Endocrine late effects of cancer treatment — formative SAQs

SAQ 1 (10 marks)

An 8-year-old boy was treated for a medulloblastoma at age 5 with surgical resection, craniospinal radiation (36 Gy to the craniospinal axis with a posterior fossa boost) and adjuvant chemotherapy. Eighteen months later his growth velocity has fallen to 3 cm/year, his height has crossed two centile lines downward, and his bone age is delayed by two years. His IGF-1 is low for age. [1] [3]

a) State the most likely endocrine diagnosis, justify it from the growth and biochemical findings, and name the exposure and dose threshold responsible. (3 marks) [1] [2]

b) Outline the next investigations, including the confirmatory test, the full pituitary axis panel, and the imaging that must precede any growth hormone therapy. (4 marks) [2] [6]

c) Describe the definitive management: the drug, the route and timing, and the single most important prerequisite before starting it. Then outline the broader surveillance plan for this survivor. (3 marks) [1] [2]

Answer

a) Growth hormone deficiency after cranial irradiation. The growth velocity of 3 cm/year is subnormal for age, the height is crossing centiles downward, the bone age is delayed, and the IGF-1 is low — the auxological and biochemical signature of growth hormone deficiency, which is the earliest and most common endocrine late effect of cranial radiation, with a dose-dependent threshold near 18 Gy and near-universal occurrence at the 36 Gy cranial dose this survivor received. [1] [2]

b) A growth hormone stimulation test (clonidine or arginine; glucagon) with a peak growth hormone below the age-appropriate cutoff confirming deficiency; a full pituitary axis panel — morning cortisol with a dynamic test (low-dose cosyntropin or insulin tolerance) for ACTH deficiency, TSH and free thyroxine for central hypothyroidism, gonadotropins and sex steroids — because the dose hierarchy means the other axes are also at risk; and a pituitary magnetic resonance imaging scan to exclude tumour recurrence, which must be obtained before any recombinant growth hormone is started because growth hormone is a mitogen. [2] [6]

c) Recombinant human growth hormone, subcutaneous once daily at bedtime, titrated to the IGF-1 in the age-appropriate range. The single most important prerequisite is a stable magnetic resonance imaging scan excluding tumour recurrence — never give growth hormone into an unimaged sella. The broader surveillance plan adds an annual morning cortisol, TSH and free thyroxine, gonadotropins at the expected age of puberty, a metabolic panel and bone density scan, and lifelong follow-up in the long-term follow-up programme. [1] [2]

SAQ 2 (10 marks)

A 12-year-old girl treated for acute lymphoblastic leukaemia at age 6 with chemotherapy and 18 Gy cranial radiation for central nervous system prophylaxis now presents with early breast development at age 9 that has progressed rapidly, with a bone age advanced by three years. Her growth velocity is above the 97th centile. [1] [3]

a) State the diagnosis and explain why a gonadotropin disturbance after cranial radiation can present as precocious puberty rather than deficiency. (3 marks) [1] [2]

b) Outline the investigations that confirm the diagnosis and exclude other causes, and explain the threat to final height. (3 marks) [2]

c) Describe the definitive management and the counselling the family needs regarding final height and ongoing surveillance. (4 marks) [1] [9]

Answer

a) Paradoxical central precocious puberty after lower-dose cranial radiation. At cranial doses between roughly 18 and 24 Gy, the radiation disinhibits the hypothalamic gonadotropin-releasing-hormone pulse generator before the gonadotroph neurones are destroyed, triggering early activation of the gonadotropin axis. At higher doses (24 to 30 Gy and above) the same axis is destroyed, producing gonadotropin deficiency — so the same exposure can produce opposite gonadal phenotypes depending on the dose and the timing. [1] [2]

b) A gonadotropin-releasing-hormone stimulation test shows a pubertal luteinising hormone response confirming central activation; pelvic ultrasound shows oestrogen-stimulated uterine and ovarian enlargement; the bone age is advanced by three years, and the rapid progression with accelerated bone-age maturation threatens a premature growth-plate fusion and a final adult height well below the genetic potential. Other causes of precocious puberty are excluded by the history of cranial radiation and the absence of an adrenal or ovarian mass on imaging. [2]

c) A gonadotropin-releasing-hormone analogue (leuprorelin or goserelin) is given to halt the gonadotropin drive, arrest the bone-age advancement, and preserve final height. The family is counselled that the therapy will halt pubertal progression, that the final height outlook depends on the degree of bone-age advancement already present, and that ongoing surveillance of the growth, thyroid, adrenal and gonadal axes is lifelong because further endocrine late effects will accumulate. The early breast development is explained as a recognised and treatable consequence of the cranial radiation, not a recurrence. [1] [9]