Multiple Endocrine Neoplasia Syndrome, Childhood

Introduction

Gigantism refers to abnormally high linear growth due to excessive action of insulin-like growth factor-I (IGF-I) while the epiphyseal growth plates are open during childhood. Acromegaly is the same disorder of IGF-I excess when it occurs after the growth plate cartilage fuses in adulthood. Gigantism is a nonspecific term that refers to any standing height more than 2 standard deviations above the mean for the person's sex, age, and Tanner stage (ie, height Z score >+2). These disorders are placed along a spectrum of IGF-I hypersecretion, wherein the developmental stage when such excess originates determine the principal manifestations. The onset of IGF-I hypersecretion in childhood or late adolescence results in tall stature. This article focuses on IGF-I excess with an onset during childhood.

The most remarkable example of a person with gigantism was Robert Wadlow, called the Alton giant, who stood 8 feet 11 inches tall at the time of his death in his mid-20s (see Media file 1). A more recent person, widely known for his wrestling and movie roles, was Andre Roussimoff, or Andre the Giant. He was 6 feet 3 inches tall at age 12 years and reached a height of 7 feet 4 inches by adulthood.

More recently, scientific breakthroughs in the molecular, genetic, and hormonal basis of growth hormone (GH) excess have provided important insights into the pathogenesis, prognosis, and treatment of this exceedingly rare disease.

Pathophysiology

Causes of excess IGF-I action may be divided into 3 categories: (1) those originating from primary GH excess released from the pituitary; (2) those caused by increased GH-releasing hormone (GHRH) secretion or hypothalamic dysregulation; and (3) hypothetically, those related to the excessive production of IGF-binding protein, which prolongs the half-life of circulating IGF-I.

By far, most people with giantism have GH-secreting pituitary adenomas or hyperplasia. Although gigantism is typically an isolated disorder, rare cases occur as a feature of other conditions, such as multiple endocrine neoplasia (MEN) type I, McCune-Albright syndrome (MAS), neurofibromatosis, tuberous sclerosis, or Carney complex.

Approximately 20% of patients with gigantism have MAS (the triad of precocious puberty, café au lait spots, fibrous dysplasia) and may have either pituitary hyperplasia or adenomas (see Media file 2).

Frequency United States

Gigantism is extremely rare, with approximately 100 reported cases to date. Acromegaly is more common than giantism, with an incidence of 3-4 cases per million people per year and a prevalence of 40-70 cases per million population.

Mortality/Morbidity

Because of the small number of people with gigantism, mortality and morbidity rates for this disease during childhood are unknown. For individuals with acromegaly, the mortality rate is 2-3 times that of the general population. Successful treatment, with normalization of IGF-I levels, may be associated with a return to normal life expectancy. For persons with acromegaly, the most frequent causes of death are cardiovascular and respiratory complications.

Researchers disagree on whether malignancy is a significant cause of increased mortality. Although benign tumors (including uterine myomas, prostatic hypertrophy, and skin tags) are frequently encountered in acromegaly, documentation for overall prevalence of malignancies in patients with acromegaly remains controversial. Most studies suggest that as many as 30% of patients may have a premalignant colon polyp at diagnosis, and as many as 5% may have a colonic malignancy. However, the long-term effect of colonic lesions on morbidity and mortality has not been established.

No clear evidence supports an increased risk for lung, breast, or prostate cancer. As a significant cause of morbidity, sleep apnea may be both obstructive and central.

Race

No predilection has been reported.

Sex

IGF-I excess equally affects men and women.

In a series of 12 children, GH-secreting adenomas occurred with a female-to-male ratio of 1:2. Given the small size of this series, these disorders are unlikely to show a sex bias during childhood.

Age

Gigantism may begin at any age before epiphyseal fusion. The mean age for onset of acromegaly is in the third decade of life. For acromegaly, the delay from the insidious onset of symptoms to diagnosis is 5-15 years, with a mean delay of 8.7 years.

Clinical History

The presentation of patients with gigantism is usually dramatic, unlike the insidious onset of acromegaly in adults. Reasons for this difference include the close monitoring of growth in children and their relatively responsive growth-plate cartilage. Children with gigantism have few soft-tissue effects (eg, peripheral edema, coarse facial features) because of their rapid linear growth.

  • Longitudinal acceleration of linear growth secondary to IGF-I excess is the cardinal clinical feature of gigantism.
  • Tumor mass may cause headaches, visual changes due to optic nerve compression, and hypopituitarism.
  • A common finding from pituitary GH excess is hyperprolactinemia, which manifests in childhood because mammosomatotrophs are the most common type of GH-secreting cells involved in childhood gigantism.


Physical

All growth parameters are affected, although not necessarily symmetrically. Over time, IGF-I excess is characterized by progressive cosmetic disfigurement and systemic organ manifestations. Physical manifestations include the following:

  • Tall stature
  • Mild-to-moderate obesity (common)
  • Macrocephaly (may precede linear growth)
  • Soft-tissue hypertrophy
  • Exaggerated growth of the hands and feet with thick fingers and toes
  • Coarse facial features
  • Frontal bossing
  • Prognathism
  • Hyperhidrosis
  • Osteoarthritis (a late feature of IGF-I excess)
  • Peripheral neuropathies (eg, carpel tunnel syndrome)
  • Cardiovascular disease (eg, cardiac hypertrophy, hypertension, left ventricular hypertrophy) if IGF-I excess is prolonged
  • Benign tumors, including uterine myomas, prostatic hypertrophy, colon polyps, and skin tags, which are frequently in acromegaly (Documentation of a high prevalence of malignancies in patients with acromegaly remains controversial.)
  • Frequently associated endocrinopathies (eg, hypogonadism, diabetes and/or impaired glucose tolerance, hyperprolactinemia)

Causes

Despite diverse pathophysiologic mechanisms, the final common abnormality is IGF-I excess. Elevated tissue levels of free IGF-I, which is produced primarily in hepatocytes in response to excess GH, mediate most if not all growth-related outcomes in gigantism. Transgenic mice that overexpress GH, GHRH, or IGF-I had dramatically accelerated somatic growth compared with control litter mates. One acromegalic patient had low serum GH levels and elevated serum total IGF-I levels; this finding implicates IGF-I as the key pathologic factor in this disease. Serum levels of IGF-I are consistently elevated in patients with acromegaly and, therefore, are used to monitor treatment success.

The conditions described below can cause IGF-I oversecretion.

  • Primary pituitary GH excess: In most individuals with GH excess, the underlying anomaly is a benign pituitary tumor composed of somatotrophs (GH-secreting cells) or mammosomatotrophs (GH-secreting and prolactin [PRL]-secreting cells) in the form of a pituitary microadenoma or an macroadenoma. The adenomas are most characteristically well-demarcated and confined to the anterior lobe of the pituitary gland. In some people with GH excess, the tumor spreads outside the sella, invading the sphenoid bone, optic nerves, and brain. GH-secreting tumors are more likely to be locally invasive or aggressive in pediatric patients than in adults.
    • Gs-alpha (Gsa) mutation: G proteins play an integral role in postligand signal transduction in many endocrine cells by stimulating adenyl cyclase, resulting in an accumulation of cyclic adenosine monophosphate (cAMP) and subsequent gene transcription. About 20% of patients with gigantism have MAS and pituitary hyperplasia or adenomas. Activating mutations of the stimulatory Gsa protein have been found in the pituitary lesions in MAS and are believed to cause the other glandular adenomas observed. Point mutations found in several tissues affected in MAS involve a single amino-acid substitution in codon 201 (exon 8) or 227 (exon 9) of the gene for Gsa. Somatic point mutations have been identified in somatotrophs of less than 40% of sporadic GH-secreting pituitary adenomas. The resulting oncogene (gsp) is thought to induce tumorigenesis by persistently activating adenyl cyclase, with subsequent GH hypersecretion.
    • Loss of band 11q13 heterozygosity: Loss of heterozygosity at the site of a putative tumor-suppressor gene on chromosome band 11q13 was first identified in tumors from patients with MEN type I and GH excess. Loss of heterozygosity at band 11q13 has also been observed in all types of sporadically occurring pituitary adenomas. It is associated with an increased propensity for tumoral invasiveness and biologic activity.
    • Abnormality at Carney loci on chromosomes 2 and 17: Carney complex is characterized by myxomas, endocrine tumors, and spotty pigmentation. It is transmitted as an autosomal dominant trait. About 8% of affected individuals have GH-producing pituitary adenomas. The causative gene for this disease was mapped to chromosome bands 2p16 and 17q22-24. Germline mutations in PRKAR1A (which encodes for the protein kinase A type I-alpha regulatory subunit, an apparent tumor-suppressor gene on chromosome arm 17q) were detected in several families with Carney complex.
  • Secondary GH excess: Causes of secondary GH excess include increased secretion of GHRH due to an intracranial or ectopic source and dysregulation of the hypothalamic-pituitary-GH axis.
    • GHRH excess: Hypothalamic GHRH excess is postulated as a cause for gigantism, possibly secondary to an activating mutation in hypothalamic GHRH neurons. Excess GHRH secretion may be due to an intracranial or ectopic tumor. Several well-documented incidents of hypothalamic GHRH excess demonstrated intracranial gangliocytomas associated with gigantism or acromegaly. Ectopic GHRH-secreting tumors have included carcinoid, pancreatic islet-cell, and bronchial neoplasms. Prolonged tumoral secretion of GHRH leads to pituitary hyperplasia, with or without adenomatous transformation, that increases levels of GH and other adenohypophyseal peptides.
    • Disruption of somatostatin tone: Tumoral infiltration into somatostatinergic pathways are hypothesized to be the basis for GH excess in rare incidents of gigantism associated with neurofibromatosis and optic glioma or astrocytomas.

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