Gigantism

A 12-year-old boy presents to the clinic with rapid growth over the past year, surpassing that of his parents. He has also developed coarse facial features and his shoe size has increased dramatically. On examination, he is noted to have a prominent jaw, enlarged hands, and a thickened heel pad on x-ray.

Pathophysiology

Gigantism is a rare condition caused by excessive growth hormone (GH) secretion during childhood, before the closure of the epiphyseal growth plates. The epiphyseal growth plates are areas of cartilage at the ends of long bones where bone growth occurs. Excessive GH leads to accelerated linear bone growth, resulting in abnormally tall stature.

GH exerts its effects through insulin-like growth factor 1 (IGF-1), primarily produced in the liver in response to GH stimulation. Elevated IGF-1 levels contribute to the increased growth and other clinical manifestations of gigantism.

Aetiology

The most common cause of gigantism is a pituitary adenoma, a benign tumour of the pituitary gland that secretes GH. In rare cases, gigantism may also be caused by:

• Ectopic GHRH or GH production: Some tumours, such as pancreatic islet cell tumours and carcinoid tumours, can secrete GH-releasing hormone (GHRH), which stimulates the pituitary to produce excess GH. These tumours may also directly secrete GH.
• Genetic mutations: Certain genetic mutations can affect the regulation of GH secretion, leading to gigantism. However, these cases are exceptionally rare.

Epidemiology & Risk Factors

Gigantism is an extremely rare disorder, with an estimated incidence of 3 cases per million per year in the UK. Risk factors associated with increased incidence of pituitary tumours include syndromes such as MEN-1, McCune-Albright, Carney Complex, Neurofibromatosis and Tuberous Sclerosis.

Clinical Features

• Accelerated linear growth: Children with gigantism grow at an abnormally rapid rate, often exceeding the 97th percentile for height.
• Skeletal abnormalities: The excessive bone growth can lead to skeletal deformities, including:
  • Enlarged hands and feet: The hands and feet become disproportionately large, with spade-like appearance.
  • Thickened heel pad: X-rays may reveal a thickened heel pad.
• Facial features:
  • Prominent jaw (prognathism)
  • Frontal bossing (prominent forehead)
  • Widely spaced teeth
  • Macroglossia (enlarged tongue)
• Other features:
  • Reduced gonadal development (hypogonadism)
  • Delayed puberty

Investigations

• Growth hormone (GH) levels: GH levels fluctuate throughout the day, making a single measurement unreliable. However, consistently elevated GH levels suggest excessive secretion.
• Serum insulin-like growth factor 1 (IGF-1): IGF-1 is a more stable marker of GH excess, and elevated levels support the diagnosis of gigantism.
• Oral glucose tolerance test (OGTT): In this test, glucose is given orally, and GH levels are measured at regular intervals. In normal individuals, GH levels should be suppressed by glucose. Failure of GH suppression during an OGTT is diagnostic of GH excess.
• Pituitary imaging: Magnetic resonance imaging (MRI) is the preferred imaging modality to visualise the pituitary gland and detect a pituitary adenoma.

Management

The primary goal of gigantism management is to reduce GH secretion and control its effects. Treatment options include:

• Surgery: Surgical removal of the pituitary adenoma is the first-line treatment for most cases of gigantism. Transsphenoidal surgery, where the tumor is accessed through the nose, is the preferred approach.
• Medical therapy: Medications can be used to suppress GH secretion or block its action:
  • Somatostatin analogues (octreotide, lanreotide): These medications mimic the hormone somatostatin, which inhibits GH release. They are effective in reducing GH and IGF-1 levels in many patients.
  • Dopamine agonists (bromocriptine, cabergoline): While primarily used for prolactinomas, dopamine agonists can sometimes suppress GH secretion in gigantism. However, their efficacy is generally lower than somatostatin analogues.
  • GH receptor antagonists (pegvisomant): This medication blocks the action of GH by binding to its receptor, effectively preventing GH from stimulating IGF-1 production.
• Radiation therapy: Radiation therapy may be considered in cases where surgery is not feasible or if medical therapy alone is insufficient to control GH excess.

Complications & Prognosis

Untreated gigantism can lead to significant morbidity and mortality. Potential complications include:

• Cardiovascular disease: Excess GH increases the risk of hypertension, cardiomyopathy and heart failure.
• Metabolic disorders: Gigantism is often associated with insulin resistance and an increased risk of developing type 2 diabetes.
• Musculoskeletal problems: Accelerated bone growth can lead to joint pain, arthritis, and skeletal deformities.
• Sleep apnoea: Due to macroglossia and soft tissue overgrowth in the pharynx and larynx.
• Premature death: Untreated gigantism can significantly shorten lifespan, primarily due to cardiovascular and metabolic complications.

With appropriate treatment, the prognosis for gigantism is generally good. Early diagnosis and intervention are crucial to minimize long-term complications.