title: Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations.
abstract: 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.
authors.affiliation: Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, Québec, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vallette-Kasic
authors.forename: Thierry
authors.initials: T
authors.lastname: Brue
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Pulichino
authors.forename: Magali
authors.initials: M
authors.lastname: Gueydan
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.forename: Michel
authors.initials: M
authors.lastname: David
authors.forename: Marc
authors.initials: M
authors.lastname: Nicolino
authors.forename: Georges
authors.initials: G
authors.lastname: Malpuech
authors.forename: Pierre
authors.initials: P
authors.lastname: Déchelotte
authors.forename: Cheri
authors.initials: C
authors.lastname: Deal
authors.forename: Guy
authors.initials: G
authors.lastname: Van Vliet
authors.forename: Monique
authors.initials: M
authors.lastname: De Vroede
authors.forename: Felix G
authors.initials: FG
authors.lastname: Riepe
authors.forename: Carl-Joachim
authors.initials: CJ
authors.lastname: Partsch
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Sippell
authors.forename: Merih
authors.initials: M
authors.lastname: Berberoglu
authors.forename: Begüm
authors.initials: B
authors.lastname: Atasay
authors.forename: Francis
authors.initials: F
authors.lastname: de Zegher
authors.forename: Dominique
authors.initials: D
authors.lastname: Beckers
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kyllo
authors.forename: Patricia
authors.initials: P
authors.lastname: Donohoue
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hahner
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
authors.forename: C
authors.initials: C
authors.lastname: Noordam
authors.forename: Leo
authors.initials: L
authors.lastname: Dunkel
authors.forename: Matti
authors.initials: M
authors.lastname: Hero
authors.forename: B
authors.initials: B
authors.lastname: Pigeon
authors.forename: Jacques
authors.initials: J
authors.lastname: Weill
authors.forename: Sevket
authors.initials: S
authors.lastname: Yigit
authors.forename: Raja
authors.initials: R
authors.lastname: Brauner
authors.forename: Juan Jorge
authors.initials: JJ
authors.lastname: Heinrich
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cummings
authors.forename: Christie
authors.initials: C
authors.lastname: Riddell
authors.forename: Alain
authors.initials: A
authors.lastname: Enjalbert
authors.forename: Jacques
authors.initials: J
authors.lastname: Drouin
mesh_terms: D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000172:deficiency*; D000328:Adult; D017668:Age of Onset; D002423:Cause of Death; D002648:Child; D005260:Female; D005808:Genes, Recessive; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics* / Q000401:mortality; D008297:Male; D009154:Mutation; D010375:Pedigree; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; C486589:TBX19 protein, human; D014157:Transcription Factors; D000324:Adrenocorticotropic Hormone