macroadenomas. Experience with pharmacologic agents in children with GH hypersecretion appears to be comparable with that observed in adults. (See 'Treatment' above.)