Short Communication
Ring chromosome 21 presenting with sacrococcygeal teratoma: prenatal diagnosis, molecular cytogenetic characterization and literature review
Chih-Ping Chen a,b,c,d,e,f,g *, Po-Jen Cheng h, Shuenn-Dyh Chang h, Yi-Xuan Lee h, Jin-Chung Shih i, Schu- Rern Chern c, Peih-Shan Wu j, Jun-Wei Su b,k, Yu-Ting Chen b, Adam Hwa-Ming Hsieh l, Teresa Hsiao-Tien Chen m, Li-Feng Chen b, Wayseen Wang c,n
a Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan
b Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
c Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
d Department of Biotechnology, Asia University, Taichung, Taiwan
e School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
f Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan
g Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
h Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Chang Gung University College of Medicine, Tao-Yuan, Taiwan
i Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
j Gene Biodesign Co. Ltd, Taipei, Taiwan
k Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
l University of Toronto, Ontario, Canada
m University of Chicago, Illinois, USA
n Department of Bioengineering, Tatung University, Taipei, Taiwan
* Correspondence to: Chih-Ping Chen, MD
Department of Obstetrics and Gynecology, Mackay Memorial Hospital 92, Section 2, Chung-Shan North Road, Taipei, Taiwan
Tel: +886-2-25433535; Fax: +886-2-25433642, +886-2-25232448 E-mail: [email protected]
Highlights
We present the prenatal diagnosis and molecular cytogenetic characterization of mosaic r(21).
The phenotype includes facial dysmorphisms and a sacrococcygeal teratoma.
We discuss cytogenetic abnormalities associated with fetal sacrococcygeal teratomas.
Abstract
We present perinatal findings and molecular cytogenetic characterization of a prenatally detected sacrococcygeal teratoma associated with mosaic r(21). This is the first report of mosaic r(21) presenting with a fetal sacrococcygeal teratoma. We discuss cytogenetic abnormalities associated with fetal sacrococcygeal teratomas.
Keywords: 21q terminal deletion; mosaicism; prenatal diagnosis; ring chromosome 21;
sacrococcygeal teratoma
Abbreviations
MoM: multiples of the median; AFP: -fetoprotein; r(21): ring chromosome 21;
idic r(21): isodicentric ring chromosome 21; aCGH: array comparative genomic hybridization;
FISH: fluorescence in situ hybridization; BAC: bacterial artificial chromosome;
i(12p): isochromosome 12p; dup: duplication; t: translocation; der: derivative
1. Introduction
A ring chromosome exhibits breakage and reunion at the breakpoints on the long and short arms of a chromosome, with possible deletions of the chromosome segments distal to the breakpoints (Chen et al., 2011, 2012). The r(21) can present with a mosaic form that is associated with a duplication of r(21) such as isodicentric r(21) [idic r(21)], and/or a deletion of r(21) such as monosomy 21 (Fryns and Kleczkowska, 1987; McGinniss et al., 1992; Miller et al., 1987).
Familial transmissions of r(21) from the mother to her children have been well described (Hertz, 1987; Ikeuchi et al., 1990; Kennerknecht et al., 1990; McGinniss et al, 1992; Melnyk et al., 1995;
Zergollern et al., 1989). The reproductive patterns in patients with an r(21) include azoospermia in male carriers, infertility in female carriers, spontaneous abortions, phenotypically normal offspring with r(21), phenotypically abnormal offspring with r(21), phenotypically normal offspring without r(21), and Down syndrome with idic r(21) or +r(21) (Bertini et al., 2008; Hammoud et al., 2009).
Here, we present prenatal diagnosis of mosaic r(21) associated with a sacrococcygeal teratoma.
To our knowledge, mosaic r(21) presenting with a sacrococcygeal teratoma has not previously been described.
2. Methods and detection 2.1. Cytogenetic analysis
Routine cytogenetic analysis by G-banding techniques at the 550 bands of resolution was performed. 20 mL amniotic fluid was collected, and the sample was subjected to in situ amniocyte culture according to the standard cytogenetic protocol. Fetal skin, and cystic component and solid component of fetal sacrococcygeal teratoma were collected, and the samples were subjected to flask tissue cell culture according to the standard cytogenetic protocol.
2.2. Array-CGH
Whole-genome aCGH on parental blood, fetal skin and solid component of the sacrococcygeal teratoma was performed using NimbleGen ISCA Plus Cytogenetic Array (Roche NimbleGen, Madison, WI, USA). The NimbleGen ISCA Plus Cytogenetic Array has 630,000 probes and a median resolution of 15-20 Kb across the entire genome according to the manufacturer’s instruction.
2.3. FISH
FISH analysis was performed on cultured interphase skin fibroblasts and the tumor cells of the cystic component of the tumor using a 21q11.2-specific BAC probe RP11-91N21 (spectrum green) according to the standard FISH protocol.
2.4. Clinical description
A 31-year-old, primigravid woman underwent amniocentesis at 18 weeks of gestation because of
fetal structural abnormalities. Prenatal ultrasound at 18 weeks of gestation revealed a singleton
fetus with a 5.6 3.3 cm cystic sacrococcygeal teratoma (Fig. S1). The maternal serum AFP level was 1.06 MoM. Amniocentesis revealed a female fetus with mosaicism for ring chromosome 21 [r(21)] and monosomy 21. The amniotic fluid AFP level was 0.9 MoM. The woman elected to terminate the pregnancy at 20 weeks of gestation. A 300-g fetus was delivered with prominent nasal bridge, downward slanting palpebral fissures, prominent forehead, long philtrum and a sacrococcygeal teratoma (Fig. 4). Histology of the sacrococcygeal teratoma confirmed immature teratoma consisting of cartilage island, skeletal muscle, skin, intestine and neuro-ectodermal tissues (10-50%). Conventional cytogenetic analyses of fetal skin, cystic part of the tumor and solid part of the tumor were carried out. Whole-genome aCGH using NimbleGen ISCA Plus Cytogenetic Array (Roche NimbleGen, Madison, WI, USA) was applied to fetal skin, solid component of the sacrococcygeal teratoma and parental blood.
3. Results
In 12 of 17 separated cultured amniocyte colonies, a karyotype of 46,XX,r(21) was found, while the other five colonies had a karyotype of 45,XX,-21. The cytogenetic result of amniocentesis was 46,XX,r(21)[12]/45,XX,-21[5]. The skin had a karyotype of 46,XX, r(21)[17]/46,XX,idic r(21) [2]/45,XX,-21[1]. Among 104 interphase skin fibroblasts, 16 had three 21q11.2-specific green signals, 45 had two signals, and 43 had only one signal. The cystic component of sacrococcygeal teratoma had a karyotype of 46,XX,r(21)[34]/45,XX,-21[4]/46,XX,idic r(21)[2] (Fig. 1). Among 94 interphase cystic component tumor cells, 11 had three 21q11.2-specific green signals, 47 had two signals, and 36 had only one signal. The solid component of the sacrococcygeal teratoma had a karyotype of 46,XX,r(21)[40]. aCGH analysis of the parental blood did not find any deletion at chromosome 21. aCGH detected a 0.15-Mb deletion at 21q22.3 or arr 21q22.3 (47,978,156- 48,129,895)1 (NCBI build 37) in the solid tumor (Fig. 2). The deletion in the tumor had a log2 ratio of –1.01. aCGH detected a 0.15-Mb deletion at 21q22.3 or arr 21q22.3 (47,978,156- 48,129,895)1~2 (NCBI build 37) in the skin (Fig. 3). The deletion in the skin had a log2 ratio of –0.79, indicating mosaicism in the skin. The 0.15-Mb deletion at 21q22.3 encompasses the genes of DIP2A, S100B, PRMT2, DSTNP1 and RPL23A4.
4. Discussion
With the advent of prenatal ultrasound and magnetic resonance imaging technology, fetal cystic sacrococcygeal teratomas can be well diagnosed and evaluated (Chen et al., 2003, 2004).
Sacrococcygeal teratomas are the most common congenital neoplasms in neonates, and have an
incidence of 1:40,000 births with a female: male ratio of 4.2:1 (Schropp et al., 1992). Teratomas
belong to germ cell tumors and are derived from three germ cell layers including embryonic
ectodermal, mesodermal and endodermal tissue derivatives. Germ cell tumors can develop in the gonads and at the extragonadal sites. The extragonadal germ cell tumors have been proposed to be caused by an aberrant migration of the primodial germ cell during embryogenesis (Chaganti et al., 1994; Hasle and Jacobsen, 1995; Veltman et al., 2003) or originated from undifferentiated pluripotent embryonic or extra-embryonic stem cells (Sano, 1999; Veltman et al., 2003).
Extragonadal teratomas tend to occur in the midline of the body such as sacrococcygeal, retroperitoneal, mediastinal, intracranial, palate, cervical and nasopharyngeal areas.
Sacrococcygeal teratomas comprise over 50% of teratomas in neonates and infants (Holzgreve et al., 1985). In teratomas, there is a 25% chance of malignancy, and surgical excision remains the mainstay of treatment (Gatcombe et al., 2004).
Very few cases of sacrococcygeal teratomas have been cytogenetically investigated (Batukan et al., 2007; Dundar et al., 2011; Golas et al., 2010; Le Caignec et al., 2003; Noguera et al., 1999;
Veltman et al., 2002, 2003, 2005; Wax et al., 2000). Table 1 shows the clinical findings and cytogenetic analyses of previously reported cases of fetal or childhood sacrococcygeal teratomas with chromosomal abnormalities. The reported cytogenetic abnormalities associated with sacrococcygeal teratomas include near haploid (Noguera et al., 1999), partial trisomy 1q (Wax et al., 2000), partial monosomy 7q and partial trisomy 2p (Le Caignec et al, 2003), partial trisomy 10q and partial monosomy 17p (Batukan et al., 2007), partial trisomy 3q (Dundar et al., 2011), amplification at 8q and 12p (Golas et al., 2010), and a breakpoint at 12q13 (Veltman et al., 2002, 2003, 2005).
Genomic gain of 12p with either i(12p) or amplification of part of 12p has been characteristics of germ cell tumors in adult patients (Atkin and Baker, 1982; Geurts van Kessel et al., 1993;
Sandberg et al., 1996; Suijkerbuijk et al., 1991, 1993, 1994; van Echten et al., 1995). The i(12p) is the most common chromosomal abnormalities detected in teratomas (Gatcombe et al., 2004; van Echten et al., 1995). The i(12p) has been considered as a pathognomonic genetic finding because it can be detected in metastatic germ cell tumors (Chaganti et al., 1994) and is associated with a significantly increased likelihood of treatment failure (Bosl et al., 1989; Dmitrovsky et al., 1990).
Genomic gain of 1q with either i(1q) or duplication of part of 1q has been associated with teratomas (Beverstock et al., 1999; Hecht et al., 1984; Hirata et al., 1994; Houri et al., 1997;
Scheres et al., 1999; Schneider et al., 2001; Schwartz et al., 1992). Hecht et al. (1984) reported
prenatal diagnosis of 46,XX,inv dup(1)(qterq21::p35qter) by amniocentesis at 31 weeks of
gestation because of polyhydramnios and fetal intracranial teratoma. The inverted duplication of
1q21qter was found in the tumor. The skin had a normal karyotype. Schwartz et al. (1992) reported prenatal diagnosis of 90% mosaicism for dup(1q) and dup(19p) in a cell line with 47 chromosomes by amniocentesis because of advanced maternal age, fetal epignathus and intracranial teratoma. The mother carried a balanced translocation of t(1;19). The teratoma had a predominance of the cell line with 47 chromosomes (96.5%), whereas the non-teratoma tissues in the fetus had a balanced translocation of t(1;19). Hirata et al. (1994) reported prenatal diagnosis of 46,XX,der(1)t(1;1)(q21;pter)/46,XX by amniocentesis because of polyhydramnios, intrauterine growth restriction and fetal cervical teratoma. The teratoma had duplication of 1q21qter, whereas the fetal blood had a normal karyotype. Houri et al. (1997) reported the occurrence of dup(1q)(1q12qter) and the karyotype of 46,XY,der(11)t(1;11)(q12;p15.5) in the cranial immature teratoma of a 53-year-old man. Beverstock et al. (1999) reported prenatal diagnosis of 47,XX,+idic(1)(q10)/46,XX by amniocentesis at 22 weeks of gestation because of polyhydramnios and fetal nasopharyngeal teratoma. The tumor had 100% of idic(1)(q10) by fluorescence in situ hybridization analysis. Scheres et al. (1999) reported tumor specific mosaic tetrasomy 1q in two cases of fetal palatal/cervical teratoma. One case had a tumor karyotype of 47,XX, +i(1)(q10) [6]/46,XX[21], and the other case had a tumor karyotype of 47,XX,+i(1)(q10)[2]/ 46,XX[5]. The skin of both cases had a karyotype of 46,XX. In a study of genetic analysis of 51 childhood germ cell tumors including 18 teratomas and 33 malignant germ cell tumors, Schneider et al. (2001) found a high frequency of chromosomal imbalances of chromosome 1 including a loss of distal 1p and a gain of 1q. The present case was associated with constitutional mosaic r(21). Loss of 21q has not previously been associated with teratoma. A gain of chromosome 21 can cause suppression of neural fate of pluripotent mouse embryonic stem cells in a teratoma model (Mensah et al., 2007). Whether a gain or a loss of distal 21q is associated with fetal sacrococcygeal teratoma is unclear at the present time and requires more cases for confirmation.
To date, at least four cases with prenatal diagnosis of r(21) have been reported (Chen et al.,
2012; Melnyk et al., 1995; Papoulidis et al., 2010; Stetten et al., 1984). Stetten et al. (1984) first
reported incidental detection of 46,XY,r(21)/45,XY,-21 with mosaicism for majority of r(21) by
amniocentesis because of a risk of sickle cell anemia in a pregnancy with apparently normal fetal
phenotype except minor developmental delay at 14 months of age. Melnyk et al. (1995) reported
prenatal diagnosis of familial r(21) derived from maternal transmission in a fetus with 46,XX,r(21)
(77%)/45,XX,-21 (23%) and normal outcome. The mother was a normal carrier of r(21).
Papoulidis et al. (2010) reported prenatal diagnosis of 46,XY,r(21)[34]/45,XY,-21[4]/46,XY[14]
in a fetus with apparently normal male phenotype because of advanced maternal age. Subsequent cytogenetic analysis of the parents showed the presence of r(21) in 1/100 blood lymphocytes, indicating a possible familial transmission. Chen et al. (2012) reported prenatal diagnosis of 46,XY,r(21)[8]/45,XY,-21[3]/46,XY,idic r(21)[1] associated with a 2-Mb deletion at 21q21.1- q21.2 and a 5-Mb deletion at 21q22.3 in a fetus with facial dysmorphisms. The present case was associated with fetal dysmorphisms. The 0.15-Mb 21q22.3 terminal deletion in this case encompasses the genes of DIP2A, S100B, PRMT2, DSTNP1 and RPL23A4. DIP2A, S100B and PRMT2 are candidate genes for dyslexia. DIP2A is important in the regulation of synaptic plasticity, S100B exerts paracrine and autocrine effects on neurons and glial cells, and PRMT2 is involved in mRNA metabolism.
We have reported discrepancy in aCGH between the skin and tumor due to discrepant mosaicism. With the recent technology of investigating genomic DNA extracted directly from uncultured tissues, aCGH has been shown to be possibly more sensitive in detecting low-level mosaicism for chromosomal abnormalities than traditional cytogenetic techniques (Ballif et al., 2006, 2007; Cheung et al., 2007).
In summary, we present perinatal findings and molecular cytogenetic characterization of a prenatally detected sacrococcygeal teratoma associated with mosaic r(21). We discuss cytogenetic abnormalities associated with fetal sacrococcygeal teratomas.
Acknowledgements
This work was supported by research grants NSC-99-2628-B-195-001-MY3 and NSC-101-2314-B-195- 011-MY3 from the National Science Council, and MMH-E-102-04 from Mackay Memorial Hospital, Taipei, Taiwan.
Appendix A. Supplementary data
Supplementary data to this article can be found online at GENE.
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Figure Captions
Fig. 1. Partial karyotype of (A) r(21) and (B) idic r(21).
Fig. 2. Whole-genome array comparative genomic hybridization analysis of the solid component of the sacrococcygeal teratoma shows a 0.15-Mb deletion at 21q22.3 or arr 21q22.3 (47,978,156- 48,129,895)1 (NCBI build 37). The deletion has a log2 ratio of –1.01.
Fig. 3. Whole-genome array comparative genomic hybridization analysis of the skin shows a 0.15-Mb deletion at 21q22.3 or arr 21q22.3 (47,978,156-48,129,895)1~2 (NCBI build 37). The deletion has a log2 ratio of –0.79, indicating mosaicism in the skin.
Fig. 4. (A) Whole body view and (B) craniofacial appearance of the fetus at birth.
Appendix A. Supplementary data
Fig. S1.(A) Two-dimensional and three-dimensional ultrasound imaging findings of a sacrococcygeal teratoma (arrow) in the fetus at 18 weeks of gestation.
