Split Hand Foot Malformation Syndrome: A Novel Heterozygous FGFR1 Mutation Detected by Next Generation Sequencing

Author(s): ​Panayiota Papasozomenou*, ​Ioannis Papoulidis, ​Themistoklis Mikos, ​Menelaos Zafrakas

Journal Name: Current Genomics

Volume 20 , Issue 3 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Split-hand/foot malformation syndrome is a rare, clinically and genetically heterogeneous group of limb malformations characterized by absence/hypoplasia and/or median cleft of hands and/or feet. It may occur as an isolated abnormality or it may be associated with a genetic syndrome.

Case Report: In the present case, isolated split-hand/split-foot malformation was diagnosed by prenatal ultrasound at 24 weeks in a male singleton fetus, with deep median cleft of the right hand, syndactyly and hypoplasia of phalanges in both hands, and oligodactyly of the right foot. During consultation, the father of the fetus revealed that he also had an isolated right foot dysplasia. The parents chose elective termination and autopsy confirmed prenatal ultrasound findings. Genetic testing of the aborted fetus with QF-PCR analysis for common aneuploidies and array comparative genomic hybridization (aCGH) showed a male genomic pattern, without aneuploidies or chromosomal imbalances. Further investigation with next generation sequencing of 49 clinically relevant genes revealed a novel heterozygous FGFR1 mutation c.787_789del (p.Ala263del) in the fetus; the father was heterozygous to the same mutation.

Conclusion: A novel heterozygous FGFR1 mutation causing split-hand/foot malformation syndrome is reported. Accurate genetic diagnosis allowed detailed counseling to be provided to the couple, including the underlying cause, recurrence risks, and detailed management plan with preimplantation genetic diagnosis for future pregnancies.

Keywords: Split-hand/foot malformation, limb malformations, prenatal diagnosis, next generation sequencing, FGFR1, novel mutation.

Czeizel, A.E.; Vitéz, M.; Kodaj, I.; Lenz, W. An epidemiological study of isolated split hand/foot in Hungary, 1975-1984. J. Med. Genet., 1993, 30(7), 593-596.
Blattner, A.; Huber, A.R.; Röthlisberger, B. Homozygous nonsense mutation in WNT10B and sporadic split-hand/foot malformation (SHFM) with autosomal recessive inheritance. Am. J. Med. Genet., 2010, 152A(8), 2053-2056.
Klopocki, E.; Lohan, S.; Doelken, S.C.; Stricker, S.; Ockeloen, C.W.; Thiele, S.; de Aguiar, R.; Lezirovitz, K.; Mingroni, N.R.C.; Jamsheer, A.; Shah, H.; Kurth, I.; Habenicht, R.; Warman, M.; Devriendt, K.; Kordass, U.; Hempel, M.; Rajab, A.; Mäkitie, O.; Naveed, M.; Radhakrishna, U.; Antonarakis, S.E.; Horn, D.; Mundlos, S. Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. J. Med. Genet., 2012, 49(2), 119-125.
Duijf, PH.; van Bokhoven, H.; Brunner, H.G. Pathogenesis of splithand/ split-foot malformation. Hum. Mol. Genet., 2003, 12(Suppl_1), R51-R60.
Scherer, S.W.; Poorkaj, P.; Allen, T.; Kim, J.; Geshuri, D.; Nunes, M.; Soder, S.; Stephens, K.; Pagon, R.A.; Patton, M.A.; Berg, M.A.; Donlon, T.; Rivera, H.; Pfeiffer, R.A.; Naritomi, K.; Hughes, H.; Genuardi, M.; Gurrieri, F.; Neri, G.; Lovrein, E.; Magenis, E.; Tsui, L.C.; Evans, J.P. Fine mapping of the autosomal dominant split hand/split foot locus on chromosome 7 band q21.3-q22.1. Am. J. Hum. Genet., 1994, 55(1), 12-20.
Nunes, M.E.; Schutt, G.; Kapur, R.P.; Luthardt, F.; Kukolich, M.; Byers, P.; Evans, J.P. A second autosomal split hand/split foot locus maps to chromosome 10q24-q25. Hum. Mol. Genet., 1995, 4(11), 2165-2170.
Gurrieri, F.; Prinos, P.; Tackels, D.; Kilpatrick, M.W.; Allanson, J.; Genuardi, M.; Vuckov, A.; Nanni, L.; Sangiorgi, E.; Garofalo, G.; Nunes, M.E.; Neri, G.; Schwartz, C.; Tsipouras, P. A split hand-split foot (SHFM3) gene is located at 10q24-25. Am. J. Med. Genet., 1996, 62(4), 427-436.
Raas-Rothschild, A.; Manouvrier, S.; Gonzales, M.; Farriaux, J.P.; Lyonnet, S.; Munnich, A. Refined mapping of a gene for split hand-split foot malformation. J. Med. Genet., 1996, 33(12), 996-1001.
Ianakiev, P.; Kilpatrick, M.W.; Toudjarska, I.; Basel, D.; Beighton, P.; Tsipouras, P. Split-hand/ split-foot malformation is caused by mutations in the p63 gene on 3q27. Am. J. Hum. Genet., 2000, 67(1), 59-66.
Boles, R.G.; Pober, B.R.; Gibson, L.H.; Willis, C.R.; McGrath, J.; Roberts, D.J.; Yang-Feng, T.L. Deletion of chromosome 2q24-q31 causes characteristic digital anomalies: case report and review. Am. J. Med. Genet., 1995, 55(2), 155-160.
Ahmad, M.; Abbas, H.; Haque, S.; Flatz, G. X-chromosomally inherited split-hand/split-foot anomaly in a Pakistani kindred. Hum. Genet., 1987, 75(2), 169-173.
Faiyaz-Ul-Haque, M.; Zaidi, S.H.; King, L.M.; Haque, S.; Patel, M.; Ahmad, M.; Siddique, T.; Ahmad, W.; Tsui, L.C.; Cohn, D.H. Fine mapping of the X-linked split-hand/split-foot malformation (SHFM2) locus to a 5.1-Mb region on Xq26.3 and analysis of candidate genes. Clin. Genet., 2005, 67(1), 93-97.
Jarvik, G.P.; Patton, M.A.; Homfray, T.; Evans, J.P. Non-Mendelian transmission in a human developmental disorder: split hand/split foot. Am. J. Hum. Genet., 1994, 55(4), 710-713.
Dicke, J.M.; Piper, S.L.; Goldfarb, C.A. The utility of ultrasound for the detection of fetal limb abnormalities-a 20-year single-center experience. Prenat. Diagn., 2015, 35(4), 348-353.
Schell, U.; Hehr, A.; Feldman, G.J.; Robin, N.H.; Zackai, E.H.; de Die-Smulders, C.; Viskochil, D.H.; Stewart, J.M.; Wolff, G.; Ohashi, H.; Price, R.A.; Cohen, M.M.; Muenke, M. Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. Hum. Mol. Genet., 1995, 4(3), 323-328.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 29 May, 2019
Page: [226 - 230]
Pages: 5
DOI: 10.2174/1389202920666190530092856
Price: $65

Article Metrics

PDF: 34
PRC: 1