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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 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 b a r t i c l e i n f o Article history: Accepted 22 January 2014 The split hand/split foot malformation (SHFM), which is also known as ectrodactyly, is a limb malformation syndrome involving the central rays of the hand or foot. The typical SHFM may present with syndactyly; median clefts of the hands and feet; and aplasia or hypoplasia (or both) of the phalanges, metacarpals, and metatarsals. Numerous human gene defects can cause SHFMs. For example, the SHFM1 gene is associated with deletions of varying extent on chromosome 7q21eq22 [1], whereas SHFM2 is associated with genes localized at Xq26eq26.16 [2]. Previous research has reported multiple types of syndromic or nonsyndromic ectrodactyly [3]. The most common mode of inheritance is autosomal dominant with reduced penetrance. These cases can occur in families or in isolation. Interfamilial variability appears to be significantly greater than intrafamilial variability, which indicates genetic heterogeneity. The syndrome is characterized by various clinical manifestations that vary significantly among affected individuals and generate various combinations. We present a case of “lobster claw hand” observed during a prenatal ultrasound examination. A 21-week pregnant 39-year-old woman (gravida 4, para 1) was referred to our hospital after the detection of SHFM during fetal ultrasound screening (Fig. 1). Ultrasonography at referral confirmed a fetus with SHFM but without any facial or genitourinary anomaly. A review of her birth history showed that her first son had syndactyly of his left hallux * Corresponding author. Department of Obstetrics and Gynecology, College of Medicine and Hospital, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 10063, Taiwan. E-mail address: [email protected] (K.-H. Chao). and second toe, but no other detectable anomaly. The child's intelligence was also of normal development. She sought genetic counseling for this pregnancy. The pregnancy was terminated because of the possible deletion of chromosomes. 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, Cambridge, UK). The genomic version of the chip is the CytoChip ISCA* version 2.0 8x60K (BlueGenome, Cambridge, UK). We employed the protocol presented in the reference manual (www.cytochip.com). The results revealed three microdeletions: 1.9 Mb deletions at 7p22.1ep22.1 (4,583,819e6,498,129), 3.9 Mb deletions at 7q11.23eq11.23 (72,119,820e75,977,247), and 4.1 Mb deletions at 7q21.3eq22.1 (97,723,732e101,812,625). Two other larger deletions were 24 Mb deletions at 19p13.3ep12 (210,424e 24,170,303) and 26.2 Mb deletions at 19q11.31eq13.43 (37,601, 047e63,787,200) (Fig. 4). Split hand/split foot malformation has been identified by numerous terms such as “ectrodactyly”, “cleft hand”, “partial terminal aphalangia”, “oligodactyly”, “central oligodactyly”, “central ray deficiency”, “crab claw malformation”, and “lobster claw anomaly/malformation”. Elliott et al [4] summarized previously reported SHFM patients. Our patient was diagnosed prenatally, which differs from numerous reported cases that are typically observed after birth. In 1995, the first case was diagnosed during pregnancy [5]. Detailed ultrasonography revealed multiple anomalies, which included oligodactyly. Split hand/split foot malformation is genetically heterogeneous with mutations identified at five loci: SHFM1 at 7q21.3, SHFM2 at Xq26, SHFM3 at 10q24, SHFM4 at 3q27, and SHFM5 at 2q31 [3]. The location heterogeneity complicated the identification and genetic counseling. 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 routine clinical diagnostic tool, and it is gradually replacing traditional cytogenetic methods [6]. 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 sensitivity in detecting subtle chromosome rearrangements (i.e., <4 Mb). Fluorescent in situ hybridization has improved the diagnostic resolution, but it is a time-consuming targeted method that requires previous knowledge of the chromosomal region. However, comparative genomic hybridization platforms can cover approximately one clone per megabase to one clone per 100 kb. Commercial whole-genome oligonucleotide arrays range from one probe per 6e70 kb. Shaikh [7] reported a detailed review and comparison of various commercial oligonucleotide array platforms. Five genomic loci have been implicated, based on cases and family studies. These loci are SHFM1 (chromosome region, 7q21eq22), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27), and SHFM5 (2q31). In the past, molecular tests such as fluorescence in situ hybridization or polymerase chain reaction were used to detect the mutated loci in people with SHFM. Because of improvements in the resolution of aCGH, it detected SHFM type 1 in our patient. The deletions at chromosome 7q21eq22 in patients with SHFM type 1 cause the deletion of several candidate genes including DLX5, DLX6, or DSS1. A knockout mouse model showed the concurrent loss of DLX5 and DLX6, and resulted in the failure of apical epidermal ridge development; this was finally expressed as the phenotype of ectrodactyly [3]. In addition to microdeletions of 7q, our patient had two other microdeletions at chromosome 19p. In the literature, there has been only one SHFM case report with genomic loci studies at 19p [8]. Aten et al [8] identified a de novo deletion of chromosome 19p13.11 in a male patient with SHFM, but no candidate genes in other SHFM loci (e.g., DSS1, FGF13, FBXW4, TP73L, and DLX2). Subsequent screening of 21 syndromic and nonsyndromic SHFM patients with no TP73L mutation failed to detect any deletion or duplication in chromosome 19, which indicated that SHFM is genetically more heterogeneous than previously reported. Chromosome 19p contained two genes (EPS15L1 and CALR3) that may be associated with limb malformations [9]. EPS15L1 functions as a substrate for tyrosine kinase activity of the epidermal growth factor receptor [10]. The signal pathway of the epidermal growth factor receptor is associated with the apical epidermal ridge, thereby affecting limb formation. We observed EPS15L1 gene deletion in our patient. However, because of the concurrent loss of SHFM type 1 gene at chromosome 7, it was difficult to identify the relationship between phenotype and genotype when both deletions are present. If a couple with fetal anomalies accepts fetal chromosome studies, aCGH could expand the ability to detect microdeletions in 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 anomalies. Conflicts of interest The authors have no conflicts of interest relevant to this article. References [1] van Silfhout AT, van den Akker PC, Dijkhuizen T, Verheij JB, OlderodeBerends MJ, Kok K, et al. Split hand/foot malformation due to chromosome 7q aberrations(SHFM1): additional support for functional haploinsufficiency as the causative mechanism. Eur J Hum Genet 2009;17:1432e8. [2] Faiyaz ul Haque M, Uhlhaas S, Knapp M, Schüler H, Friedl W, Ahmad M, et al. Mapping of the gene for X-chromosomal split-hand/split-foot anomaly to Xq26-q26.1. Hum Genet 1993;91:17e9. [3] Duijf PH, van Bokhoven H. Brunner HG Pathogenesis of split-hand/split-foot malformation. Hum Mol Genet 2003;12(Suppl. 1):R51e60. [4] Elliott AM, Evans JA, Chudley AE. Split hand foot malformation (SHFM). Clin Genet 2005;68:501e5. [5] Leung KY, MacLachlan NA. Prenatal diagnosis of ectrodactyly: the “lobster claw” anomaly. Ultrasound Obstet Gynecol 1995;6:443e6. [6] Shinawi M, Cheung SW. The array CGH and its clinical applications. Drug Discov Today 2008;13(17-18):760e70. [7] Shaikh TH. Oligonucleotide arrays for high-resolution analysis of copy number 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 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. €nnies H, Vater I, Stephani U, Holterhus PM, et al. A de novo [9] Bens S, Haake A, To 1.1Mb microdeletion of chromosome 19p13.11 provides indirect evidence for EPS15L1 to be a strong candidate for split hand split foot malformation. Eur J Med Genet 2011;54:e501e4. [10] Wong WT, Schumacher C, Salcini AE, Romano A, Castagnino P, Pelicci PG, et al. A protein-binding domain, EH, identified in the receptor tyrosine kinase substrate Eps15 and conserved in evolution. Proc Natl Acad Sci USA 1995;92: 9530e4.