Successful treatment of pituitary gigantism

Abstract

Pituitary gigantism is extremely rare, resulting from excessive secretion of growth hormone (GH) before fusion of epiphysial growth plates. We report a case of a 13-year-old boy, who presented with increased statural growth and headaches since the age of 10 years. On physical examination, his height was 180.7 cm (+3.3 SD) and Tanner stage V. Investigation revealed increased levels of serum age-adjusted and sex-adjusted insulin-like growth factor 1 (IGF-1) and failure of GH suppression during an oral glucose tolerance test (OGTT). MRI of the sellar region revealed a pituitary macroadenoma. He underwent transsphenoidal surgery and histopathological evaluation revealed mammosomatotropic adenoma. Three months after surgery, IGF-1 normalised, nadir GH during OGTT was less than 1 ng/mL and no residual tumour was found on the MRI. Genetic testing identified a mutation in the AIP gene. This case emphasises the importance of early diagnosis of gigantism, as treatment delay increases long-term morbidity.

Background

Pituitary gigantism is extremely rare, with an estimated incidence of three cases per 1 million persons and only several hundred reported cases thus far.^{1 2} Pituitary gigantism is caused by an excess of growth hormone (GH) secretion that occurs before fusion of the epiphysial growth plates, resulting in excessive linear growth.³ Most cases are sporadic, however, it may occur as part of a hereditary syndrome such as multiple endocrine neoplasia types 1 (MEN 1, MEN 1 gene) and 4 (MEN 4, CDKN1B gene), familial isolated pituitary adenoma (AIP gene), X-linked acrogigantism (GPR101 gene), McCune-Albright syndrome (GNAS gene) and Carney complex (PRKAR1A gene).¹ Gigantism may be caused by a primary pituitary GH hypersecretion, hypothalamic dysregulation with GH-releasing hormone (GHRH) hypersecretion or rarely by an ectopic source of GHRH from a pancreatic neuroendocrine tumour.^{3 4} GH-secreting pituitary adenomas, mainly macroadenomas (90%), represents the most frequent cause of gigantism.¹ Gigantism presents a male preponderance, with a median age of diagnosis about 14 years.¹ Currently, transsphenoidal surgery remains the treatment of choice for gigantism caused by a pituitary adenoma and may be curative.² Despite that, the recurrence rate after surgery is elevated, reaching approximately 40% of patients, and the risk of postsurgical hypopituitarism is also increased in these children.⁵ We report a case of a successfully treated gigantism caused by a GH-secreting pituitary macroadenoma on a patient with AIP mutation.

Case presentation

A 13-year-old boy with tall stature presented at our endocrinology department. Since the age of 8 years, he demonstrated increased height velocity and started to cross height percentiles and remained above the 97th percentile (figure 1). The patient also complained of frontal headaches for 2 years and denied visual defects. On examination, his height was 180.8 cm (+3.3 SD), weight was 57 kg (body mass index of 17.4 kg/m²) and blood pressure was 110/60 mm Hg. He displayed coarse facial features with frontal bossing and mild prognathism, large hands and feet. The palpation of the thyroid gland was normal. His pubertal status was compatible with Tanner stage V (testicular volume 20 mL). From the medical history, he was born full-term by caesarean section, with an appropriate weight for gestational age. The Apgar scores (Appearance, Pulse, Grimace, Activity, and Respiration) were 9 at 1 min and 10 at 5 min. Gestation was uncomplicated. The mid-parental height was 178.5 cm and the family history was unremarkable.

Figure 1.

Growth chart.

Investigations

Baseline pituitary investigation (table 1) showed increased levels of serum insulin-like growth factor 1 (IGF-1) (587.56 ng/mL, reference range: 74–450 ng/mL for his age and sex), random GH 11.3 ng/mL (reference range: 0.12–8.1), hyperprolactinaemia (35.1 ng/mL, reference range: 4.4–19 ng/mL), central hypothyroidism with thyroid-stimulating hormone (TSH) 2.3 µUI/mL (reference range: 0.51–4.30 µUI/mL) and fT4 6.96 pmol/L (reference range: 12.6–21 pmol), 09:00 hours cortisol of 10.3 µg/dL (reference range: 6.2–12.5 µg/dL), total testosterone 238 ng/dL (reference range: 105–545 ng/dL), follicle-stimulating hormone (FSH) 3.49 U/L (reference range: 1.5–8.6), luteinizing hormone (LH) 1.64 U/L (reference range: 1.7–8.6). His corrected calcium was normal at 2.45 mmol/L (2.2–2.6 mmol/L) with a normal parathyroid hormone (PTH) of 27.8 pg/mL (15–65) and normal phosphate of 3.1 mg/dL (2.5–4.5). He performed an oral glucose tolerance test (OGTT) demonstrating a failure of GH suppression, with a GH nadir of 8.1 ng/mL (table 2). MRI of the sellar region showed a pituitary macroadenoma, measuring 13×12×13.5 mm, without signs of cavernous sinus invasion, suprasellar extension or optic chiasm compression (figure 2). Goldmann visual field tests were normal. Bone age was coincident with his chronological age according to the Greulich and Pyle atlas.

Table 1.

Laboratory evaluation at diagnosis

Parameters	Result	Reference range
IGF-1 (ng/mL)	587.56	74–450
GH (ng/mL)	11.3	0.12–8.1
Prolactin (ng/mL)	35.1	4.4–19
TSH (µUI/mL)	2.3	0.51–4.30
fT4 (pmol/L)	6.96	12.6–21
Cortisol 09:00 hours (µg/dL)	10.3	6.2–12.5
Total testosterone (ng/dL)	238	105–545
FSH (U/L)	3.49	1.5–8.6
LH (U/L)	1.64	1.7–8.6
PTH (pg/mL)	27.8	15–65
Corrected calcium (mmol/L)	2.45	2.2–2.6
Total calcium (mg/dL)	10.1	8.4–10.2
Phosphate (mg/dL)	3.1	2.5–4.5

FSH, follicle-stimulating hormone; fT4, free thyroxine; GH, growth hormone; IGF-1, insulin-like growth factor 1; LH, luteinizing hormone; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone.

Table 2.

Oral glucose tolerance test at diagnosis

Time (min)	GH (ng/mL)	Glucose (mg/dL)
0	11.30	77
30	10.40	139
60	9.36	94
90	8.10	95

Figure 2.

MRI of the sellar region revealed a pituitary macroadenoma.

Treatment

A diagnosis of pituitary gigantism due to GH-secreting pituitary macroadenoma and associated central hypothyroidism was made. Treatment with levothyroxine was initiated and the patient underwent transsphenoidal surgery with excision of the pituitary macroadenoma, without complications. Histopathology revealed mammosomatotroph adenoma with a Ki-67 index of <1%.

Outcome and follow-up

Three months after surgery, he presented normalisation of IGF-1 levels, GH nadir during OGTT was <1 ng/mL and no residual tumour was found on the MRI. Recovery of central hypothyroidism was also observed after surgery, and the patient is currently euthyroid without levothyroxine supplementation. Genetic testing identified a mutation in the AIP gene. He remains in remission 7 years after surgery with serum IGF-1 of 308 µg/L (reference range for his age 93–449), nadir GH level <1 ng/mL during OGTT, and his height was 189.5 cm at the age of 20 years.

Discussion

Pituitary gigantism is an extremely rare and challenging disease, resulting from GH oversecretion before fusion of epiphysial growth plates.⁶ In contrast, acromegaly develops when the GH excess occurs after epiphysial closure, in adulthood.³ Pituitary gigantism classically presents with linear growth acceleration resulting in tall stature, coarsening of facial features including prognathism, frontal bossing and enlargement of hands and feet.³ Gigantism clinical picture may also include symptoms related to tumour mass effects such as headaches, visual defects and signs of hypopituitarism. Mild to moderate obesity can also be observed in these patients.² Tall stature is defined as height above 97th percentile for age and sex or 2 SD above the mean for a defined population.¹ Familial tall stature is the most frequent cause of tall stature, followed by obesity.¹ The differential diagnosis of tall stature should include endocrine causes namely hyperthyroidism, GH excess, precocious puberty and numerous non-endocrine aetiologies such as Klinefelter syndrome, homocystinuria, among others.⁷ GH-secreting pituitary adenomas (somatotropinomas) represent the most frequent cause of gigantism and are mostly macroadenomas (90%).^8–10 Gigantism demonstrates a male preponderance, with a median age of symptoms onset about 8 years.^{1 11}

Gigantism investigation includes an initial screening with measurement of IGF-1 levels.¹² IGF-1 provides a sensitive marker of GH peripheral bioactivity and exhibit a log-linear relationship with GH concentrations.^{3 12} IGF-1 concentrations remained constant throughout the day, unlike GH levels, which varies extensively, widely due to pulsatile GH secretion.¹² Insulin-like growth factor-binding protein-3, the major binding protein of IGF-1, can also be an independent marker of GH excess.⁹ The gold standard for gigantism diagnosis is demonstrating a lack of suppression of GH to <1 ng/dL during OGTT.¹² Hyperprolactinaemia, like observed in our patient, is a frequent finding in gigantism (50%), as mammosomatotroph adenoma is the most frequent histological subtype. Hyperprolactinaemia can also result from pituitary stalk compression.⁹ Evaluation of serum GHRH can be valuable in differentiating ectopic GHRH excess from other causes of gigantism.^{3 4}

After biochemical confirmation of gigantism, MRI of the sellar region should be performed to evaluate tumour size, location and invasiveness grade.¹² Somatotropinomas in paediatric patients are more likely to be aggressive than those in adults, with a higher grade of invasive growth and multiple recurrences.^{13 14}

Somatotropinomas in patients with AIP mutations are usually associated with a higher grade of aggressiveness, including younger age at onset, larger tumour size, more frequently invasive and less responsive to somatostatin analogues.¹² Therefore, multimodal therapy is often necessary and considering the pituitary gigantism rarity, these patients should be discussed in multidisciplinary meetings involving endocrinology, neurosurgery, radiotherapy and neuroradiology.¹ Currently, transsphenoidal surgery is considered the first-line treatment for gigantism caused by a pituitary adenoma and it can be curative.¹² The treatment goals are excision of the pituitary tumour, preserve pituitary function, restore GH physiological secretory pattern, normalise IGF-1 levels and improve long-term morbidity.⁹ However, surgery is associated with a risk of hypopituitarism, which appears to be greater in children than in adults, with potentially deleterious complications concerning puberty and fertility.^{1 13 14} Barzaghi et al reported a recurrence rate of pituitary gigantism after surgery of approximately 40%. In this study, most paediatric somatotropinomas undergoing surgery were macroadenomas (88.9%) and 11.1% microadenoma. The risk of recurrence was higher in macroadenoma than in microadenoma.⁵ The postsurgical remission rates appeared to be higher in patients with acromegaly compared with those with gigantism (61% vs 55.6%).⁵ Medical therapy, usually with somatostatin analogues (SSAs), is indicated in case of persistent or recurrent disease after surgery and when surgery is not feasible (eg, extensive cavernous sinus invasion, without optic chiasm compression) or contraindicated.¹² SSAs are highly effective in gigantism treatment and despite limited experience with long-acting formulations in gigantism (lanreotide and octreotide), preliminary studies suggest consistent GH and IGF-1 suppression in paediatric patients.^{12 15} Pegvisomant, a GH receptor competitive antagonist, appeared to be an effective therapy in patients resistant to SSAs in controlling growth velocity and other complications of gigantism.^{12 16–18} Dopamine agonists may also be used as adjuvant therapy for uncontrolled patients with SSA, especially if the GH and IGF-1 levels are slightly elevated.¹² Radiotherapy, preferably stereotactic radiotherapy, is seen as third-line treatment because of the elevated risk of complications, namely panhypopituitarism, and its delayed efficacy.⁸ Early detection of gigantism is essential for a good outcome, as prolonged exposure to GH excess may lead to significant morbidity, persistent growth and excessive final adult height.³ In conclusion, we report a successfully treated case of pituitary gigantism caused by a GH-secreting pituitary macroadenoma, in which the patient remains in remission 7 years after surgery.

Learning points.

• Pituitary gigantism is extremely rare, resulting from growth hormone (GH) oversecretion before fusion of epiphysial growth plates.

• GH-secreting pituitary adenoma is the most frequent cause of gigantism.

• Paediatric somatotropinomas are frequently large, invasive and often associated with plurihormonal secretion, especially prolactin hypersecretion.

• Pituitary gigantism is associated with a higher risk of recurrence after transsphenoidal surgery and hypopituitarism comparing to patients with acromegaly.

• Early diagnosis and effective treatment are crucial for gigantism management, as prolonged exposure to GH excess may lead to significant morbidity, with persistent growth and excessive final adult height.

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