Partial trisomy 9p and 14q microduplication in a patient with growth retardation: a case report and review of the literature

Abstract

Background
Trisomy is a common chromosomal aberration, which usually presents with similar phenotypic abnormalities and developmental delay. Although defined as chromosome abnormalities with recognized symptoms including growth retardation, trisomy 9p and trisomy 14q have been rarely reported to occur at the same time.

Case presentation
Here, we describe a 16-year-old adolescent female affected by developmental delay and mild intellectual disability. She was confirmed to have both partial trisomy 9p (p24.3-p23) and 14q11.2 microduplication by chromosome microarray analysis (CMA). It is speculated that the extra chromosome in the patient may be a derivative 14 chromosome inherited from the parent after 3:1 disjunction during meiosis. The extra 9p segment proves to be pathogenic while the duplicated 14q11.2 remains indefinite.

Conclusions
Further studies are needed to assign the genes responsible for the developmental delay and craniofacial dysmorphisms and appoint dosage-sensitive genes of chromosome 9p.

Full text

J Pediatr Endocrinol Metab 2020; aop
Jing Fana, Jing Zhoua, Diaozhu Lin, Ying Guo, Shaohua Li, Shaoling Zhang*, Liyang Liang
and Li Yan
Partial trisomy 9p and 14q microduplication in a
patient with growth retardation: a case report and
review of the literature
https://doi.org/10.1515/jpem-2019-0246
Received June 3, 2019; accepted November 18, 2019
Abstract
Background: Trisomy is a common chromosomal aber-
ration, which usually presents with similar phenotypic
abnormalities and developmental delay. Although defined
as chromosome abnormalities with recognized symptoms
including growth retardation, trisomy 9p and trisomy 14q
have been rarely reported to occur at the same time.
Case presentation: Here, we describe a 16-year-old ado-
lescent female affected by developmental delay and mild
intellectual disability. She was confirmed to have both
partial trisomy 9p (p24.3-p23) and 14q11.2 microdupli-
cation by chromosome microarray analysis (CMA). It is
speculated that the extra chromosome in the patient may
be a derivative 14 chromosome inherited from the parent
after 3:1 disjunction during meiosis. The extra 9p segment
proves to be pathogenic while the duplicated 14q11.2
remains indefinite.
Conclusions: Further studies are needed to assign the
genes responsible for the developmental delay and crani-
ofacial dysmorphisms and appoint dosage-sensitive genes
of chromosome 9p.
Keywords: chromosome microarray analysis (CMA); copy
number variants (CNVs); developmental delay; growth
hormone deficiency (GHD); partial trisomy 9; trisomy
14microduplication.
Background
Trisomy 9, the fourth most frequent chromosome abnor-
mality discovered, was reported in almost 200 patients
with a characteristic phenotype. The most common mani-
festations include growth retardation, cognitive disability,
craniofacial and hand abnormalities [1]. Meanwhile, fol-
lowing the first description of trisomy 14q, more than 50
patients have been recorded. This chromosome abnormal-
ity is clinically recognizable in general and characterized
by short stature, intellectual disability, craniofacial and
hand-foot dysmorphisms [2]. However, there are merely
no more than 20 patients with partial duplications of both
9p and 14q ever reported [3–7].
Here, we describe an adolescent female with a
47,XX, + mar.arr[GRCh37]9p24.3p23(208454_12613216) × 3,
14q11.2(20516277_21747366)x3 karyotype who was
diagnosed as having both partial trisomy 9p and
14q11.2microduplication.
Case presentation
A 16-year-old female patient was attended to at Sun Yat-sen
Memorial Hospital due to short stature. The proband was
the third child of healthy unrelated parents with a nega-
tive family history. She was born by vaginal delivery at
40weeks’ gestation. Intrauterine growth retardation was
noticed since she was born. The developmental mile-
stones and language development were significantly
delayed: she raised her head at 4months of age, sat at
9 months of age and independently walked and spoke
words at 2years of age. The patient was examined at the
age of 16years. She was 140cm tall (less than −3stand-
ard deviation [SD]) and her weight was 37.3 kg (less than
−2 SD), with a body mass index (BMI) of 19.0 kg/m2. Her
parents were 165.0 and 149.5 cm in height, respectively,
contributing to a 150.75 ± 8-cm target height. She had two
sisters and one brother of about 165cm height and all of
them were healthy.
aJing Fan and Jing Zhou contributed equally to this work.
*Corresponding author: Shaoling Zhang, MD, PhD, Department of
Endocrinology and Metabolism, Sun Yat-sen Memorial Hospital, Sun
Yat-sen University, 107 Yanjiang West Road, Guangzhou 510120,
People’s Republic of China, Phone: +86-20-81332286,
E-mail: zhangshaoling88@hotmail.com
Jing Fan, Jing Zhou, Diaozhu Lin, Ying Guo, Shaohua Li and LiYan:
Department of Endocrinology and Metabolism, Sun Yat-sen
Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
https://orcid.org/0000-0003-2842-3737 (J. Fan)
Liyang Liang: Department of Pediatry, Sun Yat-sen Memorial
Hospital, Sun Yat-sen University, Guangzhou, China
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2 Fan etal.: A case of partial trisomy 9p and 14q microduplication
In addition, she had moderate intellectual disability
and showed poor academic performance in school. Impair-
ment of calculation was obvious, yet the patient was coop-
erative, relevant and introverted during the conversation.
There was no sign of neural system disorders. Meningeal
irritation and nuchal rigidity were negative. Physical
examination showed a girl with a childish appearance,
including hypertelorism, mild epicanthus and a bulbous
nose (Figure 1A). Acanthosis nigricans on the neck and
rough skin on the hand were noted. There were no neck
webbing or specific palmar creases (Figure 1B).
She had severe short stature and the X-rays of the hands
and wrists revealed a 12-year-old bone age. Although basal
growth hormone (GH), insulin-like growth factor-1 (IGF-1)
and insulin-like growth factor binding protein-3 (IGFBP-3)
were within the normal range, GH in both the arginine and
levodopa activating tests was less than 5 ng/mL. Magnetic
resonance imaging (MRI) revealed poor development of
pituitary and general expansion of the ventricular system
(Figure 1C). Growth hormone deficiency (GHD) was diag-
nosed. Thyroid hormone level was also normal.
Besides, the sex gland axis was still inactivated accord-
ing to sex hormone secretion and gonadotropin-releasing
hormone (GnRH) activating test. Ultrasonography showed
a small uterus and ovary. Insulin resistance was found in
the oral glucose tolerance test with a normal glucose toler-
ance. Furthermore, metabolic indicators, including lipids,
glycosylated hemoglobin and uric acid, though within the
normal reference range of adults, were higher than those of
the same age and gender. Consultation of ophthalmologic
department suggested bilateral disk edema and ametropia.
Electrocardiogram and results of other laboratory studies
were normal (Supplementary Figure 1).
Materials and methods
This study was approved by the Local Ethics Committee and the
patient’ parents gave their written informed consent for publication
of clinical data and image.
Cytogenetic investigations (GTG banding) on 20 metaphases
obtained from phytohemagglutinin (PHA)-stimulated peripheral
lymphocytes of the patient were performed following standard pro-
tocols. Chromosome microarray analysis (CMA) was performed using
the Aymetrix CytoScan 750K SNP array (Aymetrix, Santa Clara, CA,
USA) with the Human GRCh37/hg19 genome version according to the
manufacturer’s protocols. The copy number variants (CNVs) detected
were aligned with known CNVs that were listed in databases, such
as the Database of Genomic Variants (DGV, http://dgv.tcag.ca/dgv/
app/home), Database of Chromosomal Imbalance and Phenotype
in Humans Using Ensembl Resources (DECIPHER, https://deci-
pher.sanger.ac.uk/), Online Mendelian Inheritance in Man (OMIM,
http://www.ncbi.nlm.nih.gov/omim/), International Standards for
Cytogenomic Arrays Consortium (ISCA, https://www.iscaconsor-
tium.org/) and local database. Additionally, the GTG banding was
performed by our hospital while the CMA was performed in Guang-
zhou Daan Clinical Laboratory Center.
Cytogenetic and cytogenomic results
Chromosome studies showed an extra marker chromo-
some in all 20 peripheral blood lymphocytes (Figure 2A),
basically excluding mosaic. The CMA study demonstrated
A
B
Figure 1: The proband at 16 years old.
(A) Frontal view of our patient, presented with mild craniofacial
dysmorphic features, such as hypertelorism, mild epicanthus and a
bulbous nose. (B) No characteristic hand malformations were found.
(C) MRI image showed the rudimentary pituitary and expanded
encephalocoele.
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Fan etal.: A case of partial trisomy 9p and 14q microduplication 3
that the marker coincided with one 12.4 Mb-size 9p
duplication and another 1.23 Mb-size 14q duplication
(Figure 2B, C). Aligned with known CNVs in DGV, DECI-
PHER, OMIM, ISCA and local database, the 12.4-Mb
duplication of 9p24-p23 proved to be pathogenic and
the 1.23-Mb duplication of 14q11.2was of uncertain clini-
cal significance. The final karyotype for this patient is
47,XX, + mar. arr[GRCh37] 9p24.3p23(208454_12613216) × 3,
14q11.2(20516277_21747366) × 3. Genetic studies were not
performed in both parents and her siblings.
C
Figure 1 (continued)
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4 Fan etal.: A case of partial trisomy 9p and 14q microduplication
Discussion
In this case, we present a 16-year-old female patient
affected by short stature, mild intellectual disability, men-
struation delay as well as dysmorphic features. A series
of examinations led to the diagnosis of partial trisomy 9p
and 14q microduplication.
Trisomy 9p syndrome, one of the most frequent
chromosome abnormalities ever discovered [1], affected
many systems and has specific manifestations as shown
in Supplementary Table 1. Among them, the craniofacial
and skeletal findings make this syndrome recognizable,
considered to be clues of diagnosis in clinical practice
[8], while development delay is the most common clinical
finding with pre- or postnatal onset [9]. Other symptoms,
including neural [10] and genitourinary abnormities [11]
and cardiac system defects [12], are relatively uncommon.
The extent of reported duplicated material may com-
prise part of 9p, the whole 9p or part of both 9p and 9q.
The present study shows that the minimal critical region
for the classical trisomy 9p is located at 9p22.2-22.3 [13].
The phenotypic variability depends on the extent and
region of duplicated material [14, 15], along with the fre-
quent concomitant monosomy or other chromosome
segments [4]. Phenotype-genotype correlation studies
suggested that duplication of 9pter-p11may lead to typical
craniofacial anomalies and rarely skeletal or visceral
defects, while trisomy for 9pter-q11 results in skeletal and
cardiac defects as well as typical craniofacial symptoms
[15]. Further study implies that the extra 9p mostly comes
from a parental translocation between chromosome 9
and another autosome [4]. Pure de novo originations are
rare and reported only in a few papers [10]. The latter is
usually due to the abnormal sister chromatid separation
in meiosis, presented as mosaicism.
Like other chromosome diseases, prenatal diagnosis
and intervention are of great importance to 9p trisomy.
The 2011 American College of Medical Genetics (ACMG)
Practice Guideline [1, 16] recommends genomic microar-
rays, used to assess DNA copy number, as a first-line test
in the initial postnatal evaluation of individuals with
multiple anomalies, developmental delay or intellectual
disability and autism spectrum disorders. Besides, appro-
priate follow-up is necessary in cases of chromosome
imbalance identified, including cytogenetic studies of the
patient, parental evaluation and clinical evaluation and
counseling. Among limited symptomatic treatment of
trisomy 9p syndrome, long-term therapy of recombinant
human growth hormone (rhGH) is recommended in those
with GHD [17]. However, further evidence-based studies
are needed for treatment with much safety and reliability.
Similarly, following the first report of trisomy 14q in 1972
by Allan [3], a characteristic phenotype was delineated in
more than 50 patients [2]. Partial trisomy 14q, described as a
Figure 2: (A) GTG banding techniques showed an extra marker chromosome in all 20 peripheral blood lymphocytes, basically excluding
mosaic. (B, C) The single-nucleotide polymorphism (SNP)-based array analysis showed copy number gains at 9p24.3p23 (B) and 14q11.2 (C).
The genomic coordinated (hg19): chr9: 208454_12613216 (B) and (hg19): chr14: 20516277_21747366 (C). The copy number gain regions are
denoted by a dark blue bar.
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Fan etal.: A case of partial trisomy 9p and 14q microduplication 5
recognizable pattern of malformations, includes growth and
developmental retardation, craniofacial as well as hand and
foot abnormalities [2]. Besides, as is the case with trisomy
9p, dosage of imprinted genes may influence the resulting
phenotype or severity of the manifestations [18]. Typical
regions are associated with 14pter-q22-24, while patients
with a smaller trisomy segment (14pter-q12) have similar
but milder features [19]. It can be observed that character-
istic phenotypes are overlapped in both partial trisomy 9p
and 14q, just as other duplicated chromosome syndromes,
which may lead to confusion in clinical practice.
In our case, two CNVs of 9p24.3-p23 and 14q11.2
detected by CMA led to the diagnosis of 9p partial trisomy
and 14q11.2 microduplication. The former is 12.4 Mb,
located in 208454_12613216, indicative of a partial trisomy
9p24.3-p23. The duplicated region refers to the 9p trisomy
syndrome according to the DECIPHER and ISCA data-
bases. There is one similar overlapping fragment in the
DECIPHER database (DECIPHER 338311). Phenotypes are
hypotonia, epilepsy and moderate intellectual disability.
Three almost same cases were discovered in ISCA (NSSV
579128, 145206, 13638908), characterized by developmen-
tal delay including short stature, speech and fine motor
delay. Therefore, CNV of 9p24.3-p23 duplication proves
to be pathogenic. There are totally 45 genes and 19 phe-
notypes involved in this region according to the OMIM
database. Candidate genes responsible for phenotypes of
our patient are MRD2 (OMIM 614113) and MRT16 (OMIM
614208), leading to mental retardation. Besides, HDLCQ1
(OMIM 606613) and GLIS3 (OMIM 610192), associated
with high-density lipoprotein cholesterol level and diabe-
tes, respectively, may play a role in the metabolism disor-
ders of our patient. Other morbid genes relate to deafness
(OMIM 613685), visual impairment (OMIM 610356,
613271), hematopathy (OMIM 147796) and so on.
Meanwhile, the duplicated 14q11.2 is 1.23 Mb, indicative
of a 14q11.2microduplication, seated in 20516277_21747366.
However, it involves no duplication or deletion syndrome
ever identified. No similar cases in DECIPHER or ISCA were
found. Additionally, this region contains three pathogenic
genes embodied in the OMIM database, respectively, asso-
ciated with Galloway-Mowat syndrome (OMIM 617729),
purine nucleotide deficiency (OMIM 613179) and amyo-
trophic lateral sclerosis (OMIM 611895). Due to incompat-
ible phenotypes with the above genetic diseases, it can be
inferred that the duplicated 9p24.3-p23 plays a leading role
in the pathogenic process. However, given that the infor-
mation on trisomy 14q remains still limited, along with
overlapping and confused phenotypes of different dupli-
cated chromosome syndromes, the CNV of 14q11.2 is of
uncertain clinical significance.
In summary, phenotypes of this patient are classi-
cal, compared with those given Supplementary Table1.
Growth retardation, mild intellectual disability and
marked facial appearance are noticeable. Besides, GHD is
diagnosed due to short stature (less than −3 SD), delayed
bone age (almost 4years old) and an inactivated GnRH-GH
axis. However, despite characteristic malformations, the
duplicated region in this girl, among one of the smallest
region ever reported (9p24.3-23), locating out of the criti-
cal region as well [13], is uncritical. Though duplication
of this segment is proved to pathogenic, inconsistency
in phenotype and genotype in this case may provide evi-
dence for further studies.
As mentioned earlier, most 9p trisomy owes to a mater-
nal translocation, only a few comes from a de novo origin [1,
4, 10]. It can be inferred to be a parental translocation origi-
nation due to a non-mosaic genotype. Further confirmation
needs fluorescence in situ hybridization (FISH), which is
essential to define the rearrangement around the centro-
meric region of chromosome 9, and clinical evaluation
and counseling of her family, yet were refused. The long-
term therapy of rhGH was refused due to poverty. She only
accepted calcium, vitamin D and estrogen-progestin treat-
ment. Until January 2019 estrogen retreating hemorrhage
has occurred. We suggested her to continue current medica-
tion for at least 3months. Following-up would be continued.
Learning points, what is new?
– Clinicians should be alerted to consider genetic dis-
eases in any patient with developmental delay and
other syndromic disorders.
– Genomic microarrays, used to assess DNA copy num-
ber variants, are the first-line test in the initial postna-
tal evaluation of individuals.
Author contributions: All the authors have accepted
responsibility for the entire content of this submitted
manuscript and approved submission.
Research funding: This work was supported by grants
from the Natural Science Foundation of China (81970683)
and the Natural Science Foundation of Guangdong Prov-
ince, China (2018A030313596, Funder Id: http://dx.doi.
org/10.13039/501100003453).
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played
no role in the study design; in the collection, analysis, and
interpretation of data; in the writing of the report; or in the
decision to submit the report for publication.
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6 Fan etal.: A case of partial trisomy 9p and 14q microduplication
Conflict of interest: All authors on this manuscript have
nothing to disclose.
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Supplementary Material: The online version of this article offers
supplementary material (https://doi.org/10.1515/jpem-2019-0246).
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