Vetro et al. Molecular Cytogenetics 2014, 7:41
http://www.molecularcytogenetics.org/content/7/1/41

CASE REPORTOpen AccessSevere growth hormone deficiency and pituitary
malformation in a patient with chromosome 2p25
duplication and 2q37 deletion
Annalisa Vetro1†, Sara Pagani2†, Margherita Silengo3, Mariasavina Severino4, Elena Bozzola5, Cristina Meazza2,
Orsetta Zuffardi6 and Mauro Bozzola2,7*

Abstract
We report on a male child ascertained at 4.8 years of age with severe growth failure, growth hormone (GH)deficiency, psychomotor delay with prevalent speech impairment, and a distinct phenotype. An evaluation of his
hypothalamic-pituitary region by Magnetic Resonance Imaging (MRI) revealed pituitary hypoplasia with pituitary
stalk interruption and ectopic posterior pituitary lobe, which are considered prognostic markers of permanent GH
deficiency. Prenatal chromosome analysis because of increased nuchal translucency revealed a normal male karyotype, whereas postnatal high resolution banding raised the suspicion of a 2q abnormality. Subsequently, array Comparative Genomic Hybridization (array-CGH) revealed a de novo complex genomic rearrangement consisting of a
2p25 duplication and a 2q37 deletion: arr[hg19] 2p25.3p25.1(30,341-9,588,369)x3,2q37.2q37.3(235,744,424243,041,305)x1. FISH analysis showed that the abnormal chromosome 2 mimicked the derivative of an inversion
with the duplicated 2p region located distally at 2q. This is, to the best of our knowledge, the first case with distal
2p25 duplication and 2q37 deletion and pituitary malformation leading to GH deficiency.
Keywords: 2p duplication, 2q deletion, Growth hormone deficiency, Pituitary hypoplasia

Background
The overall frequency of sub-microscopic causative deletions and duplications detected by chromosomal microarrays (CMA) in patients with intellectual disability/
multiple congenital malformations, is around 15-20%,
significantly higher in respect to that provided by conventional karyotyping [1].
Chromosome 2q37 deletion has been reported in morethan 100 patients most of whom display short stature,obesity, brachydactily and intellectual deficiency, which
are also observed in Albright syndrome [2]. The HDAC4
gene has notably been established as responsible for brachymetaphalangy and intellectual deficit observed inthese individuals [2,3]. Distal 2p duplication has also
* Correspondence: mauro.bozzola@unipv.it†
Equal contributors
2
Department of Internal Medicine and Therapeutics, Pediatric andAdolescent Unit, University of Pavia, Fondazione IRCCS San Matteo, Pavia,
Italy
7Internal Medicine and Therapeutics Department, University of Pavia,
Fondazione IRCCS San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy
Full list of author information is available at the end of the article

been reported although much more rarely and mostly inthe context of inv dup 2p syndrome [4,5]. The clinicalphenotype includes pre- and post-natal growth retardation, psychomotor delay, facial dysmorphism and, lessfrequently congenital heart malformations. To ourknowledge only three subjects have been reported tohave both the 2q deletion and 2p duplication two resulting de novo and one being the derivative of a maternal
pericentric inversion [6,7]. Due to the complexity of thechromosomal rearrangement and its rarity, a clinicaldiagnosis of this condition is almost impossible. Here,
we report on a four year-old child harboring a de novo
2p25 duplication and 2q37.1-qter deletion presenting
with severe psychomotor delay and complete GH deficiency due to pituitary hypoplasia. The molecular diagnosis had been significantly delayed since prenatal
cytogenetics analysis, performed to investigate increased
fetal nuchal translucency, resulted in a normal malekaryotype. As a consequence, the patient’s condition in
his early infancy was attributed to a Mendelian
syndrome.

© 2014 Vetro et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.

Vetro et al. Molecular Cytogenetics 2014, 7:41
http://www.molecularcytogenetics.org/content/7/1/41

Case presentation
The propositus was the second child of healthy nonconsanguineous Italian parents. His father and motherwere 40 and 37 years old, respectively. Ultrasound scanat the 22nd week of gestation revealed an increased fetal
nuchal translucency, while the amniocentesis showed anormal 46,XY fetal karyotype. The patient was born atterm (40 weeks) by spontaneous vaginal delivery. The
birth weight was 3340 g (0.51 SD), birth length 50 cm(0.53 SD), and OFC 36 cm (0.50 SD). Apgar scores were
9 and 9 at 1 and 5 minutes, respectively. Family history
was unremarkable. The father’s height was 165.8 cm andthe mother’s height was 148.5 cm with a mid-parental
height of 163.5 cm. His eight year-old sister was healthy.
At four months of age the parents noted the presenceof axial hypotonia. When first seen at one year of age,
he was noted to have dysmorphic features, including
micro-brachycephaly due to premature closure of theanterior fontanelle, prominent forehead, up-slanting palpebral fissures, low set ears and sparse hair. Brain ultrasound was normal. All developmental milestones were
delayed: he achieved head control at five months of age,sat unaided at nine months, and walked at 21 months.
He was able to speak in complete sentences at four
years. Because of a systolic murmur, at the age of threemonths a cardiac ultrasound examination revealed a mitral valve dysplasia with valve insufficiency, not requiring
surgical repair. He underwent speech therapy sessions
because of a mild perceptive hypoacusia found at fourmonths.
On physical examination at the age of 4.8 years hisheight was 89.1 cm (−4.05 SD), his weight was 11.9 kg(−0.57 SD), OFC was 48 cm (−1 SD) and growth velocity
was reduced for age (4 cm/year, i.e. -2.1 SD). He presented a characteristic phenotype including slight trigonocephaly, right palpebral ptosis, low set ears, small
mouth with a thin upper lip and micrognathia (Figure 1A), with small hands and feet with fleshy fingertips,
brachymetaphalangism (Figure 1B), bilateral single palmar creases, short neck and scoliosis. Chronic diseases
including intestinal malabsorption, celiac disease, constitutional skeletal diseases and hypothyroidism were excluded. Two pharmacological stimulus tests witharginine chlorohydrate and glucagon revealed a severe
growth hormone (GH) deficiency (peak of 1.7 and 2 ng/
ml, respectively), confirmed by IGF-I values: <25 ng/ml(−3.49 SD) that increased to 62.7 ng/ml after four subcutaneous GH injections suggesting good responsivenessto GH treatment (0.24 mg/Kg/week). No other pituitaryhormone deficiencies were found to be associated. A
brain MRI was performed with sagittal and coronal
3 mm-thick T1- and T2-weighted images for the
hypothalamic-pituitary region, revealing pituitary hypoplasia, pituitary stalk interruption and an ectopic

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Figure 1 Patient’s images. A) Patient at of 7.5 years showing facialcharacteristics including right palpebral ptosis, low set ears, andsmall mouth with thin upper lip. B) Patient’s hands
showing brachymetaphalangism.

posterior pituitary lobe (Figure 2A). Additionally, a small
focal nonspecific T2 hyperintensity was noted in theright globus pallidus that was unchanged at a 6-monthbrain MRI follow-up (Figure 2B). Substitutive GH therapy was started and led to a significant growth velocity
increase as shown in Figure 3. In fact, after the first yearof treatment, his height was 100 cm (−2.84 SD) andweight 15 Kg (−0.66 SD) with a significant increase in
growth velocity to 8.5 cm/yr (+2.51 SD). After the second year of GH therapy, his height and weight were
107.9 cm (−2.31 SD) and 17.5 Kg (−0.77 SD) respectively, with a significant increase in his growth rate to
7.9 cm (+3.04 SD).
Because of facial dysmorphisms, mitral valve dysplasia,
growth failure and mild developmental delay, Noonan
syndrome was considered in the differential diagnosis.
However, the sequencing of the PTPN11 gene, thePTPN11 gene, whose mutations can explain about 50%
of cases of Noonan syndrome [8], did not disclose any
alteration. Since the prenatal karyotype resulted to benormal, a high-resolution banding karyotype was requested, and an abnormality at the distal long arm of
one chromosome 2 was observed (Figure 4A). To
characterize the rearrangement, array-CGH analysis wasVetro et al. Molecular Cytogenetics 2014, 7:41
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Figure 2 Brain MRI of the patient at 4.8 years. A) Unenhanced midline sagittal T1-weighted image shows hyperintensity corresponding to ectopic posterior pituitary lobe at the median eminence (arrowhead). The pituitary gland and sella turcica are small, and the pituitary stalk is not visible (white arrow). B) Axial FLAIR image reveals a small nonspecific hyperintense lesion in the right globus pallidus (black arrow).

performed by using a 180 K platform (Agilent Technologies, Santa Clara, CA) [9]. A call for copy number variation (CNV) was done by at least three consecutive
probes with a log2ratio value significantly different from
0, by using Genomic Workbench v. 5.0.14 software (Agilent, ADM-2 algorithm with a threshold of 5). This analysis showed a complex genomic imbalance consisting ofa 2p25 distal duplication of about 9.6 Mb and a 2q37
distal deletion of about 7.3 Mb, containing 26 and 61
protein coding genes respectively: arr[hg19] 2p25.3p25.1(30,341-9,588,369)x3,2q37.2q37.3(235,744,424243,041,305)x1 (Figure 4B-D). Fluorescent In Situ
Hybridization (FISH) analysis, performed with subtelomeric chromosome 2 specific probes (VIJyRM2052 for
2p; D2S447 for 2q, both from Vysis TelVysion, Abbott
Molecular, Abbott Park, IL) confirmed the presence ofthe two imbalances and showed that the duplicated 2p
region was located distally at 2 q (Figure 4C). Since therearrangement was detectably by high-resolution banding, the same karyotype analysis was performed on parental blood samples showing that the rearrangement wasde novo.

Conclusion
Both 2p duplications and 2q deletions are usually observed as part of more complex duplication/deletion
syndromes, being distal imbalances frequently associatedwith the unbalanced segregation of a reciprocal translocation present in one parent or, more rarely, arisen denovo in the early embryo. Obviously, the presence of
two different imbalances, involving several genes atonce, makes clear genotype-phenotype correlations moredifficult and renders the recognition of the syndrome onclinical grounds almost impossible. Complex rearrangements involving a terminal short arm duplication and aterminal long arm deletion of the same chromosome
may result from meiotic recombination of a parental
pericentric inversion as in one patient reported by Armstrong et al., 2005 [6]. However many of these cases are
the result of a de novo event [10], suggesting that the rearrangement may occur in two steps, the first resulting
in a terminal deletion lately repaired by the capture of
the telomere of the opposite arm, thus resulting in its
duplication [9,11]. In our case both parents had a normal karyotype, suggesting that the rearrangement most
likely occurred through this mechanism.
In the literature only three viable patients with both ashort arm duplication and long arm deletion of chromosome 2 have been reported [6,7], two of them sharing
with our patient short stature, mild trigonocephaly, ptosis, low set ears, micrognathia, fleshy fingertips, scoliosis
and abnormal hearing [6]. In the third case, in which theextent of 2p duplication was not assessed, developmental
delay, short stature and dolichocephaly were reported[7]. Phenotypic findings in patients with chromosome 2q
terminal deletions correlate in some cases with breakpoints positions [2,12], although in many cases genotype–phenotype correlations have been impaired by thelack of molecular analysis or by the presence of a translocation derivative. However, almost all patients havemoderate to severe developmental delay, short stature,obesity and brachymetaphalangy [2,12,13]. The latter,
together with short stature, is characteristic of the
Albright’s hereditary osteodystrophy-like (AHO-like)Vetro et al. Molecular Cytogenetics 2014, 7:41
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Figure 3 Patient’s growth chart. In the figure height measurements from birth to 7.5 years are reported.

syndrome in patients with 2q37 deletions. Haploinsufficiency for the HDAC4 (Histone deacetylase 4) gene has
been proposed as responsible for the observed brachymetaphalangy and intellectual disability, with both deletions and truncating mutations reported in association
to this phenotype [3]. Although short stature seems to
be a common trait for both 2q terminal deletions or 2p
distal duplications, the presence of associated endocrinological defects has been rarely reported, and we areaware of only two reports of GH-deficiency in patientswith a 2q37 deletion [13,14]. We were not able to findany cases of pituitary stalk interruption in patients withsimilar rearrangements, either searching the literature orin public databases such as DECIPHER [15]. In our patient
26 and 61 protein coding genes are respectively duplicatedor deleted. Even using prioritization tools (Endeavour [16],ToppGene [17]), we were not able to find a convincing
candidate for his pituitary defect. Moreover, no pituitaryspecific expression is reported for any of the candidates.
We can speculate that in the non-deleted chromosome, agene necessary for the proper pituitary development ismutated, possibly unmasking a recessive condition.
In conclusion, this is the first case of distal 2p duplication and 2q deletion with severe short stature and pituitary hypoplasia, interrupted pituitary stalk and an ectopic
posterior pituitary lobe. These findings are consideredVetro et al. Molecular Cytogenetics 2014, 7:41
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Figure 4 Karyotype, array-CGH analysis, FISH analysis. A) Cut-out of chromosomes 2 from two metaphases. The der(2) are highlighted by thearrows. B) Array-CGH profile of patient’s chromosome 2 showing the 2p distal duplication (upper panel in the enlargement) and the concurrent
2q distal deletion (lower panel in the enlargement). The experiment was performed by using a 180 K platform (180 K SurePrint G3 Human Kit,
Agilent Technologies, Santa Clara, CA) as reported elsewhere [8]. C) FISH analysis with subtelomeric chromosome 2 specific probes (VIJyRM2052
in green, 2p; D2S447, in red, 2q; (Vysis TelVysion, Abbott Molecular, Abbott Park, IL) shows green signals at both extremities of the rearranged
chromosome 2 (yellow arrow), flanked by its normal homolog. D) The protein-coding genes included in the duplication (upper panel) and thedeletion (lower panel) are reported, according to UCSC Genome Browser (http://genome-euro.ucsc.edu/).

prognostic markers of permanent GH deficiency as detected in our patient and may be associated with otherhormonal defects causing variably severe panhypopituitarism [18] not present in our case. The diagnosis of GH
deficiency was confirmed by the significant increase in
growth rate after substitutive GH therapy.

Consent
Written informed consent was obtained from the patient’s parents for the publication of this report and any
accompanying images.

Abbreviations
GH: Growth hormone; MRI: Magnetic Resonance Imaging; CGH: Comparative
Genomic Hybridization; FISH: Fluorescent In Situ Hybridization; IGF-I: Insulinlike Growth factor I; SD: Standard deviation score.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
AV: she made substantial contribution to acquisition, analysis andinterpretation of data; she also revised the manuscript critically; SP: she madesubstantial contribution to acquisition of data and she has been involved indrafting the manuscript; MS: she revised the manuscript critically and gave
final approval of the version to be published; MS: she made substantial

Vetro et al. Molecular Cytogenetics 2014, 7:41
http://www.molecularcytogenetics.org/content/7/1/41

contribution to interpretation of data and revised the manuscript critically;
EB: she has been involved in drafting the manuscript; CM: she has been
involved in drafting the manuscript and revised the manuscript critically; OZ:
she made substantial contribution to conception design and interpretationof data; she revised the manuscript critically and gave final approval of theversion to be published; MB: he made substantial contribution to conception
design and gave final approval of the version to be published. All authors
read and approved the final manuscript.
Acknowledgement
The authors are grateful to Laurene Kelly for English revision of the paper.
Author details
1
Biotechnology Research Laboratory, Fondazione IRCCS San Matteo, Pavia,
Italy. 2Department of Internal Medicine and Therapeutics, Pediatric andAdolescent Unit, University of Pavia, Fondazione IRCCS San Matteo, Pavia,
Italy. 3Department of Public Health and Paediatric Sciences, University ofTorino, Torino, Italy. 4Neuroradiology Unit, Istituto Giannina Gaslini, Genoa,
Italy. 5Department of Pediatric Medicine, IRCCS Ospedale Pediatrico Bambino
Gesù, Rome, Italy. 6Department of Molecular Medicine, University of Pavia,
Pavia, Italy. 7Internal Medicine and Therapeutics Department, University ofPavia, Fondazione IRCCS San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy.
Received: 18 February 2014 Accepted: 27 May 2014
Published: 19 June 2014
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Cite this article as: Vetro et al.: Severe growth hormone deficiency andpituitary malformation in a patient with chromosome 2p25 duplicationand 2q37 deletion. Molecular Cytogenetics 2014 7:41.

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