This Article Full Text Full Text (PDF) All Versions of this Article: 90/3/1323    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vallette-Kasic, S. Articles by Drouin, J. Search for Related Content PubMed PubMed Citation Articles by Vallette-Kasic, S. Articles by Drouin, J. Related Collections Adrenal and Hypertension Pediatric Endocrinology

Congenital Isolated Adrenocorticotropin Deficiency: An Underestimated Cause of Neonatal Death, Explained by TPIT Gene Mutations

Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (S.V.-K., A.-M.P., J.D.), Montréal, Canada H2W 1R7; Laboratoire ICNE, Institut Jean Roche (T.B., M.G., A.B., A.E.), 13916 Marseille, France; Centre Hospitalier Lyon-Sud (M.D., M.N.), 69495 Lyon, France; Hôtel-Dieu (G.M., P.D.), 63058 Clermont-Ferrand, France; Hôpital St. Justine (C.D., G.V.V.), Montréal, Canada H3T 1C5; University Medical Center (M.D.V.), 3508 AB Utrecht, The Netherlands; Department of Pediatric Endocrinology, University Children’s Hospital, Klinikum der Christian Albrechts, University of Kiel (F.G.R., C.-J.P., W.G.S.), D-24105 Kiel, Germany; Departments of Pediatric Endocrinology and Neonatology, Faculty of Medicine, Ankara University (M.B., B.At.), 06100 Ankara, Turkey; University of Leuven (F.d.Z., D.B.), Leuven, B-3000 Belgium; Children’s Hospitals and Clinics (J.K.), St. Paul, Minnesota 55455; University of Iowa Hospitals and Clinics (P.D.), Iowa City, Iowa 52242; University of Wurzburg (M.F., S.H., B.Al.), Wurzburg, 97070 Germany; Department of Metabolic and Endocrine Diseases, University Medical Center Nijmegen (C.N.), 6500 HB Nijmegen, The Netherlands; Department of Pediatrics, University of Kuopio (L.D.), FIN-70211 Kuopio, Finland; University of Helsinki (M.H.), Helsinki, FIN-00014 Finland; Centre Hospitalier (B.P.), 59241 Armentières, France; Hôpital Jeanne de Flandre (J.W.), 59037 Lille, France; Connecticut Children’s Medical Center (S.Y.), Hartford, Connecticut 06106-1914; Hôpital Bicêtre (R.B.), 94270 Paris, France; Hospital de Ninos Dr. Ricardo Gutiérrez (J.J.H.), Buenos Aires, Argentina; and Dalhousie University/IWK Health Center (E.C., C.R.), Halifax, Canada B3H 4J1

Address all correspondence and requests for reprints to: Dr. Jacques Drouin, Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, Québec, Canada H2W 1R7. E-mail: jacques.drouin{at}ircm.qc.ca.

Tpit is a T box transcription factor important for terminal differentiation of pituitary proopiomelanocortin-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 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 of 27 patients. We identified 10 different TPIT mutations, with one mutation found in five 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, suggesting 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.

This article has been cited by other articles:

				P.-L. Lavoie, L. Budry, A. Balsalobre, and J. Drouin Developmental Dependence on NurRE and EboxNeuro for Expression of Pituitary Proopiomelanocortin Mol. Endocrinol., July 1, 2008; 22(7): 1647 - 1657. [Abstract] [Full Text] [PDF]

				S. Vallette-Kasic, C. Couture, A. Balsalobre, Y. Gauthier, L. Metherell, M. Dattani, and J. Drouin The TPIT Gene Mutation M86R Associated with Isolated Adrenocorticotropin Deficiency Interferes with Protein: Protein Interactions J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3991 - 3999. [Abstract] [Full Text] [PDF]

				D. Kelberman and M. T. Dattani Hypothalamic and pituitary development: novel insights into the aetiology Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S3 - S14. [Abstract] [Full Text] [PDF]

				X. Zhu, A. S. Gleiberman, and M. G. Rosenfeld Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks Physiol Rev, July 1, 2007; 87(3): 933 - 963. [Abstract] [Full Text] [PDF]

				R. J. Weil, A. O. Vortmeyer, L. K. Nieman, H. L. DeVroom, J. Wanebo, and E. H. Oldfield Surgical Remission of Pituitary Adenomas Confined to the Neurohypophysis in Cushing's Disease J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2656 - 2664. [Abstract] [Full Text] [PDF]

				N. Weintrob, J. Drouin, S. Vallette-Kasic, E. Taub, D. Marom, Y. Lebenthal, G. Klinger, E. Bron-Harlev, and M. Shohat Low Estriol Levels in the Maternal Triple-Marker Screen as a Predictor of Isolated Adrenocorticotropic Hormone Deficiency Caused by a New Mutation in the TPIT Gene Pediatrics, February 1, 2006; 117(2): e322 - e327. [Abstract] [Full Text] [PDF]