Gigantism

Gigantism is excess linear growth caused by growth hormone excess before closure of the epiphyseal growth plates. It is almost always caused by a pituitary somatotroph adenoma and is very rare.

It is diagnosed mainly in childhood and adolescence. Most cases are sporadic. Genetic causes are an important minority.

Genetic causes are AIP variants (a large share of pituitary gigantism), duplication at Xq26.3 involving GPR101 (X-linked acrogigantism, with onset in infancy), MEN1, McCune-Albright syndrome (GNAS), Carney complex (PRKAR1A) and SDHx variants.

Pathophysiology.

Excess growth hormone and hepatic insulin like growth factor 1 stimulate growth plate chondrocytes. Excess exposure also drives soft tissue overgrowth, insulin resistance and cardiac effects.

Tumours are usually macroadenomas, frequently co-secreting prolactin. Gonadal failure or delayed puberty can prolong growth by delaying epiphyseal closure.

• Height z-score over 3 for age, rapid growth velocity, large hands and feet, coarse features, prognathism and sweating.
• Headache, visual field loss, delayed or arrested puberty, galactorrhoea, glucose intolerance, hypertension and cardiomyopathy.

Red flags.

• Visual loss, severe headache or pituitary apoplexy.
• Infant onset or a family history of pituitary disease (genetic form).

• Age- and sex adjusted IGF-1 raised. Growth hormone not suppressed to under 1 microgram/L (0.4 microgram/L with ultrasensitive assays) during a 75 g oral glucose tolerance test (1.75 g/kg, maximum 75 g, in children).
• Prolactin, thyroid function, gonadal and adrenal axes, and electrolytes.
• MRI of the pituitary, visual fields and acuity, bone age, and echocardiogram.
• Genetic testing (AIP, GPR101, MEN1, GNAS, PRKAR1A, SDHx) and family screening. Calcium and parathyroid hormone if MEN1 is possible.

Differential diagnosis.

• Constitutional or familial tall stature (IGF-1 normal for age).
• Klinefelter syndrome, Marfan syndrome, Sotos syndrome, Beckwith-Wiedemann syndrome and homocystinuria.
• Precocious puberty, hyperthyroidism, aromatase or oestrogen receptor defects.
• Ectopic growth hormone releasing hormone production (rare).

• Transsphenoidal surgery is first line for resectable tumours, in a high volume pituitary centre.
• Medical therapy for residual or unresectable disease: octreotide long acting 20 mg intramuscularly every 4 weeks (range 10 to 40 mg); lanreotide 90 to 120 mg deep subcutaneous every 4 weeks; pasireotide long acting 40 mg intramuscularly every 4 weeks (up to 60 mg); pegvisomant 10 mg subcutaneously daily after a loading dose (40 mg in some labels, 80 mg in others), titrated by 5 mg every 4 to 6 weeks to a maximum of 30 mg daily with liver tests; cabergoline 0.5 to 3 mg weekly as an adjunct or if prolactin is raised.
• Aim for a normal age- and sex adjusted IGF-1 and a random growth hormone under 1 microgram/L.
• Stereotactic radiotherapy for tumour remnant or regrowth. Replace pituitary hormone deficits. Sex steroids to hasten epiphyseal fusion are used only in selected cases by specialists.
• Treat hypertension, diabetes, sleep apnoea and cardiomyopathy.

Special groups. Children and adolescents: manage in a paediatric endocrine team with pubertal staging, bone age and height prediction, and genetic counselling for families.

Monitoring. IGF-1 every 3 months at first, then every 6 to 12 months; MRI at 3 to 6 months after surgery, then yearly; visual fields; pituitary function; glucose and echocardiography.

Referral and escalation. Pituitary multidisciplinary team (endocrinology, neurosurgery, ophthalmology, radiotherapy) at diagnosis; urgent review for visual loss or apoplexy.