Which disease is caused by hypersecretion of growth hormone during childhood?

Abstract

Hypersecretion of growth hormone (GH) before epiphyseal closure leads to gigantism. With regard to its causes, gigantism can be classified into: growth hormone excess, growth hormone-releasing hormone excess, GNAS1 gene mutations, C-type natriuretic peptide overproduction, MEN1 gene mutations, CDKN1B gene mutations, PRKAR1A gene mutations, AIP gene mutations and GH Excess by Somatostatin Deficiency. Genetic syndromes presenting with gigantism include: Klinefelter syndrome (47, XXY), Beckwith-Wiedemann syndrome, Sotos syndrome, Proteus syndrome, Simpson-Golabi-Behmel syndrome type 1, Weaver syndrome, Marfan syndrome and Homocystinuria.

5.1 GPR101 duplication

Gigantism due to GH oversecretion in childhood can be due to different genetic causes. AIP mutations (29%–41%) are the most common genetic cause of gigantism.2 Gigantism resulting from AIP mutations typically exhibits clinical traits in the second decade of life. By contrast, XLAG results in early-onset gigantism due to germline or somatic microduplication of GPR101.6 In two reports with large numbers of cases of pituitary gigantism, XLAG represents 7.8% and 10% of the cases, respectively.6,46 Up to now, 33 XLAG patients have been identified, with 9 males and 24 females, 26 patients with germline GPR101 duplication, 6 patients with somatic GPR101 duplication, and 1 patient undermined.2

Patients with XLAG usually display excessive growth before the age of one, even as young as 2–3 months in some patients, though born with normal body sizes.2 Growth in prenatal stage is mediated mainly by IGF-2, while growth in neonatal life is regulated by the GHRH/SST-GH-IGF-1 axis.5 It may be speculated that IGF-2 secretion is independent of GPR101, and abnormal growth during neonatal life is induced by increased circulating GH due to the pituitary lesion.2,3 Although histopathological observation reveals significant hyperplasia of somatotrophs, lactotrophs, and mammosomatotrophs (cells expressing both GH and prolactin) in some XLAG patients,47,48 most XLAG patients harbor pituitary adenoma.2 In three patients, pituitary adenoma was surrounded by hyperplasia, implying that hyperplasia to adenoma progression occurs in these XLAG patients.2 Increased circulating GHRH, IGF-1 and prolactin levels are also observed in some XLAG patients and GHRH upregulation may further increase the already elevated basal GH and prolactin levels and the hyperplasia to adenoma progression.3,49

Associated Disorders

Gigantism can result from pituitary tumors if they occur in children before the fusion of the long bones and closure of the epiphyses. Gigantism is characterized by excessive height. After epiphyseal closure, acromegalic features may become apparent. Acromegaly occurs in adults when excessive secretion of growth hormone causes soft tissues and bones to become dense and enlarged. Cushing's syndrome is caused by excessive ACTH secretion due to corticotropic adenomas, which enhance cortisol secretion from the adrenal glands. Symptoms associated with this condition include immunosuppression, salt and water imbalance, muscle wasting, high blood sugar, and fat redistribution (moon face). In some cases, fat is deposited between the shoulder blades (buffalo obesity). With prolactinoma, females experience abnormal discharge of milk in the absence of pregnancy.

V.B Human GHRH-Secreting Tumors

Gigantism or acromegaly secondary to eutopic (hypothalamic hamartomas, gliomas, and astrocytomas) or ectopic (pancreatic, lung, thymus, and gastrointestinal neoplasias) GHRH secretion occurs rarely and is frequently associated with multiple endocrine neoplasia. The clinical presentation is related to GH/IGF-I and GHRH excess as well as to syndromes related to primary tumor mass localization and function. Patients also present with pituitary hyperplasia and/or adenomatous transformation, as observed in genetically altered mice (Table 2). Somatotroph adenomas overexpressing intratumoral GHRH also show more aggressive tumor behavior.

Table 2. Clinical Features of GHRH Receptor Abnormalities and GHRH-Secreting Neoplasias in Humans

Reproductive system

Gigantism of the breasts, probably induced by bucillamine, has been reported [16].

After attempts with chrysotherapy and lobenzarit, a 24-year-old woman was given bucillamine 300 mg/day and a glucocorticoid, predonine, for rheumatoid arthritis. After 10 months she noticed bilateral breast enlargement, which over 6 months progressed to extreme proportions, the left breast ultimately reaching as far as her pubis. The skin of the breasts was thin and erythematous, with marked dilatation of the superficial veins. The nipple areola complexes were elongated and poorly defined from the surrounding skin. There were no abnormalities of prolactin, sex hormones, growth hormone, or TSH (but the values were not stated). Bilateral total mastectomy was performed and the nipple-areola complexes were removed from the resected tissue and grafted on to the breasts after insertion of a tissue expander. The breast tissue removed from the right side weighed 5 kg and that from the left side 7 kg. Histologically there was increased fibrosis and duct dilatation and no malignancy.

This reaction, attributed here to bucillamine, is a rare but well-established adverse reaction to penicillamine. Although the patient had also taken isoniazid for pulmonary tuberculosis, that was unlikely to have played a part, since the breast enlargement started earlier and progressed after the isoniazid had been withdrawn.

2 Gigantism in Limpets

Gigantism is not uncommon in invertebrate species (Vermeij, 2012), and there are many factors and evolutionary forces that favour organisms to attain extreme large sizes. For instance, high oxygen availability and the absence of constraints to access food resources are some advantages of extreme size (Vermeij, 2012). Certain limpet species can potentially grow to achieve significantly conspicuous dimensions. Referred to as giant limpets in the scientific literature, these species have several common characteristics (Creese et al., 1990). For example, these larger limpet species are often territorial and show specialised trophic behaviours. The size of giant limpets, together with their presence in high densities in easily accessible coastal zones at low tide, has determined their intensive use in ecological studies, becoming “guinea pigs” in research focusing on, among other subjects, adaptations to the harshness of their environment (e.g. desiccation) and the bioenergetics of growth (Lindberg, 2007).

As is the case for many invertebrate species, maximum size in limpets is known to be correlated with gradients of primary productivity (Bosman et al., 1987; Vermeij, 1978, 1980). This correlation has been shown for the giant limpet Patella ferruginea (the ribbed Mediterranean limpet), which attains its record size (11.4 cm) in Ceuta Harbor, North Africa, where primary production is higher than in comparison with nearby waters (Espinosa et al., 2008a). However, South Africa, with highly productive waters (up to 800 g C m− 2 year− 1) due to the upwelling zones associated with the Benguela Current (Mann, 2000; Walsh, 1988), hosts the majority of giant limpets. The ability of some of the South African limpets (particularly those belonging to the genus Cymbula) to consume large drifting algae may have contributed to the evolution of large size in these herbivores (Estes et al., 2005). The Northeast and Northwest Pacific also host exceptionally large-bodied species of molluscs, and the maximum size of giant limpets has been observed in these basins (313 mm in the Northeast Pacific Ocean, 210 mm in the Northwest; see Vermeij, 2012). Still, gigantism in limpets is not solely associated with distribution. The maximum size of these limpets has increased over geological time, from the Early Miocene to the present, in the North Pacific Ocean, South African waters, and the Northeast Atlantic Ocean (the areas where many giant limpets occur).

It might be noted that a positive feedback occurs between grazers and primary producers, in the sense that herbivores with high metabolic demands exert strong selection on prey species performing higher biomass turnover on them. Such selection allows herbivores to become larger and more abundant where production and consumption remain stable for extended periods of time (Vermeij, 2012). Otherwise, large body size becomes disadvantageous when food supply is reduced or becomes unstable (e.g. if access to food is restricted by extreme conditions). As a consequence, regions that have historically had low extinction rates are the most favourable for the evolution of very large size (Vermeij, 2012).

As we have described, gigantism confers organisms with a series of biological particularities, lending them, for example, increased capacity to structure the ecosystem, greater interspecific competition and increased resistance to pressure from predators. Creese et al. (1990) pointed out that this is also the case for giant limpets, as there is much more intense inter- and intraspecific interaction. Nevertheless, large size also makes them more vulnerable and the frequent target of human collection because they are a large biomass that is often easily accessible.

The maximum sizes of the 14 species included in this review are included in Fig. 1 and Table 1. There is no apparent phylogenetic connection between the maximum size that animals can attain, and giant limpets that are found across lineages. It is interesting to note that when comparing maximum length with mean size within a genus, there is a similarity among phylogenetic lineages (see Fig. 1). Nevertheless, within the genus Scutellastra, the two largest limpets ever recorded: Scutellastra kermadecensis, with a maximum recorded size of 174 mm, and the largest known limpet, Scutellastra mexicana, with a maximum size of 355 mm. While the genera Patella, Cellana and Lottia have only one giant species each, the genus Cymbula has the largest proportion of giant species. Rather than being associated with phylogeny, gigantism in limpets seems to be more strongly associated with behavioural traits. Nonmigratory and territorial taxa attain larger size in comparison with migratory and nonterritorial taxa (Lindberg, 2007). In fact, the status of largest-sized within a guild is retained briefly and phylogenetic usurpation of this top status is the rule (Vermeij, 2012). In fact, a trait (in this case a large size), with supposed adaptive advantages, is very much contingent upon the identity of the clades with that trait or the sources of selection favouring the trait, since the results of the evolution are more predictable than the actors in the evolutionary theatre (see Vermeij, 2006, 2010).

Table 1. List of Giant Limpet Species

Below, we briefly review current knowledge regarding the biology and ecology of these giant limpets, providing insight regarding their characteristics and behavioural traits.

Breasts

Gigantism of the breasts (macromastia) can occur in patients using penicillamine [293,378–382]. Gynecomastia in men can also occur rarely [381,383]. There is resemblance to the pubertal form of massive breast enlargement. It can be painful and has been encountered in pre- and postmenopausal women, with normal and increased prolactin concentrations. Histological examination mainly shows increased connective tissue and no changes in the glandular tissue. In one patient, the breasts were tender and grew progressively larger during each menstrual period.

A 55-year-old premenopausal woman took penicillamine 1 g/day for 2 years for localized scleroderma [384]. She used no other drugs. She noticed a gradual enlargement of her breasts, from a size B to size D + bra cup. There were no palpable masses or tenderness. The only abnormal laboratory test finding was a positive test for homogeneous antinuclear antibodies (titer < 1:80), which is often found in patients with scleroderma. Serum prolactin was normal. Penicillamine was withdrawn and the breast enlargement regressed over 3 months; the bra cup size reverted to B.

A 25-year-old woman with Wilson's disease took penicillamine (1.5 g/day) and developed hirsutism, mainly of the face [293]. After she started to use an oral contraceptive, her breasts enlarged rapidly and she experienced cyclic mastodynia; in addition, gingival hyperplasia developed. All her symptoms improved on withdrawal of penicillamine, but additional mammoplasty was needed.

The sequence of events in the last patient suggested that the use of the oral contraceptive contributed to the development of macromastia.

In one case breast enlargement was accompanied by systemic lupus erythematosus [385].

A 37-year-old woman with a 7-year history of rheumatoid arthritis had taken penicillamine for about 1–2 years (dose not specified). When she presented at the Cambridge Breast Unit she had had rapidly increasing painful enlargement of the breasts for 7 months. The breasts were symmetrically enlarged (from an A cup to DD) and had thickened and erythematous skin. There were several palpable masses; mammography showed no evidence of malignancy and an ultrasound scan showed large hypo-echoic nodules with engorged vessels. Histology of a large lump in the left breast showed a fibroadenoma. Immunohistochemistry for estrogen receptors showed 50% nuclear staining. She had stopped taking penicillamine 2 months before because of a lupus- like syndrome with thrombocytopenia, lymphopenia, and positive ANA and DNA antibodies (whether single-stranded or double-stranded was not stated).

Although breast gigantism is a rare manifestation of idiopathic SLE, in this case autoimmune substances could have stimulated mammary duct proliferation or mimicked estrogen or other growth factors in the breast.

Excessive GH Secretion

Pituitary gigantism occurs with pituitary adenomas that produce excessive GH secretion during childhood. There is excessive skeletal and visceral growth often to a marked degree; it is extremely rare. Circulating GH concentrations may not be strikingly elevated in the unstimulated state. GH concentrations usually fail to suppress after a glucose load, and there is a “paradoxical” rise in GH to stimulation with thyrotropin-releasing hormone. Care must be exercised, however, in evaluating GH secretion in tall adolescents as the pubertal changes in GH secretion can produce findings similar to those observed in pituitary gigantism. In this situation, 24 h GH profiles can be helpful in distinguishing the two conditions.

Acromegaly is a far commoner condition that follows the development of a pituitary adenoma in adults when growth has ceased. There is still bony overgrowth, but it mostly affects membranous bones because of the fusion of the growth plates in the long bones of the skeleton. As with pituitary gigantism, there are a number of important metabolic sequelae of which the most important is diabetes mellitus and also an increased risk of colonic carcinoma in a number of acromegalic patients.

Pituitary surgery to remove the adenoma is the mainstay of therapy in both conditions. Treatment with agents such as somatostatin may be required along with radiotherapy in some cases. More specific GH receptor therapies such as the antagonist Pegvisomant are also of value in long-term management.

19.8.1 Pituitary Disorders

a.

Gigantism. Gigantism results from excessive production of somatotrophic hormone and consequent overstimulation of growth cartilages and gigantic proportions of the skeleton.

Acromegaly. Acromegaly is similarly caused by an overly productive pituitary, but after the epiphyses are fused. The most dramatic osteological manifestation of acromegaly is growth at the mandibular condyle and a resulting elongation and distortion of the lower jaw.

Pituitary dwarfism. Dwarfism is a general term for a variety of disorders that lead to greatly reduced stature and/or body proportions. Pituitary dwarfism results from an underactive pituitary gland, leading to reduced production of growth hormone and resulting in a normally proportioned but abnormally short individual.

Tumors

Pituitary gigantism is a rare condition, analogous to acromegaly in the adult (see Chapter 9).929-931 GH-secreting tumors of the pituitary are typically eosinophilic or chromophobic adenomas. Their cause is uncertain, although many result from somatic mutations that generate constitutively activated G proteins with reduced GTPase activity (see Chapter 9).932 The resulting increase in intracellular cAMP in the pituitary leads to increased GH secretion. Somatotropic tumors with excess GH secretion may occur in McCune-Albright syndrome, which is caused by mutations resulting in constitutive activation of G proteins.933,934 GH-secreting tumors have also been reported in multiple endocrine neoplasia (MEN) and in association with neurofibromatosis and tuberous sclerosis.935

GH excess that occurs before epiphyseal fusion results in rapid growth and attainment of adult heights above expected adult potential. When GH hypersecretion is accompanied by gonadotropin deficiency, accelerated linear growth may persist for decades, as was the case for the Alton giant, who reached a height of 280 cm by the time of his death in his 20s.936 Manifestations typical of acromegaly may also appear, such as soft tissue swelling; enlargement of the nose, ears, and jaw with coarsening of facial features; pronounced increases in hand and foot size; diaphoresis; galactorrhea; and menstrual irregularity.