Download Split hand/foot malformations with microdeletions at chromosomes

Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 92e94
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Research Letter
Split hand/foot malformations with microdeletions at chromosomes
7 and 19 detected using array comparative genomic hybridization
Chin-Jui Wu a, Yi-Ning Su b, c, Tzu-Hung Lin b, c, Li-Hui Tseng d, Kuang-Han Chao a, *
a
Department of Obstetrics and Gynecology, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
c
Dianthus Maternal Fetal Medicine Clinic, Taipei, Taiwan
d
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
b
a r t i c l e i n f o
Article history:
Accepted 22 January 2014
The split hand/split foot malformation (SHFM), which is also
known as ectrodactyly, is a limb malformation syndrome involving
the central rays of the hand or foot. The typical SHFM may present
with syndactyly; median clefts of the hands and feet; and aplasia
or hypoplasia (or both) of the phalanges, metacarpals, and
metatarsals.
Numerous human gene defects can cause SHFMs. For example,
the SHFM1 gene is associated with deletions of varying extent on
chromosome 7q21eq22 [1], whereas SHFM2 is associated with
genes localized at Xq26eq26.16 [2]. Previous research has reported
multiple types of syndromic or nonsyndromic ectrodactyly [3]. The
most common mode of inheritance is autosomal dominant with
reduced penetrance. These cases can occur in families or in isolation. Interfamilial variability appears to be significantly greater than
intrafamilial variability, which indicates genetic heterogeneity. The
syndrome is characterized by various clinical manifestations that
vary significantly among affected individuals and generate various
combinations.
We present a case of “lobster claw hand” observed during a
prenatal ultrasound examination. A 21-week pregnant 39-year-old
woman (gravida 4, para 1) was referred to our hospital after the
detection of SHFM during fetal ultrasound screening (Fig. 1).
Ultrasonography at referral confirmed a fetus with SHFM but
without any facial or genitourinary anomaly. A review of her birth
history showed that her first son had syndactyly of his left hallux
* Corresponding author. Department of Obstetrics and Gynecology, College of
Medicine and Hospital, National Taiwan University Hospital, No. 7, Chung-Shan
South Road, Taipei, 10063, Taiwan.
E-mail address: [email protected] (K.-H. Chao).
and second toe, but no other detectable anomaly. The child's intelligence was also of normal development.
She sought genetic counseling for this pregnancy. The pregnancy was terminated because of the possible deletion of chromosomes. The abortus exhibited a specific characteristic of
deficiency of the second and third toes (Fig. 2). Both hands were
claw-like (Fig. 3). The placental tissue was examined using
oligonucleotide-based array comparative genomic hybridization
(aCGH) analysis with a CytoChip Oligo array (BlueGenome, Cambridge, UK). The genomic version of the chip is the CytoChip ISCA*
version 2.0 8x60K (BlueGenome, Cambridge, UK). We employed the
protocol presented in the reference manual (www.cytochip.com).
The results revealed three microdeletions: 1.9 Mb deletions
at 7p22.1ep22.1 (4,583,819e6,498,129), 3.9 Mb deletions
at 7q11.23eq11.23 (72,119,820e75,977,247), and 4.1 Mb deletions
at 7q21.3eq22.1 (97,723,732e101,812,625). Two other larger deletions were 24 Mb deletions at 19p13.3ep12 (210,424e
24,170,303) and 26.2 Mb deletions at 19q11.31eq13.43 (37,601,
047e63,787,200) (Fig. 4).
Split hand/split foot malformation has been identified by
numerous terms such as “ectrodactyly”, “cleft hand”, “partial terminal aphalangia”, “oligodactyly”, “central oligodactyly”, “central
ray deficiency”, “crab claw malformation”, and “lobster claw
anomaly/malformation”. Elliott et al [4] summarized previously
reported SHFM patients. Our patient was diagnosed prenatally,
which differs from numerous reported cases that are typically
observed after birth. In 1995, the first case was diagnosed during
pregnancy [5]. Detailed ultrasonography revealed multiple anomalies, which included oligodactyly. Split hand/split foot malformation is genetically heterogeneous with mutations identified at five
loci: SHFM1 at 7q21.3, SHFM2 at Xq26, SHFM3 at 10q24, SHFM4 at
3q27, and SHFM5 at 2q31 [3]. The location heterogeneity complicated the identification and genetic counseling.
Array comparative genomic hybridization is a technique that
enables high-resolution, genome-wide screening of segmental
genomic copy number variations. It is becoming an essential and
routine clinical diagnostic tool, and it is gradually replacing traditional cytogenetic methods [6].
http://dx.doi.org/10.1016/j.tjog.2014.01.006
1028-4559/Copyright © 2014, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
C.-J. Wu et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 92e94
93
Fig. 1. Ultrasound images of (A) a split foot and (B) a split hand.
A shortcome of classical karyotype analysis is that it lacks
sensitivity in detecting subtle chromosome rearrangements (i.e.,
<4 Mb). Fluorescent in situ hybridization has improved the diagnostic resolution, but it is a time-consuming targeted method that
requires previous knowledge of the chromosomal region. However,
comparative genomic hybridization platforms can cover approximately one clone per megabase to one clone per 100 kb. Commercial whole-genome oligonucleotide arrays range from one
probe per 6e70 kb. Shaikh [7] reported a detailed review and
comparison of various commercial oligonucleotide array platforms.
Five genomic loci have been implicated, based on cases and
family studies. These loci are SHFM1 (chromosome region,
7q21eq22), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27), and
SHFM5 (2q31). In the past, molecular tests such as fluorescence in
situ hybridization or polymerase chain reaction were used to detect
the mutated loci in people with SHFM. Because of improvements in
the resolution of aCGH, it detected SHFM type 1 in our patient. The
deletions at chromosome 7q21eq22 in patients with SHFM type 1
cause the deletion of several candidate genes including DLX5, DLX6,
or DSS1. A knockout mouse model showed the concurrent loss of
DLX5 and DLX6, and resulted in the failure of apical epidermal ridge
development; this was finally expressed as the phenotype of
ectrodactyly [3].
In addition to microdeletions of 7q, our patient had two other
microdeletions at chromosome 19p. In the literature, there has
been only one SHFM case report with genomic loci studies at 19p
[8]. Aten et al [8] identified a de novo deletion of chromosome
19p13.11 in a male patient with SHFM, but no candidate genes in
other SHFM loci (e.g., DSS1, FGF13, FBXW4, TP73L, and DLX2). Subsequent screening of 21 syndromic and nonsyndromic SHFM patients with no TP73L mutation failed to detect any deletion or
duplication in chromosome 19, which indicated that SHFM is
genetically more heterogeneous than previously reported. Chromosome 19p contained two genes (EPS15L1 and CALR3) that may be
associated with limb malformations [9]. EPS15L1 functions as a
substrate for tyrosine kinase activity of the epidermal growth factor
receptor [10]. The signal pathway of the epidermal growth factor
receptor is associated with the apical epidermal ridge, thereby
affecting limb formation.
We observed EPS15L1 gene deletion in our patient. However,
because of the concurrent loss of SHFM type 1 gene at chromosome
7, it was difficult to identify the relationship between phenotype
and genotype when both deletions are present.
If a couple with fetal anomalies accepts fetal chromosome
studies, aCGH could expand the ability to detect microdeletions in
genetic diseases. During genetic counseling, physicians should
Fig. 2. Symmetric defect of the left foot.
Fig. 3. Symmetric defect of the right hand.
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C.-J. Wu et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 92e94
Fig. 4. Array comparative genomic hybridization shows several deletions in chromosomes 7 and 19.
recommend an aCGH test for patients with a family history of fetal
anomalies.
Conflicts of interest
The authors have no conflicts of interest relevant to this article.
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