Significant Benefits of AIP Testing and Clinical Screening in Familial Isolated and Young-onset Pituitary Tumors
Authors: Marques Pedro , Caimari Francisca , Hernández-Ramírez Laura C , Collier David , Iacovazzo Donato , Ronaldson Amy , Magid Kesson , Lim Chung Thong , Stals Karen , Ellard Sian , Grossman Ashley B , Korbonits Márta ,   FIPA Consortium, Abraham Prakash , Aflorei Elena , Agha Amar , Ahlquist James , Akker Scott A , Alexandraki Krystallenia , Alföldi Sándor , Anselmo João , Arlt Wiebke , Atkinson Brew , Aulinas-Masó Anna , Aylwin Simon J , Baborie Atik , Backeljauw Philippe F , Badiu Corin , Baldeweg Stephanie , Ball Steve , Bano Gul , Barkan Ariel , Barton John , Barwell Julian , Bates Peter , Bernal-González Carmen , Besser Michael , Bevan John S , Bickerton Alex , Blair Jo , Bolanowski Marek , Bouloux Pierre , Bradley Lisa , Bradley Karin , Brain Caroline , Brooke Antonia , Brown Roger , Buchfelder Michael , Burren Christine , Cakir Mehtap , Canham Natalie , Capraro Joel , Carroll Paul , Carter Philippa , Carty David , Cavlan Dominic , Chahal Harvinder S , Cheetham Tim , Chentli Farida , Choong Catherine , Christ-Crain Mirjam , Chung Teng-Teng , Clayton Peter , Clayton Richard N , Cohen Mark , Courtney Hamish , Cove David , Crowne Elizabeth , Cuthbertson Daniel , Dal Jacob , Dalantaeva Nadezhda , Damjanovic Svetozar , Daousi Christina , Darzy Ken , Dattani Mehul , Davies Michaela , Davies Justin , Davis Julian , de Castro Margaret , de Marinis Laura , Deal Cheri , Dénes Judit , Dimitri Paul , Dorward Neil , Dow Graham , Drake William , Druce Maralyn , Drummond Juliana , Dutta Pinaki , Dzeranova Larisa , Edén-Engström Britt , Eeles Rosalind , Elfving Maria , Ellis Kate , Elston Marianne , Emmerson Louise , Ezzat Shereen , Fersht Naomi , Fica Simona , Fischli Stefan , Fleseriu Maria , Forsythe Elizabeth , Foulkes William , Freda Pamela , Friedman Theodore , Gadelha Mónica , Gainsborough Mary , Gallacher Stephen , Gallego Patricia , Gan Hoong-Wei , Georgescu Carmen , Gevers Evelien , Gilkes Catherine , Glynn Nigel , Goldman James E , Goldstone Anthony P , Góth Miklós , Green Andrew , Greenhalgh Lynn , Grieve Joan , Griz Luiz , Guitelman Mirtha , Gürlek Alper , Gurnell Mark , Hamblin Peter Shane , Hana Vaclav , Harding Philip , Hay Eleanor , Hilton David A , Ho Winnie , Hong Greg , Horváth Katalin , Howell Simon , Howlett Trevor A , Höybye Charlotte , Hunter Steven , Idampitiya Chandi , Igaz Péter , Imran Ali , Inder Warrick J , Iwata Takeo , Izatt Louise , Jagadeesh Sujatha , Johnston Colin , Jose Biju , Kaltsas Gregory , Kaplan Felicity , Karavitaki Niki , Kastelan Darko , Katz Michelle , Kearney Tara , Kershaw Melanie , Khoo Bernard , Kiraly-Borri Cathy , Knispelis Robertas , Kovács Gábor L , Kumar Anand , Kumar Ajith V , Kun Imre Zoltan , Kyriaku Angelos , Lambrescu Ioana , Lampe Anne Katrin , Laws Edward R , Lebek-Szatanska Agnieszka , Lechan Ronald M , Leese Graham , Levy Andrew , Levy Miles J , Lewandowski Krzysztof , Lin Eleanor , Lo Janet , Lyons Catherine , Maartens Niki , Maghnie Mohamad , Makaya Taffy , Marcus Hani , Niedziela Marek , Martin Niamh , Matsuno Akira , McGowan Barbara , McQuaid Siobhán E , Medic-Stojanoska Milica , Mendoza Nigel , Mercado-Atri Moisés , Mettananda Sachith , Mezősi Emese , Miljic Dragana , Miller Karen K , Modenesi Silvia , Molitch Mark E , Monson John , Morris Damian G , Morrison Patrick J , Mosterman Barbara , Munir Alia , Murray Robert D , Musat Madalina , Musolino Nina , Nachtigall Lisa , Nagi Dinesh , Nair Ramesh , Nelson Richard , Newell-Price John , Nikookam Khash , Ogilivie Arla , Orme Steve M , O´Weickert Martin , Pal Aparna , Pascanu Ionela , Patócs Attila , Patterson Catherine , Pearce Simon H , Pecori Giraldi Francesca , Penney Lynette , Perez-Rivas Luis Gustavo , Pfeifer Marija , Pirie Fraser , Poplawski Nicola , Popovic Vera , Powell Michael , Pullan Peter , Quinton Richard , Radian Serban , Randeva Harpal , Reddy Narendra , Rees Aled , Renals Valerie , de Oliveira António Ribeiro , Richardson Tristan , Rodd Celia , Ross Richard J M , Roncaroli Federico , Ryan Fiona , Salvatori Roberto , Schöfl Christof , Shears Debbie , Shotliff Kevin , Skelly Robert , Snape Katie , Soares Beatriz S , Somasundaram Noel , Spada Anna , Sperber James , Spoudeas Helen , Stelmachowska-Banas Maria , Stewart Susan , Storr Helen L , Strasburger Christian , Street Maria Elisabeth , Suter-Widmer Isabelle , Suthers Graeme , Swords Francesca , Syro Luis V , Swantje Brede , Sze Candy , Taylor Juliet , Thakker Rajesh V , Tham Elaine , Thompson Chris , Thorner Michael O , Tóth Miklós , Trainer Peter J , Tsagarakis Stylianos , Twine Gina , Tzanela Marinella , Vadasz Janos , Vaidya Bijay , Vaks Vladimir , Vance Mary Lee , Verkauskiene Rasa , Von Esch Hilde , Wass John A , Waterhouse Mona , Webb Susan , Weber Astrid , Wernig Florian , Widell Hakan , Yamada Shozo , Yap Patrick , Yarman Sema , Yeoh Philip , Yoshimoto Katsuhiko , Yuen Kevin , Zammitt Nicola N 
Published: January 2020

Abstract

Context
Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).

Objective
To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.

Design
12-year prospective, observational study.

Participants & Setting
We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.

Interventions & Outcome
AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).

Results
Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).

Conclusions
Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.