Chromosome 15q overgrowth syndrome: prenatal diagnosis, molecular cytogenetic characterization and perinatal findings in a fetus with dup(15)(q26.2q26.3)

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Case Report

Chromosome 15q overgrowth syndrome: Prenatal diagnosis, molecular

cytogenetic characterization, and perinatal findings in a fetus with

dup(15)(q26.2q26.3)

Chih-Ping Chen

a,b,c,d,e,f,

*

, Yi-Hui Lin

g

, Heng-Kien Au

h

, Yi-Ning Su

i

, Chin-Yuan Hsu

a

,

Yu-Peng Liu

j,k

, Pei-Chen Wu

a

, Schu-Rern Chern

b

, Yu-Ting Chen

b

, Li-Feng Chen

a

,

Adam Hwa-Ming Hsieh

l

, Wayseen Wang

b,m a

Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan b

Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan c_{Department of Biotechnology, Asia University, Taichung, Taiwan}

d_{School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan} e_{Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan} f_{Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan}

g_{Department of Obstetrics and Gynecology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan} h_{Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan}

i_{Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan} j_{Department of Radiology, Mackay Memorial Hospital Hsinchu Branch, Hsinchu, Taiwan}

k

Mackay Medicine, Nursing and Management College, Taipei, Taiwan l

University of Toronto, Ontario, Canada m

Department of Bioengineering, Tatung University, Taipei, Taiwan Accepted 30 May 2011

Abstract

Objective: To present molecular cytogenetic characterization of a prenatally detected duplication of 15q26.2

/ q26.3 in a fetus with overgrowth.

Case Report: A 34-year-old para 0 woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis

revealed a derivative chromosome 15, or der(15), with additional material at the end of the long arm of one chromosome 15. Parental karyotypes

were normal. Fetal overgrowth was first noted at 21 weeks of gestation. Repeated amniocentesis was performed at 22 weeks of gestation. Array

comparative genomic hybridization revealed a 4.71-Mb duplication from 15q26.2 to 15q26.3 encompassing the IGF1R gene. Fluorescence in

situ hybridization analysis using the bacterial artificial chromosome clone probes specific for 15q26.2-q26.3 and the subtelomeric region of 15q

showed a direct duplication and no terminal deletion in the der(15). Polymorphic DNA marker analysis determined a paternal origin of the

duplication of 15q. Level II ultrasound at 23 weeks of gestation revealed a fetal biometry equivalent to 26 weeks. The pregnancy was

subsequently terminated, and a 1062-g (>99

th

centile) malformed fetus was delivered at 24 weeks of gestation with craniofacial dysmorphism,

craniosynostosis, and overgrowth.

Conclusion: The present case provides evidence for prenatal overgrowth, craniosynostosis, and characteristic facial dysmorphism in association

with a duplication of 15q26.2

/ q26.3 and a duplication of the IGF1R gene. Prenatal diagnosis of fetal overgrowth should include a differential

diagnosis of the chromosome 15q overgrowth syndrome.

Copyright

Ó 2011, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.

Keywords: dup(15q); Duplication; 15q Overgrowth syndrome; Prenatal diagnosis

* Corresponding author. Department of Obstetrics and Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei, Taiwan. E-mail address:[email protected](C.-P. Chen).

Taiwanese Journal of Obstetrics & Gynecology 50 (2011) 359e365

www.tjog-online.com

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Introduction

The chromosome 15q overgrowth syndrome is an

over-growth syndrome caused by increased gene dosage of IGF1R

through duplication or triplication of the 15q26.1-qter region

involving 15q26.3 because of trisomy and tetrasomy of distal

chromosome 15q

[1]

. This syndrome is characterized by the

clinical features of overgrowth, learning difficulties, a

charac-teristic facial appearance of a long thin face with a prominent

chin and nose, and renal anomalies of renal agenesis,

horse-shoe kidneys, and hydronephrosis

[1]

. Prenatal diagnosis of

the chromosome 15q overgrowth syndrome is unusual. Here

we report prenatal diagnosis, molecular cytogenetic

charac-terization, and perinatal findings in a fetus with a duplication

of 15q26.2

/ q26.3 and overgrowth.

Case report

A 34-year-old, gravid 2, para 0, woman underwent

amnio-centesis at 18 weeks of gestation because of her advanced

maternal age. The woman had experienced two spontaneous

abortions. Her husband was 35 years old. Cytogenetic analysis

then revealed a derivative chromosome 15, or der(15), with

additional material at the end of the long arm of one

chromo-some 15 (

Fig. 1

). The parental karyotypes were normal. Prenatal

ultrasound examinations had revealed a fetal biometry

equiva-lent to 16 weeks [biparietal diameter (BPD)

¼ 2.9 cm (16

th

centile), femur length (FL)

¼ 2.2 cm (79

th

centile)] at 16 weeks

of gestation and a fetal biometry equivalent to 23 weeks

[BPD

¼ 5.78 cm (>99

th

centile), FL

¼ 3.54 cm (72

nd

centile)]

at 21 weeks of gestation. The woman requested amniocentesis at

22 weeks of gestation. Using uncultured amniocytes,

oligonu-cleotide (oligo)-based array comparative genomic hybridization

(aCGH) (CytoChip Oligo; BlueGnome, Cambridge, UK)

demonstrated a 4.71-Mb duplication from 15q26.2 to 15q26.3

(95,490,272e100,200,967 bp) (NCBI build 36, March 2006)

(

Fig. 2

). The result of oligo-aCGH was arr cgh 15q26.2q26.3

(95,490,272e100,200,967)3. For fluorescence in situ

hybrid-ization (FISH) determination of the orientation of the

duplica-tion and no terminal deleduplica-tion in the der(15), the bacterial

artificial chromosome (BAC) clone probes mapping the

genomic region of 15q26.2-q26.3 and the subtelomeric region

of 15q were used. The BAC clone probes RP11-308P12

(96,148,983e96,341,797) (spectrum green) and RP11-66B24

(99,149,459e99,322,865) (spectrum red) were used to

deter-mine the orientation of the duplication. FISH analysis showed an

orientation of green-[(red-green) or yellow]-red consistent with

the diagnosis of a direct duplication of distal 15q (

Fig. 3

). The

BAC clone probe RP11-259N2 (100,094,760e100,248,597)

(spectrum green) was used to determine the presence of the

subtelomeric region of the der(15). FISH analysis showed no

terminal deletion in the der(15) (

Fig. 4

). The karyotype of the

fetus was 46,XY,dup(15) (q26.2q26.3) (

Fig. 1

). Level II

ultra-sound at 23 weeks of gestation revealed a fetal biometry

equivalent to 26 weeks [BPD

¼ 6.7 cm (>99

th

centile),

abdominal circumference

¼ 21.6 cm (>99

th

centile), and

FL

¼ 4.56 cm (>99

th

centile). The internal organs were

unre-markable. The parents elected to terminate the pregnancy, and

a 1062-g (

>99

th

centile) malformed fetus was delivered at 24

weeks of gestation. The fetus manifested macrocephaly, an

elongated face, a sloping forehead, down-slanting palpebral

fissures, hypertelorism, a down-turned mouth, and a prominent

nose and chin (

Fig. 5

). Three-dimensional computed

tomog-raphy scans of the skull showed premature synostosis of the

metopic and coronal sutures (

Fig. 6

). Quantitative fluorescent

polymerase chain reaction analysis using polymorphic DNA

markers determined a paternal origin of the duplication (

Fig. 7

)

(

Table 1

).

Discussion

The

present

case

had

a

direct

duplication

of

15q26.2

/ q26.3 and a duplication of the IGF1R gene, and

manifested prenatal overgrowth, craniosynostosis, and

char-acteristic facial dysmorphism. Insulin-like growth factor 1

receptor [Online Mendelian Inheritance in Man (OMIM)

147370] is the receptor for type 1 insulin-like growth factor

(IGF1) (OMIM 147440). The IGF1R gene is mapped to

15q26.3 and is involved in growth, insulin-related phenotypes,

and longevity. The IGF1R gene is expressed equally from the

maternal and paternal alleles in humans and has not been

known to be imprinted

[2,3]

. Insulin-like growth factor 1

Fig. 1. (A) A karyotype 46,XY,dup(15)(q26.2q26.3) in the fetus. (B) Partial G-banded karyotype of the fetus showing one normal chromosome 15 and one derivative chromosome 15, or der(15), with dup(15q)(q26.2q26.3). The arrows indicate the breakpoints. dup¼ duplication.

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receptor is required for normal fetal and postnatal growth.

Gene dosage increase of IGF1R can lead to overgrowth,

whereas gene dosage decrease of IGF1R can cause growth

retardation. Okubo et al

[4]

reported accelerated growth of the

skin fibroblasts in a tall child with three copies of the IGF1R

gene and slower growth of the skin fibroblasts in a short child

with one copy of the IGF1R gene. Faivre et al

[5]

observed

a specific phenotype of macrosomia at birth, overgrowth,

macrocephaly, and mild developmental delay in patients with

trisomy 15q26.1-qter. Kant et al

[6]

reported tall stature and

mental retardation in patients with trisomy 15q26-qter and

a duplication of the IGF1R gene. Abuzzahab et al

[7]

postu-lated that mutations in the IGF1R gene may result in IGF1

resistance and underline intrauterine growth retardation and

subsequent short stature. Bonafe` et al

[8]

hypothesized that the

polymorphic variants of IGF1R play a role in systemic IGF1

regulation and human longevity by down-regulating the IGF1

pathway or IGF1 plasma levels.

Fig. 2. Oligonucleotide-based array comparative genomic hybridization shows a 4.71-Mb duplication from 15q26.2 to 15q26.3 [arr cgh 15q26.2q26.3 (95,490,272e100,200,967)3] (arrow). arr cgh ¼ array comparative genomic hybridization.

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Pure trisomy for distal 15q has been described in at least 15

patients

[1,4,6,9e14]

. In case of mixed or non-pure trisomy for

distal 15q, the chromosome aberration has arisen from an

unbalanced reciprocal translocation inherited from the parent

and contains a deletion of another chromosome. The phenotype

of such a case thus can be attributed to monosomy of the

involved chromosome in addition to partial trisomy 15q. The

reported monosomies associated with non-pure trisomy 15q

include monosomic components of chromosomes 2q

[6,15e18]

,

12p

[19]

, 13q

[5,20,21]

, 14p

[1]

, 15p

[1]

, and 20p

[5]

. Inv dup

del(15q) has been reported in one case

[30]

. Genesio et al

[30]

reported an inverted duplication of 15q and a terminal 15q

deletion in a case with three copies of the IGF1R gene, marked

intrauterine growth restriction, congenital heart defects,

horse-shoe kidneys, hand contractures, and club feet. In case of

tet-rasomy for distal 15q, the tettet-rasomy is the result of an acentric

inverted duplication of distal 15q in the form of mosaic or

non-mosaic distribution of an analphoid supernumerary marker

chromosome

[1,22e29]

. To date, about 41 patients with trisomy

or tetrasomy for distal 15q have been reported. Among the 41

reported cases with trisomy or tetrasomy for distal 15q, only six

cases manifested craniosynostosis

[15,19e21,25]

. Our case

adds to the list of trisomy or tetrasomy for distal 15q with

craniosynostosis.

Prenatal diagnosis of fetal overgrowth should include

a differential diagnosis of incorrect gestational dating; normal

Fig. 3. Fluorescence in situ hybridization using bacterial artificial chromosome

clone probes RP11-308P12 (96,148,983e96,341,797) (spectrum green) at 15q26.2-q26.3 and RP11-66B24 (99,149,459e99,322,865) (spectrum red) at 15q26.3. A direct duplication of 15q in the orientation of green-[(red-green) or yellow]-red is evident in the der(15). The inset shows the amplified der(15) and chromosome 15.

Fig. 4. Fluorescence in situ hybridization using bacterial artificial chromosome clone probes RP11-259N2 (100,094,760e100,248,597) (spectrum green) at 15q26.3 and RP11-138H15 (19,375,579e19,534,126) (spectrum red) at 15q11.2 as internal control shows presence of the green signal in the der(15).

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variants such as familial tall stature or familial rapid

matura-tion; secondary overgrowth which is due to humorally

medi-ated factors outside the skeletal system such as diabetic

macrosomia or congenital nesidioblastosis; and primary

overgrowth which is due to intrinsic cellular hyperplasia

[31,32]

. Genetic considerations of primary overgrowth in

prenatal-onset overgrowth include trisomy or tetrasomy for

distal 15q or the chromosome 15q overgrowth syndrome

[1]

,

proximal 4p deletion

[33]

, deletion or microdeletion of 9q22.3

involving PTCH1, the gene responsible for Gorlin syndrome

(OMIM 109400) (autosomal dominant at 9q22.3)

[34e37]

,

duplication of 4p16.3

[38]

, deletion of 22q13

[39,40]

, mosaic

tetrasomy 12p or Pallister-Killian syndrome (OMIM 601803)

(sporadic)

[41e43]

, trisomy 12p

[44]

, Beckwith-Wiedemann

syndrome (OMIM 130650) (imprinting defects, sporadic or

autosomal dominant) caused by loss of methylation at maternal

imprinting center 2 or differentially methylated region 2,

paternal uniparental disomy 11p15.5, mutations in CDKN1C,

gain of methylation at maternal imprinting center 1 or

differ-entially methylated region 1, 11p15.5 chromosome

trans-location/inversion or duplication, or unknown etiology

[45,46]

,

Sotos syndrome (OMIM 117550) (sporadic or autosomal

dominant at 5q35) caused by NSD1 disease-causing mutations,

deletion or microdeletion of 5q35

[47,48]

, Weaver syndrome

(OMIM 277590) (sporadic and autosomal dominant at 5q35)

with some patients with mutations in the NSD1 gene

[49]

,

Perlman syndrome (OMIM 267000) (autosomal recessive)

[50,51]

, Simpson-Golabi-Behmel syndrome (type I, OMIM

312870; X-linked recessive at Xq26.2) (type II, OMIM

300209; X-linked recessive at Xp22) caused by GPC3

muta-tions, deletion, or microdeletion of Xq26.2 in type I; and

CXORF5 mutations, deletion, or microdeletion of Xp22 in type

II

[52e55]

, Costello syndrome (OMIM 218040) (autosomal

dominant at 11p15.5) caused by mutations in the HRAS gene

[56e60]

, Macrocephaly-capillary malformation syndrome

(OMIM 602501) (sporadic)

[61e63]

, Nevo syndrome (OMIM

601451) (autosomal recessive) caused by mutations in PLOD1

gene

[64]

, and PTEN hamartoma tumor syndrome such as

Bannayan-Riley-Ruvalcaba syndrome (OMIM 153480)

(auto-somal dominant at 10q23.31)

[65,66]

and Proteus syndrome

(OMIM 176920) (sporadic)

[66,67]

, caused by mutations in the

PTEN gene.

In conclusion, the present case provides evidence for

prenatal

overgrowth,

craniosynostosis,

and

characteristic

facial dysmorphism in association with a duplication of

15q26.2

/ q26.3 and a duplication of the IGF1R gene. Prenatal

diagnosis of fetal overgrowth should include a differential

diagnosis of the chromosome 15q overgrowth syndrome.

Fig. 6. Three-dimensional computed tomography scans of the skull shows

premature synostosis of the metopic and coronal sutures.

Fig. 7. Representative electrophoretograms of quantitative fluorescent poly-merase chain reaction assays. The marker D15S533 shows two peaks (368 bp: 380 bp; maternal and paternal, respectively) of unequal fluorescent activity from two different parental alleles in the fetal tissues with a dosage ratio of 1:2 (maternal:paternal) indicating a paternal origin of the duplication.

Table 1

Molecular results using polymorphic DNA markers specific for chromosome 15qa

Markers Father Mother Fetus Location

D15S526 273, 281 257, 277 257, 281 15q26.1 (90,387,342e90,387,627)

D15S531 376, 376 360, 376 360, 376 15q26.2 (94,521,647e94,521,997)

D15S533 352, 380 356, 368 368, 380, 380 15q26.2 (98,082,884e98,083,244)

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Acknowledgments

This work was supported by research grants

NSC-97-2314-B-195-006-MY3 and NSC-99-2628-B-195-001-MY3 from the

National Science Council, and MMH-E-100-04 from Mackay

Memorial Hospital, Taipei, Taiwan.

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