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This version published online on December 21, 2004
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1300
A more recent version of this article appeared on March 1, 2005
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Submitted on July 5, 2004
Accepted on November 23, 2004

CONGENITAL ISOLATED ACTH DEFICIENCY, AN UNDERESTIMATED CAUSE OF NEONATAL DEATH, EXPLAINED BY TPIT MUTATIONS

Sophie Vallette-Kasic, Thierry Brue, Anne-Marie Pulichino, Magali Gueydan, Anne Barlier, Michel David, Marc Nicolino, Georges Malpuech, Pierre Déchelotte, Cheri Deal, Guy Van Vliet, Monique De Vroede, Felix G. Riepe, Carl-Joachim Partsch, Wolfgang G. Sippell, Merih Berberoglu, Begüm Atasay, Francis de Zegher, Dominique Beckers, Jennifer Kyllo, Patricia Donohoue, Martin Fassnacht, Stefanie Hahner, Bruno Allolio, C. Noordam, Leo Dunkel, Matti Hero, B. Pigeon, Jacques Weill, Sevket Yigit, Raja Brauner, Juan Jorge Heinrich, Elizabeth Cummings, Christie Riddell, Alain Enjalbert, and Jacques Drouin*

Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal, CANADA; Laboratoire ICNE, Institut Jean-Roche, Marseille FRANCE; Centre Hospitalier Lyon-Sud, Lyon FRANCE; Hôtel-Dieu, Clermont-Ferrand FRANCE; Hôpital St-Justine, Montréal CANADA; University Medical Centre, Utrecht THE NETHERLANDS; Pediatric Endocrinology, University Children's Hospital, Klinikum der Christian-Albrechts, University of Kiel, GERMANY; Ankara University, Faculty of Medicine, Departments of Pediatric Endocrinology and Neonatology, Ankara TURKEY; University of Leuven, Leuven BELGIUM; Children's Hospitals and Clinics, St-Paul Minnesota USA; University of Iowa Hospitals and Clinics, Iowa City USA; University of Wurzburg, Wurzburg GERMANY; Department of Metabolic and Endocrine Diseases, Nijmegen THE NETHERLANDS; Department of Pediatrics, University of Kuopio, FINLAND; University of Helsinki, Helsinki FINLAND; Centre Hospitalier, Armentières FRANCE; Hôpital Jeanne de Flandre, Lille FRANCE; Connecticut Children's Medical Center, Hartford USA; Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris, FRANCE; Hospital de Ninos "Dr Ricardo Gutiérrez", Buenos Aires ARGENTINA; Dalhousie University / IWK Health Center, Halifax CANADA

* To whom correspondence should be addressed. E-mail: jacques.drouin{at}ircm.qc.ca.

Tpit is a T-box transcription factor important for terminal differentiation of pituitary POMC-expressing cells. We demonstrated that human and mouse mutations of the Tpit gene cause a neonatal onset form of congenital isolated ACTH deficiency (IAD). In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency. This clinical entity was not previously well characterized because of the small number of published cases. Since the identification of the first TPIT mutations, we have enlarged our series of neonatal IAD patients to 27 patients from 21 unrelated families. We found TPIT mutations in 17/27 patients. We identified 10 different TPIT mutations with one mutation found in 5 unrelated families. All patients appeared to be homozygous or compound heterozygous for TPIT mutations and their unaffected parents are heterozygous carriers, confirming a recessive mode of transmission. We compared the clinical and biological phenotype of the 17 IAD patients carrying a TPIT mutation with the 10 IAD patients with normal TPIT coding sequences. This series of neonatal IAD patients revealed a highly homogeneous clinical presentation and suggested that this disease may be an underestimated cause of neonatal death. Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy.
Key words: Tbx19 • ACTH deficiency • hypocortisolism • secondary adrenal insufficiency




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