Trisomy of chromosome 16p13.3 due to an unbalanced insertional translocation into chromosome 22p13.

Abstract

A dysmorphic boy with severe mental retardation was found on array CGH to have an insertional translocation of chromosome 16p13.3 into the short arm of chromosome 22, karyotype 46,XY,.ish der(22),ins(22;16)(p13;p13.3p13.3) de novo. His clinical features overlap with the reported cases of 'duplication 16p' syndrome, namely a round face, hypertelorism, a long philtrum, micrognathia, a thin upper lip, a posterior cleft palate and low set, simple ears, clubbed feet, severe developmental delay, psychomotor retardation and seizures. This 4-year boy with trisomy 16p13.3 has the smallest duplication reported of this critical region, which could not be detected without array CGH. The maximal duplicated region is gene rich and contains about 80 genes and/or candidate genes. Assignment of the genes that contribute to the observed phenotype awaits the characterisation of other patients with small duplications in this region.

Full text

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Chromosomal imbalance letter
Trisomy of chromosome 16p13.3 due to
an unbalanced insertional translocation into
chromosome 22p13
Thomy de Ravel, M.B.B.Ch., F.C.P. (S.A.), B.Sc. Hons.a,*,
PeterAerssens, M.D.b, Joris R.Vermeesch, Ph.D.a,
Jean-Pierre Fryns, M.D., Ph.D.a
aUniversity Hospital, Centre for Human-Genetics, Herestraat 49, Leuven, Belgium
bVirga-Jesse ZH, Hasselt, Belgium
Available online 13 June 2005
Abstract
A dysmorphic boy with severe mental retardation was found on array CGH to have an insertional
translocation of chromosome 16p13.3 into the short arm of chromosome 22, karyotype 46,XY,.ish
der(22),ins(22;16)(p13;p13.3p13.3) de novo. His clinical features overlap with the reported cases of
‘duplication 16p’ syndrome, namely a round face, hypertelorism, a long philtrum, micrognathia, a
thin upper lip, a posterior cleft palate and low set, simple ears, clubbed feet, severe developmental
delay, psychomotor retardation and seizures. This 4-year boy with trisomy 16p13.3 has the smallest
duplication reported of this critical region, which could not be detected without array CGH. The
maximal duplicated region is gene rich and contains about 80 genes and/or candidate genes.Assign-
ment of the genes that contribute to the observed phenotype awaits the characterisation of other
patients with small duplications in this region.
© 2005 Elsevier SAS.All rights reserved.
Keywords: Trisomy 16p13.3; Duplication chromosome 16p; Micro-arrays; Comparative genomic hybridisation;
Array CGH; Insertional translocation
1. Array CGH
Giemsa-banded karyotypes at an 800 band-level obtained from PHA stimulated lym-
phocyte cultures from the patient and both parents were normal. FISH analysis for dele-
* Corresponding author.
E-mail address: Thomy.deRavel@uz.kuleuven.ac.be (T. de Ravel).
European Journal of Medical Genetics 48 (2005) 355–359
www.elsevier.com/locate/ejmg
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doi:10.1016/j.ejmg.2005.05.009

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tions of chromosome 22q11 and all subtelomeres was normal as well as the screening of
selective exons in theATRX gene.Array CGH was performed [5].
2. Chromosomal anomaly
A de novo insertional translocation of chromosome 16p13.3 into the short arm of chro-
mosome 22 was present (Figs. 2,3). The minimal size of the insertion is 4.5 Mb, the maxi-
mal size 7 Mb (flanking clones within the duplication region are RP11-433P17 at 3.4 Mb
and RP11-148F10 at 7.9 Mb).
The karyotype is 46,XY, ish der(22),ins(22;16)(p13;p13.3p13.3) de novo.
This karyotype was confirmed by FISH and also to be de novo as both parents had no
translocations.
3. Clinical description
The maternal serum screening for chromosomal anomalies carried out at 15 weeks ges-
tation in the first and spontaneous pregnancy of a non-consanguineous couple indicated an
increased risk of 1 in 72 for trisomy 18. Echography at 16 weeks gestation indicated mild
polyhydramnios, marked foetal ascites, an enlarged liver, clubbed feet, relatively short
femora, a relatively large biparietal diameter and a thick placenta. A normal male karyo-
type 46,XY was found on amniocentesis.
Delivery occurred at 37 weeks gestation by caesarean section for poor labour progress
resulting from dystocia. Apgar scores were 5 and 9 at 1 and 5 min, respectively. The dys-
morphic newborn weighed 2750 g (P25–50), his length was 47 cm (P25–50) and head
circumference 34 cm (P75). The ascites and generalised oedema resorbed spontaneously
within a few days, whilst the remaining lax abdominal wall improved in tone over the
years. A poor suck reflex was associated with feeding problems, which persisted for the
first few years.
The large placenta weighed 650 g (95th centile = 470 g at 37 weeks gestation) and had a
para-marginal implantation of the three-vessel cord. Histology was normal.
The child maintained a length, weight and head circumference between the 25th and
50thcentiles.Hehasaroundface,brachycephaly,ahighforeheadandafrontalhairupsweep.
Hypertelorism,apparentmicrocorneae(cornealdiameters10and9.5mm = median),hyper-
metropiaandastigmatismarepresent.Theearsaresimple,small,cuppedandareimplanted
low. A pre-auricular fistula was present on the right. Retrognathia with a carp-like, wide
mouth with down-turned corners and fine lips, mild tongue-tie and a median cleft soft
palate, repaired at 20 months, were noted. He has a long philtrum and a short nose (Fig. 1).
Theclubbedfeetwithaverticaltaluswerecorrectedbyaperi-talusreleasewithposition-
pinning and an arthrotomy of the talo-navicular joint at 15 months of age whilst the dupli-
cated left thumb was surgically reduced at 18 months.
A microphallus and a small scrotal sac with testes are present. Myoclonic fits occurred
on day 1 and sodium valproate therapy is needed at 4 years of age.
Cardiac echography indicated a normal heart. Echography of the head and the abdomi-
nal organs was normal, as well as the CT scan of the brain.An electro-encephalogram and
BAEP were normal.
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Fig. 1. Photograph of the patient showing the round face, frontal hair upsweep, the low-placed, dysplastic, pro-
minent ears, the short nose, long philtrum and down-turned corners to the mouth.
Fig. 2. The array comparative genomic hybridisation of chromosome 16. The Y-axis represents the log 2 of the
intensity ratios of both dye swap experiments of patient/control DNA. The X-axis represents the chromosome
16 from the p arm telomere (left) to the q telomere. The interstitial duplication of chromosome 16p13.3 is indi-
cated by the markers around the log scale of 0.58.
Fig. 3. FISH analysis with BAC RP11-148F10 (green signal) indicating the two normal chromosomes
16p13.3 regions and a third signal on chromosome 22p (arrow).
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He has markedly delayed psychomotor development.At 18 months he began using sign
language and he said his first words at 20–24 months. Tone improved and he began crawl-
ing at 22 months of age.At 27 months the receptive and expressive aspects of his language
development were below the 12-month equivalent and developmental milestones were at a
9–11 months level, gross motor development at 7–12 months, and his fine motor skills at
15months.Visuomotororganisationwasequivalentto11months.At4yearsofageheuses
predominantly signs and noises to communicate.
4. Discussion
Pureinterstitialtrisomy16p13.3hasonlytwicepreviouslybeenreported.Apatientwith
an insertional duplication of 16p–16q, and a familial case resulting from paternal transmis-
sion of a chromosome with an ins(1;16)(q42;p13.1p13.3) have been reported [2]. Non-
detectioninthecasereportedherewaspossiblybecausetheresolutionoftraditionalkaryo-
typing could not discriminate between a terminal duplication and duplication at 2 Mb from
the telomere. Also, the insertion into the satellites of chromosome 22 makes it virtually
impossible to detect this duplication by regular karyotyping and reinforces the power of
array CGH for the detection of chromosomal imbalances.
Thepresentcasewithtrisomy16p13.3hasclinicalfeaturesoverlappingwiththereported
casesofterminalduplication16pter->p13[2–4].Althoughthereportedcaseshavealsohad
other chromosomes involved, the patients had features frequently seen in the ‘duplication
16p’syndrome and seen in this case, namely a round face, hypertelorism, a long philtrum,
micrognathia, a thin upper lip, a posterior cleft palate and low set, simple ears. Severe
developmental delay, psychomotor retardation, seizures and clubbed feet are also associ-
ated with this chromosomal anomaly (see review by Kokalj-Vokac et al., 2000 [2]).
Less frequently reported features seen in this patient include microcornea and a lax
abdominal skin (reported in one other case, [1]).Although hypoplastic thumbs are usually
seen [1], this patient had a duplicated left thumb.A micropenis, also found in this case, was
seen in the boy with a trisomy 16p13.1->pter associated with a deletion of 9p24->pter [4].
Survival in patients with trisomy 16p is usually limited. The 13-year old boy reported by
Kokalj-Vokac et al. [2] had a partial trisomy involving only the critical region 16p31.1–
16p31.3. The present 4-year boy with trisomy 16p13.3 is progressing steadily and has the
smallest duplication reported of this critical region.
The maximal duplicated region is gene rich and contains about 80 genes and/or candi-
dategenes.Assignmentofthegenesthatcontributetotheobservedphenotypeinthispatient
awaits the characterisation of other patients with small duplications in this region.
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