OR20-6 Gigantism: Results of an International Clinical and Genetic Study

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR20-Genetics of Growth
Bench to Bedside
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:30 PM
Room 122 (Moscone Center)
Liliya Rostomyan*1, Adrian F Daly1, Anurag Lila2, Anne-Lise Lecoq3, Emil Nachev4, Andreas Moraitis5, Luciana Ansaneli Naves6, Dianne Kranenburg7, Ian MacMurray Holdaway8, Silvia Filipponi9, Caroline Jung-Sievers10, Mona Sahnoun-Fathallah11, Marja Ojaniemi12, Ekaterina Sorkina13, Maria Tichomirowa1, Irena Ilovaiskaya14, Margaret Zacharin15, Jerome Yves Bertherat16, Elena Malchiodi17, Roberto Salvatori18, Sandrine Laboureau-Soares Barbosa19, Dominique M Maiter20, Ann I McCormack21, Klaus Von Werder22, Jacob Dal23, Elena Nazzari24, Renata Simona Auriemma25, Daniel L Metzger26, Jens Otto Jorgensen23, Tapani Ebeling12, Diego Ferone24, Gunter Karl Stalla10, Paolo Beck-Peccoz17, Lauri Aaltonen27, Annamaria Colao25, Vyacheslav Pronin13, Anne Barlier28, Thierry Brue*11, Vincent Rohmer19, Satinath Mukhopadhyay29, Francoise Borson-Chazot30, Sebastian JCMM Neggers7, Marie-Lise Jaffrain-Rea31, Constantine A Stratakis32, Philippe Chanson3, Sabina Zacharieva4, Patrick Petrossians1, Nalini Shah2 and Albert Beckers1
1CHU de Liège-University of Liège, Liège, Belgium, 2KEM Hospital, Mumbai, India, 3Hosp Bicetre, Le Kremlin-Bicetre, Paris, France, 4Medical University, Sofia, Bulgaria, 5NICHD/NIH, Bethesda, MD, 6University of Brasilia, Brasilia, Brazil, 7Erasmus MC, Netherlands, 8Greenlane Clinical Centre, Auckland, New Zealand, 9University of L’Aquila, L’Aquila & Pozzilli, Italy, 10Max-Planck Institute for Psychiatry, Munich, Germany, 11Hopital de la Timone, Marseille, France, 12University of Oulu, Oulu, Finland, 13I.M. Sechenov First Moscow State Medical University, Moscow, Russia, 14Moscow Regional Research & Clinical Institute named by MF Vladimirsky, Moscow, Russia, 15Royal Children's Hospital, University of Melbourne, Parkville, Australia, 16Hopital Cochin, Paris, France, 17IRCCS Cà Granda H Maggiore Policlinico, Milan, Italy, 18Johns Hopkins Univ Sch of Med, Baltimore, MD, 19CHU d'Angers, Angers, France, 20Univ of Louvain, Brussels, Belgium, 21St. Vincent Hospital, Naremburn - NSW, Australia, 22Schlosspark Klinik, Fischbachau, Germany, 23NBG/THG, Aarhus University Hospital, Aarhus, Denmark, 24Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy, 25Federico II Univ of Naples, Naples, Italy, 26BC Children's Hospital, Vancouver, BC, Canada, 27Biomedicum Helsinki, University of Helsinki, Helsinki, Finland, 28Faculte de Med Nord, Marseille, France, 29Institute of Postgraduate Medical Education & Research, Calcutta, India, 30Universite de Lyon, Bron Cedex, France, 31University of L’Aquila & Neuromed, L'Aquila & Pozzilli, Italy, 32National Institutes of Health (NIH), Bethesda, MD
Introduction: Despite being a classical growth disorder, gigantism has not been studied previously in a standardized way.

Aim: To characterize comprehensively a large series of patients (pts) with pituitary gigantism. Standard case report forms were used with height assessments related to local country norms.

Results: 199 pts were recruited and 158 (129 male) had GH-excess and abnormal growth velocity for age or final height > 2SD over local norms  Median age at diagnosis was significantly lower in females vs. males (16.5yr vs. [10.5;26.5] 23yr [19;29], p=0.006). Median delay in diagnosis was 5yr [2;10]. 96% had acromegalic changes at time of diagnosis. Macroadenomas occurred in 84% with extrasellar extension in 77% and invasion in 54%. >3 distinct treatment types were used in 40% of cases; in these only 43% had disease control. Hypopituitarism rose from 24% at baseline to 69% at last follow-up. 134 patients had stopped growing at age of 20yr. The difference from calculated target height was greater in those with control of GH-excess after 20 yr of age than before 20 yr of age (10.9% over MPH [8.4;15] vs 7.9% over MPH [5.9;10.3], p=0.012). Genetic/inherited features were seen in 34% at presentation and included syndromes like FIPA, McCune-Albright, Carney complex, and familial pituitary hyperplasia. Germline mutations in the AIP gene (AIPmut) were found in 52.9% (27/52) of those tested.  There were no differences between AIPmut positve and negative pts with gigantism regarding tumor size. AIPmut positive pts had a significantly younger age at first symptoms (p=0.02) and diagnosis (p=0.047) than AIPmut negative pts. Median height Z-scores were +3.5SD [2.7;4.7] and +3SD [2.5;4.3] in AIPmut positive and negative groups, respectively. At last follow-up in the height Z-scores of AIPmut positive pts was positively correlated with age at diagnosis (r=0.31, p=0.048).  While median follow up did not differ between the groups (7.4yrs. [2;16] vs. 8yrs [4;17], p=0.4), disease control was more frequent in the AIPmut negative group (p=0.039) despite less use of multimodal treatment in AIPmut negative pts.

Conclusions: Pituitary gigantism pts have characteristic features of male predominance and larger tumors that are difficult to control. Treatment delay may increase the harm from GH-excess, particularly on excess stature. Syndromic or genetic features occurred in 1/3 of pts; AIPmut are common. Improved recognition and early diagnosis may help to decrease excessive height.

Nothing to Disclose: LR, AFD, AL, ALL, EN, AM, LAN, DK, IMH, SF, CJ, MS, MO, ES, MT, II, MZ, JYB, EM, RS, SL, DMM, AIM, KV, JD, EN, RSA, DLM, JOJ, TE, DF, GKS, PB, LA, AC, VP, AB, TB, VR, SM, FB, SJN, MLJ, CAS, PC, SZ, PP, NS, AB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Fonds d'Investissment pour la Recherche Scientifique (FIRS) du Centre Hospitalier Universitaire de Liège
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