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Holoprosencephaly: A Rare Finding in Mosaic Trisomy 9 Syndrome

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Serdar Mermer at Gazi University
Serdar Mermer
M. Özek
M. Özek
M. Özek
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Ferda Percin
Ferda Percin
Ferda Percin
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Meral Yirmibes Karaoguz at Gazi University
Meral Yirmibes Karaoguz
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Abstract

Mosaic trisomy 9 syndrome is a rare chromosomal abnormality and is well defined with dysmorphologic features such as upslanting and short palpebral fissures; deeply set eyes; micrognathia; and cardiovascular, genital, and brain abnormalities. Holoprosencephaly, a developmental brain abnormality, is a rarely seen in patients with mosaic trisomy 9 syndrome. Here we present a case of a patient with mosaic trisomy 9 syndrome with alobar type holoprosencephaly who died in the first hour of the natal period. As per the literature, this is the third case of mosaic trisomy 9 with holoprosencephaly to be reported. Therefore, we believe that holoprosencephaly might take part among the classic dysmorphic features of mosaic trisomy 9 syndrome.
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CASE REPORT
54
1Department of Medical
Genetics, Gazi University
Faculty of Medicine, Ankara,
Turkey
2Department of Perinatology,
Gazi University Faculty of
Medicine, Ankara, Turkey
Submitted
05.08.2017
Accepted
25.01.2018
Correspondence
Serdar Mermer, Department
of Medical Genetics,
Gazi University Faculty of
Medicine, Ankara, Turkey
Phone: +90312 202 44 44
e.mail:
doctorserdar@gmail.com,
doctorserdar@yahoo.com
©Copyright 2018
by Erciyes University Faculty of
Medicine - Available online at
www.erciyesmedj.com
Holoprosencephaly: A Rare Finding in Mosaic
Trisomy 9 Syndrome
Serdar Mermer1, Murat Özek2, Ferda Perçin1, Meral Karaoğuz1, Merih Bayram2
ABSTRACT Mosaic trisomy 9 syndrome is a rare chromosomal abnormality and is well defined with dysmorphologic features such as
upslanting and short palpebral fissures; deeply set eyes; micrognathia; and cardiovascular, genital, and brain abnormalities.
Holoprosencephaly, a developmental brain abnormality, is a rarely seen in patients with mosaic trisomy 9 syndrome. Here we
present a case of a patient with mosaic trisomy 9 syndrome with alobar type holoprosencephaly who died in the first hour of
the natal period. As per the literature, this is the third case of mosaic trisomy 9 with holoprosencephaly to be reported. There-
fore, we believe that holoprosencephaly might take part among the classic dysmorphic features of mosaic trisomy 9 syndrome.
Keywords: Holoprosencephaly, mosaic trisomy 9, PTCH1
Erciyes Med J 2018; 40(1): 54-6 • DOI: 10.5152/etd.2018.17094
INTRODUCTION
Holoprosencephaly (HPE), one of the most common developmental anomalies of the brain, is a clinical presen-
tation resulting from the failure of the prosencephalon to develop into two hemispheres in the early stages of
embryogenesis (1). Even though HPE, which displays genetic heterogeneity, can occur alongside numerical and
structural chromosomal abnormalities, it is also associated with monogenic and oligogenic syndromes as well as
environmental factors. While chromosomal abnormalities are identified in 24%–45% of HPE cases, trisomy 13 is
most frequently reported (2, 3). The case of holoprosencephaly presented here is accompanied by mosaic trisomy
9 syndrome, and based on our research, this is the third such reported case in the literature (4, 5).
CASE REPORT
Fetal ultrasound and echocardiography performed on the fetus of a 36-year-old woman during her first pregnancy
within the 21st week of gestation revealed intrauterine growth retardation (IUGR), absent nasal bone, bilateral
microphthalmia, holoprosencephaly, diaphragmatic hernia, atrioventricular septal defect, tricuspid atresia, and
pulmonary hypoplasia. The family, who were recommended amniocentesis, refused the invasive procedure, and
the baby was born through spontaneous vaginal delivery in the 39th week of pregnancy, with an Apgar score
of 3/6. The infant developed cardiopulmonary arrest and was unresponsive to resuscitation, resulting in death.
The deceased female infant was referred to our medical genetics department for genetic examination. A post-
mortem dysmorphological examination of the infant resulted in the discovery of brachycephaly, narrow forehead,
hypotelorism, deeply set eyes, microphthalmia, flattened nasal bridge with one nostril, posteriorly rotated ears,
camptodactyly, and bilateral single palmar crease (Figures 1 and 2). post-mortem brain tomography of the infant
revealed alobar holoprosencephaly (Figure 3), and the cytogenetic analysis of the fibroblast cell culture from two
separate flasks of skin biopsy from the antecubital region of the infant revealed mosaic trisomy 9 syndrome (mos
47,XX,+9[6]/46,XX[54]).
In this present case, the study of possible mutations, mainly in genes such as sonic hedgehog (SHH) and PTCH1,
related with the etiology of HPE, could not be performed because the limited amount of post-mortem skin material
was used up in the long-term tissue culture to obtain the metaphase plaques.
DISCUSSION
Mosaic trisomy 9 syndrome is a rare chromosomal anomaly wherein the affected cases usually exhibit IUGR,
micrognathia, low-set ears, rocker-bottom feet, and congenital heart anomalies. In certain rarer cases, various
anomalies of the central nervous system, including hydrocephaly, lissencephaly, and agenesis of the corpus cal-
losum as well as microcephaly, microphthalmia, cleft lip and palate, diaphragmatic hernia, simian crease, and
Cite this article as:
Mermer S, Özek M,
Perçin F, Karaoğuz
M, Bayram M.
Holoprosencephaly: A
rare nding in mosaic
trisomy 9 syndrome.
Erciyes Med J 2018;
40(1): 54-6.
genitourinary anomalies, can also be seen (6). Holoprosencephaly
is a heterogeneous clinical situation linked to various genetic com-
ponents where chromosomal aberrations also play a role. Non-
syndromic holoprosencephaly can be related with heterozygous
mutation of the SHH, ZIC2, SIX3, and TIGF1 genes; however,
in rare cases, a possible link to the patched1 (PTCH1) gene lo-
calized to the ninth chromosome and that suppresses the SHH
pathway has also been reported (7). SHH, a morphogen that plays
a role in the reproduction, position, and organization of cells within
developing tissue during the embryonic stage, is linked to Type
3 HPE (MIM: 142945), and the PTCH1 gene that encodes the
receptors for SHH is linked to Type 7 HPE (MIM: 610828) (8, 9).
In addition to suppressing the SHH pathway, a further relation is
also suggested between HPE and a mutation or gene duplication
resulting in an increase in the functions of the PTCH1 gene (10).
In the present case, the study of possible mutations, particularly in
genes such as SHH and PTCH1 related with the etiology of HPE,
could not be performed, as the limited amount of post-mortem
skin material was used up in the long-term tissue culture to obtain
the metaphase plaques.
Two other cases with similar clinical findings to ours (IUGR, flat-
tened nasal bridge, low-set ears, ventricular septal defect), where
HPE and mosaic trisomy 9 syndrome are found together, exist
in the literature. In contrast to our case, HPE is of the lobar type
in these cases (4, 5). In addition, no HPE was discovered in the
brain tomography of the Kaminker et al. (11) case diagnosed with
mosaic trisomy 9 syndrome. Nevertheless, taking into account the
imaging technology available at the time, it is possible that either
HPE was not discovered or the case may have been a microform
of HPE. Moreover, holoprosencephaly detected in our case may
have developed as a result of a dose increase in the PTCH1 gene
located on the ninth chromosome. Structural brain abnormalities
such as lissencephaly, hydrocephaly, and corpus callosum agenesis
have been reported in a comprehensive study of mosaic trisomy
9 syndrome cases. However, no holoprosencephaly anomaly was
detected in any of the 25 patients included in the article (12).
CONCLUSION
The fact that all three independent mosaic trisomy 9 syndrome
cases were accompanied by HPE supports the notion that HPE
may be a symptom of this aneuploidy as well as the suggestion by
other researchers that gain-of-function mutations of the PTCH1
gene may also cause HPE. However, further research is needed
to explain why this symptom is not present in all trisomy 9 cases.
Informed Consent: Written informed consent was obtained from patients
who participated in this study.
Peer-review: Externally peer-reviewed.
Author Contributions: Conceived and designed the experiments or case:
SM, MYK, FP. Performed the experiments or case: SM, MYK, MB, MO.
Analyzed the data: SM, MYK. Wrote the paper: SM, MYK.
All authors have read and approved the final manuscript.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study has received no
financial support.
Figure 1. Hypotelorism, flat nasal bridge, and microphthalmia
Figure 2. Single nostril
Figure 3. Alobar holoposencephaly in post-mortem cranial CT
55
Mermer et al. Holoprosencephaly with Mosaic Trisomy 9 SyndromeErciyes Med J 2018; 40(1): 54-6
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ResearchGate has not been able to resolve any citations for this publication.
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