CLINICAL REPORT
Partial Trisomy of 11q23.3-q25 Inherited from a Maternal Low-Level Mosaic Unbalanced Translocation Jungyoon Choi,1 Hojung Lee,2 and Cha Gon Lee1* 1
Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University, Seoul, Korea
2
Department of Pathology, Eulji General Hospital, College of Medicine, Eulji University, Seoul, Korea
Manuscript Received: 10 September 2014; Manuscript Accepted: 29 December 2014
Partial trisomy of 11q is characterized by pre/postnatal growth retardation, microcephaly, dysmorphic craniofacial features, cognitive disability, abnormal muscle tone, inguinal hernia, and possible congenital heart defects. Here, we describe a 17year-old male with a 17.77 Mb-sized [arr 11q23.3-q25 (116,667,559 –134,434,130) 3] partial trisomy resulting from the unbalanced translocation between chromosomes 11 and 22. The terminal translocation was detected using oligonucleotide array comparative genomic hybridization (CGH) with fluorescence in situ hybridization (FISH) confirmation. The partial trisomy was inherited from his mother who had the low-level (22.7%) mosaic unbalanced translocation and a normal phenotype. The patient showed most of the common features of partial trisomy 11q syndrome, with additional findings, including mesenteric fibromatosis. Ó 2015 Wiley Periodicals, Inc.
Key words: partial trisomy; translocation; chromosomes human pair 11; chromosome 11 partial trisomy 11q; mesenteric fibromatosis
INTRODUCTION Since the first description of partial trisomy of 11q in 1977, partial trisomy of the long arm of chromosome 11 has remained a rare duplication syndrome [Francke et al., 1977]. As indicated in most previously reported cases, partial trisomy 11q is associated with partial or total monosomy of another chromosome derived from an unaffected parent with balanced translocation [Pihko et al., 1981; Yelavarthi and Zunich, 2004; Klaassens et al., 2006; Burnside et al., 2009; Zimberg-Bossira et al., 2011; Ben-AbdallahBouhjar et al., 2013; Kayhan et al., 2013]. The duplication region at breakage points, such as 11q13-qter, 11q21-qter, and 11q23qter, and the presence of other chromosome deletions or duplication determine the main clinical features of partial trisomy 11q. For example, Emanuel syndrome is the result of partial trisomy of chromosome 11q23-qter, combined with duplication of 22q10q11 [Choudhary et al., 2013; Ohye et al., 2014]. Partial trisomy of 11q without a copy number change of another chromosome is very rare [Zarate et al., 2007; Gohring et al., 2008; Burnside et al., 2009; Kayhan et al., 2013]. Given the rarity of this syndrome and
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Choi J, Lee H, Lee CG. 2015. Partial trisomy of 11q23.3-q25 inherited from a maternal low-level mosaic unbalanced translocation. Am J Med Genet Part A. 167A:1859–1864.
minimal use of high-resolution techniques, such as array CGH, the genotype-phenotype correlation of partial trisomy of 11q has been poorly defined to date. Here, we describe a male with a 17.7 Mb-sized partial trisomy of 11q23.3-q25, identified by oligonucleotide array CGH with fluorescence in situ hybridization (FISH) confirmation. He had most of the common clinical features of partial trisomy 11q syndrome, with additional findings, including mesenteric fibromatosis and atopic dermatitis, not reported previously in cases of this syndrome. Interestingly, the trisomy of 11q23.3-q25 in our case was inherited from the mother who had mosaic (22.7%) unbalanced terminal translocation and a normal phenotype. This is the first report of mosaic partial trisomy of 11q.
CLINICAL REPORT A 17-year-old Korean male visited Eulji General Hospital due to onset of unprovoked generalized tonic-clonic seizures on November 5, 2012. He was the third child of a healthy nonconsanguineous 28-year-old mother and 29-year-old father. After an unremarkable Conflict of interest: none. Grant sponsor: EMBRI; Grant number: 2012EMBRISN0004. Correspondence to: Cha Gon Lee, MD., Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University, 68 Hangeulbiseok-ro, Nowon-gu, Seoul 139-711, Korea. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 5 May 2015 DOI 10.1002/ajmg.a.36980
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1860 pregnancy, he was born vaginally with a birth weight of 3,800 g at a gestational age of 40 weeks. He had two older siblings, both of whom were healthy. There was no family history of neurological disease or developmental delay. Psychomotor development was severely delayed. His head control developed at 12 months of age. He did not start walking independently until he was 5 years old. He showed obvious language developmental problems, never mastering speech. He had a severe intellectual disability with an IQ of below 30. He had behavioral problems, including self-injurious behavior and features of autism spectrum disorder. At the age of 17, he presented with diffuse acute abdominal pain and peritonitis upon examination. An abdomen computed tomography showed nonspecific findings, including mechanical ileus, with no visible mesenteric mass (Fig. 1A). Segmental resection of the small bowel, measuring 15 cm in length, was performed. Small multifocal grayish-white fibrotic nodules were found on the serosal surface, with stricture and perforation of the intestinal wall (Fig. 1B and C). The perforated site showed hemorrhage and necrosis. Subsequent histology revealed a benign fibromatosis tumor. Staining was positive for smooth muscle actin (SMA) and beta-catenin staining but negative for CD117, CD34, S-100, and calretinin. He was diagnosed with mesenteric fibromatosis with a perforation. When he visited our clinic as a 17-year-old, he exhibited growth retardation. His body weight was 43 kg ( 3.65 standard deviation
AMERICAN JOURNAL OF MEDICAL GENETICS PART A [SD] [Moon et al., 2008]), his height was 162 cm ( 2.05 SD), and his body mass index (BMI) was 16.4 kg/m2 ( 2.81 SD). In the craniofacial examination, relative microcephaly (49 cm, 1.65 SD), flattening of the occiput, sparse lateral eyebrows, upslanting palpebral fissures, prominent ears, a high palate, thick lips, and freckles were observed (Fig. 2A and B). The lung fields were clear, with symmetrical air entry. There was no chest wall deformity. His heart examination was normal, without murmurs. There were no skeletal abnormalities. Except for atopic dermatitis, there were no lesions on the skin, hair, or nails. Neurologically, he was alert but made only very brief eye contact. Cranial nerve examinations were normal. Muscle tone and strength were normal. There were no pathological reflexes or traces of clonus. The clinical characteristics are summarized in Table I.
CYTOGENETIC RESULTS Chromosomal analysis was carried out by applying GTG-banding to the patient and the patient’s parents at a 550 band-level resolution, according to International System for Human Cytogenetic Nomenclature (ISCN) 2009. Cytogenetic analysis was performed on peripheral blood. The patient’s G-banded analysis showed the derivative chromosome, der(22) t(11;22), and revealed segmental direct duplication of chromosome 11q23.3-qter (Fig. 3A). G-band-
FIG. 1. A: Erect abdomen radiograph demonstrates multiple air-fluid levels in the dilated loops in a typical configuration of a small bowel mechanical obstruction. B: The serosal surface is pinkish-gray and smooth, with small, multifocal grayish-white fibrotic nodules. A strictured and sutured site with a suspected previous perforation is present at one-third position of the segment. C: Two-thirds of the mucosa, including the sutured site, is diffusely edematous and hemorrhagic. The perforated site shows hemorrhage and necrosis.
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FIG. 2. A-B: The patient shows sparse lateral eyebrows, up-slanting palpebral fissures, prominent ears, thick lips, freckles, and an itchy rash due to atopic dermatitis. C: The patient’s lateral skull X-ray reveals a flattened occiput and protrusion of the maxilla. D: Interictal sleep electroencephalogram exhibits sharp and abnormally slow waves on the frontal lobe region.
ing analysis of the patient’s mother showed a mosaic trisomy (22.7%) of chromosome 11q23.3-qter due to an unbalanced terminal translocation between the long arm of chromosome 22 and the distal long arm of chromosome 11 (Fig. 3B). The corresponding ISCN designation is mos46,XX,inv(9)(p12q13), der(22) t(11;22)(q23.3;q13.3) [17]/46,XX,inv(9) [58]. The patient’s father and two siblings had normal karyotypes. Therefore, the ISCN for patient’s karyotype is 46,XY,der(22) t(11;22) (q23.3;q13.3)mat. Oligonucleotide-based microarray analyses were performed in April 2013 with a 135 K-feature whole-genome microarray (SignatureChip Oligo Solution made for Signature Genomic Laboratories by Roche NimbleGen, Madison, WI). Array CGH revealed a region of gain spanning 17.77–17.80 Mb on chromosome 11q23.3q25. Based on National Center for Biotechnology Information (NCBI) human genome build 36 (NCBI36/hg18; Mar. 2006), the minimum start and stop points for this duplication were estimated at 116,667,559 and 134,434,130 with a total of 1,668 probes arr 11q23.3-q25 (116,667,559 –134,434,130) 3 [NCBI36/hg18]. This region of gain contained 115 Online Mendelian Inheritance in Man (OMIM) genes (Fig. 3C). There was no terminal deletion on chromosome 22q using by array CGH. In order to confirm the result of array CGH, fluorescence in situ hybridization (FISH) analysis, using two BAC clones with 11q24.3 green probe (Macrogen) and TelVysion 22q orange probe (Vysis), was performed on peripheral blood lymphocytes of patient. FISH on metaphase cells showed that additional material (green color: 11q24.3 probe) was inserted into the long arm of chromosome 22 (orange color: 22q13.33 subtelomic probe).
DISCUSSION Chromosome 11 spans approximately 135 million base pairs and represents about 4% of the total DNA in cells. It likely contains 1,300–1,400 genes that provide instructions for proteins synthesis, and it is one of the most gene-rich chromosomes in the human genome. Of these genes, dosage-sensitive genes are associated with deletion and duplication syndromes. Most constitutional segmental aneusomies generally occur in a random fashion. However, there are fragile hotspots on chromosome 11. Jacobsen syndrome (OMIM#147791) is well known as an 11q deletion disorder or partial monosomy 11q syndrome, resulting from deletion of the terminal region of chromosome 11 [Mattina et al., 2009]. Approximately 80% of the known 11q terminal deletion breakpoint is a rare folate-sensitive fragile site in band 11q23.3 (FRA11B) [Penny et al., 1995]. The opposite syndrome of Jacobsen syndrome is partial trisomy 11q syndrome such as our case. Partial trisomy of 11q is relatively less common than Jacobsen syndrome, and the reported breakpoints cover a wide range, from 11q12 to 11q23. Of these, partial trisomy 11q23-qter has well-defined clinical characteristics [Ben-Abdallah-Bouhjar et al., 2013]. Most cases of partial trisomy of 11q23-qter are associated with a second chromosomal imbalance, usually chromosome 22q, which makes defining the phenotype of 11q partial trisomy difficult [Ben-Abdallah-Bouhjar et al., 2013]. The most common, partial 11q syndrome is Emanuel Syndrome (OMIM# 609029) [Carter et al., 2009]. In more than 99% of cases, one of the parents of Emanuel syndrome is a balanced carrier of a t(11;22)(q23;q11.2) and is phenotypically normal. The clinical phenotype of the Emanuel syndrome arises from
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TABLE I. Clinical Features and Molecular Characteristics of the Patient and Patient’s Mother Trait Age at test/sex Birth history Head Face Cardiovascular Gastrointestinal Renal and genitourinary Muscular and skeletal Skin Growth retardation Psychomotor development Behavior problem Seizure
Patient partial trisomy 11q23.3-q25
Mother 22.7% mosaic partial trisomy11q23.3-q25
17 years/male Term AGA (3800 g), NSVD Microcephaly (HC 49 cm, 1.64 SDS), flattening of occiput Sparse lateral eyebrows, upslanting palpebral fissures, prominent ears, high palate, thick lips, freckles None Mesenteric fibromatosis None None Atopic dermatitis Bw 43 kg (-3.65 SDS), Ht 162 cm (-2.05 SDS), BMI 16.38 kg/m2 ( 2.81 SDS) Severe intellectual disability, no speech development Autism spectrum disorder, self-injurious behavior Generalized tonic-clinic seizures; treated with lamotrigine
45 years/female Term AGA None (HC 53 cm, 1.67 SDS) None None None None None None Bw 70 kg (1.79 SDS), Ht 165 cm (0.83 SDS), BMI 25.71 kg/m2 (1.53 SDS) None None None
AGA: appropriate for gestational age; NSVD: normal spontaneous vaginal delivery; HC: head circumference; SDS: standard deviation score; Bw: body weight; Ht: height; BMI: body mass index; ASD: atrial septal defect; PS: Pulmonic stenosis
duplication of 22q10–22q11 and duplication of 11q23-qter. The break points of t(11;22) s have been identified within palindromic AT-rich repeats (PATRRs) on 11q23 (PATRR11) and 22q11 (PATRR22) [Kurahashi et al., 2006]. The FRA11B and PATRR11 at chromosome 11q23 are the hot spots for deletion and translocation breakpoints. The fragile site FRA11B has been localized to the p(CCG)n repeat of the CBL2 gene (chr11:118,575, 702 – 118,775,922) in NCBI36/hg18. The PATRR11 is located between ZNF259 (chr11:116,154,486 – 116,163,949) and Apo gene cluster (chr11:116,165,296 – 116,213,548) in NCBI36/hg18 [Kurahashi et al., 2000]. The 11q23.3 (116,667,559 – 134,434,130) breakpoint of our case was quite near to PATRR11 shown as Figure 3C. Common segmental aneusomies result from deletion, duplication, triplication, terminal translocation, and insertional translocation [Kang et al., 2010; Assawamakin et al., 2012; Thierry et al., 2013]. Our patient showed segmental trisomy of 11q23.3-q25 with no copy number changes in another chromosome. Especially, our patient did not have a copy number change of chromosome 22 by oligonucleotide array CGH confirmed with locus-specific 22q subtelomeric FISH probes. We suggest that our case is one of so-called “pure” partial trisomy due to terminal translocation. Based on a literature review, the majority of cases with unbalanced translocation are result from a balanced translocation present in a phenotypically normal parent [Thierry et al., 2013]. In the present case, the patient inherited the trisomy from a maternal mosaic unbalanced terminal translocation, der(22) t(11;22)
(q23.3;q13.3), with the mosaic trisomy 22.7% of 11q23.3-q25. This is the first documentation of mosaic trisomy of 11q23.3–25. Despite the presence of low-level mosaic partial trisomy of 11q23.3-q25, the mother did not show any of the characteristic signs and symptoms of partial trisomy 11q syndrome. This duplicated region contains about 115 OMIM genes, many of which have not been well characterized. We do not yet know which genes are particularly dosage-sensitive and contribute to the phenotypes of partial trisomy 11q syndrome. In addition, the number of gene dosage changes that are required to exert disruptive effects on the gene structure and function and contribute substantially to this syndrome is not known. However, this study suggests that low-level mosaic trisomy of 11q23-qter, up to 22.7%, does not cause the characteristic abnormal findings of this syndrome. Interestingly, our patient exhibited some new clinical features, including mesenteric fibromatosis, atopic dermatitis, and delayed puberty. Mesenteric fibromatosis is a rare benign fibrous tumor affecting the mesentery that occurs spontaneously or develops as a consequence of surgical trauma. It may also be associated with genetic syndromes, such as familiar adenomatous polyposis or Gardner’s syndrome [Bethune and Amin, 2006; Wronski et al., 2011]. To date, mesenteric fibromatosis has not been described in relation to partial trisomy of 11q. In summary, we described the clinical features of a patient with partial trisomy of 11q23.3-q25 and the patient’s mother with lowlevel mosaic trisomy of 11q 23.3-q25. Our study provides additional information that contributes to understanding and delineation of partial trisomy of 11q and mosaic partial trisomy of 11q.
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FIG. 3. A: G-banded karyotype of patient reveals 46,XY,der(22) t(11;22)(q23.3;q13.3)mat at a 550 band-level resolution. B-1: G-banded karyotype of patient’s mother shows 46,XX,inv(9)(p12q13), der(22) t(11;22)(q23.3;q13.3) at a 550 band-level resolution. B-2: Partial Gbanded karyotype of maternal chromosomes 11 and 22 and diagram of the unbalanced terminal translocation. C: Array comparative genomic hybridization (CGH) analysis shows a 17.77–17.80 Mb region of gain on chromosome 11q23.3-q25, arr 11q23.3-q25 (116,667,559 – 134,434,130) 3 [NCBI36/hg18]. The breakpoint region of our case is closer to PATRR11 (blue arrow) than FRA11B (green arrow). D: In metaphase FISH assay, chromosome painting probe specific for the 11q24.3 region (green signals) shows three signals, consistent with a duplication of 11q24. The subtelomeric region of chromosome 22q was normal (orange signals).
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ETHICS STATEMENT The use of human clinical materials and blood in this study was approved by the Ethical Committee of the Eulji General Hospital (IRB#2013–08-001–001). We received the written informed consent from patient’s parent.
REFERENCES Assawamakin A, Wattanasirichaigoon D, Tocharoentanaphol C, Waeteekul S, Tansatit M, Thongnoppakhun W, Limwongse C. 2012. A novel maternally-derived insertional translocation resulting in partial trisomy 4q13.2-q22.1 with complex translocation t(8;20) in a family with intellectual disability. Am J Med Genet A 158A:901–908. Ben-Abdallah-Bouhjar I, Mougou-Zerelli S, Hannachi H, Ben-Khelifa H, Soyah N, Labalme A, Sanlaville D, Elghezal H, Saad A. 2013. Phenotype and Micro-array characterization of duplication 11q22.1-q25 and review of the literature. Gene 519:135–141. Bethune R, Amin A. 2006. Mesenteric fibromatosis: A rare cause of acute abdominal pain. Ann R Coll Surg Engl 88:1–2. Burnside RD, Lose EJ, Dominguez MG, Sanchez-Corona J, Rivera H, Carroll AJ, Mikhail FM. 2009. Molecular cytogenetic characterization of two cases with constitutional distal 11q duplication/triplication. Am J Med Genet A 149A: 1:1516–1522. Carter MT, St Pierre SA, Zackai EH, Emanuel BS, Boycott KM. 2009. Phenotypic delineation of Emanuel syndrome (supernumerary derivative 22 syndrome): Clinical features of 63 individuals. Am J Med Genet A 149A: 1:1712–1721. Choudhary MG, Babaji P, Sharma N, Dhamankar D, Naregal G, Reddy VS. 2013. Derivative 11;22 (emanuel) syndrome: A case report and a review. Case Rep Pediatr 2013:237935. Francke U, Weber F, Sparkes RS, Mattson PD, Mann J. 1977. Duplication 11 (q21 to 23 leads to qter) syndrome. Birth Defects Orig Artic Ser 13:167–186. Gohring I, Blumlein HM, Hoyer J, Ekici AB, Trautmann U, Rauch A. 2008. 6.7 Mb interstitial duplication in chromosome band 11q24.2q25 associated with infertility, minor dysmorphic features and normal psychomotor development. Eur J Med Genet 51:666–671. Kang SH, Shaw C, Ou Z, Eng PA, Cooper ML, Pursley AN, Sahoo T, Bacino CA, Chinault AC, Stankiewicz P, Patel A, Lupski JR, Cheung SW. 2010. Insertional translocation detected using FISH confirmation of arraycomparative genomic hybridization (aCGH) results. Am J Med Genet A 152A: 1:1111–1126.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kayhan G, Cavdarli B, Yirmibes Karaoguz, Percin M, Ozturk EF, Kaymak A, Biri A, Ergun MA. 2013. Molecular karyotyping of an isolated partial trisomy 11q patient with additional findings. Gene 524:355–360. Klaassens M, Scott DA, van Dooren M, Hochstenbach R, Eussen HJ, Cai WW, Galjaard RJ, Wouters C, Poot M, Laudy J, Lee B, Tibboel D, de Klein A. 2006. Congenital diaphragmatic hernia associated with duplication of 11q23-qter. Am J Med Genet A 140:1580–1586. Kurahashi H, Inagaki H, Ohye T, Kogo H, Kato T, Emanuel BS. 2006. Palindrome-mediated chromosomal translocations in humans. DNA repair 5:1136–1145. Kurahashi H, Shaikh TH, Hu P, Roe BA, Emanuel BS, Budarf ML. 2000. Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22). Hum Mol Genet 9:1665–1670. Mattina T, Perrotta CS, Grossfeld P. 2009. Jacobsen syndrome. Orphanet J Rare Dis 4:9. Moon JS, Lee SY, Nam CM, Choi JM, Choe BK, Seo JW, Oh K, Jang MJ, Hwang SS, Yoo MH, Kim YT, Lee CG. 2008. Korean National Growth Charts: Review of developmental process and an outlook. 2007 51: 1–25. Ohye T, Inagaki H, Kato T, Tsutsumi M, Kurahashi H. 2014. Prevalence of Emanuel syndrome: theoretical frequency and surveillance result. Pediatr Int. 56:462–466. . Penny LA, Dell’Aquila M, Jones MC, Bergoffen J, Cunniff C, Fryns JP, Grace E, Graham JM, Jr., Kousseff B, Mattina T, et al. 1995. Clinical and molecular characterization of patients with distal 11q deletions. Am J Hum Genet 56:676–683. Pihko H, Therman E, Uchida IA. 1981. Partial 11q trisomy syndrome. Hum Genet 58:129–134. Thierry G, Pichon O, Briand A, Poulain D, Sznajer Y, David A, Le Caignec C. 2013. Autosomal insertional translocation mimicking an X-linked mode of inheritance. Eur J Med Genet 56:46–49. Wronski M, Ziarkiewicz-Wroblewska B, Slodkowski M, Cebulski W, Gornicka B, Krasnodebski IW. 2011. Mesenteric fibromatosis with intestinal involvement mimicking a gastrointestinal stromal tumour. Radiol Oncol 45:59–63. Yelavarthi KK, Zunich J. 2004. Familial interstitial duplication of 11q; partial trisomy (11)(q13.5q21). Am J Med Genet A 126A:423–426. Zarate YA, Kogan JM, Schorry EK, Smolarek TA, Hopkin RJ. 2007. A new case of de novo 11q duplication in a patient with normal development and intelligence and review of the literature. Am J Med Genet A 143:265–270. Zimberg-Bossira A, Smolkin T, Gildish A, Moustafa-Hawash N, Blazer S, Gershoni-Baruch R, Makhoul IR. 2011. ’Pure’ partial trisomy 11q (11q23.1–>11qter): Expanding the phenotype. Clin Dysmorphol 20:225–228.
Partial Trisomy of 11q23.3-q25 Inherited from a Maternal Low-Level Mosaic Unbalanced Translocation Jungyoon Choi,1 Hojung Lee,2 and Cha Gon Lee1* 1
Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University, Seoul, Korea
2
Department of Pathology, Eulji General Hospital, College of Medicine, Eulji University, Seoul, Korea
Manuscript Received: 10 September 2014; Manuscript Accepted: 29 December 2014
Partial trisomy of 11q is characterized by pre/postnatal growth retardation, microcephaly, dysmorphic craniofacial features, cognitive disability, abnormal muscle tone, inguinal hernia, and possible congenital heart defects. Here, we describe a 17year-old male with a 17.77 Mb-sized [arr 11q23.3-q25 (116,667,559 –134,434,130) 3] partial trisomy resulting from the unbalanced translocation between chromosomes 11 and 22. The terminal translocation was detected using oligonucleotide array comparative genomic hybridization (CGH) with fluorescence in situ hybridization (FISH) confirmation. The partial trisomy was inherited from his mother who had the low-level (22.7%) mosaic unbalanced translocation and a normal phenotype. The patient showed most of the common features of partial trisomy 11q syndrome, with additional findings, including mesenteric fibromatosis. Ó 2015 Wiley Periodicals, Inc.
Key words: partial trisomy; translocation; chromosomes human pair 11; chromosome 11 partial trisomy 11q; mesenteric fibromatosis
INTRODUCTION Since the first description of partial trisomy of 11q in 1977, partial trisomy of the long arm of chromosome 11 has remained a rare duplication syndrome [Francke et al., 1977]. As indicated in most previously reported cases, partial trisomy 11q is associated with partial or total monosomy of another chromosome derived from an unaffected parent with balanced translocation [Pihko et al., 1981; Yelavarthi and Zunich, 2004; Klaassens et al., 2006; Burnside et al., 2009; Zimberg-Bossira et al., 2011; Ben-AbdallahBouhjar et al., 2013; Kayhan et al., 2013]. The duplication region at breakage points, such as 11q13-qter, 11q21-qter, and 11q23qter, and the presence of other chromosome deletions or duplication determine the main clinical features of partial trisomy 11q. For example, Emanuel syndrome is the result of partial trisomy of chromosome 11q23-qter, combined with duplication of 22q10q11 [Choudhary et al., 2013; Ohye et al., 2014]. Partial trisomy of 11q without a copy number change of another chromosome is very rare [Zarate et al., 2007; Gohring et al., 2008; Burnside et al., 2009; Kayhan et al., 2013]. Given the rarity of this syndrome and
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Choi J, Lee H, Lee CG. 2015. Partial trisomy of 11q23.3-q25 inherited from a maternal low-level mosaic unbalanced translocation. Am J Med Genet Part A. 167A:1859–1864.
minimal use of high-resolution techniques, such as array CGH, the genotype-phenotype correlation of partial trisomy of 11q has been poorly defined to date. Here, we describe a male with a 17.7 Mb-sized partial trisomy of 11q23.3-q25, identified by oligonucleotide array CGH with fluorescence in situ hybridization (FISH) confirmation. He had most of the common clinical features of partial trisomy 11q syndrome, with additional findings, including mesenteric fibromatosis and atopic dermatitis, not reported previously in cases of this syndrome. Interestingly, the trisomy of 11q23.3-q25 in our case was inherited from the mother who had mosaic (22.7%) unbalanced terminal translocation and a normal phenotype. This is the first report of mosaic partial trisomy of 11q.
CLINICAL REPORT A 17-year-old Korean male visited Eulji General Hospital due to onset of unprovoked generalized tonic-clonic seizures on November 5, 2012. He was the third child of a healthy nonconsanguineous 28-year-old mother and 29-year-old father. After an unremarkable Conflict of interest: none. Grant sponsor: EMBRI; Grant number: 2012EMBRISN0004. Correspondence to: Cha Gon Lee, MD., Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University, 68 Hangeulbiseok-ro, Nowon-gu, Seoul 139-711, Korea. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 5 May 2015 DOI 10.1002/ajmg.a.36980
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1860 pregnancy, he was born vaginally with a birth weight of 3,800 g at a gestational age of 40 weeks. He had two older siblings, both of whom were healthy. There was no family history of neurological disease or developmental delay. Psychomotor development was severely delayed. His head control developed at 12 months of age. He did not start walking independently until he was 5 years old. He showed obvious language developmental problems, never mastering speech. He had a severe intellectual disability with an IQ of below 30. He had behavioral problems, including self-injurious behavior and features of autism spectrum disorder. At the age of 17, he presented with diffuse acute abdominal pain and peritonitis upon examination. An abdomen computed tomography showed nonspecific findings, including mechanical ileus, with no visible mesenteric mass (Fig. 1A). Segmental resection of the small bowel, measuring 15 cm in length, was performed. Small multifocal grayish-white fibrotic nodules were found on the serosal surface, with stricture and perforation of the intestinal wall (Fig. 1B and C). The perforated site showed hemorrhage and necrosis. Subsequent histology revealed a benign fibromatosis tumor. Staining was positive for smooth muscle actin (SMA) and beta-catenin staining but negative for CD117, CD34, S-100, and calretinin. He was diagnosed with mesenteric fibromatosis with a perforation. When he visited our clinic as a 17-year-old, he exhibited growth retardation. His body weight was 43 kg ( 3.65 standard deviation
AMERICAN JOURNAL OF MEDICAL GENETICS PART A [SD] [Moon et al., 2008]), his height was 162 cm ( 2.05 SD), and his body mass index (BMI) was 16.4 kg/m2 ( 2.81 SD). In the craniofacial examination, relative microcephaly (49 cm, 1.65 SD), flattening of the occiput, sparse lateral eyebrows, upslanting palpebral fissures, prominent ears, a high palate, thick lips, and freckles were observed (Fig. 2A and B). The lung fields were clear, with symmetrical air entry. There was no chest wall deformity. His heart examination was normal, without murmurs. There were no skeletal abnormalities. Except for atopic dermatitis, there were no lesions on the skin, hair, or nails. Neurologically, he was alert but made only very brief eye contact. Cranial nerve examinations were normal. Muscle tone and strength were normal. There were no pathological reflexes or traces of clonus. The clinical characteristics are summarized in Table I.
CYTOGENETIC RESULTS Chromosomal analysis was carried out by applying GTG-banding to the patient and the patient’s parents at a 550 band-level resolution, according to International System for Human Cytogenetic Nomenclature (ISCN) 2009. Cytogenetic analysis was performed on peripheral blood. The patient’s G-banded analysis showed the derivative chromosome, der(22) t(11;22), and revealed segmental direct duplication of chromosome 11q23.3-qter (Fig. 3A). G-band-
FIG. 1. A: Erect abdomen radiograph demonstrates multiple air-fluid levels in the dilated loops in a typical configuration of a small bowel mechanical obstruction. B: The serosal surface is pinkish-gray and smooth, with small, multifocal grayish-white fibrotic nodules. A strictured and sutured site with a suspected previous perforation is present at one-third position of the segment. C: Two-thirds of the mucosa, including the sutured site, is diffusely edematous and hemorrhagic. The perforated site shows hemorrhage and necrosis.
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FIG. 2. A-B: The patient shows sparse lateral eyebrows, up-slanting palpebral fissures, prominent ears, thick lips, freckles, and an itchy rash due to atopic dermatitis. C: The patient’s lateral skull X-ray reveals a flattened occiput and protrusion of the maxilla. D: Interictal sleep electroencephalogram exhibits sharp and abnormally slow waves on the frontal lobe region.
ing analysis of the patient’s mother showed a mosaic trisomy (22.7%) of chromosome 11q23.3-qter due to an unbalanced terminal translocation between the long arm of chromosome 22 and the distal long arm of chromosome 11 (Fig. 3B). The corresponding ISCN designation is mos46,XX,inv(9)(p12q13), der(22) t(11;22)(q23.3;q13.3) [17]/46,XX,inv(9) [58]. The patient’s father and two siblings had normal karyotypes. Therefore, the ISCN for patient’s karyotype is 46,XY,der(22) t(11;22) (q23.3;q13.3)mat. Oligonucleotide-based microarray analyses were performed in April 2013 with a 135 K-feature whole-genome microarray (SignatureChip Oligo Solution made for Signature Genomic Laboratories by Roche NimbleGen, Madison, WI). Array CGH revealed a region of gain spanning 17.77–17.80 Mb on chromosome 11q23.3q25. Based on National Center for Biotechnology Information (NCBI) human genome build 36 (NCBI36/hg18; Mar. 2006), the minimum start and stop points for this duplication were estimated at 116,667,559 and 134,434,130 with a total of 1,668 probes arr 11q23.3-q25 (116,667,559 –134,434,130) 3 [NCBI36/hg18]. This region of gain contained 115 Online Mendelian Inheritance in Man (OMIM) genes (Fig. 3C). There was no terminal deletion on chromosome 22q using by array CGH. In order to confirm the result of array CGH, fluorescence in situ hybridization (FISH) analysis, using two BAC clones with 11q24.3 green probe (Macrogen) and TelVysion 22q orange probe (Vysis), was performed on peripheral blood lymphocytes of patient. FISH on metaphase cells showed that additional material (green color: 11q24.3 probe) was inserted into the long arm of chromosome 22 (orange color: 22q13.33 subtelomic probe).
DISCUSSION Chromosome 11 spans approximately 135 million base pairs and represents about 4% of the total DNA in cells. It likely contains 1,300–1,400 genes that provide instructions for proteins synthesis, and it is one of the most gene-rich chromosomes in the human genome. Of these genes, dosage-sensitive genes are associated with deletion and duplication syndromes. Most constitutional segmental aneusomies generally occur in a random fashion. However, there are fragile hotspots on chromosome 11. Jacobsen syndrome (OMIM#147791) is well known as an 11q deletion disorder or partial monosomy 11q syndrome, resulting from deletion of the terminal region of chromosome 11 [Mattina et al., 2009]. Approximately 80% of the known 11q terminal deletion breakpoint is a rare folate-sensitive fragile site in band 11q23.3 (FRA11B) [Penny et al., 1995]. The opposite syndrome of Jacobsen syndrome is partial trisomy 11q syndrome such as our case. Partial trisomy of 11q is relatively less common than Jacobsen syndrome, and the reported breakpoints cover a wide range, from 11q12 to 11q23. Of these, partial trisomy 11q23-qter has well-defined clinical characteristics [Ben-Abdallah-Bouhjar et al., 2013]. Most cases of partial trisomy of 11q23-qter are associated with a second chromosomal imbalance, usually chromosome 22q, which makes defining the phenotype of 11q partial trisomy difficult [Ben-Abdallah-Bouhjar et al., 2013]. The most common, partial 11q syndrome is Emanuel Syndrome (OMIM# 609029) [Carter et al., 2009]. In more than 99% of cases, one of the parents of Emanuel syndrome is a balanced carrier of a t(11;22)(q23;q11.2) and is phenotypically normal. The clinical phenotype of the Emanuel syndrome arises from
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TABLE I. Clinical Features and Molecular Characteristics of the Patient and Patient’s Mother Trait Age at test/sex Birth history Head Face Cardiovascular Gastrointestinal Renal and genitourinary Muscular and skeletal Skin Growth retardation Psychomotor development Behavior problem Seizure
Patient partial trisomy 11q23.3-q25
Mother 22.7% mosaic partial trisomy11q23.3-q25
17 years/male Term AGA (3800 g), NSVD Microcephaly (HC 49 cm, 1.64 SDS), flattening of occiput Sparse lateral eyebrows, upslanting palpebral fissures, prominent ears, high palate, thick lips, freckles None Mesenteric fibromatosis None None Atopic dermatitis Bw 43 kg (-3.65 SDS), Ht 162 cm (-2.05 SDS), BMI 16.38 kg/m2 ( 2.81 SDS) Severe intellectual disability, no speech development Autism spectrum disorder, self-injurious behavior Generalized tonic-clinic seizures; treated with lamotrigine
45 years/female Term AGA None (HC 53 cm, 1.67 SDS) None None None None None None Bw 70 kg (1.79 SDS), Ht 165 cm (0.83 SDS), BMI 25.71 kg/m2 (1.53 SDS) None None None
AGA: appropriate for gestational age; NSVD: normal spontaneous vaginal delivery; HC: head circumference; SDS: standard deviation score; Bw: body weight; Ht: height; BMI: body mass index; ASD: atrial septal defect; PS: Pulmonic stenosis
duplication of 22q10–22q11 and duplication of 11q23-qter. The break points of t(11;22) s have been identified within palindromic AT-rich repeats (PATRRs) on 11q23 (PATRR11) and 22q11 (PATRR22) [Kurahashi et al., 2006]. The FRA11B and PATRR11 at chromosome 11q23 are the hot spots for deletion and translocation breakpoints. The fragile site FRA11B has been localized to the p(CCG)n repeat of the CBL2 gene (chr11:118,575, 702 – 118,775,922) in NCBI36/hg18. The PATRR11 is located between ZNF259 (chr11:116,154,486 – 116,163,949) and Apo gene cluster (chr11:116,165,296 – 116,213,548) in NCBI36/hg18 [Kurahashi et al., 2000]. The 11q23.3 (116,667,559 – 134,434,130) breakpoint of our case was quite near to PATRR11 shown as Figure 3C. Common segmental aneusomies result from deletion, duplication, triplication, terminal translocation, and insertional translocation [Kang et al., 2010; Assawamakin et al., 2012; Thierry et al., 2013]. Our patient showed segmental trisomy of 11q23.3-q25 with no copy number changes in another chromosome. Especially, our patient did not have a copy number change of chromosome 22 by oligonucleotide array CGH confirmed with locus-specific 22q subtelomeric FISH probes. We suggest that our case is one of so-called “pure” partial trisomy due to terminal translocation. Based on a literature review, the majority of cases with unbalanced translocation are result from a balanced translocation present in a phenotypically normal parent [Thierry et al., 2013]. In the present case, the patient inherited the trisomy from a maternal mosaic unbalanced terminal translocation, der(22) t(11;22)
(q23.3;q13.3), with the mosaic trisomy 22.7% of 11q23.3-q25. This is the first documentation of mosaic trisomy of 11q23.3–25. Despite the presence of low-level mosaic partial trisomy of 11q23.3-q25, the mother did not show any of the characteristic signs and symptoms of partial trisomy 11q syndrome. This duplicated region contains about 115 OMIM genes, many of which have not been well characterized. We do not yet know which genes are particularly dosage-sensitive and contribute to the phenotypes of partial trisomy 11q syndrome. In addition, the number of gene dosage changes that are required to exert disruptive effects on the gene structure and function and contribute substantially to this syndrome is not known. However, this study suggests that low-level mosaic trisomy of 11q23-qter, up to 22.7%, does not cause the characteristic abnormal findings of this syndrome. Interestingly, our patient exhibited some new clinical features, including mesenteric fibromatosis, atopic dermatitis, and delayed puberty. Mesenteric fibromatosis is a rare benign fibrous tumor affecting the mesentery that occurs spontaneously or develops as a consequence of surgical trauma. It may also be associated with genetic syndromes, such as familiar adenomatous polyposis or Gardner’s syndrome [Bethune and Amin, 2006; Wronski et al., 2011]. To date, mesenteric fibromatosis has not been described in relation to partial trisomy of 11q. In summary, we described the clinical features of a patient with partial trisomy of 11q23.3-q25 and the patient’s mother with lowlevel mosaic trisomy of 11q 23.3-q25. Our study provides additional information that contributes to understanding and delineation of partial trisomy of 11q and mosaic partial trisomy of 11q.
KIM ET AL.
FIG. 3. A: G-banded karyotype of patient reveals 46,XY,der(22) t(11;22)(q23.3;q13.3)mat at a 550 band-level resolution. B-1: G-banded karyotype of patient’s mother shows 46,XX,inv(9)(p12q13), der(22) t(11;22)(q23.3;q13.3) at a 550 band-level resolution. B-2: Partial Gbanded karyotype of maternal chromosomes 11 and 22 and diagram of the unbalanced terminal translocation. C: Array comparative genomic hybridization (CGH) analysis shows a 17.77–17.80 Mb region of gain on chromosome 11q23.3-q25, arr 11q23.3-q25 (116,667,559 – 134,434,130) 3 [NCBI36/hg18]. The breakpoint region of our case is closer to PATRR11 (blue arrow) than FRA11B (green arrow). D: In metaphase FISH assay, chromosome painting probe specific for the 11q24.3 region (green signals) shows three signals, consistent with a duplication of 11q24. The subtelomeric region of chromosome 22q was normal (orange signals).
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ETHICS STATEMENT The use of human clinical materials and blood in this study was approved by the Ethical Committee of the Eulji General Hospital (IRB#2013–08-001–001). We received the written informed consent from patient’s parent.
REFERENCES Assawamakin A, Wattanasirichaigoon D, Tocharoentanaphol C, Waeteekul S, Tansatit M, Thongnoppakhun W, Limwongse C. 2012. A novel maternally-derived insertional translocation resulting in partial trisomy 4q13.2-q22.1 with complex translocation t(8;20) in a family with intellectual disability. Am J Med Genet A 158A:901–908. Ben-Abdallah-Bouhjar I, Mougou-Zerelli S, Hannachi H, Ben-Khelifa H, Soyah N, Labalme A, Sanlaville D, Elghezal H, Saad A. 2013. Phenotype and Micro-array characterization of duplication 11q22.1-q25 and review of the literature. Gene 519:135–141. Bethune R, Amin A. 2006. Mesenteric fibromatosis: A rare cause of acute abdominal pain. Ann R Coll Surg Engl 88:1–2. Burnside RD, Lose EJ, Dominguez MG, Sanchez-Corona J, Rivera H, Carroll AJ, Mikhail FM. 2009. Molecular cytogenetic characterization of two cases with constitutional distal 11q duplication/triplication. Am J Med Genet A 149A: 1:1516–1522. Carter MT, St Pierre SA, Zackai EH, Emanuel BS, Boycott KM. 2009. Phenotypic delineation of Emanuel syndrome (supernumerary derivative 22 syndrome): Clinical features of 63 individuals. Am J Med Genet A 149A: 1:1712–1721. Choudhary MG, Babaji P, Sharma N, Dhamankar D, Naregal G, Reddy VS. 2013. Derivative 11;22 (emanuel) syndrome: A case report and a review. Case Rep Pediatr 2013:237935. Francke U, Weber F, Sparkes RS, Mattson PD, Mann J. 1977. Duplication 11 (q21 to 23 leads to qter) syndrome. Birth Defects Orig Artic Ser 13:167–186. Gohring I, Blumlein HM, Hoyer J, Ekici AB, Trautmann U, Rauch A. 2008. 6.7 Mb interstitial duplication in chromosome band 11q24.2q25 associated with infertility, minor dysmorphic features and normal psychomotor development. Eur J Med Genet 51:666–671. Kang SH, Shaw C, Ou Z, Eng PA, Cooper ML, Pursley AN, Sahoo T, Bacino CA, Chinault AC, Stankiewicz P, Patel A, Lupski JR, Cheung SW. 2010. Insertional translocation detected using FISH confirmation of arraycomparative genomic hybridization (aCGH) results. Am J Med Genet A 152A: 1:1111–1126.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kayhan G, Cavdarli B, Yirmibes Karaoguz, Percin M, Ozturk EF, Kaymak A, Biri A, Ergun MA. 2013. Molecular karyotyping of an isolated partial trisomy 11q patient with additional findings. Gene 524:355–360. Klaassens M, Scott DA, van Dooren M, Hochstenbach R, Eussen HJ, Cai WW, Galjaard RJ, Wouters C, Poot M, Laudy J, Lee B, Tibboel D, de Klein A. 2006. Congenital diaphragmatic hernia associated with duplication of 11q23-qter. Am J Med Genet A 140:1580–1586. Kurahashi H, Inagaki H, Ohye T, Kogo H, Kato T, Emanuel BS. 2006. Palindrome-mediated chromosomal translocations in humans. DNA repair 5:1136–1145. Kurahashi H, Shaikh TH, Hu P, Roe BA, Emanuel BS, Budarf ML. 2000. Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22). Hum Mol Genet 9:1665–1670. Mattina T, Perrotta CS, Grossfeld P. 2009. Jacobsen syndrome. Orphanet J Rare Dis 4:9. Moon JS, Lee SY, Nam CM, Choi JM, Choe BK, Seo JW, Oh K, Jang MJ, Hwang SS, Yoo MH, Kim YT, Lee CG. 2008. Korean National Growth Charts: Review of developmental process and an outlook. 2007 51: 1–25. Ohye T, Inagaki H, Kato T, Tsutsumi M, Kurahashi H. 2014. Prevalence of Emanuel syndrome: theoretical frequency and surveillance result. Pediatr Int. 56:462–466. . Penny LA, Dell’Aquila M, Jones MC, Bergoffen J, Cunniff C, Fryns JP, Grace E, Graham JM, Jr., Kousseff B, Mattina T, et al. 1995. Clinical and molecular characterization of patients with distal 11q deletions. Am J Hum Genet 56:676–683. Pihko H, Therman E, Uchida IA. 1981. Partial 11q trisomy syndrome. Hum Genet 58:129–134. Thierry G, Pichon O, Briand A, Poulain D, Sznajer Y, David A, Le Caignec C. 2013. Autosomal insertional translocation mimicking an X-linked mode of inheritance. Eur J Med Genet 56:46–49. Wronski M, Ziarkiewicz-Wroblewska B, Slodkowski M, Cebulski W, Gornicka B, Krasnodebski IW. 2011. Mesenteric fibromatosis with intestinal involvement mimicking a gastrointestinal stromal tumour. Radiol Oncol 45:59–63. Yelavarthi KK, Zunich J. 2004. Familial interstitial duplication of 11q; partial trisomy (11)(q13.5q21). Am J Med Genet A 126A:423–426. Zarate YA, Kogan JM, Schorry EK, Smolarek TA, Hopkin RJ. 2007. A new case of de novo 11q duplication in a patient with normal development and intelligence and review of the literature. Am J Med Genet A 143:265–270. Zimberg-Bossira A, Smolkin T, Gildish A, Moustafa-Hawash N, Blazer S, Gershoni-Baruch R, Makhoul IR. 2011. ’Pure’ partial trisomy 11q (11q23.1–>11qter): Expanding the phenotype. Clin Dysmorphol 20:225–228.
