Content uploaded by Rossella Cannarella
Author content
All content in this area was uploaded by Rossella Cannarella on Sep 14, 2017
Content may be subject to copyright.
Available via license: CC BY 4.0
Content may be subject to copyright.
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
6
7
Endocrine Connections
6:7 528–539
R Cannarella Case report and review of the literature
Endocrine Connections
Open Access
Chromosome 15 structural
abnormalities: effect on IGF1R gene
expression and function
RossellaCannarella1, TeresaMattina2, RositaACondorelli1, LauraMMongioì1,
GiuseppePandini1, SandroLaVignera1 and AldoECalogero1
1Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
2Genetics, University of Catania, Catania, Italy
Abstract
Insulin-like growth factor 1 receptor (IGF1R), mapping on the 15q26.3 chromosome, is
required for normal embryonic and postnatal growth. The aim of the present study was
to evaluate the IGF1R gene expression and function in three unrelated patients with
chromosome 15 structural abnormalities. We report two male patients with the smallest
15q26.3 chromosome duplication described so far, and a female patient with ring
chromosome 15 syndrome. Patient one, with a 568 kb pure duplication, had overgrowth,
developmental delay, mental and psychomotor retardation, obesity, cryptorchidism,
borderline low testis volume, severe oligoasthenoteratozoospermia and gynecomastia.
We found a 1.8-fold increase in the IGF1R mRNA and a 1.3-fold increase in the IGF1R
protein expression (P < 0.05). Patient two, with a 650 kb impure duplication, showed
overgrowth, developmental delay, mild mental retardation, precocious puberty, low
testicular volume and severe oligoasthenoteratozoospermia. The IGF1R mRNA and
protein expression was similar to that of the control. Patient three, with a 46,XX r(15)
(p10q26.2) karyotype, displayed intrauterine growth retardation, developmental delay,
mental and psychomotor retardation. We found a <0.5-fold decrease in the IGF1R
mRNA expression and an undetectable IGF1R activity. After reviewing the previously
96 published cases of chromosome 15q duplication, we found that neurological
disorders, congenital cardiac defects, typical facial traits and gonadal abnormalities are
the prominent features in patients with chromosome 15q duplication. Interestingly,
patients with 15q deletion syndrome display similar features. We speculate that both
the increased and decreased IGF1R gene expression may play a role in the etiology of
neurological and gonadal disorders.
Introduction
Insulin-like growth factor 1 receptor (IGF1R) gene,
made up of 315,991 base pairs, maps on the 15q26.3
chromosome. It encodes for a protein with a tyrosine
kinase domain, which binds the IGF1 and is responsible
for its biological activity. Chromosomal 15q structural
abnormalities, such as distal duplication or ring 15, can
alter the IGF1R expression and function.
Up to now, more than seventy patients with
chromosome 15q terminal duplication have been reported
(1). The majority of them have a terminal duplication
with a proximal breakpoint ranging from 15q25.1 or
15q26.1 to the terminus (2). This structural chromosomal
abnormality causes a common phenotype that includes
prenatal and postnatal overgrowth, intellectual
10.1530/EC-17-0158
Correspondence
should be addressed
to A E Calogero
Email
acaloger@unict.it
Key Words
fIGF1
fIGF1R
fcryptorchidism
Endocrine Connections
(2017) 6, 528–539
528–539
Case report and review of the
literature
R Cannarella etal.
Research
Open Access
528:6
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
6
7
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:529
529–539
disability, characteristic craniofacial dimorphism and
renal abnormalities (3), resulting in the so-called 15q
overgrowth syndrome. However, failure to thrive and/
or intrauterine growth retardation (IUGR) have been
reported in some patients with chromosome 15q terminal
duplication (2, 4, 5), thus suggesting that triplication of
the IGF1R gene does not seem to be sufficient to cause
somatic overgrowth.
Patients with ring chromosome 15 have been associated
with growth delay, microcephaly, triangular face and a
variable degree of mental retardation (6). Approximately
40 cases have been reported in literature(7).
The aim of the present study was to evaluate the
IGF1R mRNA and protein expression and the IGF1R
protein activity in two male patients with chromosome
15q duplication and in one female patient with ring
chromosome 15. The phenotypes of these three patients
have been framed in the context of those found in the
other published cases by reviewing the literature.
Patients and methods
Case report
Patient one Patient 1 was a 19-year-old male, who had
attended the endocrinology outpatient clinic since the age
of 14years, complaining from tall stature. His birth weight
was 3150 g and he had a left undescended testis, that was
rescued by hCG administration for 6weeks when he was
2years old. He was also diagnosed for a moderate mental
and psychomotor retardation, crossness, uneasiness and
he had a marked defective speech capacity. The cardiologic
counseling revealed no abnormality.
On physical examination, he had high-arched palate,
ptosis and scoliosis. At the age of 8 years, he weighed
56.2 kg (>97th percentile), he was 144.9 cm (>99th
percentile) tall and had a cranial circumference (CC)
that measured 56 cm (>97th percentile). At the age of
14 years, these measurements were, respectively, 97 kg
(>97th percentile), 176 cm (90th percentile) and 57.5 cm
(>97th percentile). The testicular volume (TV) was 4 mL
bilaterally and both testes had an increased consistency.
Basal serum luteotropin hormone (LH), follicle-
stimulating hormone (FSH) and testosterone (T) levels
were 5.61 IU/mL (normal values (n.v.): 1.5–9.3 IU/mL),
5.37 IU/mL (n.v.: 1.4–18.1 IU/mL) and 1.87 ng/mL (n.v.:
3–9 ng/mL), respectively. When he was 15 years old,
the TV measured 8 mL bilaterally, and the T levels were
2.9 ng/mL. When he was 17 years old, he was at Tanner
stage 3, he had a triangular distribution of pubic hair and
a bilateral TV of 12 mL. Serum LH, FSH and T levels were,
in turn, 4.8 IU/mL, 9.1 IU/mL and 3.96 ng/mL, and the
IGF1 levels were 411.3 ng/mL (n.v.: 119–395 ng/mL). He
was 180 cm (50th–75th percentile; target height: 166.5 cm)
tall. At the age of 19years, the sperm analysis detected a
severe oligoasthenoteratozoospermia (total sperm count
0.5 million/ejaculate – n.v. >39 million/ejaculate, forward
sperm motility 3% – n.v. >32%, total sperm motility
10% – n.v. >40%, normally shaped spermatozoa 2% –
n.v.>4%).
Genetic analysis excluded both Prader–Willi and
Kallmann syndrome (KAL1, FGFR1, PROK2, PROK2R were
evaluated and no mutations resulted). He had a 46,XY
karyotype and a 568 kb pure duplication on the 15q26.3
chromosome, diagnosed by array-CGH. This duplication
was not detected in the mother. The father could not be
evaluated because he was not alive. The patient sister had
a normal psychophysical development, and she did not
show overgrowth.
Patient two Patient 2 was a 16-year-old male, admitted
for the first time to the Department of Pediatrics, teaching
hospital ‘G. Rodolico’, University of Catania, at the age
of 7years, for clinical signs of precocious puberty. He had
a marked defective speech capacity, a low-grade mental
retardation (IQ 66), a benign tachycardia and a low-
grade insufficiency of pulmonary valve. The abdomen
ultrasound, the brain magnetic resonance and the
electroencephalogram revealed no abnormality.
On physical examination, performed at the age of
7years, he weighed 39.8 kg (97th percentile), and he was
147.5 cm (>97th percentile) tall. The CC measured 54 cm
(75th percentile). Seven café-au-lait spots were detected,
the larger (7 × 4 cm) in the right groin, the others in the
right clavicular region, left lower limb, left hip and right
gluteus. He was at Tanner stage 3, and both testes had a
volume of 8 mL. His serum T levels were higher for his
age; the bone age was advanced by two years. The GnRH
analog test showed results compatible with precocious
puberty (serum hormone levels not available). On this
basis, he was prescribed Gonapeptyl Depot (1 injection
every 28days), which was administered from the age of 8
to that of 11years.
At the age of 11years, serum IGF1 levels were in the
normal range (262.8 ng/mL; n.v.: 49–520 ng/mL). At the age
of 14years, he weighed 77 kg (95th percentile) and he was
171 cm (75th percentile) tall. He was at Tanner stage 5 and
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:530
530–539
his LH and T serum levels were, respectively, 3.18 IU/mL
and 3.74 ng/mL. At the age of 16years, the TV was 11 mL,
bilaterally, and the LH, FSH and T values were, in turn,
2.93 IU/mL, 1.94 IU/mL and 5.26 ng/mL. The sperm
analysis detected a severe oligoastenotheratozoospermia
(total sperm count 0.15 million/ejaculate, forward
motility 3%, total motility 13%, normally shaped
spermatozoa2%).
The genetic analysis showed a 46,XY karyotype with
a 650 kb impure duplication on the 15q26.3 chromosome
(a 600 kb deletion on the 16p11.2 chromosome was also
found). The NF-1 (exons 1–58), OMG (exon 2), ASPA
(exon 6), PMP22 (exon 3), TRAF4 (exon 2, 4), SSH2 (exon
4, 14), BLMH (exon 2), CPD (exon 12), SUZ12P (exon 1,
3), CRLF3 (exon 3), ATAD5 (exon 2), ADAP2 (exon 3),
RNF 135 (exon 2), UTP6 (exon 14), SUZ12 (exon 10),
LRRC37B (exon 1), ZNF207 (exon 9), PSMD11 (exon
2, 6) and MYO1D (exon 2, 7) genes were evaluated to
exclude the presence of neurofibromatosis. The genetic
testing revealed no abnormality. The clinical history of
his biological parents is unknown since he was adopted.
Patient three Patient 3 was a 6-year-old female patient
presented to the Department of Pediatrics, teaching
hospital ‘G. Rodolico’, University of Catania, at the age
of 6 years, complaining from developmental delay. Her
birth weight was 1860 g, and her length was 44 cm. She
had mental and psychomotor retardation.
On physical examination, she weighed 10.3 kg (<3rd
percentile), she was 92 cm (<3rd percentile) tall and the
CC measured 41 cm (<3rd percentile). Café-au-lait spots
in the left side of chest, in the right leg, in the groin
and vitiligo in the right side of chest were detected. The
diagnosis of neurofibromatosis was clinically excluded.
She had triangular face, microcephaly, thin hairs, arched
eyebrows, blepharophimosis, broad nasal bridge and
slight superior lip. She had clinodactyly and shortness
of the second finger. The X-ray showed a bilateral extra
phalanx in the third finger, a bilateral hypoplasia of the
phalanx of the third finger and a bilateral dysmorphic and
hypoplastic phalanx in the second finger. FISH analysis
detected a 46,XX r(15) (p10q26.2) karyotype. According
to array-CGH results, she had a deletion of the last 5 Mb
of chromosome 15 and a duplication of 2 Mb. An absence
of paternal alleles in the terminal 15q chromosome
(from 95.258 Mb to qter) was found at the microsatellites
analysis. Thus, she did not have a paternal origin of the
rearrangement. At the age of 11years, serum IGF1 levels
were 186 ng/mL (n.v.: 87.4–399.3 ng/mL). She underwent
GH replacement therapy from the age of 14years until the
age of 16years.
Cell cultures
Lymphocytes were isolated from whole blood by Ficoll,
according to the manufacturer’s instructions using
Ficoll-Paque Plus (Amersham). The cells obtained with
this procedure were grown for 48 h in RPMI medium
supplemented with 10% FBS, 1% glutamine and 2 µg/mL
phytohemagglutinin, divided in two aliquots: one for
RNA extraction and one for protein analysis.
Real-time PCR
Total RNA (5 µg) was reverse-transcribed by ThermoScript
RT (Invitrogen) with Oligo dT primers. Synthesized cDNA
(25 ng) was then used for a quantitative real-time PCR,
using the following primers: 5′-GGG-CCA-TCA-GGA-
TTG-AGA-AA-3′ (forward) and 5′-CAC-AGG-CCG-TGT-
CGT-TGT-CA-3′ (reverse) specific for the IGF1R (fragment
size, 330 bp) and 5′-ATT-GAA-GAA-ATT-GCA-GGC-TC-3′
(forward) and 5′-TGG-AGA-AGA-GGA-GCT-GTA-TCT-3′
(reverse) specific for the ELE1 (housekeeping gene)
(fragment size, 280 bp), on an ABI Prism 7500 (PE Applied
Biosystems) using Sybr Green PCR Master Mix (PE Applied
Biosystems) following manufacturer’s instructions.
Amplification reactions were checked for the presence
of nonspecific products by dissociation curve analysis.
Relative quantitative determination of target gene
levels was performed by comparing ΔCt, as described by
Ginzinger. The PCR products were analyzed by 2% agarose
gel electrophoresis and stained by Sybr Safe.
IGF1R autophosphorylation
Lymphocytes cultured for 48 h were serum-starved for 24 h
being cultured in serum-free medium before undergoing
stimulation with 10 nM IGF1 for 5 min. Cells were lysed in
cold RIPA buffer containing 50 mM Tris pH 7.4, 150 mM
NaCl, 1% Triton X-100, 0.25% sodium deoxycolate,
10 mM sodium pyrophosphate, 1 mM NaF, 1 mM sodium
orthovanadate, 2 mM PMSF, 10 µg/mL aprotinin, 10 µg/mL
pepstatin, 10 µg/mL leupeptin and the insoluble material
separated by centrifugation at 10,000 g for 15 min at
4°C. Cell lysates were subjected to SDS-PAGE and the
resolved proteins were transferred to nitrocellulose
membranes, immunoblotted with anti-phospho-IR/IGF1R
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
CTL Patient 2Patient 1
*
Patient 3
Fold increase
0
0.5
1.0
1.5
2.0
*
Panel A
IGF1
R
ELE1
350
bp
300
bp
250
bp
MW CTL Patient 1Patient 2Patient 3
Panel B
Figure1
IGF1R mRNA expression. One microgram of RNA extracted from
lymphocytes was used as template for real-time RT-PCR, as described in
‘Methods’ section. Panel A: IGF1R mRNA was evaluated by quantitative
real-time PCR. Data were normalized with respect to ELE1 mRNA
expression. Results are given as fold-changes of control (CTL). Data are
the mean ± s.e.m. for two independent experiments. *P < 0.05. Panel B: The
PCR product were analyzed in a 2% agarose gel electrophoresis and
stained by SyBr Safe. CTL, control; MW, molecular weight; ELE, elongated
empty glume (housekeeping gene).
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:531
531–539
(Tyr1158/Tyr1162/Tyr1163) antibody and detected by
ECL. The nitrocellulose membrane was then stripped with
buffer Restore (Pierce) and, subsequently, reprobed with
an anti-IGF1R rabbit polyclonal antibody. The membranes
were blotted with an anti β-actin antibody to control for
protein loading.
Statistical analysis
Results are expressed as mean ± s.e.m. The data were analyzed
by one-way analysis of variance (ANOVA) followed by
Bonferroni post hoc test. SPSS 22.0 for Windows was used
for statistical analysis (SPSS). Statistical significance was
accepted when the P value was lower than 0.05.
Consent has been obtained from each patient or
subject after full explanation of the purpose and nature of
all procedures used. An approval by an ethical Committee
was not required because the data presented were obtained
during the routine diagnostic workout, which the three
patients underwent to within the Teaching Hospital of
the University of Catania.
Results
IGF1R mRNA expression
The IGF1R mRNA expression, evaluated in lymphocytes
using a relative quantification by real-time PCR, is shown
in Fig. 1. A healthy 17-year-old male with a normal
karyotype served as control. We found that the IGF1R
mRNA expression was significantly higher (1.8 ± 0.25
fold) in Patient 1 compared to the average IGF1R mRNA
expression of the control, whereas Patient 2 had a IGF1R
mRNA expression similar to that found in the control.
The IGF1R mRNA expression was significantly lower in
Patient 3, resulting in a decrease <0.5-fold compared
to that found in the control (Fig. 1A). Relative IGF1R
mRNA expression was normalized to the abundance
of ELE1 mRNA. Amplification reactions were checked
for the presence of nonspecific products by agarose gel
electrophoresis (Fig.1B).
IGF1R content and IGF1R tyrosine kinase activity in
response to IGF1
To confirm the results obtained by the real-time PCR,
lymphocyte lysates underwent to SDS-PAGE to evaluate
the IGF1R protein relative content and the IGF1R tyrosine
kinase activity after stimulation with 10 nM IGF1 (Fig.2).
After densitometric analysis and normalization by
β-actin, we found that Patient 1 had a significantly higher
IGF1R content (1.3 fold) than that of the control, Patient
2 had an IGF1R content similar to that of the control,
whereas the IGF1R content was lower in Patient 3
compared to that of the control (Fig.2A). After stimulation
with 10 nM IGF1, IGF1R was activated in both Patients
1 and 2 (Fig.2A), although in the Patient 1, due to the
higher IGF1R content, with a major increase respect to the
relative unstimulated control (Fig.2B). As expected, the
IGF1R autophosphorylation was undetectable in Patient
3 (Fig.2B).
Discussion
In the present study, we report two cases of chromosome
15q26.3 duplication and one case of ring chromosome
15 syndrome. Despite the genetic heterogeneity of
these patients, we recognized some common clinical
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
-+-+-+-+
Densitometric units
IGF1 10 nM
P-IGF1
R
Panel A
P-IGF-1R
IGF-1R
β-actin
IGF-1- + -+ -+ -+
CTLPatient 2Patient 1
Panel B
Patient 3
CTLPaent 1Paent 2Paent 3
*
*
*
*
IGF1R
Figure2
IGF1R autophosphorylation and IGF1R protein expression. Lymphocytes
isolated as described in the ‘Materials and methods’ section were lysed in
RIPA buffer. Panel A: Cell lysates underwent to SDS-PAGE and the
resolved proteins were transferred to nitrocellulose membranes,
immunoblotted with anti-phospho-1R/IGF1R (Tyr1158/Tyr1162/Tyr1163)
antibody and detected by ECL. The nitrocellulose membrane was then
stripped with buffer Restore and, subsequently, reprobed with an
anti-IGF1R rabbit polyclonal antibody. The membranes were blotted with
an anti-β-actin antibody to control for protein loading. Panel B:
Densitometric analysis was performed on two independent experiments.
Data are the mean ± s.e.m. of two independent experiments. *P < 0.05. CTL,
control; P-IGF1R, phosphorylated IGF1R.
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:532
532–539
features, which became clearer after reviewing the already
published cases.
Chromosome 15q duplication
To our knowledge, only one case of a de novo chromosome
15q26.3 duplication has been reported to date (8). Two
familial 15q26.3 duplications, respectively of 1.48 and
0.77 Mb, have recently been described (9). To understand
the role that this specific breakpoint has in the clinical
feature of the 15q overgrowth syndrome, we evaluated the
IGF1R gene expression, the IGF1R biochemical activity,
serum IGF1 levels and the clinical feature of Patients 1
and 2, respectively having a 568 kb pure and a 650 kb
impure (Patient 2 had also a 600 16p11.2 kb deletion,
this latter known as an autism susceptibility locus (10))
chromosome 15q26.3 duplication. These represent the
smallest chromosome 15q duplications described so far.
A review of all cases of chromosome 15q duplication
described up to now follows.
Chromosome 15q duplication: review of literature
and prevalence of the clinical characteristics The
structural abnormalities of chromosome 15q are rare. To
the best of our knowledge, up to now, 96 patients with
chromosome 15q duplication have been reported in
literature. Among these, 28 patients showed distal 15q
tetrasomy due to a mosaicism or to a neocentromer
marker chromosome (NMC) (2, 3, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)
and the others had 15q distal trisomy (1, 2, 3, 4, 5, 8,
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59). The
duplication of 15q chromosome can be classified in pure
and impure forms, based on the presence of another
chromosome abnormality (e.g. a deletion) in addition to
the duplication. The comparison of the clinical findings
between patients with pure and impure 15q duplication
did not show major phenotypic differences with the
exception for the life-span that seems lower in patients
with impure15q duplication (1, 5).
We carefully reviewed the clinical features of all
published patients with chromosome 15q duplication to
estimate the prevalence of each of them. Patients with
unknown measures or reports with no sufficient clinical
data available were excluded from this analysis. The
prevalence of each feature is summarized in Table1.
Mental retardation Mental retardation is a common
feature in patients with 15q distal duplication. Patients 1
and 2 share with patients previously reported in literature
neurological symptoms such as developmental delay,
mental and psychomotor retardation, marked defective
speech capacity (Table 1). As Chen and coworkers
reported, the region 15q24.3-qter contains several genes
involved in brain development and functioning (Table2)
(58). However, both Patients 1 and 2 had a chromosome
15q26.3 duplication, and none of these genes map in on
this duplicated segment. Thus, neurological symptoms
such as mental and psychomotor retardation, defective
speech capacity and developmental delay found in the
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:533
533–539
patients described in this study may be due to genes
mapping on the chromosomal band 15q26.3.
Overgrowth and IUGR Overgrowth is another common
feature in patients with 15q distal duplication (3, 8,
12, 13, 16, 17, 23, 42, 48, 49, 51, 52, 54, 57, 59). Up to
now, overgrowth has been attributed to the IGF1R gene
overexpression (52).
Interestingly, IUGR and failure to thrive have also been
described in these patients (2, 4, 5, 11, 18, 33, 35, 40, 43,
45, 46, 53, 55). Thus, triplication of the IGF1R gene does
not seem to be sufficient to cause somatic overgrowth.
Roggenbuck and coworkers hypothesized that the
discordance genotype–phenotype may be attributed to
the specific breakpoint, which may juxtapose the IGF1R
gene next to a very active promoter or, alternatively, may
remove it from its normal regulatory sequences (5). A
similar explanation has also been given by other authors.
Genesio and coworkers described the case of a multiple
malformed female with a de novo inverted duplication
of 15q (q21.3→26.3) associated with the deletion of the
15q telomere and part of the 15q26.3 band. She had a
severe clinical course due to congenital heart defect,
horseshoe kidney, hand contractures and clubfeet and
death occurred after 20days from birth because of cardio-
respiratory failure. Curiously, she had marked IUGR. This
feature was first ascribed to the 15q26.3 deletion, but FISH
analysis revealed three copies of the IGF1R gene. Since this
finding is not in agreement with the patient’s phenotype,
the authors hypothesized that the clinical feature may
depends on the global transcription dysregulation more
than to the impairment of a single gene specifically
correlated to the malformation (6). Finally, it has been
also hypothesized that the discordance between the
phenotype and the chromosome abnormalities may be
explained by an hidden mosaicism, since failure to thrive
has also been described in a 20-month-old female with
a 24 Mb chromosome 15q25.1q26.3 duplication and
mosaicism (2).
Facial and skeletal abnormalities Patients with
chromosome 15q distal duplication commonly have
facial abnormalities. The facial features more frequently
reported are down-slanting palpebral fissures, prominent
nose, low-set ears, micrognatia and high-arched palate.
Long face, puffy cheeks, long philtrum, pointed chin and
prominent occiput have also been reported (1, 3, 35, 40,
Table 1 Prevalence of the main clinical features in the patients described in this and in previously published studies (patients with chromosome 15q distal pure and
impure duplication, chromosome 15q tetrasomy, 15q deletion syndrome and chromosome ring 15).
15q duplication 15q deletion
15q pure duplication 15q impure duplication 15q tetrasomy 15q trisomy Ring chr. 15 syndrome 15q deletion syndrome
Patient 1 Literature Patient 2 Literature Literature Literature Patient 3 LiteratureaLiteratureb
Mental retardation + 100% (16/16) Yes 97.6% (40/41) 100% (12/12) 97.8% (44/45) Yes 95% Ye s
Developmental delay + 93.8% (15/16) Yes 97.3% (37/38) 17/17 (100%) 94.6% (35/37) Yes −Ye s
Defective speech capacity + 87.5% (14/16) Yes 68.8% (11/16) 50% (2/4) 82.1% (23/28) No 39% No
Overgrowth + 45.0% (9/20) No 44.9% (22/49) 52.9% (9/17) 42.3% (22/52) No −No
IUGR/growth retardation −20. % (4/20) No 22.4% (11/49) 11.8% (2/17) 25% (13/52) Yes 100% Ye s
Cardiac malformations −33.3% (6/18) Yes 50.0% (18/36) 16.7% (1/6) 47.9% (23/48) No 30% Yes
Kidneys malformations −38.9% (7/18) No 14.3% (5/35) 33.3% (7/21) 15.6% (5/32) No −No
Genital/gonadal abnormalitiesd+ 40.0% (2/5) No 45.9% (17/37) 18.2% (2/11) 54.8% (17/31) No 30% Yes
Cryptorchidism + 25.0% (1/4) Not knownc57.1% (8/14) 0% (0/3) 60.0% (9/15) / 30% Yes
Sperm abnormalities + NR Ye s NR NR NR / NR NR
Facial abnormalitiese+ 100.0% (19/19) Yes 98.0% (50/51) 100% (15/15) 98.2% (54/55) Ye s Ye s Yes
Hands abnormalities + 92.9% (13/14) No 70.3% (45/64) 95.6% (22/23) 65.4% (36/55) Yes Ye s Yes
Arachnodactyly −7.1% (1/14) No 25.0% (16/64) 21.7% (5/23) 21.8% (12/55) No No No
Café-au-lait spots −0% (0/12) Yes 5.0% (1/20) 0% (0/17) 6.7% (1/15) Yes 30% No
aFeatures reported by Butler etal. (66); bfrom OMIM database (http://omim.org/clinicalSynopsis/612626?highlight=15%20syndrome%20deletion); cthe patient was adopted; dincluding
cryptorchidism, hypoplasia of genitalia, hypospadias, congenital bilateral inguinal hernia, congenital hydrocele; eincluding down-slanting palpebral features, micrognathia, low-set ears,
high-arched palate, prominent nose, frontal bossing.
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:534
534–539
43, 49, 52, 59). In addition, they have hands abnormalities,
which more frequently consist of arachnodactyly
(Table1), but syndactyly, clinodactyly, long fingers and
joint contractures have also been reported (4, 5, 8, 31,
45,52, 53).
Cardiac malformation Cardiac malformations have
been found in about a half of patients (Table 1). These
include patent ductus arteriosus, mitral valve stenosis,
mitral valve arcade, patent foramen ovale, atrial and
ventricular septum defect, cardiomegaly, atrio-ventricular
canal, subaortic stenosis, Ebstein anomaly and Wolf–
Parkinson–White (WPW) syndrome. Almost three genes
related to the chromosome 15q duplication have been
pointed out to be the potential cause of cardiac and vessel
malformation: ADAMTSL3 (OMIM 609199 – cytogenetic
locations: 15q25.2) (29, 30, 60), MESP1 (OMIM: 608689
– cytogenetic locations: 15q26.1) and MESP2 (OMIM:
605195 – cytogenetic locations: 15q26.1) (29). ADAMTSL3
gene overexpression has been proposed also to interfere
with kidney function (60). This hypothesis is in line
with the absence of a major cardiovascular or kidney
malformation in patients 1 and 2 of the present study,
since ADAMTSL3, MEPS1 and MEPS2 genes do not map in
their duplicated region (15q26.3).
Gonadal and genital abnormalities Cryptorchidism (34,
38, 40, 43, 44) and genital abnormalities (including
hypospadias, hypoplasia of external genitalia, congenital
bilateral hernia and congenital hydrocele) (5, 25, 45,
51) have been reported in men with pure and impure
chromosome 15q distal duplication. Unfortunately, it
is noteworthy that the absence of a genital physical
examination (e.g. no information on TV) and of
gonadal function (e.g. serum LH, FSH and T levels) in
the vast majority of the studies that we reviewed may
underestimate the prevalence of gonadal abnormalities
in these patients. Furthermore, no study has evaluated
sperm parameters in these patients.
Ring chromosome 15
Patient 3 had a ring chromosome 15 syndrome (46,XX
r(15) (p10q26.2) karyotype) with a deletion of the terminal
5 Mb of chromosome 15. She had IUGR, developmental
delay, mental and psychomotor retardation, café-au-lait
spots, vitiligo and she underwent GH administration.
Her clinical feature was similar to that of patients with a
chromosome 15q26-qter deletion syndrome.
Jacobsen and coworkers were the first to describe the
ring chromosome 15 syndrome and since then, about
40 cases have been reported in literature. Among these,
only four cases were diagnosed prenatally (61). A ring
chromosome origins from a breakage in both the arms
of the chromosome and a fusion of the breakpoints,
with consequent loss of the distal fragments. This
results in monosomy of the distal short and long arms
of the chromosome involved (7). In several cases of ring
chromosome 15 syndrome, the IGF1R gene is deleted
suggesting a role of IGF1R in the observed growth
retardation (62, 63, 64, 65). In a review of 25 cases, the
following main features were found: IUGR (100%),
variable degree of mental retardation (95%), microcephaly
(88%), hypertelorism (46%) and triangular facies (42%),
delayed bone age (75%), brachydactyly (44%), speech
delay (39%) frontal bossing (36%), anomalous ears (30%),
café-au-lait spots (30%), cryptorchidism (30%), cardiac
abnormalities (30%) (66). These findings are in line with
those of the latest clinical reports. In addition, congenital
diaphragmatic hernia (CDH) is another clinical feature
described in these patients (7, 61, 67, 68).
The clinical features of chromosome 15q26-qter
deletion syndrome have been already summarized (http://
omim.org/clinicalSynopsis/612626?highlight=15%20
syndrome%20deletion): these patients have short
stature, low birth weight, failure to thrive, microcephaly,
neurological symptoms (delayed psychomotor
development and mental retardation), typical facial
abnormalities (micrognathia, triangular facies, low-set
ears, strabismus, blepharophimosis and broad nasal
bridge), congenital cardiac anomalies (septal defects), male
genitalia abnormalities (hypospadias, cryptorchidism and
Table 2 Genes involved in brain development and functioning located in the region 15q25.2–15q26.1.
Gene name OMIM Mapping on Encoding for
AP3B2 602166 15q25.2 Adaptor-related protein complex 3, β2 subunit
HOMER2 604799 15q25.2 Homer homolog 2 (Drosophila)
SH3GL3 603362 15q25.2 SH3-domain GRB2-like 3
NMB 162340 15q25.2–q25.3 Neuromedin B
CHD2 602119 15q26.1 Chromodomain helicase DNA-binding protein 2
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:535
535–539
micropenis), hand and feet abnormalities (brachidactyly,
absent or hypoplastic middle phalanges of hands, talipes
equinovarus).
Candidate genes
As it is simple to note, mental retardation, delayed
psychomotor development, IUGR, failure to thrive,
congenital cardiac defects, gonadal and genital
abnormalities and some facial traits (micrognathia, low-
set ears, broad nasal bridge) are described both in patients
with chromosome 15q duplication and in patients
with ring 15 chromosome syndrome. Consequently,
these clinical features may arise not from a decreased or
increased expression of genes mapping on chromosome
15q, but from an imbalanced expression of these genes.
Patients 1 and 2 of the present study, who share the
15q26.3 breakpoint, showed the same clinical findings
commonly described in previously reported patients
with 15q duplication (Table1), who generally have more
proximal breakpoint sites and longer duplications. Hence,
the clinical findings of patients with chromosome 15q
duplication might be reasonably due to the impaired
expression of genes mapped in the 15q26.3 chromosomal
band. In addition, all patients with a ring 15 chromosome
syndrome have a deletion of the 15q26.3 chromosomal
band. Thus, the candidate genes responsible for the
clinical characteristic described both in patients with 15q
duplication and in patients with ring 15 chromosome
syndrome might map within the 15q26.3 band.
Interestingly, an OMIM database research shows
that some of the genes mapped on this chromosomal
band are involved in cardiac, skeletal and neurological
abnormalities. In fact, the MEF2A gene (OMIM 600660)
encodes for a protein that maintains the appropriate
mitochondrial content and the cytoarchitectural
integrity in the postnatal heart in mice (69) and seems
to be responsible for cardiac abnormalities (coronary
artery disease and myocardial infarction) in humans
(70). Moreover, MEF2A has been suggested as a plausible
candidate gene responsible for CDH (71). In addition,
MEF2A mRNA is found in brain (72) and may play a
role during nervous system development (73). Thus,
MEF2A gene may be a candidate gene for cardiac and
neurological abnormalities in patients with chromosome
15q duplication and ring 15 chromosome syndrome, and
for CDH in patients with ring 15 chromosome syndrome.
CHSY1 gene (OMIM 608183) encodes for the
chondroitin sulfate synthase 1 that synthetizes a
glycosaminoglycan expressed on the surface of most
cells and in extracellular matrices. It causes the temtamy
preaxial brachydactyly syndrome (73). Li and coworkers
showed that in developing zebrafish, both loss and gain
of CHSY1 gene function lead to defects similar to those
in human patients with temtamy preaxial brachydactyly
syndrome, such as reduced body length, compromised
formation of the pectoral fin, severe midline deficiencies
in the cartilage of the neurocranium and compromised
formation of the epithelial protrusions and semicircular
canals in the inner ear (74). Hence, CHSY1 might be a
candidate gene responsible for skeletal abnormalities in
patients with chromosome 15q duplication and ring 15
chromosome syndrome.
MTR27 gene (OMIM 614340) has been reported to be
responsible for delayed psychomotor development with
very poor or lack of speech, head nodding, mild flattening
of the midface and hypotonia (75). It might play a role in
the incoming of neurological disorders in patients with
15q duplication and with ring 15 chromosome syndrome.
IGF1R gene may also be involved in the etiology of
neurological symptoms of these patients. In fact, IGF1
protein has been reported to pass through the blood–brain
barrier, and it is involved in normal central nervous system
(CNS) development by promoting neuronal cell survival
and synaptic maturation, thus facilitating functional
plasticity in the brain (76). It has been hypothesized that
elevated IGF1 levels in the cerebrospinal fluid may, in
combination with a reduced IGF1R gene expression due
to a chromosome 15q deletion or to a ring chromosome
15 syndrome, alter brain normal development (76).
None of the genes mapped in the chromosome
15q26.3 band seems to play a role in the etiology of
gonadal abnormalities, apart from the IGF1R gene. A
rational explanation of the presence of this feature has
been hypothesized by Nef and coworkers (77). They
reported that the insulin receptor (IR) tyrosine kinase
family (comprising IR, IGF1R and IR-related receptor (IRR))
is required for the development of male gonads and thus
for male sexual differentiation. In fact, XY mice that were
mutant for all 3 receptors developed ovaries and showed
a completely female phenotype. The decreased expression
of both Sry gene and the early testis-specific marker Sox9
in these mice suggests that the insulin signaling pathway
is required for male sex determination (77). In addition,
they observed sex-reversed phenotypes only when both
IGF1R alleles were mutated, while male embryos with one
mutant allele for IR or no mutant alleles for IRR showed
a partially sex-reversed phenotype. These data support
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:536
536–539
the idea that a threshold of insulin family signaling is
required to mediate normal male gonad differentiation:
in particular, the overall contribution of IGF1R is crucial
and higher than that of IR, which is itself higher than that
of IRR (77).
Similar studies in human do not exist. The evaluation
of the IGF1R gene expression in men with gonadal
abnormalities would help to better understand the role
that this gene might have in the development of male
gonads and in male sex differentiation in humans.
Finally, as far as we know, the presence of café-au-lait
spots has been hardly reported in patients with
chromosome 15q duplications. We describe the case of a
patient with an impure chromosome 15q duplication and
café-au-lait spots. This feature has also been reported in
30% of patients with ring 15 chromosome (66). Although
there is no evidence for a role of IGF1R on café-au-lait
spot pathogenesis, some GH-excess syndromes (e.g.
neurofibromatosis, McCune-Albright) include café-au-lait
spots (78). On the other hand, café-au-lait spots might
be ascribed also to the presence of the ring chromosome,
apart from the specifically involved chromosome, as
previously described (79). In the light of these evidences,
further studies are needed to evaluate the possible role of
the GHRH/GH/IGF1 axis, if any, in the etiopathogenesis
of this sign.
The limitations of our study include the use of a
17-year-old male as control: although it could be a good
choice for patients 1 and 2, its age and sex differ from
those of patient 3. However, we think that the results
found in this latter patient are reliable, because they fit
well with the clinical case. Furthermore, the prevalence
of gonadal and genital abnormalities (Table 1) may
be underestimated, since the major of studies did not
include the gonadal/genital evaluation at the physical
examination.
Conclusions
In conclusion, we found that the IGF1R mRNA and
protein expression were elevated in a patient with a 568 kb
15q26.3 pure duplication, normal in a patient with an
impure 15q26.3 650 kb duplication and a 16p11.2 600 kb
deletion and decreased in a patient with ring chromosome
15. IGF1R function was normal in both patients 1 and
2 and undetectable in patient 3. Clinically, patient 1
had overgrowth, moderate mental and psychomotor
retardation, marked defective speech, right hand
cryptorchidism, severe oligoasthenoteratozoospermia,
obesity, borderline low TV, borderline low serum T levels,
gynecomastia and triangular distribution of pubic hair.
Patient 2 had overgrowth, mild mental retardation,
marked defective speech, café-au-lait patches, precocious
puberty and severe oligoasthenoteratozoospermia.
Finally, patient 3 had IUGR, failure to thrive, mental and
psychomotor retard, café-au-lait patches.
We reviewed 96 patients with chromosome 15q
duplication and we summarized the main clinical
features in Table1. We found that some clinical features
of these patients, such as mental retardation, delayed
psychomotor development, congenital cardiac defects,
genitalia abnormalities and some facial traits are shared
also by patients with ring 15 chromosome syndrome. We
suggest that these common clinical features might be due
both to the over and down expression of genes mapped
on the chromosome 15q26.3.
We speculate that the IGF1R gene may play a role
in the etiology of neurological disorders and of gonadal
abnormalities in these patients. Accordingly, the relevance
of IGF1R in the male gonads development has been
already shown in mice (77). Further studies are necessary
to evaluate the role that the IGF1R gene plays in the
development of male gonads, in male sex differentiation
and sperm abnormalities in humans.
Declaration of interest
The authors declare that there is no conict of interest that could be
perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specic grant from funding agencies in
the public, commercial, or not-for-prot sectors.
Authors’ contribution statement
Rossella Cannarella: Conception and design of the study, data acquisition,
analysis and interpretation of data, drafting of the article, nal approval
of the version submitted. Teresa Mattina: Analysis and interpretation of
data, drafting of the article, nal approval of the version submitted. Rosita
A Condorelli: Acquisition of data, analysis and interpretation of data,
drafting of the article, nal approval of the version submitted. Sandro La
Vignera: Acquisition of data, analysis and interpretation of data, drafting
of the article, nal approval of the version submitted. Laura M Mongioì:
Acquisition of data, analysis and interpretation of data, nal approval of
the version submitted, drafting of the article. Giuseppe Pandini: Acquisition
of data, analysis and interpretation of data, drafting of the article, nal
approval of the version submitted. Aldo E Calogero: Conception and
design of the study, analysis and interpretation of data, critical revision of
the manuscript and nal approval of the version submitted.
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:537
537–539
References
1 Gutiérrez-Franco Mde L, Madariaga-Campos Mde L, Vásquez-
Velásquez AI, Matute E, Guevara-Yáñez R & Rivera H. A girl with 15q
overgrowth syndrome and dup(15)(q24q263) that included telomeric
sequences. Korean Journal of Laboratory Medicine 2010 30 318–324.
(doi:10.3343/kjlm.2010.30.3.318)
2 Luo M, Mulchandani S, Dubbs HA, Swarr D, Pyle L, Zackai EH,
Spinner NB & Conlin LK. Detection of mutually exclusive mosaicism
in a girl with genotype-phenotype discrepancies. American Journal
of Medical Genetics Part A 2015 167A 3091–3095. (doi:10.1002/
ajmg.a.37261)
3 Tatton-Brown K, Pilz DT, Orstavik KH, Patton M, Barber JC,
Collinson MN, Maloney VK, Huang S, Crolla JA, Marks K, et al. 15q
overgrowth syndrome: a newly recognized phenotype associated with
overgrowth, learning difficulties, characteristic facial appearance,
renal anomalies and increased dosage of distal chromosome 15q.
American Journal of Medical Genetics Part A 2009 149A 147–154.
(doi:10.1002/ajmg.a.32534)
4 Genesio R, De Brasi D, Conti A, Borghese A, Di Micco P, Di
CostanzoP, Paladini D, Ungaro P & Nitsch L. Inverted duplication
of 15q with terminal deletion in a multiple malformed newborn
with intrauterine growth failure and lethal phenotype. American
Journal of Medical Genetics Part A 2004 128A 422–428. (doi:10.1002/
ajmg.a.30112)
5 Roggenbuck JA, Mendelsohn NJ, Tenenholz B, Ladda RL & Fink JM.
Duplication of the distal long arm of chromosome 15: report of
three new patients and review of the literature. American Journal
of Medical Genetics Part A 2004 126A 398–402. (doi:10.1002/
ajmg.a.20617)
6 Jacobsen P, Mikkelsen M, Froland A & Dupont A. Familial
transmission of a translocation between two non-homologous
large acrocentric chromosomes clinical, cytogenetic and
autoradiographic studies. Annals of Human Genetics 1966 29 391–402.
(doi:10.1111/j.1469-1809.1966.tb00537.x)
7 Manolakos E, Vetro A, Kitmirides S, Papoulidis I, Kosyakova N,
MrasekK, Weise A, Agapitos E, Orru S, Peitsidis P, et al. Prenatal
diagnosis of a fetus with ring chromosome 15 characterized by
array-CGH. Prenatal Diagnosis 2009 29 884–888. (doi:10.1002/
pd.2295)
8 Kim JH, Lee WM, Ryoo NH, Ha JS, Jeon DS, Kim JR, Kim JS & Lee SY.
A case of partial trisomy 15q253-qter. Korean Journal of Laboratory
Medicine 2009 29 66–70. (doi:10.3343/kjlm.2009.29.1.66)
9 Leffler M, Puusepp S, Žilina O, Zhu Y, Kuuse K, Bain N, BurgessT,
Õunap K & Field M. Two familial microduplications of 15q263
causing overgrowth and variable intellectual disability with normal
copy number of IGF1R. European Journal of Medical Genetics 2016 59
257–262. (doi:10.1016/j.ejmg.2015.12.002)
10 Fernandez BA, Roberts W, Chung, B, Weksberg R, Meyn S, Szatmari P,
Joseph-George AM, MacKay S, Whitten K, Noble B, et al. Phenotypic
spectrum associated with de novo and inherited deletions and
duplications at 16p112 in individuals ascertained for diagnosis
of autism spectrum disorder. Journal of Medical Genetics 2010 47
195–203. (doi:10.1136/jmg.2009.069369)
11 Yip MY, Parsons A & Hultén MA. A de novo tandem duplication
15(q21 leads to qter) mosaic. Clinical Genetics 2008 22 1–6.
(doi:10.1111/j.1399-0004.1982.tb01401.x)
12 Blennow E, Telenius H, de Vos D, Larsson C, Henriksson P,
JohanssonO, Carter NP & Nordenskjöld M. Tetrasomy 15q: two
marker chromosomes with no detectable alpha-satellite DNA.
American Journal of Human Genetics 1994 54 877–883.
13 Van den Enden A, Verschraegen-Spae MR, Van Roy N, DecaluweW,
De Praeter C & Speleman F. Mosaic tetrasomy 15q25–>qter in
a newborn infant with multiple anomalies. American Journal
of Medical Genetics 1996 63 482–485. (doi:10.1002/(SICI)1096-
8628(19960614)63:3<482::AID-AJMG13>3.0.CO;2-I)
14 Depinet TW, Zackowski JL, Earnshaw WC, Kaffe S, Sekhon GS,
Stallard R, Sullivan BA, Vance GH, Van Dyke DL, Willard HF, et al.
Characterization of neo-centromeres in marker chromosomes lacking
detectable alpha-satellite DNA. Human Molecular Genetics 1997 6
1195–1204. (doi:10.1093/hmg/6.8.1195)
15 Huang B, Ning Y, Lamb AN, Sandlin CJ, Jamehdor M, Ried T &
BartleyJ. Identification of an unusual marker chromosome by
spectral karyotyping. American Journal of Medical Genetics 1998 80
368–372. (doi:10.1002/(SICI)1096-8628(19981204)80:4<368::AID-
AJMG12>3.0.CO;2-B)
16 Rowe AG, Abrams L, Qu Y, Chen E & Cotter PD. Tetrasomy
15q25–>qter: cytogenetic and molecular characterization of
an analphoid supernumerary marker chromosome. American
Journal of Medical Genetics 2000 93 393–398. (doi:10.1002/1096-
8628(20000828)93:5<393::AID-AJMG9>3.0.CO;2-Z)
17 Hu J, McPherson E, Surti U, Hasegawa SL, Gunawardena S &
Gollin SM. Tetrasomy 15q253–>qter resulting from an analphoid
supernumerary marker chromosome in a patient with multiple
anomalies and bilateral Wilms tumors. American Journal of Medical
Genetics 2002 113 82–88. (doi:10.1002/ajmg.10708)
18 Spiegel M, Hickmann G, Senger G, Kozlowski P & Bartsch O. Two new
cases of analphoid marker chromosomes. American Journal of Medical
Genetics A 2003 116A 284–289. (doi:10.1002/ajmg.a.10916)
19 Ventura M, Mudge JM, Palumbo V, Burn S, Blennow E, PierluigiM,
Giorda R, Zuffardi O, Archidiacono N, Jackson MS, et al.
Neocentromeres in 15q24–26 map to duplicons which flanked an
ancestral centromere in 15q25. Genome Research 2003 13 2059–2068.
(doi:10.1101/gr.1155103)
20 Chen CP, Lin CC, Li YC, Chern SR, Lee CC, Chen WL, Lee MS,
Wang W & Tzen CY. Clinical, cytogenetic, and molecular analyses
of prenatally diagnosed mosaic tetrasomy for distal chromosome
15q and review of the literature. Prenatal Diagnosis 2004 24 767–773.
(doi:10.1002/pd.977)
21 Faivre L, Rousseau T, Laurent N, Gosset P, Sanlaville D, Thauvin-
Robinet C, Cusin V, Lionnais S, Callier P, Khau Van Kien P, et al. Prenatal
overgrowth and mosaic trisomy 15q25-qter including the IGF1 receptor
gene. Prenatal Diagnosis 2004 24 393–395. (doi:10.1002/pd.891)
22 James PA, Aftimos S & Oei P. Partial tetrasomy 15 due to a unique
inverted triplication of chromosome 15q24–q26. American Journal of
Medical Genetics 2004 130A 208–210. (doi:10.1002/ajmg.a.30238)
23 Huang XL, de Michelena MI, Mark H, Harston R, Benke PJ, Price SJ &
Milunsky A. Characterization of an analphoid supernumerary marker
chromosome derived from 15q25–>qter using high-resolution CGH
and multiplex FISH analyses. Clinical Genetics 2005 68 513–519.
(doi:10.1111/j.1399-0004.2005.00523.x)
24 Dalprà L, Giardino D, Finelli P, Corti C, Valtorta C, Guerneri
S, IlardiP, Fortuna R, Coviello D, Nocera G, et al. Cytogenetic
and molecular evaluation of 241 small supernumerary marker
chromosomes: cooperative study of 19 Italian laboratories. Genetics in
Medicine 2005 7 620–625. (doi:10.1097/01.gim.0000182876.57766.2d)
25 Mahjoubi F, Peters GB, Malafiej P, Shalhoub C, Turner A, Daniel A &
Hill RJ. An analphoid marker chromosome inv dup(15)(q261qter),
detected during prenatal diagnosis and characterized via chromosome
microdissection. Cytogenetic and Genome Research 2005 109 485–490.
(doi:10.1159/000084207)
26 Schluth C, Mattei MG, Mignon-Ravix C, Salman S, Alembik Y,
WilligJ, Ginglinger E & Jeandidier E. Intrachromosomal triplication
for the distal part of chromosome 15q. American Journal of Medical
Genetics A 2005 136 179–184. (doi:10.1002/ajmg.a.30745)
27 Liehr T, Utine GE, Trautmann U, Rauch A, Kuechler A, Pietrzak J,
Bocian E, Kosyakova N, Mrasek K, Boduroglu K, et al. Neocentric small
supernumerary marker chromosomes (sSMC) – three more cases and
review of the literature. Cytogenetic and Genome Research 2007 118
31–37. (doi:10.1159/000106438)
28 Levy B, Tegay D, Papenhausen P, Tepperberg J, Nahum O, Tsuchida T,
Pletcher BA, Ala-Kokko L, Baker S, Frederick B, et al. Tetrasomy 15q26:
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:538
538–539
a distinct syndrome or Shprintzen-Goldberg syndrome phenocopy?
Genetics in Medicine 2012 14 811–818. (doi:10.1038/gim.2012.54)
29 George-Abraham JK, Zimmerman SL, Hinton RB, Marino BS, Witte
DP & Hopkin RJ. Tetrasomy 15q252→qter identified with SNP
microarray in a patient with multiple anomalies including complex
cardiovascular malformation. American Journal of Medical Genetics A
2012 158A 1971–1976. (doi:10.1002/ajmg.a.35428)
30 Xu H, Xiao B, Ji X, Hu Q, Chen Y & Qiu W. Nonmosaic tetrasomy
15q252→qter identified with SNP microarray in a patient with
characteristic facial appearance and review of the literature.
European Journal of Medical Genetics 2014 57 329–333. (doi:10.1016/j.
ejmg.2014.04.011)
31 Fujimoto A, Towner JW, Ebbin AJ, Kahlstrom EJ & Wilson MG.
Inherited partial duplication of chromosome No 15. Journal of Medical
Genetics 1974 11 287–291. (doi:10.1136/jmg.11.3.287)
32 Pedersen C. Letter: partial trisomy 15 as a result of an unbalanced 12/15
translocation in a patient with a cloverleaf skull anomaly. Clinical
Genetics 1976 9 378–380. (doi:10.1111/j.1399-0004.1976.tb01591.x)
33 Zabel B & Baumann W. Trisomie partielle pour la partie distale du bras
long du chromosome 15 par translocation X/15 maternelle. Annales
de Génétique 1977 20 285–289.
34 Turleau C, de Grouchy J, Chavin-Colin F & Roubin M. Trisomie 15q
distale. Annales de Génétique 1977 20 214–216.
35 Chandler K, Schrander-Stumpel CT, Engelen J, Theunissen P & Fryns
JP. Partial trisomy 15q: report of a patient and literature review.
Genetic Counseling 1997 8 91–97.
36 Coco R & Penchaszadeh VB. Inherited parital duplication deficiency
of chromosome 15 (p12;q22). Journal of Human Genetics 1978 26
203–210.
37 Pai GS, Thomas GH, Mahoney W & Migeon BR. Complex
chromosome rearrangements: report of a new case and
literature review. Clinical Genetics 1980 18 436–444.
(doi:10.1111/j.1399-0004.1980.tb01790.x)
38 Tzancheva M, Krachounova M & Damjanova Z. Two familial cases
with trisomy 15q dist due to a rcp(5;15)(p14;q21). Human Genetics
1981 56 275–277. (doi:10.1007/BF00274678)
39 Gregoire MJ, Boue J, Junien C, Pernot C, Gilgenkrantz S &
ZergollernL. Duplication 15q22 to 15qter and its phenotypic
expression. Human Genetics 1981 59 429–433. (doi:10.1007/
BF00295485)
40 Howard-Peebles PN, Scarbrough PR, Sharpe J, Finley WH & Finley SC.
A complex chromosome rearrangement resulting in trisomy 15q22
to qter. Journal of Medical Genetics 1982 19 224–227. (doi:10.1136/
jmg.19.3.224)
41 Annerén G & Gustavson KH. A boy with proximal trisomy 15 and a
male fetus with distal trisomy 15 due to a familial 13p;15q translocation.
Clinical Genetics 1982 22 16–21. (doi:10.1111/j.1399-0004.1982.tb01404.x)
42 Kristoffersson U & Bergwall B. Partial trisomy 15(q25qter) in two brothers.
Hereditas 1984 100 7–10. (doi:10.1111/j.1601-5223.1984.tb00097.x)
43 Schnatterly P, Bono KL, Robinow M, Wyandt HE, Kardon N & Kelly
TE. Distal 15q trisomy: phenotypic comparison of nine cases in an
extended family. American Journal of Human Genetics 1984 36 444–451.
44 García-Cruz D, García-Esquivel L, Rivera H, Vaca G, Rolón A & Cantú JM.
Trisomy 15q23–qter due to a de novo t(11;15)(q25;q23) and assignment
of the critical segment. Annales de Génétique 1985 28 193–196.
45 Lacro RV, Jones KL, Mascarello JT, Jones OW, Wilson N & Jones MC.
Duplication of distal 15q: report of five new cases from two different
translocation kindreds. American Journal of Medical Genetics 1987 26
719–728. (doi:10.1002/ajmg.1320260327)
46 Goldstein DJ, Ward RE, Nichols WC & Palmer CG. Familial t(8;15)
(p233;q223): report of two cases with dup(15) (q223–qter). Journal of
Medical Genetics 1987 24 684–687. (doi:10.1136/jmg.24.11.684)
47 Van Allen MI, Siegel-Bartelt J, Feigenbaum A & Teshima IE.
Craniosynostosis associated with partial duplication of 15q and
deletion of 2q. American Journal of Medical Genetics 1992 43 688–692.
(doi:10.1002/ajmg.1320430407)
48 Wieczorek D1, Engels H, Viersbach R, Henke B, Schwanitz G &
Passarge E. Analysis of a familial three way translocation involving
chromosomes 3q, 6q, and 15q by high resolution banding and
fluorescent in situ hybridisation (FISH) shows two different
unbalanced karyotypes in sibs. Journal of Medical Genetics 1998 35
545–553. (doi:10.1136/jmg.35.7.545)
49 Zollino M, Tiziano F, Di Stefano C & Neri G. Partial duplication of
the long arm of chromosome 15: confirmation of a causative role in
craniosynostosis and definition of a 15q25-qter trisomy syndrome.
Genetics 1999 87 391–394.
50 Cora T, Acar H & Oran B. A partial trisomy 15q due to 15;17
translocation detected by conventional cytogenetic and FISH
techniques. Genetic Counseling 2000 11 25–32.
51 Nagai T, Shimokawa O, Harada N, Sakazume S, Ohashi H,
MatsumotoN, Obata K, Yoshino A, Murakami N, Murai T, et al.
Postnatal overgrowth by 15q-trisomy and intrauterine growth
retardation by 15q-monosomy due to familial translocation t(13;15):
dosage effect of IGF1R? American Journal of Medical Genetics 2002 113
173–177. (doi:10.1002/ajmg.10717)
52 Faivre L, Gosset P, Cormier-Daire V, Odent S, Amiel J, Giurgea I,
Nassogne MC, Pasquier L, Munnich A, Romana S, et al. Overgrowth
and trisomy 15q261-qter including the IGF1 receptor gene: report of
two families and review of the literature. European Journal of Human
Genetics 2002 10 699–706. (doi:10.1038/sj.ejhg.5200879)
53 Abe Y, Tanaka D, Soga T, Takeuchi T & Iikura Y. A case of de novo
distal duplication of chromosome 15. Clinical Genetics 2003 63 76–78.
(doi:10.1034/j.1399-0004.2003.630113.x)
54 Okubo Y, Siddle K, Firth H, O’Rahilly S, Wilson LC, Willatt L,
Fukushima T, Takahashi S, Petry CJ, Saukkonen T, et al. Cell
proliferation activities on skin fibroblasts from a short child with
absence of one copy of the type 1 insulin-like growth factor receptor
(IGF1R) gene and a tall child with three copies of the IGF1R gene.
Journal of Clinical Endocrinology and Metabolism 2003 88 5981–5988.
(doi:10.1210/jc.2002-021080)
55 Miller MS, Rao PN, Dudovitz RN & Falk RE. Ebstein anomaly and
duplication of the distal arm of chromosome 15: report of two
patients. American Journal of Medical Genetics A 2005 139A 141–145.
(doi:10.1002/ajmg.a.30921)
56 Bonati MT, Finelli P, Giardino D, Gottardi G, Roberts W & LarizzaL.
Trisomy 15q252-qter in an autistic child: genotype-phenotype
correlations. American Journal of Medical Genetics A 2005 133A
184–188. (doi:10.1002/ajmg.a.30503)
57 Kant SG, Kriek M, Walenkamp MJ, Hansson KB, van Rhijn A, Clayton-
Smith J, Wit JM & Breuning MH. Tall stature and duplication of the
insulin-like growth factor I receptor gene. European journal of Medical
Genetics 2007 50 1–10. (doi:10.1016/j.ejmg.2006.03.005)
58 Chen CP, Su YN, Tsai FJ, Lin HH, Chern SR, Lee MS, Hwang JK, Chen
TH & Wang W. Terminal 2q deletion and distal 15q duplication:
prenatal diagnosis by array comparative genomic hybridization using
uncultured amniocytes. Taiwan Journal of Obstetric Gynecology 2009 48
441–445. (doi:10.1016/S1028-4559(09)60343-0)
59 Chen CP, Lin SP, Chern SR, Tsai FJ, Wu PC, Lee CC, Chen LF, Lee
MS & Wang W. Deletion 2q373->qter and duplication 15q243->qter
characterized by array CGH in a girl with epilepsy and dysmorphic
features. Genetic Counseling 2010 21 263–267.
60 Hall NG, Klenotic P, Anand-Apte B & Apte SS. ADAMTSL-3/punctin-2,
a novel glycoprotein in extracellular matrix related to the ADAMTS
family of metalloproteases. Matrix Biology 2003 22 501–510.
(doi:10.1016/S0945-053X(03)00075-1)
61 Britto IS, Herbest S, Tedesco GD, Drummond CL, Bussamra LC, Araujo
Júnior E, Ruano R, Ruano SH & Aldrighi JM. Prenatal diagnosis of
a fetus with ring chromosomal 15 by two- and three-dimensional
ultrasonography. Case Reports in Obstetrics and Gynecology 2014 2014
4957020. (doi:10.1155/2014/495702)
62 Roback EW, Barakat AJ, Dev VG, Mbikay M, Chrétien M & Butler
MG. An infant with deletion of the distal long arm of chromosome
AUTHOR COPY ONLY
This work is licensed under a Creative Commons
Attribution 4.0 International License.
DOI: 10.1530/EC-17-0158
http://www.endocrineconnections.org © 2017 The authors
Published by Bioscientica Ltd
Research R Cannarella etal. Case report and review of the
literature
Endocrine Connections
6:539
539–539
15 (q261–qter) and loss of insulin-like growth factor 1 receptor gene.
American Journal of Medical Genetics 1991 38 74–79. (doi:10.1002/
ajmg.1320380117)
63 Tamura T, Tohma T, Ohta T, Soejima H, Harada N, Abe K &
NiikawaN. Ring chromosome 15 involving deletion of the insulin-
like growth factor 1 receptor gene in a patient with features of Silver-
Russell syndrome. Clinical Dysmorphology 1993 2 106–113.
64 Peoples R, Milatovich A & Francke U. Hemizygosity at the insulin-
like growth factor I receptor (IGF1R) locus and growth failure in the
ring chromosome 15 syndrome. Cytogenetic Cell Genetic 1995 70
228–234. (doi:10.1159/000134040)
65 Lacerda L, Carvalho JA, Stannard B, Werner H, Boguszewski MC,
Sandrini R, Malozowski SN, Leroith D & Underwood LE. In vitro and
in vivo responses to short-term recombinant human insulin-like
growth factor-1 (IGF-I) in a severely growth-retarded girl with ring
chromosome 15 and deletion of a single allele for the type 1 IGF
receptor gene. Clinical Endocrinology 1999 51 541–550. (doi:10.1046/
j.1365-2265.1999.00799.x)
66 Butler MG, Fogo AB, Fuchs DA, Collins FS, Dev VG & Phillips JA 3rd.
Two patients with ring chromosome 15 syndrome. American Journal of
Medical Genetics 1988 29 149–154. (doi:10.1002/ajmg.1320290119)
67 Tümer Z, Harboe TL, Blennow E, Kalscheuer VM, Tommerup N
& Brøndum-Nielsen K. Molecular cytogenetic characterization
of ring chromosome 15 in three unrelated patients. American
Journal of Medical Genetics A 2004 130A 340–344. (doi:10.1002/
ajmg.a.30035)
68 Hatem E, Meriam BR, Walid D, Adenen M, Moez G & Ali S. Molecular
characterization of a ring chromosome 15 in a fetus with intra uterine
growth retardation and diaphragmatic hernia. Prenatal Diagnosis 2007
27 471–474. (doi:10.1002/pd.1707)
69 Naya FJ, Black BL, Wu H, Bassel-Duby R, Richardson JA, Hill JA & Olson
EN. Mitochondrial deficiency and cardiac sudden death in mice lacking
the MEF2A transcription factor. Nature Medicine 2002 8 1303–1309.
(doi:10.1038/nm789)
70 Wang L, Fan C, Topol SE, Topol EJ & Wang Q. Mutation of MEF2A in
an inherited disorder with features of coronary artery disease. Science
2003 302 1578–1581. (doi:10.1126/science.1088477)
71 Biggio JR Jr, Descartes MD, Carroll AJ & Holt RL. Congenital
diaphragmatic hernia: is 15q261-262 a candidate locus? American
Journal of Medical Genetics 2004 126A 183–185. (doi:10.1002/
ajmg.a.20464)
72 Yu YT, Breitbart RE, Smoot LB, Lee Y, Mahdavi V & Nadal-GinardB.
Human myocyte-specific enhancer factor 2 comprises a group
of tissue-restricted MADS box transcription factors. Genes and
Development 1992 6 1783–1798. (doi:10.1101/gad.6.9.1783)
73 Mao Z, Bonni A, Xia F, Nadal-Vicans M & Greenberg ME. Neuronal
activity-dependent cell survival mediated by transcription
factor MEF2. Science 1999 286 785–790. (doi:10.1126/
science.286.5440.785)
74 Li Y, Laue K, Temtamy S, Aglan M, Kotan LD, Yigit G, CananH,
Pawlik B, Nurnberg G, Wakeling EL, et al. Temtamy preaxial
brachydactyly syndrome is caused by loss-of-function mutations
in chondroitin synthase 1 a potential target of BMP signaling.
American Journal of Human Genetics 2010 87 757–767. (doi:10.1016/j.
ajhg.2010.10.003)
75 Akawi NA, Al-Jasmi F, Al-Shamsi AM, Ali BR & Al-Gazali L. LINS,
a modulator of the WNT signaling pathway, is involved in
human cognition. Orphanet Journal of Rare Diseases 2013 8 87.
(doi:10.1186/1750-1172-8-87)
76 Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu
DD, Flannery R, Jaenisch R & Sur M. Partial reversal of Rett
syndrome-like symptoms in MeCP2 mutant mice. PNAS 2009
106 2029–2034. (doi:10.1073/pnas.0812394106)
77 Nef S, Verma-Kurvari S, Merenmies J, Vassalli JD, Efstratiadis A,
AcciliD & Parada LF. Testis determination requires insulin receptor
family function in mice. Nature 2003 426 291–295. (doi:10.1038/
nature02059)
78 Kanaka-Gantenbein C, Kogia C, Abdel-Naser MB & Chrousos GP.
Skin manifestations of growth hormone-induced diseases. Reviews
in Endocrine and Metabolic Disorders 2016 17 259–267. (doi:10.1007/
s11154-016-9378-8)
79 Shah KN. The diagnostic and clinical significance of café-au-lait
macules. Pediatric Clinics of North America 2010 57 1131–1153.
(doi:10.1016/j.pcl.2010.07.002)
Received in nal form 17 August 2017
Accepted 18 August 2017
