Introduction: Genetic obesity is rare and quite challenging for pediatricians in terms of early identification. Src-homology-2 (SH2) B adapter protein 1 (SH2B1) is an important component in the leptin-melanocortin pathway and is found to play an important role in leptin and insulin signaling and therefore in the pathogenesis of obesity and diabetes. Microdeletions in chromosome 16p11.2, encompassing the SH2B1 gene, are known to be associated with obesity, insulin resistance, hyperphagia, and developmental delay. The aim of our study is to report on a case series of young individuals with 16p11.2 microdeletions, including the SH2B1 gene, and provide detailed information on body mass index (BMI) development and obesity-associated comorbidities. In this way, we want to raise awareness of this syndromic form of obesity as a differential diagnosis of genetic obesity. Methods: We describe the phenotype of 7 children (3 male; age range: 2.8–18.0 years) with 16p11.2 microdeletions, encompassing the SH2B1 gene, and present their BMI trajectories from birth onward. Screening for obesity-associated comorbidities was performed at the time of genetic diagnosis. Results: All children presented with severe, early-onset obesity already at the age of 5 years combined with variable developmental delay. Five patients presented with elevated fasting insulin levels, 1 patient developed diabetes mellitus type 2, 4 patients had dyslipidemia, and 4 developed nonalcoholic fatty-liver disease. Discussion/Conclusion: Chromosomal microdeletions in 16p11.2, including the SH2B1 gene, in children are associated with severe, early-onset obesity and comorbidities associated with insulin resistance. Early genetic testing in suspicious patients and early screening for comorbidities are recommended.

1.
Farooqi
IS
,
O'Rahilly
S
.
Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity
.
Nat Clin Pract Endocrinol Metab
.
2008 Oct
;
4
(
10
):
569
77
. .
2.
Styne
DM
,
Arslanian
SA
,
Connor
EL
,
Farooqi
IS
,
Murad
MH
,
Silverstein
JH
,
Pediatric obesity-assessment, treatment, and prevention: an endocrine society clinical practice guideline
.
J Clin Endocrinol Metab
.
2017 Mar 1
;
102
(
3
):
709
57
. .
3.
El-Sayed Moustafa
JS
,
Froguel
P
.
From obesity genetics to the future of personalized obesity therapy
.
Nat Rev Endocrinol
.
2013 Jul
;
9
(
7
):
402
13
. .
4.
Vollbach
H
,
Brandt
S
,
Lahr
G
,
Denzer
C
,
von Schnurbein
J
,
Debatin
KM
,
Prevalence and phenotypic characterization of MC4R variants in a large pediatric cohort
.
Int J Obes
.
2017 Jan
;
41
(
1
):
13
22
. .
5.
von Schnurbein
J
.
Monogene adipositas
. In:
Wabitsch
M
,
Kiess
W
,
Hebebrand
J
,
Zwiauer
K
, editors.
Adipositas bei kindern und jugendlichen
.
Springer
;
2015
.
6.
Ren
D
,
Li
M
,
Duan
C
,
Rui
L
.
Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice
.
Cell Metab
.
2005 Aug
;
2
(
2
):
95
104
. .
7.
Rui
L
.
SH2B1 regulation of energy balance, body weight, and glucose metabolism
.
World J Diabetes
.
2014 Aug 15
;
5
(
4
):
511
26
. .
8.
Jiang
L
,
Su
H
,
Wu
X
,
Shen
H
,
Kim
MH
,
Li
Y
,
Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease
.
Nat Commun
.
2020
;
11
(
1
):
1517
7
. .
9.
Li
Z
,
Zhou
Y
,
Carter-Su
C
,
Myers
MG
 Jr
,
Rui
L
.
SH2B1 enhances leptin signaling by both Janus kinase 2 Tyr813 phosphorylation-dependent and -independent mechanisms
.
Mol Endocrinol
.
2007 Sep
;
21
(
9
):
2270
81
. .
10.
Duan
C
,
Yang
H
,
White
MF
,
Rui
L
.
Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance
.
Mol Cell Biol
.
2004 Sep
;
24
(
17
):
7435
43
. .
11.
Li
M
,
Ren
D
,
Iseki
M
,
Takaki
S
,
Rui
L
.
Differential role of SH2-B and APS in regulating energy and glucose homeostasis
.
Endocrinology
.
2006 May
;
147
(
5
):
2163
70
. .
12.
Bachmann-Gagescu
R
,
Mefford
HC
,
Cowan
C
,
Glew
GM
,
Hing
AV
,
Wallace
S
,
Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity
.
Genet Med
.
2010 Oct
;
12
(
10
):
641
7
. .
13.
Bochukova
EG
,
Huang
N
,
Keogh
J
,
Henning
E
,
Purmann
C
,
Blaszczyk
K
,
Large, rare chromosomal deletions associated with severe early-onset obesity
.
Nature
.
2010 Feb 4
;
463
(
7281
):
666
70
. .
14.
Barge-Schaapveld
DQ
,
Maas
SM
,
Polstra
A
,
Knegt
LC
,
Hennekam
RC
.
The atypical 16p11.2 deletion: a not so atypical microdeletion syndrome?
Am J Med Genet A
.
2011 May
;
155A
(
5
):
1066
72
. .
15.
Doche
ME
,
Bochukova
EG
,
Su
HW
,
Pearce
LR
,
Keogh
JM
,
Henning
E
,
Human SH2B1 mutations are associated with maladaptive behaviors and obesity
.
J Clin Invest
.
2012 Dec
;
122
(
12
):
4732
6
. .
16.
Volckmar
AL
,
Bolze
F
,
Jarick
I
,
Knoll
N
,
Scherag
A
,
Reinehr
T
,
Mutation screen in the GWAS derived obesity gene SH2B1 including functional analyses of detected variants
.
BMC Med Genomics
.
2012 Dec 27
;
5
:
65
. .
17.
Flores
A
,
Argetsinger
LS
,
Stadler
LKJ
,
Malaga
AE
,
Vander
PB
,
DeSantis
LC
,
Crucial role of the SH2B1 PH domain for the control of energy balance
.
Diabetes
.
2019 Nov
;
68
(
11
):
2049
62
. .
18.
Jacquemont
S
,
Reymond
A
,
Zufferey
F
,
Harewood
L
,
Walters
RG
,
Kutalik
Z
,
Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus
.
Nature
.
2011 Aug 31
;
478
(
7367
):
97
102
. .
19.
Kohlsdorf
K
,
Nunziata
A
,
Funcke
JB
,
Brandt
S
,
von Schnurbein
J
,
Vollbach
H
,
Early childhood BMI trajectories in monogenic obesity due to leptin, leptin receptor, and melanocortin 4 receptor deficiency
.
Int J Obes
.
2018 Sep
;
42
(
9
):
1602
9
. .
20.
Zorn
S
,
von Schnurbein
J
,
Kohlsdorf
K
,
Denzer
C
,
Wabitsch
M
.
Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency
.
Mol Cell Pediatr
.
2020 Nov 3
;
7
(
1
):
15
. .
21.
Clément
K
,
van den Akker
E
,
Argente
J
,
Bahm
A
,
Chung
WK
,
Connors
H
,
Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials
.
Lancet Diabetes Endocrinol
.
2020 Dec
;
8
(
12
):
960
70
. .
22.
Kelly
TL
,
Wilson
KE
,
Heymsfield
SB
.
Dual energy X-ray absorptiometry body composition reference values from NHANES
.
PLoS One
.
2009 Sep 15
;
4
(
9
):
e7038
. .
23.
Kromeyer-Hauschild
K
,
Wabitsch
M
,
Kunze
D
,
Geller
F
,
Geiß
HC
,
Hesse
V
,
Perzentile für den body-mass-index für das kindes- und jugendalter unter heranziehung verschiedener deutscher stichproben
.
Monatsschr Kinderheilkd
.
2001 Aug 1
;
149
(
8
):
807
18
. .
24.
Dykens
EM
,
Maxwell
MA
,
Pantino
E
,
Kossler
R
,
Roof
E
.
Assessment of hyperphagia in Prader-Willi syndrome
.
Obesity
.
2007 Jul
;
15
(
7
):
1816
26
. .
25.
Blum
WF
,
Englaro
P
,
Hanitsch
S
,
Juul
A
,
Hertel
NT
,
Müller
J
,
Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone
.
J Clin Endocrinol Metab
.
1997 Sep
;
82
(
9
):
2904
10
. .
26.
Fernandez
BA
,
Roberts
W
,
Chung
B
,
Weksberg
R
,
Meyn
S
,
Szatmari
P
,
Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder
.
J Med Genet
.
2010 Mar
;
47
(
3
):
195
203
. .
27.
Walters
RG
,
Jacquemont
S
,
Valsesia
A
,
de Smith
AJ
,
Martinet
D
,
Andersson
J
,
A new highly penetrant form of obesity due to deletions on chromosome 16p11.2
.
Nature
.
2010 Feb 4
;
463
(
7281
):
671
5
. .
28.
Jacquemont
S
,
Reymond
A
,
Zufferey
F
,
Harewood
L
,
Walters
RG
,
Kutalik
Z
,
Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus
.
Nature
.
2011
;
478
(
7367
):
97
102
. .
29.
Morris
DL
,
Cho
KW
,
Zhou
Y
,
Rui
L
.
SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins
.
Diabetes
.
2009 Sep
;
58
(
9
):
2039
47
. .
30.
Jiang
L
,
Su
H
,
Wu
X
,
Shen
H
,
Kim
MH
,
Li
Y
,
Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease
.
Nat Commun
.
2020 Mar 23
;
11
(
1
):
1517
. .
31.
Thorleifsson
G
,
Walters
GB
,
Gudbjartsson
DF
,
Steinthorsdottir
V
,
Sulem
P
,
Helgadottir
A
,
Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity
.
Nat Genet
.
2009 Jan
;
41
(
1
):
18
24
. .
32.
Perez-Diaz-Del-Campo
N
,
Abete
I
,
Cantero
I
,
Marin-Alejandre
BA
,
Monreal
JI
,
Elorz
M
,
Association of the SH2B1 rs7359397 gene polymorphism with steatosis severity in subjects with obesity and non-alcoholic fatty liver disease
.
Nutrients
.
2020
;
12
(
5
):
1260
. .
33.
Zachurzok
A
,
Ranke
MB
,
Flehmig
B
,
Jakubek-Kipa
K
,
Marcinkiewicz
K
,
Mazur
A
,
Relative leptin deficiency in children with severe early-onset obesity (SEOO) – results of the Early-onset Obesity and Leptin – German-Polish Study (EOL-GPS)
.
J Pediatr Endocrinol Metab
.
2020 Feb 25
;
33
(
2
):
255
63
. .
34.
Roth
CL
,
von Schnurbein
J
,
Elfers
C
,
Moss
A
,
Wabitsch
M
.
Changes in satiety hormones in response to leptin treatment in a patient with leptin deficiency
.
Horm Res Paediatr
.
2018
;
90
(
6
):
424
30
. .
35.
Hsiung
HM
,
Hertel
J
,
Zhang
XY
,
Smith
DP
,
Smiley
DL
,
Heiman
ML
,
A novel and selective beta-melanocyte-stimulating hormone-derived peptide agonist for melanocortin 4 receptor potently decreased food intake and body weight gain in diet-induced obese rats
.
Endocrinology
.
2005 Dec
;
146
(
12
):
5257
66
. .
36.
Emmerson
PJ
,
Fisher
MJ
,
Yan
LZ
,
Mayer
JP
.
Melanocortin-4 receptor agonists for the treatment of obesity
.
Curr Top Med Chem
.
2007
;
7
(
11
):
1121
30
. .
37.
Otvos
L
 Jr
,
Terrasi
M
,
Cascio
S
,
Cassone
M
,
Abbadessa
G
,
De Pascali
F
,
Development of a pharmacologically improved peptide agonist of the leptin receptor
.
Biochim Biophys Acta
.
2008 Oct
;
1783
(
10
):
1745
54
. .
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.