Introduction: A variable near adult height (NAH) outcome after growth hormone (GH) therapy in Noonan syndrome (NS) patients with short stature has been reported. The main objective of this study was to evaluate NAH and body mass index (BMI) evolution in a large Belgian cohort of NS patients treated for short stature. The secondary objectives were to investigate whether sex, genotype, the presence of a thoracic deformity, and/or a heart anomaly might affect NAH and to validate the recently developed NAH prediction model by Ranke et al. Methods: Clinical and auxological data of GH treated short NS patients born before 2001 were extracted from the national Belgrow registry. NAH was available in 54 (35 male) genotyped NS using a gene panel of 9 genes, showing pathogenic variants in PTPN11 in 32 and in SOS1 in 5 patients, while in 17 patients gene panel analysis was inconclusive (no-mutation group). Results: After a median (P10; P90) duration of 5.4 (2.2; 10.3) years of GH therapy with a median dose of 0.05 mg/kg/day NS patients reached a median NAH of −1.7 (−3.1; −0.8) SDS. Median total height gain was 1.1 (0.1; 2.3) SDS. Sex, genotype, and the presence of a thoracic or cardiac malformation did not correlate with NAH or total height gain. Linear regression modelling revealed that height SDS at start (β = 0.90, p < 0.001), mid-parental height SDS (β = 0.27; p = 0.005), birth weight SDS (β = 0.15; p = 0.051), age at start (β = 0.07; p = 0.032) were independently associated with NAH SDS. Median BMI SDS increased significantly (p < 0.001) from −1.0 (−2.5; 0.0) at start to −0.2 (−1.5; 0.9) at NAH. The observed NAH in a subgroup of 44 patients with more than 3 years of GH treatment was not statistically different from the predicted NAH by the Noonan NAH prediction model of Ranke. Conclusion: Long-term GH therapy at a dose of 0.05 mg/kg/day in short NS patients is effective in improving adult height and BMI, irrespective of the genotype and presence or absence of cardiac and or thoracic anomalies.

1.
van der Burgt
I
.
Noonan syndrome
.
Orphanet J Rare Dis
.
2007
;
2
:
4
. doi: .
2.
Allanson
JE
.
Noonan syndrome
.
J Med Genet
.
1987
;
24
(
1
):
9
13
. doi: .
3.
Sharland
M
,
Patton
MA
,
Talbot
S
,
Chitolie
A
,
Bevan
DH
.
Coagulation-factor deficiencies and abnormal bleeding in Noonan’s syndrome
.
Lancet
.
1992
;
339
(
8784
):
19
21
. doi: .
4.
Carcavilla
A
,
Suárez-Ortega
L
,
Sánchez
AR
,
Gonzalez-Casado
I
,
Ramón-Krauel
M
,
Labarta
JI
, et al
.
[Noonan syndrome: genetic and clinical update and treatment options]
.
An Pediatr
.
2020
;
93
(
1
):
61.e1
61.e14
. doi: .
5.
Marino
B
,
Digilio
MC
,
Toscano
A
,
Giannotti
A
,
Dallapiccola
B
.
Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal
.
J Pediatr
.
1999
;
135
(
6
):
703
6
. doi: .
6.
Leoni
C
,
Blandino
R
,
Delogu
AB
,
De Rosa
G
,
Onesimo
R
,
Verusio
V
, et al
.
Genotype-cardiac phenotype correlations in a large single-center cohort of patients affected by RASopathies: clinical implications and literature review
.
Am J Med Genet
.
2022
;
188
(
2
):
431
45
. doi: .
7.
Pierpont
ME
,
Digilio
MC
.
Cardiovascular disease in Noonan syndrome
.
Curr Opin Pediatr
.
2018
;
30
(
5
):
601
8
. doi: .
8.
Linglart
L
,
Gelb
BD
.
Congenital heart defects in Noonan syndrome: diagnosis, management, and treatment
.
Am J Med Genet C Semin Med Genet
.
2020
;
184
(
1
):
73
80
. doi: .
9.
Lee
CK
,
Chang
BS
,
Hong
YM
,
Yang
SW
,
Lee
CS
,
Seo
JB
.
Spinal deformities in Noonan syndrome: a clinical review of sixty cases
.
J Bone Jt Surg Am
.
2001
;
83
(
10
):
1495
502
. doi: .
10.
Andreescu
N
,
Sharma
A
,
Mihailescu
A
,
Zimbru
CG
,
David
VL
,
Horhat
R
, et al
.
Chest wall deformities and their possible associations with different genetic syndromes
.
Eur Rev Med Pharmacol Sci
.
2022
;
26
(
14
):
5107
14
. doi: .
11.
Lee
BH
,
Kim
JM
,
Jin
HY
,
Kim
GH
,
Choi
JH
,
Yoo
HW
.
Spectrum of mutations in Noonan syndrome and their correlation with phenotypes
.
J Pediatr
.
2011
;
159
(
6
):
1029
35
. .
12.
El Bouchikhi
I
,
Belhassan
K
,
Moufid
FZ
,
Iraqui Houssaini
M
,
Bouguenouch
L
,
Samri
I
, et al
.
Noonan syndrome-causing genes: molecular update and an assessment of the mutation rate
.
Int J Pediatr Adolesc Med
.
2016
;
3
(
4
):
133
42
. .
13.
Lepri
FR
,
Scavelli
R
,
Digilio
MC
,
Gnazzo
M
,
Grotta
S
,
Dentici
ML
, et al
.
Diagnosis of Noonan syndrome and related disorders using target next generation sequencing
.
BMC Med Genet
.
2014
;
15
:
14
. doi: .
14.
Rodríguez
F
,
Gaete
X
,
Cassorla
F
.
Etiology and treatment of growth delay in noonan syndrome
.
Front Endocrinol
.
2021
;
12
:
691240
. .
15.
Roberts
AE
,
Allanson
JE
,
Tartaglia
M
,
Gelb
BD
.
Noonan syndrome
.
Lancet
.
2013
;
381
(
9863
):
333
42
. doi: .
16.
Cessans
C
,
Ehlinger
V
,
Arnaud
C
,
Yart
A
,
Capri
Y
,
Barat
P
, et al
.
Growth patterns of patients with Noonan syndrome: correlation with age and genotype
.
Eur J Endocrinol
.
2016
;
174
(
5
):
641
50
. doi: .
17.
Chinton
J
,
Huckstadt
V
,
Moresco
A
,
Gravina
LP
,
Obregon
MG
.
Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina
.
Arch Argent Pediatr
.
2019
;
117
(
5
):
330
7
. doi: .
18.
Ferrero
GB
,
Baldassarre
G
,
Delmonaco
AG
,
Biamino
E
,
Banaudi
E
,
Carta
C
, et al
.
Clinical and molecular characterization of 40 patients with Noonan syndrome
.
Eur J Med Genet
.
2008
;
51
(
6
):
566
72
. doi: .
19.
Ranke
MB
,
Heidemann
P
,
Knupfer
C
,
Enders
H
,
Schmaltz
AA
,
Bierich
JR
.
Noonan syndrome: growth and clinical manifestations in 144 cases
.
Eur J Pediatr
.
1988
;
148
(
3
):
220
7
. doi: .
20.
Malaquias
AC
,
Brasil
AS
,
Pereira
AC
,
Arnhold
IJP
,
Mendonca
BB
,
Bertola
DR
, et al
.
Growth standards of patients with Noonan and Noonan-like syndromes with mutations in the RAS/MAPK pathway
.
Am J Med Genet
.
2012
;
158A
(
11
):
2700
6
. doi: .
21.
Malaquias
AC
,
Noronha
RM
,
Souza
TTO
,
Homma
TK
,
Funari
MFA
,
Yamamoto
GL
, et al
.
Impact of growth hormone therapy on adult height in patients with PTPN11 mutations related to noonan syndrome
.
Horm Res Paediatr
.
2019
;
91
(
4
):
252
61
. doi: .
22.
De Schepper
J
,
Otten
BJ
,
François
I
,
Bourguignon
JP
,
Craen
M
,
Van der Burgt
I
, et al
.
Growth hormone therapy in pre-pubertal children with Noonan syndrome: first year growth response and comparison with Turner syndrome
.
Acta Paediatr
.
1997
;
86
(
9
):
943
6
. doi: .
23.
Kirk
JM
,
Betts
PR
,
Butler
GE
,
Donaldson
MD
,
Dunger
DB
,
Johnston
DI
, et al
.
Short stature in Noonan syndrome: response to growth hormone therapy
.
Arch Dis Child
.
2001
;
84
(
5
):
440
3
. doi: .
24.
Osio
D
,
Dahlgren
J
,
Wikland
KA
,
Westphal
O
.
Improved final height with long-term growth hormone treatment in Noonan syndrome
.
Acta Paediatr
.
2005
;
94
(
9
):
1232
7
. doi: .
25.
Cotterill
AM
,
McKenna
WJ
,
Brady
AF
,
Sharland
M
,
Elsawi
M
,
Yamada
M
, et al
.
The short-term effects of growth hormone therapy on height velocity and cardiac ventricular wall thickness in children with Noonan’s syndrome
.
J Clin Endocrinol Metab
.
1996
;
81
(
6
):
2291
7
. doi: .
26.
Raaijmakers
R
,
Noordam
C
,
Karagiannis
G
,
Gregory
JW
,
Hertel
NT
,
Sipilä
I
, et al
.
Response to growth hormone treatment and final height in Noonan syndrome in a large cohort of patients in the KIGS database
.
J Pediatr Endocrinol Metab
.
2008
;
21
(
3
):
267
73
. doi: .
27.
Noordam
C
,
Peer
PGM
,
Francois
I
,
De Schepper
J
,
van den Burgt
I
,
Otten
BJ
.
Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11
.
Eur J Endocrinol
.
2008
;
159
(
3
):
203
8
. doi: .
28.
Tamburrino
F
,
Gibertoni
D
,
Rossi
C
,
Scarano
E
,
Perri
A
,
Montanari
F
, et al
.
Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: patterns of growth, puberty and final height data
.
Am J Med Genet
.
2015
;
167A
(
11
):
2786
94
. doi: .
29.
Libraro
A
,
D’Ascanio
V
,
Cappa
M
,
Chiarito
M
,
Digilio
MC
,
Einaudi
S
, et al
.
Growth in children with noonan syndrome and effects of growth hormone treatment on adult height
.
Front Endocrinol
.
2021
;
12
:
761171
. doi: .
30.
Dahlgren
J
.
GH therapy in Noonan syndrome: review of final height data
.
Horm Res
.
2009
;
72
(
Suppl 2
):
46
8
. doi: .
31.
Noonan
JA
,
Kappelgaard
AM
.
The efficacy and safety of growth hormone therapy in children with noonan syndrome: a review of the evidence
.
Horm Res Paediatr
.
2015
;
83
(
3
):
157
66
. doi: .
32.
Giacomozzi
C
,
Deodati
A
,
Shaikh
MG
,
Ahmed
SF
,
Cianfarani
S
.
The impact of growth hormone therapy on adult height in noonan syndrome: a systematic review
.
Horm Res Paediatr
.
2015
;
83
(
3
):
167
76
. doi: .
33.
Sodero
G
,
Cipolla
C
,
Pane
LC
,
Sessa
L
,
Malavolta
E
,
Arzilli
F
, et al
.
Efficacy and safety of growth hormone therapy in children with Noonan syndrome
.
Growth Horm IGF Res
.
2023
;
69-70
:
101532
. doi: .
34.
Massart
F
.
Height outcome of the recombinant human growth hormone treatment in subjects with noonan syndrome: a meta-analysis
.
J Genet Syndr Gene Ther
.
2014
;
05
(
05
). doi: .
35.
Stagi
S
,
Ferrari
V
,
Ferrari
M
,
Priolo
M
,
Tartaglia
M
.
Inside the Noonan « universe »: literature review on growth, GH/IGF axis and rhGH treatment: facts and concerns
.
Front Endocrinol
.
2022
;
13
:
951331
. doi: .
36.
Ranke
MB
,
Lindberg
A
,
Carlsson
M
,
Camacho-Hübner
C
,
Rooman
R
.
Treatment with growth hormone in noonan syndrome observed during 25 years of KIGS: near adult height and outcome prediction
.
Horm Res Paediatr
.
2019
;
91
(
1
):
46
55
. doi: .
37.
Isojima
T
,
Sakazume
S
,
Hasegawa
T
,
Ogata
T
,
Nakanishi
T
,
Nagai
T
, et al
.
Growth references for Japanese individuals with Noonan syndrome
.
Pediatr Res
.
2016
;
79
(
4
):
543
8
. doi: .
38.
Binder
G
,
Neuer
K
,
Ranke
MB
,
Wittekindt
NE
.
PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome
.
J Clin Endocrinol Metab
.
2005
;
90
(
9
):
5377
81
. doi: .
39.
Yart
A
,
Edouard
T
.
Noonan syndrome: an update on growth and development
.
Curr Opin Endocrinol Diabetes Obes
.
2018
;
25
(
1
):
67
73
. doi: .
40.
Tanner
JM
,
Whitehouse
RH
.
Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty
.
Arch Dis Child
.
1976
;
51
(
3
):
170
9
. doi: .
41.
Niklasson
A
,
Ericson
A
,
Fryer
JG
,
Karlberg
J
,
Lawrence
C
,
Karlberg
P
.
An update of the Swedish reference standards for weight, length and head circumference at birth for given gestational age (1977-1981)
.
Acta Paediatr Scand
.
1991
;
80
(
8–9
):
756
62
. doi: .
42.
Roelants
M
,
Hauspie
R
,
Hoppenbrouwers
K
.
References for growth and pubertal development from birth to 21 years in Flanders, Belgium
.
Ann Hum Biol
.
2009
;
36
(
6
):
680
94
. doi: .
43.
Prader
A
,
Largo
RH
,
Molinari
L
,
Issler
C
.
Physical growth of Swiss children from birth to 20 years of age. First Zurich longitudinal study of growth and development
.
Helv Paediatr Acta Suppl
.
1989
;
52
:
1
125
.
44.
Ranke
MB
.
Towards a consensus on the definition of idiopathic short stature
.
Horm Res
.
1996
;
45
(
Suppl 2
):
64
6
. doi: .
45.
Becker
M
,
Thomas
M
,
Brachet
C
,
Heinrichs
C
,
Dotremont
H
,
De Schepper
J
, et al
.
Growth response of syndromic versus non-syndromic children born small for gestational age (SGA) to growth hormone therapy: a Belgian study
.
Front Endocrinol
.
2023
;
14
:
1112938
. doi: .
46.
Romano
AA
,
Dana
K
,
Bakker
B
,
Davis
DA
,
Hunold
JJ
,
Jacobs
J
, et al
.
Growth response, near-adult height, and patterns of growth and puberty in patients with noonan syndrome treated with growth hormone
.
J Clin Endocrinol Metab
.
2009
;
94
(
7
):
2338
44
. doi: .
47.
Rohrer
TR
,
Abuzzahab
J
,
Backeljauw
P
,
Birkegård
AC
,
Blair
J
,
Dahlgren
J
, et al
.
Long-term effectiveness and safety of childhood growth hormone treatment in noonan syndrome
.
Horm Res Paediatr
.
2020
;
93
(
6
):
380
95
. doi: .
48.
Brown
DC
,
Macfarlane
CE
,
McKenna
WJ
,
Patton
MA
,
Dunger
DB
,
Savage
MO
, et al
.
Growth hormone therapy in Noonan’s syndrome: non-cardiomyopathic congenital heart disease does not adversely affect growth improvement
.
J Pediatr Endocrinol Metab
.
2002
;
15
(
6
):
851
2
. doi: .
49.
Jorge
AAL
,
Edouard
T
,
Maghnie
M
,
Pietropoli
A
,
Kelepouris
N
,
Romano
A
, et al
.
Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status
.
Endocr Connect
.
2022
;
11
(
4
):
e210615
. doi: .
50.
Choi
JH
,
Lee
BH
,
Jung
CW
,
Kim
YM
,
Jin
HY
,
Kim
JM
, et al
.
Response to growth hormone therapy in children with Noonan syndrome: correlation with or without PTPN11 gene mutation
.
Horm Res Paediatr
.
2012
;
77
(
6
):
388
93
. doi: .
51.
Ferreira
LV
,
Souza
SAL
,
Arnhold
IJP
,
Mendonca
BB
,
Jorge
AAL
.
PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome
.
J Clin Endocrinol Metab
.
2005
;
90
(
9
):
5156
60
. .
52.
Jo
KJ
,
Kim
YM
,
Yoon
JY
,
Lee
YJ
,
Han
YM
,
Yoo
HW
, et al
.
Comparison of effectiveness of growth hormone therapy according to disease-causing genes in children with Noonan syndrome
.
Korean J Pediatr
.
2019
;
62
(
7
):
274
80
. doi: .
53.
da Silva
FM
,
Jorge
AA
,
Malaquias
A
,
da Costa Pereira
A
,
Yamamoto
GL
,
Kim
CA
, et al
.
Nutritional aspects of Noonan syndrome and Noonan-related disorders
.
Am J Med Genet
.
2016
;
170
(
6
):
1525
31
. doi: .
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