Abstract
Introduction:GATA6 is a gene that encodes a transcription factor with a key role in the development of several organ systems, including the development of the pancreas. It is associated with neonatal diabetes but also with other extra-pancreatic anomalies. Case Presentation: This report describes the association of tracheoesophageal fistula (TEF), pulmonary vein stenosis (PVS), and neonatal diabetes caused by a novel mutation of the GATA6 gene in a small for gestational-age male neonate born at 32 weeks of gestation. Next-generation sequencing revealed the novel heterozygous variant c.1502C>G in the GATA6 gene, which determines the introduction of the premature stop codon p.Ser501Ter at the protein level. This de novo nonsense variant was not detected in the analyzed parental DNA samples and has not been previously described in the literature. At about 2 months of life, a PVS was suspected. The PVS progressively increased with the development of an intramural component, resulting in severe postcapillary pulmonary hypertension. The child died at about 4 months of life. Conclusion: TEF can be associated with GATA6 variants. In the case of neonatal diabetes and TEF, neonatologists should be aware of this association and should also investigate the child for complex congenital heart disorders, such as in our case, with a cardiac computed tomography.
References
1.
Iafusco
D
, Massa
O
, Pasquino
B
, Colombo
C
, Iughetti
L
, Bizzarri
C
, et al. Minimal incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births
. Acta Diabetol
. 2012
;49
(5
):405
–8
. 2.
Rubio-Cabezas
O
, Hattersley
AT
, Njølstad
PR
, Mlynarski
W
, Ellard
S
, White
N
, et al. The diagnosis and management of monogenic diabetes in children and adolescents
. Pediatric Diabetes
. 2014
;15
(S20
):47
–64
. 3.
Greeley
SAW
, Polak
M
, Njølstad
PR
, Barbetti
F
, Williams
R
, Castano
L
, et al. ISPAD Clinical Practice Consensus Guidelines 2022: the diagnosis and management of monogenic diabetes in children and adolescents
. Pediatr Diabetes
. 2022
;23
(8
):1188
–211
. 4.
De Franco
E
, Flanagan
SE
, Houghton
JA
, Lango Allen
H
, Mackay
DJ
, Temple
IK
, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study
. Lancet
. 2015
;386
(9997
):957
–63
. 5.
Mitra
S
, McNamara
PJ
. Patent ductus arteriosus–time for a definitive trial
. Clin Perinatol
. 2020
;47
(3
):617
–39
. 6.
Richards
S
, Aziz
N
, Bale
S
, Bick
D
, Das
S
, Gastier-Foster
J
, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology
. Genet Med
. 2015
;17
(5
):405
–24
. 7.
Stanescu
DE
, Hughes
N
, Patel
P
, De León
DD
. A novel mutation in GATA6 causes pancreatic agenesis
. Pediatr Diabetes
. 2015
;16
(1
):67
–70
. 8.
Allen
HL
, Flanagan
SE
, Shaw-Smith
C
, De Franco
E
, Akerman
I
, Caswell
R
, et al. GATA6 haploinsufficiency causes pancreatic agenesis in humans
. Nat Genet
. 2011
;44
(1
):20
–2
. 9.
Bonnefond
A
, Sand
O
, Guerin
B
, Durand
E
, De Graeve
F
, Huyvaert
M
, et al. GATA6 inactivating mutations are associated with heart defects and, inconsistently, with pancreatic agenesis and diabetes
. Diabetologia
. 2012
;55
(10
):2845
–7
. 10.
Catli
G
, Abaci
A
, Flanagan
SE
, De Franco
E
, Ellard
S
, Hattersley
A
, et al. A novel GATA6 mutation leading to congenital heart defects and permanent neonatal diabetes: a case report
. Diabetes Metab
. 2013
;39
(4
):370
–4
. 11.
De Franco
E
, Shaw-Smith
C
, Flanagan
SE
, Shepherd
MH
; International NDM Consortium
; Hattersley
AT
, et al. GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency
. Diabetes
. 2013
;62
(3
):993
–7
. 12.
Eifes
S
, Chudasama
KK
, Molnes
J
, Wagner
K
, Hoang
T
, Schierloh
U
, et al. A novel GATA6 mutation in a child with congenital heart malformation and neonatal diabetes
. Clin Case Rep
. 2013
;1
(2
):86
–90
. 13.
Gong
M
, Simaite
D
, Kühnen
P
, Heldmann
M
, Spagnoli
F
, Blankenstein
O
, et al. Two novel GATA6 mutations cause childhood-onset diabetes mellitus, pancreas malformation and congenital heart disease
. HRP
. 2013
;79
(4
):250
–6
. 14.
McMillan
T
, Girgis
R
, Sellers
EAC
. Neonatal diabetes and protein losing enteropathy: a case report
. BMC Med Genet
. 2016
;17
:32
. 15.
Raghuram
N
, Marwaha
A
, Greer
MLC
, Gauda
E
, Chitayat
D
. Congenital hypothyroidism, cardiac defects, and pancreatic agenesis in an infant with GATA6 mutation
. Am J Med Genet
. 2020
;182
(6
):1496
–9
. 16.
Du
YT
, Moore
L
, Poplawski
NK
, De Sousa
SMC
. Familial GATA6 mutation causing variably expressed diabetes mellitus and cardiac and renal abnormalities
. Endocrinol Diabetes Metab Case Rep
. 2019
;2019
:19-0022
. 17.
Gaisl
O
, Konrad
D
, Joset
P
, Lang-Muritano
M
. A novel GATA6 variant in a boy with neonatal diabetes and diaphragmatic hernia: a familial case with a review of the literature
. J Pediatr Endocrinol Metab
. 2019
;32
(9
):1027
–30
. 18.
Suzuki
S
, Nakao
A
, Sarhat
AR
, Furuya
A
, Matsuo
K
, Tanahashi
Y
, et al. A case of pancreatic agenesis and congenital heart defects with a novel GATA6 nonsense mutation: evidence of haploinsufficiency due to nonsense-mediated mRNA decay
. Am J Med Genet
. 2014
;164A
(2
):476
–9
. 19.
Yau
D
, De Franco
E
, Flanagan
SE
, Ellard
S
, Blumenkrantz
M
, Mitchell
JJ
. Case report: maternal mosaicism resulting in inheritance of a novel GATA6 mutation causing pancreatic agenesis and neonatal diabetes mellitus
. Diagn Pathol
. 2017
;12
:1
. 20.
Chao
CS
, McKnight
KD
, Cox
KL
, Chang
AL
, Kim
SK
, Feldman
BJ
. Novel GATA6 mutations in patients with pancreatic agenesis and congenital heart malformations
. PLoS One
. 2015
;10
(2
):e0118449
. 21.
Sanchez-Lechuga
B
, Saqlain
M
, Ng
N
, Colclough
K
, Woods
C
, Byrne
M
. Case report: adult onset diabetes with partial pancreatic agenesis and congenital heart disease due to a de novo GATA6 mutation
. BMC Med Genet
. 2020
;21
(1
):70
. 22.
Tuhan
H
, Catli
G
, Anik
A
, Özmen
D
, Türkmen
MA
, Bober
E
, et al. Neonatal diabetes mellitus due to a novel mutation in the GATA6 gene accompanying renal dysfunction: a case report
. Am J Med Genet
. 2015
;167A
(4
):925
–7
. 23.
Bui
PH
, Dorrani
N
, Wong
D
, Perens
G
, Dipple
KM
, Quintero-Rivera
F
. First report of a de novo 18q11.2 microdeletion including GATA6 associated with complex congenital heart disease and renal abnormalities
. Am J Med Genet
. 2013
;161A
(7
):1773
–8
. 24.
Lin
X
, Huo
Z
, Liu
X
, Zhang
Y
, Li
L
, Zhao
H
, et al. A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect
. J Hum Genet
. 2010
;55
(10
):662
–7
. 25.
Yorifuji
T
, Matsumura
M
, Okuno
T
, Shimizu
K
, Sonomura
T
, Muroi
J
, et al. Hereditary pancreatic hypoplasia, diabetes mellitus, and congenital heart disease: a new syndrome
. J Med Genet
. 1994
;31
(4
):331
–3
. 26.
Molkentin
JD
. The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression
. J Biol Chem
. 2000
;275
(50
):38949
–52
. 27.
Morrisey
EE
, Ip
HS
, Lu
MM
, Parmacek
MS
. GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm
. Dev Biol
. 1996
;177
(1
):309
–22
. 28.
Jacobs
IJ
, Que
J
. Genetic and cellular mechanisms of the formation of esophageal atresia and tracheoesophageal fistula
. Dis Esophagus
. 2013
;26
(4
):356
–8
. 29.
Durkin
N
, De Coppi
P
. Anatomy and embryology of tracheo-esophageal fistula
. Semin Pediatr Surg
. 2022
;31
(6
):151231
. 30.
Brosens
E
, Brouwer
RWW
, Douben
H
, van Bever
Y
, Brooks
AS
, Wijnen
RMH
, et al. Heritability and de novo mutations in oesophageal atresia and tracheoesophageal fistula aetiology
. Genes
. 2021
;12
(10
):1595
. 31.
Pedersen
RN
, Calzolari
E
, Husby
S
, Garne
E
; EUROCAT Working group
. Oesophageal atresia: prevalence, prenatal diagnosis and associated anomalies in 23 European regions
. Arch Dis Child
. 2012
;97
(3
):227
–32
. 32.
Goss
AM
, Tian
Y
, Tsukiyama
T
, Cohen
ED
, Zhou
D
, Lu
MM
, et al. Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut
. Dev Cell
. 2009
;17
(2
):290
–8
. 33.
Litingtung
Y
, Lei
L
, Westphal
H
, Chiang
C
. Sonic hedgehog is essential to foregut development
. Nat Genet
. 1998
;20
(1
):58
–61
. 34.
Mendelsohn
C
, Lohnes
D
, Decimo
D
, Lufkin
T
, LeMeur
M
, Chambon
P
, et al. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants
. Development
. 1994
;120
(10
):2749
–71
. 35.
Xuan
S
, Sussel
L
. GATA4 and GATA6 regulate pancreatic endoderm identity through inhibition of hedgehog signaling
. Development
. 2016
;143
(5
):780
–6
. 36.
Wier
HA
, Kuhn
RJ
. Pancreatic enzyme supplementation
. Curr Opin Pediatr
. 2011
;23
(5
):541
–4
. 37.
Maitra
M
, Koenig
SN
, Srivastava
D
, Garg
V
. Identification of GATA6 sequence variants in patients with congenital heart defects
. Pediatr Res
. 2010
;68
(4
):281
–5
. 38.
Kodo
K
, Nishizawa
T
, Furutani
M
, Arai
S
, Yamamura
E
, Joo
K
, et al. GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling
. Proc Natl Acad Sci USA
. 2009
;106
(33
):13933
–8
. 39.
Vanderlaan
RD
, Rome
J
, Hirsch
R
, Ivy
D
, Caldarone
CA
. Pulmonary vein stenosis: treatment and challenges
. J Thorac Cardiovasc Surg
. 2021
;161
(6
):2169
–76
. 40.
Quinonez
LG
, Gauvreau
K
, Borisuk
M
, Ireland
C
, Marshall
AM
, Mayer
JE
, et al. Outcomes of surgery for young children with multivessel pulmonary vein stenosis
. J Thorac Cardiovasc Surg
. 2015
;150
(4
):911
–7
. 41.
Seale
AN
, Webber
SA
, Uemura
H
, Partridge
J
, Roughton
M
, Ho
SY
, et al. Pulmonary vein stenosis: the UK, Ireland and Sweden collaborative study
. Heart
. 2009
;95
(23
):1944
–9
. 42.
Kalfa
D
, Belli
E
, Bacha
E
, Lambert
V
, di Carlo
D
, Kostolny
M
, et al. Primary pulmonary vein stenosis: outcomes, risk factors, and severity score in a multicentric study
. Ann Thorac Surg
. 2017
;104
(1
):182
–9
. 43.
Feins
EN
, Ireland
C
, Gauvreau
K
, Chávez
M
, Callahan
R
, Jenkins
KJ
, et al. Pulmonary vein stenosis: anatomic considerations, surgical management, and outcomes
. J Thorac Cardiovasc Surg
. 2022
;163
(6
):2198
–207.e3
. 44.
Yorifuji
T
, Kawakita
R
, Hosokawa
Y
, Fujimaru
R
, Yamaguchi
E
, Tamagawa
N
. Dominantly inherited diabetes mellitus caused by GATA6 haploinsufficiency: variable intrafamilial presentation
. J Med Genet
. 2012
;49
(10
):642
–3
. 45.
Diaz
GA
, Banikazemi
M
, Oishi
K
, Desnick
RJ
, Gelb
BD
. Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome
. Nat Genet
. 1999
;22
(3
):309
–12
. 46.
Subramanya
SB
, Subramanian
VS
, Sekar
VT
, Said
HM
. Thiamin uptake by pancreatic acinar cells: effect of chronic alcohol feeding/exposure
. Am J Physiol Gastrointest Liver Physiol
. 2011
;301
(5
):G896
–904
. 47.
Labay
V
, Raz
T
, Baron
D
, Mandel
H
, Williams
H
, Barrett
T
, et al. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness
.Nat Genet
. 1999
;22
(3
):300
–4
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