Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients

Abstract

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height O2 S.D. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were R10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (rZ0.23, PZ0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 -X-linked acrogigantism (X-LAG) -occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in O50% of cases.

Resistant Paediatric Somatotropinomas due to <b><i>AIP</i></b> Mutations: Role of Pegvisomant

“…Hypopituitarism is reported in 64% of pituitary gigantism, the gonadal axis being most commonly affected [12], with delayed epiphyseal fusion increasing the time for growth, as in our patients. Epiphyseal fusion was successfully accelerated, with growth truncation in patient 1 who had an estimated final height of 240 cm, by using adult doses of testosterone for aromatization to oestrogen, plus a short course of oestrogen.…”

“…A 2011 a review of paediatric somatotropinomas reported 7 children, of whom 4 showed a clinical and biochemical response [11]. Combined pegvisomant with somatostatin analogues and dopamine agonists in pituitary gigantism has reported control in 53.5% cases [12], as seen in our case. Potential concern with pegvisomant includes the risk of tumour expansion, not seen in our patients.…”

Growth Disturbances in Childhood Cancer Survivors

“…Progressive macrocephaly has also been reported in children and may be the initial symptom, particularly during infancy [88]. Other features include coarsening of facial features, excessive sweating, and acral enlargement [89-91]. Although data is limited in children with GH excess regarding the risk of secondary malignances/cancer, studies in adults suggest that the overall cancer incidence in adults with acromegaly is not increased [92, 93].…”

“…GH-secreting adenomas may be more aggressive and invasive than in adults [88, 94-97], have cosecretion of prolactin, and be associated with other pituitary hormone deficiencies in up to 25% of cases [91, 98-100], and they can be sporadic or associated with certain conditions including Carney complex, McCune Albright syndrome, MEN-1 syndrome, MEN-4 syndrome, and 3P association [101-104]. …”

The role of AIP mutations in pituitary adenomas: 10 years on

“…Patients with sporadic pituitary macroadenomas that occur during childhood/adolescence and early adulthood also should be considered to be at risk for an AIP mutation (12-20%). The young age at onset and the propensity for causing somatotropinomas means that AIP mutations are strongly associated with pituitary gigantism and represent the single most frequent genetic cause of pituitary gigantism [13]. The study by Ramírez-Rentería et al confirms that AIP mutations explain a small minority (7%) of sporadic acromegaly patients and that these patients exhibit aggressive features and an earlier age at onset than non-mutated cases.…”