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 >2 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 ≥10 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 (r=0.23, P=0.02). 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 >50% of cases.

Keywords: X-linked acrogigantism (X-LAG) syndrome; aryl hydrocarbon receptor interacting protein gene; familial isolated pituitary adenoma (FIPA); gigantism; growth hormone; pituitary adenoma; somatotropinoma.

Figure 1

Schematic representation of treatments used in the management of patients with pituitary gigantism. Numbers in parentheses indicate the number of patients. RadioThx =Radiotherapy, DA =Dopamine agonists, SSA = Somatostatin analogs, PegV = Pegvisomant. *2 patients had primary radiotherapy (1 controlled); 4 recently diagnosed patients awaiting treatment; **Follow up- 168 months [62;235]

Figure 2

Age and Z-scores for height of patients at last follow-up. Of the total population of 208 patients, 57 patients had an absolute height >200 cm at the last measurement (eight are still growing) and the tallest patient was 247 cm. Eleven that were controlled before the end of the liner growth had a height at the last follow-up of <+2SD (seven of these later had disease recurrence).

Figure 3

Genetic results in the study population. Numbers for each sector show the number of patients in the subgroup and its prevalence in the total group. AIP+ = AIP mutation affected; MAS = McCune-Albright Syndrome; X-LAG = X-linked acrogigantism syndrome; MEN1 = Multiple endocrine neoplasia type 1.

Figure 4

Comparisons of characteristics among genetically distinct groups of pituitary gigantism patients (genetically negative, AIP mutation positive (AIP+) and X-linked acrogigantism syndrome (X-LAG)), showing statistically distinct patterns of age at first symptoms (A), age at diagnosis (B) and no inter-group difference in terms of maximal tumor diameter at diagnosis (C). Panel D demonstrates the female and male predominance of X-LAG and AIP+ related gigantism cases; the genetically-negative group was also male-predominant although less markedly so than the AIPmut group.