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Split Hand/Foot Malformations with Microdeletions at Chromosomes 7 and 19 Detected Using Array Comparative Genomic Hybridization

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Split Hand/Foot Malformations with Microdeletions at Chromosomes 7 and 19 Detected Using Array Comparative Genomic Hybridization Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 92e94 Contents lists available at ScienceDirect Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com Research Letter Split hand/foot malformations with microdeletions at chromosomes 7 and 19 detected using array comparative genomic hybridization * Chin-Jui Wu a, Yi-Ning Su b, c, Tzu-Hung Lin b, c, Li-Hui Tseng d, Kuang-Han Chao a, a Department of Obstetrics and Gynecology, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan b Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan c Dianthus Maternal Fetal Medicine Clinic, Taipei, Taiwan d Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan article info Article history: and second toe, but no other detectable anomaly. The child's in- Accepted 22 January 2014 telligence was also of normal development. She sought genetic counseling for this pregnancy. The preg- nancy was terminated because of the possible deletion of chro- mosomes. The abortus exhibited a specific characteristic of deficiency of the second and third toes (Fig. 2). Both hands were claw-like (Fig. 3). The placental tissue was examined using oligonucleotide-based array comparative genomic hybridization (aCGH) analysis with a CytoChip Oligo array (BlueGenome, Cam- The split hand/split foot malformation (SHFM), which is also bridge, UK). The genomic version of the chip is the CytoChip ISCA* known as ectrodactyly, is a limb malformation syndrome involving version 2.0 8x60K (BlueGenome, Cambridge, UK). We employed the the central rays of the hand or foot. The typical SHFM may present protocol presented in the reference manual (www.cytochip.com). with syndactyly; median clefts of the hands and feet; and aplasia The results revealed three microdeletions: 1.9 Mb deletions or hypoplasia (or both) of the phalanges, metacarpals, and at 7p22.1ep22.1 (4,583,819e6,498,129), 3.9 Mb deletions metatarsals. at 7q11.23eq11.23 (72,119,820e75,977,247), and 4.1 Mb deletions Numerous human gene defects can cause SHFMs. For example, at 7q21.3eq22.1 (97,723,732e101,812,625). Two other larger de- the SHFM1 gene is associated with deletions of varying extent on letions were 24 Mb deletions at 19p13.3ep12 (210,424e chromosome 7q21eq22 [1], whereas SHFM2 is associated with 24,170,303) and 26.2 Mb deletions at 19q11.31eq13.43 (37,601, genes localized at Xq26eq26.16 [2]. Previous research has reported 047e63,787,200) (Fig. 4). multiple types of syndromic or nonsyndromic ectrodactyly [3]. The Split hand/split foot malformation has been identified by most common mode of inheritance is autosomal dominant with numerous terms such as “ectrodactyly”, “cleft hand”, “partial ter- reduced penetrance. These cases can occur in families or in isola- minal aphalangia”, “oligodactyly”, “central oligodactyly”, “central tion. Interfamilial variability appears to be significantly greater than ray deficiency”, “crab claw malformation”, and “lobster claw intrafamilial variability, which indicates genetic heterogeneity. The anomaly/malformation”. Elliott et al [4] summarized previously syndrome is characterized by various clinical manifestations that reported SHFM patients. Our patient was diagnosed prenatally, vary significantly among affected individuals and generate various which differs from numerous reported cases that are typically combinations. observed after birth. In 1995, the first case was diagnosed during We present a case of “lobster claw hand” observed during a pregnancy [5]. Detailed ultrasonography revealed multiple anom- prenatal ultrasound examination. A 21-week pregnant 39-year-old alies, which included oligodactyly. Split hand/split foot malforma- woman (gravida 4, para 1) was referred to our hospital after the tion is genetically heterogeneous with mutations identified at five detection of SHFM during fetal ultrasound screening (Fig. 1). loci: SHFM1 at 7q21.3, SHFM2 at Xq26, SHFM3 at 10q24, SHFM4 at Ultrasonography at referral confirmed a fetus with SHFM but 3q27, and SHFM5 at 2q31 [3]. The location heterogeneity compli- without any facial or genitourinary anomaly. A review of her birth cated the identification and genetic counseling. history showed that her first son had syndactyly of his left hallux Array comparative genomic hybridization is a technique that enables high-resolution, genome-wide screening of segmental genomic copy number variations. It is becoming an essential and * Corresponding author. Department of Obstetrics and Gynecology, College of Medicine and Hospital, National Taiwan University Hospital, No. 7, Chung-Shan routine clinical diagnostic tool, and it is gradually replacing tradi- South Road, Taipei, 10063, Taiwan. tional cytogenetic methods [6]. E-mail address: [email protected] (K.-H. Chao). http://dx.doi.org/10.1016/j.tjog.2014.01.006 1028-4559/Copyright © 2014, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved. C.-J. Wu et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 92e94 93 Fig. 1. Ultrasound images of (A) a split foot and (B) a split hand. A shortcome of classical karyotype analysis is that it lacks In addition to microdeletions of 7q, our patient had two other sensitivity in detecting subtle chromosome rearrangements (i.e., microdeletions at chromosome 19p. In the literature, there has <4 Mb). Fluorescent in situ hybridization has improved the diag- been only one SHFM case report with genomic loci studies at 19p nostic resolution, but it is a time-consuming targeted method that [8].Atenetal[8] identified a de novo deletion of chromosome requires previous knowledge of the chromosomal region. However, 19p13.11 in a male patient with SHFM, but no candidate genes in comparative genomic hybridization platforms can cover approxi- other SHFM loci (e.g., DSS1, FGF13, FBXW4, TP73L, and DLX2). Sub- mately one clone per megabase to one clone per 100 kb. Com- sequent screening of 21 syndromic and nonsyndromic SHFM pa- mercial whole-genome oligonucleotide arrays range from one tients with no TP73L mutation failed to detect any deletion or probe per 6e70 kb. Shaikh [7] reported a detailed review and duplication in chromosome 19, which indicated that SHFM is comparison of various commercial oligonucleotide array platforms. genetically more heterogeneous than previously reported. Chro- Five genomic loci have been implicated, based on cases and mosome 19p contained two genes (EPS15L1 and CALR3) that may be family studies. These loci are SHFM1 (chromosome region, associated with limb malformations [9]. EPS15L1 functions as a 7q21eq22), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27), and substrate for tyrosine kinase activity of the epidermal growth factor SHFM5 (2q31). In the past, molecular tests such as fluorescence in receptor [10]. The signal pathway of the epidermal growth factor situ hybridization or polymerase chain reaction were used to detect receptor is associated with the apical epidermal ridge, thereby the mutated loci in people with SHFM. Because of improvements in affecting limb formation. the resolution of aCGH, it detected SHFM type 1 in our patient. The We observed EPS15L1 gene deletion in our patient. However, deletions at chromosome 7q21eq22 in patients with SHFM type 1 because of the concurrent loss of SHFM type 1 gene at chromosome cause the deletion of several candidate genes including DLX5, DLX6, 7, it was difficult to identify the relationship between phenotype or DSS1. A knockout mouse model showed the concurrent loss of and genotype when both deletions are present. DLX5 and DLX6, and resulted in the failure of apical epidermal ridge If a couple with fetal anomalies accepts fetal chromosome development; this was finally expressed as the phenotype of studies, aCGH could expand the ability to detect microdeletions in ectrodactyly [3]. genetic diseases. During genetic counseling, physicians should Fig. 2. Symmetric defect of the left foot. Fig. 3. Symmetric defect of the right hand. 94 C.-J. Wu et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 92e94 Fig. 4. Array comparative genomic hybridization shows several deletions in chromosomes 7 and 19. recommend an aCGH test for patients with a family history of fetal [4] Elliott AM, Evans JA, Chudley AE. Split hand foot malformation (SHFM). Clin e anomalies. Genet 2005;68:501 5. [5] Leung KY, MacLachlan NA. Prenatal diagnosis of ectrodactyly: the “lobster claw” anomaly. Ultrasound Obstet Gynecol 1995;6:443e6. fl [6] Shinawi M, Cheung SW. The array CGH and its clinical applications. Drug Con icts of interest Discov Today 2008;13(17-18):760e70. [7] Shaikh TH. Oligonucleotide arrays for high-resolution analysis of copy number The authors have no conflicts of interest relevant to this article. alteration in mental retardation/multiple congenital anomalies. Genet Med 2007;9:617e25. [8] Aten E, den Hollander N, Ruivenkamp C, Knijnenburg J, van Bokhoven H, den References Dunnen J, et al. Split hand-foot malformation, tetralogy of Fallot, mental retardation and a 1 Mb 19p deletion-evidence for further heterogeneity? Am J Med Genet A 2009;149A(Suppl. 5):975e81. [1] van Silfhout AT, van den Akker PC, Dijkhuizen T, Verheij JB, Olderode- [9] Bens S, Haake A, Tonnies€ H, Vater I, Stephani U, Holterhus PM, et al. A de novo Berends MJ, Kok K, et al. Split hand/foot malformation due to chromosome 7q 1.1Mb microdeletion of chromosome 19p13.11 provides indirect evidence for aberrations(SHFM1): additional support for functional haploinsufficiency as EPS15L1 to be a strong candidate for split hand split foot malformation. Eur J e the causative mechanism. Eur J Hum Genet 2009;17:1432 8. Med Genet 2011;54:e501e4. [2] Faiyaz ul Haque M, Uhlhaas S, Knapp M, Schüler H, Friedl W, Ahmad M, et al. [10] Wong WT, Schumacher C, Salcini AE, Romano A, Castagnino P, Pelicci PG, et al. Mapping of the gene for X-chromosomal split-hand/split-foot anomaly to A protein-binding domain, EH, identified in the receptor tyrosine kinase e Xq26-q26.1. Hum Genet 1993;91:17 9. substrate Eps15 and conserved in evolution.
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