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Interstitial deletion of chromosome 5 in a neonate due to maternal insertion ins(8;5)(p23;q33q35)

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American Journal of Medical Genetics 86:289–293 (1999)
Brief Clinical Report
Interstitial Deletion of Chromosome 5 in a Neonate
Due to Maternal Insertion, ins(8;5)(p23;q33q35)
Barbara Gibbons,1,3* Siew Yee Tan,1 Su Keyau Kee,1 Roger Quaife,1 and Seh Teen Lim2
1
Cytogenetics Laboratory, Gleneagles Hospital, Singapore
Department of Paediatrics, Hospital Sultanah Aminah, Johore Bahru, Malaysia
3
Cytogenetics Laboratory, Academic Department of Haematology, Royal Free and University College Medical School,
London, United Kingdom
2
We describe an infant girl with an interstitial deletion of chromosome bands 5q33 to
5q35 inherited from a maternal interchromosomal insertion ins(8;5)(p23;q33q35)
which was demonstrated by fluorescent in
situ hybridization with whole chromosome
paints. Physical anomalies included hypertonicity, microcephaly, short neck, apparently low-set ears, micrognathia, camptodactyly, mild rocker bottom feet, and hammer toe. Cardiac anomalies included a large
ventricular septal defect, patent ductus arteriosus, pulmonary hypertension and hypoplastic right ventricle. She died at age 3
months. Am. J. Med. Genet. 86:289–293,
1999. © 1999 Wiley-Liss, Inc.
KEY WORDS: interstitial 5q deletion; partial 5q deletion; del(5)
(q33q35); maternal insertion
INTRODUCTION
There are few descriptions of small terminal or subterminal deletions of distal 5q, here defined as 5q315qter. The largest deletion, 5q31.3-qter was described
by Lazjuk et al. [1985] in a malformed, stillborn infant.
Smaller deletions seen in liveborn infants have been
described as del(5)(q33q34) [Giltay et al., 1997], 5q33ter [Flannery et al., 1988], del(5)(q35) [Joseph et al.,
1990], del(5)(q35.1) [Kleczkowska et al., 1993], and
del(5)(q35.3) [Stratton et al., 1994]. A further patient
*Correspondence to: Barbara Gibbons, BSc(Hons) FRCPath,
Cytogenetics Laboratory, Queen Square House, Second Floor, Institute of Neurology, Queen Square, London W1CN 3BG, UK.
Received 7 October 1998; Accepted 21 April 1999
© 1999 Wiley-Liss, Inc.
with deletion of 5q from the pre-banding era was described by Lindenbaum and Butler [1971]. This small
number of cases has not permitted the delineation of a
recognizable resulting syndrome. Here we describe an
infant girl with an interstitial deletion of 5q33 to 5q35
inherited from a maternal interchromosomal insertion
ins(8;5)(p23;q33q35). Although more proximal interstitial deletions due to intrachromosomal insertion involving 5q have been previously described [Barber et
al., 1994; Cross et al., 1992], this is the first report of
interstitial distal deletion of 5q arising from a parental
balanced interchromosomal insertion.
CLINICAL REPORT
The patient, a girl, was born to non-consanguineous
Chinese parents at term with birth weight of 3.1 kg
(50th centile), length 55 cm (90th centile for weight),
and OFC 33.5 cm (<10th centile). No complications of
pregnancy or delivery were noted. Family history was
unremarkable.
At birth it was observed that the infant had some
facial anomalies and poor feeding. On the 21st day of
life she developed recurrent cyanotic spells following
bouts of coughing. On admission she was found to be
hypertonic with stiffness of all four limbs and in respiratory distress with intermittent cyanosis. She was
ventilated mechanically for 1 week.
Physical anomalies included microcephaly, hypertelorism with prominent epicanthic folds, short neck with
redundant skin, apparently low-set ears with normal
pinna and helix, micrognathia (Fig. 1), camptodactyly,
mild rocker bottom feet, and a hammer toe (Fig. 2).
Two-dimensional echocardiogram showed a large ventricular septal defect, patent ductus arteriosus, pulmonary hypertension, and hypoplastic right ventricle. She
remained in the hospital for another month during
which she was treated for heart failure and intercurrent infection. She was discharged at 2 months with
anti-heart-failure medication. However, she was readmitted again 10 days later for pneumonia which
290
Gibbons et al.
Fig. 1. A,B: Facial appearance of the patient.
needed ventilation. She died 2 weeks later. Consent for
autopsy was not granted.
CYTOGENETIC FINDINGS
Karyotyping was performed on G-banded metaphase
chromosomes after routine peripheral blood culture.
Synchronization by thymidine block [Gosden et al.,
1992] was used to obtain high resolution G-banded
chromosomes. Analysis of the patient’s chromosomes
showed an apparent deletion of chromosome 5q. The
parents were karyotyped to investigate if either was
a translocation carrier. The father’s karyotype was
normal 46,XY but the mother was found to be a carrier of a rearrangement between chromosomes 5 and
8 (Fig. 3). Metaphase cells from both the patient and
her mother were examined after fluorescent in situ
hybridization (FISH) with whole chromosome paints
Fig. 2. A,B: Camptodactyly and mild rocker bottom feet.
Inherited Deletion 5q
291
for chromosomes 5 and 8 (WCP 5, WCP 8, Cytocell),
which was performed following the manufacturer’s
instructions. Hybridization showed that the maternal
rearrangement was a balanced insertion (Fig. 4), the
mother’s karyotype being 46,XX,ins(8;5)(p23;q33q35)
and the child’s karyotype 46,XX,der(5)ins(8;5)(p23;
q33q35)mat.
DISCUSSION
Fig. 3. Partial karyotypes of the patient and her mother showing the
normal and derivative chromosomes of the ins(8;5)(p23;q33q35). The
mother has both derivative chromosomes, the patient has the derivative
chromosome 5 but not the derivative 8.
Fig. 4.
and 8.
The main clinical findings of the present and previously described cases with distal deletion of chromosome 5 are presented in Table I. The common region of
deletion in the cases of Kleczkowska et al. [1993], Joseph et al. [1990], Flannery et al. [1988], Lazjuk et al.
[1985], and the present case was 5q35.1. However, the
deletions are of different size (Fig. 5) and not surprisingly, although respiratory and feeding problems, limb
anomalies, and non-specific facial anomalies were reported, no specific clinical syndrome has been delineated. Neither the patient of Flannery et al. [1988] nor
Patient 2 of Lazjuk et al. [1985] had pure deletions of
chromosome 5q; the former had a ring chromosome involving deletion of distal 5p and the latter had duplication of band 10q26 arising from a maternal translocation, thus complicating the clinical picture.
Metaphase cell from the patient’s mother showing insertion ins(8;5)(p23;q33q35) by FISH with whole chromosome paints for chromosomes 5
292
Gibbons et al.
TABLE I. Clinical Manifestations in Partial 5q Deletion Syndrome*
Patient
Stratton
et al.,
1994
Kleczkowska
et al.,
1993
Deleted segment
Gender
q35.3-ter
M
q35.1-ter
F
q35-ter
F
Age
15 m
9m
died 19 d
Birth weight
Developmental delay
Respiratory problems
Feeding problems
Limb anomalies
Clinodactyly
Camptodactyly
Fingers
3913 g
mild
2980 g
severe
3448 g
Edema of the hands/feet
Nails
Head anomalies
Micro/macrocephaly
Brachycephaly
High protruding forehead
Potter-like facies
Epicanthus
Telecanthus/hypertelorism
Anteverted nares
Wide/flat nasal bridge
High arched palate
Retrognathia/hypognathia
Ear anomalies
CNS anomalies
Dandy-Walker malformation
hydrocephalus
polymicrogyria
cortical anomalies
heterotopia
agenesis corpus callosum
abnormal neuronal migration
Hypo/hypertonic
Cardiac anomalies
Urogenital anomalies
Ano/rectal anomalies
Redundant nuchal or neck skin
Abnormal chest wall
Dermatoglyphics
Excess fingertip whorls
Single transverse palmar crease
Joseph
et al.,
1990
Flannery
et al.,
1988
Lazjuk
et al.,
1985
?p14?q33
M
hermaphrodite
2.5 m
Lindenbaum
and Butler,
1971
Gibbons
et al.,
1999
Giltay
et al.,
1997
q31.3-ter
F
?
M
q33q35
F
q33q34
F
stillbirth
32 w
9m
died 3 m
6y
3030 g
severe
+
3100 g
3200 g
mild
severe
+
+
+
+
+
+
short
+
short
syndactyly
long
hypoplastic
hyperconvex
macro
micro
+
+
+
macro
+
micro
+
+
+
+
+
+
+
+
+
+
+
micro
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
low-set
+
+
+
+
+
+
hypo
ASD
hyper
PDA
multiple
inc
VSD
ASD
diastasis
recti
+
+
+
hypo
VSD
diastasis
recti
hypo
+
absent
anus
abnormal
rectum
hyper
+
+
+
+
+
+
hyper
multiple
inc
VSD
PDA
+
+
+
*inc ⳱ including; VSD ⳱ ventricular septal defect; ASD ⳱ atrial septal defect; PDA ⳱ patent ductus arteriosus.
The only notable facial similarity is between the
patients of Stratton et al. [1994] and Kleczkowska et
al. [1993], both with small distal deletions involving
only band 5q35. However, cardiac anomalies were
noted in 5 patients, and ano–rectal anomalies in 3 patients, suggesting the presence of developmental genes
at a distal 5q locus. The 3 hypotonic infants [Flannery
et al., 1988; Lindenbaum and Butler, 1971; Stratton
et al., 1994] also had an excess of fingertip whorls and/
or evidence of edema of the hands and/or feet as has
been seen in patients with more proximal 5q deletion
[Flannery et al., 1988]. Although CNS data were only
available on 5 patients, 4 had CNS anomalies and of
these the patient of Joseph et al. [1990] had abnormal
cortical layers, heterotopias, polymicrogyria, and a
Dandy-Walker malformation. Patient 2 of Lazjuk et al.
[1985] had abnormal neuronal migration, and Lindenbaum and Butler [1971] described a child with polymicrogyria and absent corpus callosum. Although chromosome breakpoints are uncertain in the case of Lindenbaum and Butler [1971], the data suggest the
possibility of a distal 5q locus affecting neuronal migration.
The deletion breakpoints in these cases have been
interpreted on the basis of G-banding and more precise
breakpoint assignments would require the application
of band-specific probes as illustrated by Giltay et al.
[1997]. Elucidation of clear clinical syndromes for deletions of distal 5q awaits further cases and precise
mapping of the breakpoints involved.
Inherited Deletion 5q
293
chromosome 5 resulting from a maternal intrachromosomal insertion.
J Med Genet 31:312–316.
Cross I, Delhanty J, Chapman P, Bowles LV, Griffin D, Wolstenholme J,
Bradburn M, Brown J, Wood C, Gunn A, Burn J. 1992. An intrachromosomal insertion causing 5q22 deletion and familial adenomatous
polyposis coli in two generations. J Med Genet 29:175–179.
Flannery DB, Rogers WG, Byrd JR. 1988. Ring chromosome 5. Clin Genet
34:74–78.
Giltay JC, Gerssen-Schoorl KBJ, Luitse GHJ, Dauwerse HG (1997). A case
of de novo interstitial deletion of chromosomne 5(q33q34). Clin Genet
52:173–176.
Gosden CM, Davidson C, Robertson M. 1992. Lymphocyte Culture in Human Cytogenetics A Practical Approach. Chapter 2. Eds Rooney DE
and Czepulkowski BH. Oxford. IRL Press.
Joseph P, Kimm J, Kalyan-Raman UP, Nixon JP. Hiller J. 1990. Terminal deletion of the long arm of chromosome 5. Am J Hum Genet
47:A31.
Fig. 5. Idiogram of chromosome 5 showing the deletions of (a) Stratton
et al. [1994], (b) Kleczkowska et al. [1993], (c) Joseph et al. [1990], (d)
Flannery et al. [1988], (e) Lazjuk et al. [1985], (f) present case, and (g)
Giltay et al. [1997].
Kleczkowska A, Fryns JP, van den Berghe H. 1993. A distinct multiple
congenital anomalies syndrome associated with distal 5q deletion
(q35.1qter). Ann Genet 36:126–128.
Lazjuk GI, Lurie IW, Kirillova IA, Zaletajev DV, Gurevich DB, Shved IA,
Ostrovskaya TI. 1985. Partial trisomy 5q and partial monosomy 5q
within the same family. Clin Genet 28:122–129.
REFERENCES
Lindenbaum RH, Butler LJ. 1971. Child with multiple anomalies and a
group B(4-5) long arm deletion (Bq-). Arch Dis Child 46:99–101.
Barber JC, Ellis KH, Bowles LV, Delhanty JD, Ede RF, Male BM, Eccles
DM. 1994. Adenomatous polyposis coli and a cytogenetic deletion of
Stratton RF, Tedrowe NA, Tolworthy JA, Patterson RM, Ryan SG, Young
RS. 1994. Deletion 5q35.3. Am J Med Genet 51:150–152.
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p23, q33q35, interstitial, due, insertion, chromosome, maternal, deletion, neonate, ins
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