Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations.
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.
Vallette-Kasic
Sophie
S
Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, Québec, Canada.
Brue
Thierry
T
Pulichino
Anne-Marie
AM
Gueydan
Magali
M
Barlier
Anne
A
David
Michel
M
Nicolino
Marc
M
Malpuech
Georges
G
Déchelotte
Pierre
P
Deal
Cheri
C
Van Vliet
Guy
G
De Vroede
Monique
M
Riepe
Felix G
FG
Partsch
Carl-Joachim
CJ
Sippell
Wolfgang G
WG
Berberoglu
Merih
M
Atasay
Begüm
B
de Zegher
Francis
F
Beckers
Dominique
D
Kyllo
Jennifer
J
Donohoue
Patricia
P
Fassnacht
Martin
M
Hahner
Stefanie
S
Allolio
Bruno
B
Noordam
C
C
Dunkel
Leo
L
Hero
Matti
M
Pigeon
B
B
Weill
Jacques
J
Yigit
Sevket
S
Brauner
Raja
R
Heinrich
Juan Jorge
JJ
Cummings
Elizabeth
E
Riddell
Christie
C
Enjalbert
Alain
A
Drouin
Jacques
J
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*
D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; C486589:TBX19 protein, human; D014157:Transcription Factors; D000324:Adrenocorticotropic Hormone