Abstract
Background/Aims: There is little information how rhGH treatment affects height in NS. This study aims to analyze data from the NS patients assembled in KIGS over 25 years. Patients/Methods: Of 613 (389 m/224 f) NS patients documented, 476 (302 m/174 f) were treated for 1 year, 237 (160 m/77 f) of which served to develop a 1st year height velocity (HV) prediction algorithm. One-hundred and forty (74 m/66 f) had reached near adult height (NAH). Factors affecting NAH on rhGH were determined. Results: At the start of rhGH, the NAH groups were (median, m, f) 11.0 and 10.3 years, with a height SDS of –3.2 and –3.8 SDS (Prader), respectively. The total gain after 6.3 and 5.6 years on rhGH (0.27 and 0.30 mg/kg/week) was 1.2 and 1.3 SDS. Age at the start of rhGH (negative), height at the start of rhGH, rhGH dose, number of rhGH injections/wk and birth weight (all positive) explained 36% of the variability of 1st year HV. Height at the start of rhGH, 1st year growth on rhGH, birth weight, and gender explained 74% of the variability of NAH. Causes for rhGH treatment discontinuation and adverse events were also analyzed. Conclusion: rhGH treatment increases NAH in NS. Prediction algorithms may optimize treatment in the future.
References
1.
Roberts
AE
, Allanson
JE
, Tartaglia
M
, Gelb
BD
. Noonan syndrome
. Lancet
. 2013
Jan
;381
(9863
):333
–42
.
[PubMed]
0140-67362.
Noonan
J
, Emke
DA
. Associated non-cardiac malformation in children with congenital heart disease
. J Pediatr
. 1963
;63
:468
–70
.0022-34763.
Noonan
JA
. Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease
. Am J Dis Child
. 1968
Oct
;116
(4
):373
–80
.
[PubMed]
0002-922X4.
Allanson
JE
, Hall
JG
, Hughes
HE
, Preus
M
, Witt
RD
, Opitz
JM
, et al. Noonan syndrome: the changing phenotype
. Am J Med Genet
. 1985
Jul
;21
(3
):507
–14
.
[PubMed]
0148-72995.
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]
1061-40366.
Zenker
M
, Lehmann
K
, Schulz
AL
, Barth
H
, Hansmann
D
, Koenig
R
, et al. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations
. J Med Genet
. 2007
Feb
;44
(2
):131
–5
.
[PubMed]
0022-25937.
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
Dec
;159
(6
):1029
–35
.
[PubMed]
0022-34768.
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]
0027-84249.
Duncan
WJ
, Fowler
RS
, Farkas
LG
, Ross
RB
, Wright
AW
, Bloom
KR
, et al. A comprehensive scoring system for evaluating Noonan syndrome
. Am J Med Genet
. 1981
;10
(1
):37
–50
.
[PubMed]
0148-729910.
van der Burgt
I
, Berends
E
, Lommen
E
, van Beersum
S
, Hamel
B
, Mariman
E
. Clinical and molecular studies in a large Dutch family with Noonan syndrome
. Am J Med Genet
. 1994
Nov
;53
(2
):187
–91
.
[PubMed]
0148-729911.
Ahmed
ML
, Foot
AB
, Edge
JA
, Lamkin
VA
, Savage
MO
, Dunger
DB
. Noonan’s syndrome: abnormalities of the growth hormone/IGF-I axis and the response to treatment with human biosynthetic growth hormone
. Acta Paediatr Scand
. 1991
Apr
;80
(4
):446
–50
.
[PubMed]
0001-656X12.
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
.
[PubMed]
1663-281813.
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]
1663-281814.
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]
0031-400515.
Ranke
MB
. The Kabi Pharmacia International Growth Study: aetiology classification list with comments
. Acta Paediatr Scand Suppl
. 1991
;379
s379
:87
–92
.
[PubMed]
0300-884316.
Lindberg
A
, Ranke
MB
. Data analysis within KIGS. In: Ranke
MB
, Price
DA
, Reiter
EO
, editors. Growth Hormone Therapy in Pediatrics – 20 Years of KIGS
. Basel
: Karger
; 2007
. pp. 23
–8
. 17.
Greulich
WW
, Pyle
SI
. Radiographic atlas of skeletal development of the hand and wrist
. 2nd ed. Stanford
: Stanford University Press
; 1959
. 18.
Ranke
MB
. Who stops growth hormone in KIGS – and why. In: Ranke
M
, Price
DA
, Reiter
EO
, editors. Growth hormone therapy in pediatrics – 20 years of KIGS
. Basel
: Karger
; 2007
. pp. 183
–8
. 19.
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010) U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES, National Institutes of Health, National Cancer Institute, NIH Publication No. 09-5410, Revised June
2010
20.
Prader
A
, Largo
RH
, Molinari
L
, Issler
C
; First Zurich Longitudinal Study of Growth and Development
. 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
Jun
;52
Suppl 52
:1
–125
.
[PubMed]
0073-181121.
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
Aug-Sep
;80
(8-9
):756
–62
.
[PubMed]
0001-656X22.
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]
0340-619923.
Freeman
JV
, Cole
TJ
, Chinn
S
, Jones
PR
, White
EM
, Preece
MA
. Cross sectional stature and weight reference curves for the UK, 1990
. Arch Dis Child
. 1995
Jul
;73
(1
):17
–24
.
[PubMed]
0003-988824.
Ranke
MB
, Lindberg
A
, Chatelain
P
, Wilton
P
, Cutfield
W
, Albertsson-Wikland
K
, et al. Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with idiopathic GH deficiency. KIGS International Board. Kabi Pharmacia International Growth Study
. J Clin Endocrinol Metab
. 1999
Apr
;84
(4
):1174
–83
.
[PubMed]
0021-972X25.
SAS Institute Inc
. The REG procedure. SAS/STAT® 9.1 User’s Guide
. Cary (NC)
: SAS Institute Inc
; 2004
. pp. 3797
–968
.26.
27.
Ranke
MB
, Lindberg
A
, Ferrández Longás
A
, Darendeliler
F
, Albertsson-Wikland
K
, Dunger
D
, et al.; KIGS International Board
. Major determinants of height development in Turner syndrome (TS) patients treated with GH: analysis of 987 patients from KIGS
. Pediatr Res
. 2007
Jan
;61
(1
):105
–10
.
[PubMed]
0031-399828.
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]
0003-988829.
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]
0803-525330.
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]
0804-464331.
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]
0021-972X32.
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]
0334-018X33.
Ranke
MB
, Lindberg
A
, Tanaka
T
, Camacho-Hübner
C
, Dunger
DB
, Geffner
ME
. Baseline Characteristics and Gender Differences in Prepubertal Children Treated with Growth Hormone in Europe, USA, and Japan: 25 Years’ KIGS® Experience (1987-2012) and Review
. Horm Res Paediatr
. 2017
;87
(1
):30
–41
.
[PubMed]
1663-281834.
Binder
G
, Grathwol
S
, von Loeper
K
, Blumenstock
G
, Kaulitz
R
, Freiberg
C
, et al. Health and quality of life in adults with Noonan syndrome
. J Pediatr
. 2012
Sep
;161
(3
):501
–505.e1
.
[PubMed]
0022-347635.
Ranke
MB
, Partsch
CJ
, Lindberg
A
, Dorr
HG
, Bettendorf
M
, Hauffa
BP
, et al. Adult height after GH therapy in 188 Ullrich-Turner syndrome patients: results of the German IGLU Follow-up Study 2001
. Eur J Endocrinol
. 2002
Nov
;147
(5
):625
–33
.
[PubMed]
0804-464336.
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]
0021-972X37.
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]
0021-972X38.
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]
0021-972X39.
Ranke
MB
, Lindberg
A
, Mullis
PE
, Geffner
ME
, Tanaka
T
, Cutfield
WS
, et al. Towards optimal treatment with growth hormone in short children and adolescents: evidence and theses
. Horm Res Paediatr
. 2013
;79
(2
):51
–67
.
[PubMed]
1663-281840.
Ranke
MB
, Lindberg
A
, Chatelain
P
, Wilton
P
, Cutfield
W
, Albertsson-Wikland
K
, et al. KIGS International Board & Kabi International Growth Study: Prediction of long term response to recombinant human growth hormone in Turner Syndrome: development and validation of mathematical models
. J Clin Endocrinol Metab
. 2000
;85
(11
):4212
–8
.
[PubMed]
0021-972X41.
Fisher
BG
, Acerini
CL
. Understanding the growth hormone therapy adherence paradigm: a systematic review
. Horm Res Paediatr
. 2013
;79
(4
):189
–96
.
[PubMed]
1663-281842.
Hasle
H
. Malignant diseases in Noonan syndrome and related disorders
. Horm Res
. 2009
Dec
;72
Suppl 2
:8
–14
.
[PubMed]
0301-016343.
Smpokou
P
, Zand
DJ
, Rosenbaum
KN
, Summar
ML
. Malignancy in Noonan syndrome and related disorders
. Clin Genet
. 2015
Dec
;88
(6
):516
–22
.
[PubMed]
0009-916344.
McWilliams
GD
, SantaCruz
K
, Hart
B
, Clericuzio
C
. Occurrence of DNET and other brain tumors in Noonan syndrome warrants caution with growth hormone therapy
. Am J Med Genet A
. 2016
Jan
;170A
(1
):195
–201
.
[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.
