Abstract
Objectives: The aim of this study was to evaluate the response to recombinant human growth hormone (rhGH) treatment in patients with Noonan syndrome (NS). Materials and Methods: Forty-two patients (35 PTPN11+) were treated with rhGH, and 17 were followed-up until adult height. The outcomes were changes in growth velocity (GV) and height standard deviation scores (SDS) for normal (height-CDC SDS) and Noonan standards (height-NS SDS). Results: The pretreatment chronological age was 10.3 ± 3.5 years. Height-CDC SDS and height-NS SDS were –3.1 ± 0.7 and –0.5 ± 0.6, respectively. PTPN11+ patients had a better growth response than PTPN11– patients. GV SDS increased from –1.2 ± 1.8 to 3.1 ± 2.8 after the first year of therapy in PTPN11+ patients, and from –1.9 ± 2.6 to –0.1 ± 2.6 in PTPN11– patients. The gain in height-CDC SDS during the first year was higher in PTPN11+ than PTPN11– (0.6 ± 0.4 vs. 0.1 ± 0.2, p = 0.008). Similarly, the gain was observed in height-NS SDS (0.6 ± 0.3 vs. 0.2 ± 0.2, respectively, p < 0.001). Among the patients that reached adult height (n = 17), AH-CDC SDS and AH-NS SDS were –2.1 ± 0.7 and 0.7 ± 0.8, respectively. The total increase in height SDS was 1.3 ± 0.7 and 1.5 ± 0.6 for normal and NS standards, respectively. Conclusions: This study supports the advantage of rhGH therapy on adult height in PTPN11+ patients. In comparison, PTPN11– patients showed a poor response to rhGH. However, this PTPN11– group was small, preventing an adequate comparison among different genotypes and no guarantee of response to therapy in genes besides PTPN11.
References
1.
Nora
JJ
, Nora
AH
, Sinha
AK
, Spangler
RD
, Lubs
HA
. The Ullrich-Noonan syndrome (Turner phenotype)
. Am J Dis Child
. 1974
Jan
;127
(1
):48
–55
.
[PubMed]
0002-922X2.
Romano
AA
, Allanson
JE
, Dahlgren
J
, Gelb
BD
, Hall
B
, Pierpont
ME
, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines
. Pediatrics
. 2010
Oct
;126
(4
):746
–59
.
[PubMed]
0031-40053.
Mendez
HM
, Opitz
JM
, Reynolds
JF
. Noonan syndrome: a review
. Am J Med Genet
. 1985
Jul
;21
(3
):493
–506
.
[PubMed]
0148-72994.
Tartaglia
M
, Mehler
EL
, Goldberg
R
, Zampino
G
, Brunner
HG
, Kremer
H
, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome
. Nat Genet
. 2001
Dec
;29
(4
):465
–8
.
[PubMed]
1061-40365.
Carta
C
, Pantaleoni
F
, Bocchinfuso
G
, Stella
L
, Vasta
I
, Sarkozy
A
, et al. Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype
. Am J Hum Genet
. 2006
Jul
;79
(1
):129
–35
.
[PubMed]
0002-92976.
Cirstea
IC
, Kutsche
K
, Dvorsky
R
, Gremer
L
, Carta
C
, Horn
D
, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome
. Nat Genet
. 2010
Jan
;42
(1
):27
–9
.
[PubMed]
1061-40367.
Cordeddu
V
, Di Schiavi
E
, Pennacchio
LA
, Ma’ayan
A
, Sarkozy
A
, Fodale
V
, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair
. Nat Genet
. 2009
Sep
;41
(9
):1022
–6
.
[PubMed]
1061-40368.
Martinelli
S
, De Luca
A
, Stellacci
E
, Rossi
C
, Checquolo
S
, Lepri
F
, et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype
. Am J Hum Genet
. 2010
Aug
;87
(2
):250
–7
.
[PubMed]
0002-92979.
Pandit
B
, Sarkozy
A
, Pennacchio
LA
, Carta
C
, Oishi
K
, Martinelli
S
, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy
. Nat Genet
. 2007
Aug
;39
(8
):1007
–12
.
[PubMed]
1061-403610.
Schubbert
S
, Zenker
M
, Rowe
SL
, Böll
S
, Klein
C
, Bollag
G
, et al. Germline KRAS mutations cause Noonan syndrome
. Nat Genet
. 2006
Mar
;38
(3
):331
–6
.
[PubMed]
1061-403611.
Roberts
AE
, Araki
T
, Swanson
KD
, Montgomery
KT
, Schiripo
TA
, Joshi
VA
, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome
. Nat Genet
. 2007
Jan
;39
(1
):70
–4
.
[PubMed]
1061-403612.
Chen
PC
, Yin
J
, Yu
HW
, Yuan
T
, Fernandez
M
, Yung
CK
, et al. Next-generation sequencing identifies rare variants associated with Noonan syndrome
. Proc Natl Acad Sci USA
. 2014
Aug
;111
(31
):11473
–8
.
[PubMed]
0027-842413.
Aoki
Y
, Niihori
T
, Banjo
T
, Okamoto
N
, Mizuno
S
, Kurosawa
K
, et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome
. Am J Hum Genet
. 2013
Jul
;93
(1
):173
–80
.
[PubMed]
0002-929714.
Flex
E
, Jaiswal
M
, Pantaleoni
F
, Martinelli
S
, Strullu
M
, Fansa
EK
, et al. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis
. Hum Mol Genet
. 2014
Aug
;23
(16
):4315
–27
.
[PubMed]
0964-690615.
Yamamoto
GL
, Aguena
M
, Gos
M
, Hung
C
, Pilch
J
, Fahiminiya
S
, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome
. J Med Genet
. 2015
Jun
;52
(6
):413
–21
.
[PubMed]
0022-259316.
Aoki
Y
, Niihori
T
, Inoue
S
, Matsubara
Y
. Recent advances in RASopathies
. J Hum Genet
. 2016
Jan
;61
(1
):33
–9
.
[PubMed]
1434-516117.
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
May
;174
(5
):641
–50
.
[PubMed]
0804-464318.
Croonen
EA
, Draaisma
JM
, van der Burgt
I
, Roeleveld
N
, Noordam
C
. First-year growth in children with Noonan syndrome: associated with feeding problems?
Am J Med Genet A
. 2018
Apr
;176
(4
):951
–8
.
[PubMed]
1552-482519.
Malaquias
AC
, Brasil
AS
, Pereira
AC
, Arnhold
IJ
, 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 A
. 2012
Nov
;158A
(11
):2700
–6
.
[PubMed]
1552-482520.
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
Dec
;148
(3
):220
–7
.
[PubMed]
0340-619921.
Witt
DR
, Keena
BA
, Hall
JG
, Allanson
JE
. Growth curves for height in Noonan syndrome
. Clin Genet
. 1986
Sep
;30
(3
):150
–3
.
[PubMed]
0009-916322.
Ranke
MB
, Wit
JM
. Growth hormone - past, present and future
. Nat Rev Endocrinol
. 2018
May
;14
(5
):285
–300
.
[PubMed]
1759-502923.
Kirk
JM
, Betts
PR
, Butler
GE
, Donaldson
MD
, Dunger
DB
, Johnston
DI
, et al.; Group tU
. Short stature in Noonan syndrome: response to growth hormone therapy
. Arch Dis Child
. 2001
May
;84
(5
):440
–3
.
[PubMed]
0003-988824.
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
Mar
;21
(3
):267
–73
.
[PubMed]
0334-018X25.
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
Jul
;94
(7
):2338
–44
.
[PubMed]
0021-972X26.
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 A
. 2015
Nov
;167A
(11
):2786
–94
.
[PubMed]
1552-482527.
Osio
D
, Dahlgren
J
, Wikland
KA
, Westphal
O
. Improved final height with long-term growth hormone treatment in Noonan syndrome
. Acta Paediatr
. 2005
Sep
;94
(9
):1232
–7
.
[PubMed]
0803-525328.
Noordam
C
, Peer
PG
, 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
Sep
;159
(3
):203
–8
.
[PubMed]
0804-464329.
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
.
[PubMed]
1663-281830.
Ferreira
LV
, Souza
SA
, Arnhold
IJ
, Mendonca
BB
, Jorge
AA
. PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome
. J Clin Endocrinol Metab
. 2005
Sep
;90
(9
):5156
–60
.
[PubMed]
0021-972X31.
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
Sep
;90
(9
):5377
–81
.
[PubMed]
0021-972X32.
Limal
JM
, Parfait
B
, Cabrol
S
, Bonnet
D
, Leheup
B
, Lyonnet
S
, et al. Noonan syndrome: relationships between genotype, growth, and growth factors
. J Clin Endocrinol Metab
. 2006
Jan
;91
(1
):300
–6
.
[PubMed]
0021-972X33.
Şıklar
Z
, Genens
M
, Poyrazoğlu
Ş
, Baş
F
, Darendeliler
F
, Bundak
R
, et al. The Growth Characteristics of Patients with Noonan Syndrome: Results of Three Years of Growth Hormone Treatment: A Nationwide Multicenter Study
. J Clin Res Pediatr Endocrinol
. 2016
Sep
;8
(3
):305
–12
.
[PubMed]
1308-572734.
Usher
R
, McLean
F
. Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation
. J Pediatr
. 1969
Jun
;74
(6
):901
–10
.
[PubMed]
0022-347635.
Kuczmarski
RJ
, Ogden
CL
, Grummer-Strawn
LM
, Flegal
KM
, Guo
SS
, Wei
R
, et al. CDC growth charts: united States
. Adv Data
. 2000
Jun
;(314
):1
–27
.
[PubMed]
0147-395636.
Tanner
JM
, Whitehouse
RH
, Takaishi
M
. Standards from birth to maturity for height, weight, height velocity, and weight velocity: british children, 1965. I
. Arch Dis Child
. 1966
Oct
;41
(219
):454
–71
.
[PubMed]
0003-988837.
Tanner
JM
, Whitehouse
RH
, Takaishi
M
. Standards from birth to maturity for height, weight, height velocity, and weight velocity: british children, 1965. II
. Arch Dis Child
. 1966
Dec
;41
(220
):613
–35
.
[PubMed]
0003-988838.
De Rocca Serra-Nédélec
A
, Edouard
T
, Tréguer
K
, Tajan
M
, Araki
T
, Dance
M
, et al. Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature
. Proc Natl Acad Sci USA
. 2012
Mar
;109
(11
):4257
–62
.
[PubMed]
0027-842439.
Chen
PC
, Wakimoto
H
, Conner
D
, Araki
T
, Yuan
T
, Roberts
A
, et al. Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation
. J Clin Invest
. 2010
Dec
;120
(12
):4353
–65
.
[PubMed]
0021-973840.
Wu
X
, Simpson
J
, Hong
JH
, Kim
KH
, Thavarajah
NK
, Backx
PH
, et al. MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation
. J Clin Invest
. 2011
Mar
;121
(3
):1009
–25
.
[PubMed]
0021-973841.
Chen
Y
, Wen
R
, Yang
S
, Schuman
J
, Zhang
EE
, Yi
T
, et al. Identification of Shp-2 as a Stat5A phosphatase
. J Biol Chem
. 2003
May
;278
(19
):16520
–7
.
[PubMed]
0021-925842.
Stofega
MR
, Argetsinger
LS
, Wang
H
, Ullrich
A
, Carter-Su
C
. Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha
. J Biol Chem
. 2000
Sep
;275
(36
):28222
–9
.
[PubMed]
0021-925843.
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
.
[PubMed]
1663-281844.
Van Pareren
Y
, Mulder
P
, Houdijk
M
, Jansen
M
, Reeser
M
, Hokken-Koelega
A
. Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial
. J Clin Endocrinol Metab
. 2003
Aug
;88
(8
):3584
–90
.
[PubMed]
0021-972X45.
Carel
JC
, Chatelain
P
, Rochiccioli
P
, Chaussain
JL
. Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: results of a randomized controlled study
. J Clin Endocrinol Metab
. 2003
Apr
;88
(4
):1587
–93
.
[PubMed]
0021-972X46.
Dahlgren
J
, Wikland
KA
; Swedish Study Group for Growth Hormone Treatment
. Final height in short children born small for gestational age treated with growth hormone
. Pediatr Res
. 2005
Feb
;57
(2
):216
–22
.
[PubMed]
0031-399847.
van Dijk
M
, Bannink
EM
, van Pareren
YK
, Mulder
PG
, Hokken-Koelega
AC
. Risk factors for diabetes mellitus type 2 and metabolic syndrome are comparable for previously growth hormone-treated young adults born small for gestational age (sga) and untreated short SGA controls
. J Clin Endocrinol Metab
. 2007
Jan
;92
(1
):160
–5
.
[PubMed]
0021-972X48.
Stephure
DK
, Committee
CG
; Canadian Growth Hormone Advisory Committee
. Impact of growth hormone supplementation on adult height in turner syndrome: results of the Canadian randomized controlled trial
. J Clin Endocrinol Metab
. 2005
Jun
;90
(6
):3360
–6
.
[PubMed]
0021-972X49.
MacFarlane
CE
, Brown
DC
, Johnston
LB
, Patton
MA
, Dunger
DB
, Savage
MO
, et al. Growth hormone therapy and growth in children with Noonan’s syndrome: results of 3 years’ follow-up
. J Clin Endocrinol Metab
. 2001
May
;86
(5
):1953
–6
.
[PubMed]
0021-972X50.
Noordam
C
, Draaisma
JM
, van den Nieuwenhof
J
, van der Burgt
I
, Otten
BJ
, Daniels
O
. Effects of growth hormone treatment on left ventricular dimensions in children with Noonan’s syndrome.
Horm Res. 2001
;56(3--4):110--3. 51.
Ozono
K
, Ogata
T
, Horikawa
R
, Matsubara
Y
, Ogawa
Y
, Nishijima
K
, et al. Efficacy and safety of two doses of Norditropin® (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients
. Endocr J
. 2018
Feb
;65
(2
):159
–74
.
[PubMed]
0918-895952.
Villani
A
, Greer
MC
, Kalish
JM
, Nakagawara
A
, Nathanson
KL
, Pajtler
KW
, et al. Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk
. Clin Cancer Res
. 2017
Jun
;23
(12
):e83
–90
.
[PubMed]
1078-043253.
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 Joint Surg Am
. 2001
Oct
;83-A
(10
):1495
–502
.
[PubMed]
0021-935554.
Smpokou
P
, Tworog-Dube
E
, Kucherlapati
RS
, Roberts
AE
. Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome
. Am J Med Genet A
. 2012
Dec
;158A
(12
):3106
–11
.
[PubMed]
1552-4825© 2019 S. Karger AG, Basel
2019
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
