Introduction: Pseudohypoparathyroidism 1A (PHP1A) is the best-known representative of inactivating parathyroid hormone (PTH)/PTHrP-signaling disorders (iPPSD). The associated phenotype develops over time and often includes hormonal resistances, short stature, and osteoma cutis. More complex and very early manifestations have also been reported. Neonatal complications may indicate a more severe course of the disease. Here, we report 3 patients with heterozygous GNAS variants and infancy onset of iPPSD2/PHP1A. Case Presentations: Patient 1 is a 15-month-old boy who presented with severe chronic noninfectious diarrhea and elevated thyroid-stimulating hormone (TSH) beginning at 1 month of age, leading to life-threatening failure to thrive. Patient 2 is a 4-year-old boy with a history of bronchopulmonary dysplasia as well as neonatal-onset severe pulmonary complications, including critical pulmonary bleeding and recurring pulmonary infections and TSH elevation. Patient 3 is a 4-year-old girl who exhibited signs of PTH resistance and progressive osteoma cutis at the age of 1–2 weeks and obesity at the age of 3 months. Conclusion: The phenotypic spectrum of iPPSD2/PHP1A in neonates and infants may include severe gastrointestinal, pulmonary, and endocrine manifestations, which may delay diagnosis if not recognized as a spectrum disorder of Gsα deficiency. The cases support the hypothesis that early-life manifestations may indicate a more complicated course of the disease. Elevated PTH or TSH in infants with unclear symptoms or conditions should prompt evaluation for disorders of the iPPSD spectrum. In the absence of reliable predictors for the individual courses of PHP1A, in-depth clinical screening for possible manifestations beyond the classical spectrum is warranted even in infancy.

1.
Mantovani
G
,
Bastepe
M
,
Monk
D
,
de Sanctis
L
,
Thiele
S
,
Ahmed
SF
, et al
.
Recommendations for diagnosis and treatment of pseudohypoparathyroidism and related disorders: an updated practical tool for physicians and patients
.
Horm Res Paediatr
.
2020
;
93
(
3
):
182
96
.
2.
Thiele
S
,
Mantovani
G
,
Barlier
A
,
Boldrin
V
,
Bordogna
P
,
De Sanctis
L
, et al
.
From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network
.
Eur J Endocrinol
.
2016
;
175
(
6
):
P1
17
.
3.
Del Sindaco
G
,
Berkenou
J
,
Pagnano
A
,
Rothenbuhler
A
,
Arosio
M
,
Mantovani
G
, et al
.
Neonatal and early infancy features of patients with inactivating PTH/PTHrP signaling disorders/pseudohypoparathyroidism
.
J Clin Endocrinol Metab
.
2023
;
108
(
11
):
2961
9
.
4.
Kelsey
G
.
Imprinting on chromosome 20: tissue-specific imprinting and imprinting mutations in the GNAS locus
.
Am J Med Genet C Semin Med Genet
.
2010
;
154C
(
3
):
377
86
.
5.
Linglart
A
,
Levine
MA
,
Jüppner
H
.
Pseudohypoparathyroidism
.
Endocrinol Metab Clin North Am
.
2018
;
47
(
4
):
865
88
.
6.
Elli
FM
,
Pereda
A
,
Linglart
A
,
Perez de Nanclares
G
,
Mantovani
G
.
Parathyroid hormone resistance syndromes: inactivating PTH/PTHrP signaling disorders (iPPSDs)
.
Best Pract Res Clin Endocrinol Metab
.
2018
;
32
(
6
):
941
54
.
7.
Cussac
D
,
Pasteau
V
,
Millan
MJ
.
Characterisation of Gs activation by dopamine D1 receptors using an antibody capture assay: antagonist properties of clozapine
.
Eur J Pharmacol
.
2004
;
485
(
1–3
):
111
7
.
8.
Turan
S
,
Bounoutas
G
,
Fernandez-Rebollo
E
,
Aydin
C
,
Zoto
T
,
Reyes
M
, et al
.
Postnatal establishment of allelic gαs silencing as a plausible explanation for delayed onset of parathyroid hormone resistance owing to heterozygous gαs disruption
.
J Bone Miner Res
.
2014
;
29
(
3
):
749
60
.
9.
Munteanu
M
,
Kiewert
C
,
Matar
N
,
Hauffa
BP
,
Unger
N
,
Hiort
O
, et al
.
Resistance to GHRH but Not to PTH in a 15-year-old boy with pseudohypoparathyroidism 1A
.
J Endocr Soc
.
2019
;
3
(
7
):
1383
9
.
10.
European Perinatal Health Report
.
2019
.
11.
Braegger
C
,
Jenni
O
,
Konrad
D
,
Molinari
L
.
Neue Wachstumskurven für die Schweiz. Paediatrica: Bulletin der Schweizerischen Gesellschaft für Pädiatrie
.
2011
.
12.
Kromeyer-Hauschild
K
,
Wabitsch
M
,
Kunze
D
,
Geller
F
,
Geiß
HC
,
Hesse
V
, et al
.
Perzentile für den Body-mass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben
.
Monatsschr Kinderheilkd
.
2001
;
149
(
8
):
807
18
.
13.
Voigt
M
,
Fusch
C
,
Olbertz
D
,
Hartmann
K
,
Rochow
N
,
Renken
C
, et al
.
Analyse des Neugeborenenkollektivs der Bundesrepublik Deutschland
.
Geburtshilfe Frauenheilkd
.
2006
;
66
(
10
):
956
70
.
14.
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
.
15.
Makita
N
,
Sato
J
,
Rondard
P
,
Fukamachi
H
,
Yuasa
Y
,
Aldred
MA
, et al
.
Human G mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle
.
Proc Natl Acad Sci U S A
.
2007
;
104
(
44
):
17424
9
.
16.
Moreno
JJ
.
Eicosanoid receptors: targets for the treatment of disrupted intestinal epithelial homeostasis
.
Eur J Pharmacol
.
2017
;
796
:
7
19
.
17.
Schmidt
AR
,
Ramamoorthy
C
.
Bronchopulmonary dysplasia
.
Paediatr Anaesth
.
2022
;
32
(
2
):
174
80
.
18.
Shoemaker
AH
,
Jüppner
H
.
Nonclassic features of pseudohypoparathyroidism type 1A
.
Curr Opin Endocrinol Diabetes Obes
.
2017
;
24
(
1
):
33
8
.
19.
Bikle
DD
.
Vitamin D regulation of immune function
.
Curr Osteoporos Rep
.
2022
;
20
(
3
):
186
93
.
20.
Walaschewski
R
,
Begrow
F
,
Verspohl
EJ
.
Impact and benefit of A(2B)-adenosine receptor agonists for the respiratory tract: mucociliary clearance, ciliary beat frequency, trachea muscle tonus and cytokine release
.
J Pharm Pharmacol
.
2013
;
65
(
1
):
123
32
.
21.
Buttarelli
FR
,
Fanciulli
A
,
Pellicano
C
,
Pontieri
FE
.
The dopaminergic system in peripheral blood lymphocytes: from physiology to pharmacology and potential applications to neuropsychiatric disorders
.
Curr Neuropharmacol
.
2011
;
9
(
2
):
278
88
.
22.
Ricciotti
E
,
FitzGerald
GA
.
Prostaglandins and inflammation
.
Arterioscler Thromb Vasc Biol
.
2011
;
31
(
5
):
986
1000
.
23.
Snanoudj
S
,
Molin
A
,
Colson
C
,
Coudray
N
,
Paulien
S
,
Mittre
H
, et al
.
Maternal transmission ratio distortion of GNAS loss-of-function mutations
.
J Bone Miner Res
.
2020
;
35
(
5
):
913
9
.
24.
Sippelli
F
,
Briuglia
S
,
Ferraloro
C
,
Capra
AP
,
Agolini
E
,
Abbate
T
, et al
.
Identification of a novel GNAS mutation in a family with pseudohypoparathyroidism type 1A
.
BMC Pediatr
.
2024
;
24
(
1
):
271
.
You do not currently have access to this content.