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foot malformation with long bone deficiency
Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 574e576
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Case Report
The role of ultrasound and genetic counsel in prenatal diagnosis of split hand/foot malformation with long bone deficiency ska-Chahwan a, *, Dominika Szcze˛ sniak b, Beata Nowakowska c, Anna Kucin Tomasz Roszkowski a a b c
Clinic of Gynecology Oncology and Obstetrics, Centre of Postgraduate Medical Education, Warsaw, Poland Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 3 January 2019
Objective: The aim of the report is to highlight importance of careful ultrasound examination and genetic counsel in case of split hand/foot prenatal diagnosis. Evaluation of the accompanying long bone deficiency indicates that array comparative genomic hybridization (aCGH) should be used. Case report: We present a prenatal diagnosis of split hand/foot malformation with long bone deficiency type 3 (SHFLD3) in a patient suffering from congenital limb anomalies but without previous molecular diagnosis. Genetic consultation and prenatal testing were offered. While karyotype was normal, aCGH revealed microduplication in locus 17p33.3. Microarray analysis was carried out also in pregnant patient and her asymptomatic mother and gave positive results on both. Conclusion: Prenatal diagnosis of SHFLD3 either imaging or cytogenetic is possible. Both methods should be used to make a correct diagnosis. Due to reduced penetrance of SHFLD3 not all individuals carrying microduplication present clinical findings. Therefore, pedigree analysis and genetic counsel is important for whole family and not only for affected members. Advances in genetics may allow to establish exact diagnosis in previously undiagnosed patients. © 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Ectrodactyly Genetic counsel Microduplication Split hand/foot Tibial aplasia
Introduction
Case report
Major limb anomalies are individually rare, variable and complex, what makes exact diagnosis difficult. It is even more difficult or impossible in the prenatal examination. However, some malformations have a recognizable pattern and correct diagnosis can be established. Genetic counsel is valuable and can bring on a recognition of the syndrome. We present a prenatal diagnosis of split hand/foot malformation with long bone deficiency type 3 (SHFLD3) and prenatal genetic counsel implication for the affected family. The syndrome is designated in Online Mendelian Inheritance in Man database (OMIM) by unique number #612576. Hash tag (#) before a number indicates that molecular basis for phenotype description is known.
A 21-year-old patient presented in 20 weeks of her first pregnancy to our Ultrasound Department for the anomaly scan. The patient was recognized at birth to have a right hand split and major malformation of the left lower leg and foot (medical records were not retained by the patient). For improvement of walking ability by prosthetic the left knee-level amputation was performed at the age of 11 years. Genetic diagnosis was not established as molecular basis of the malformation was not discovered yet at that time. During pregnancy obstetric ultrasound examination revealed monodactyly in one hand, single bones in both lower legs and deformation of both feet in a female fetus [Fig. 1a and c]. Genetic consultation and prenatal testing were offered. Based on clinical presentation in the patient and the fetus a suspicion of split hand/ foot malformation with long bone deficiency (SHFLD) has been raised. Amniocentesis for karyotyping and for array comparative genomic hybridization (aCGH) was performed. While karyotype was normal, aCGH revealed 233 kb microduplication in locus 17p33.3 with coordinates arr [hg19] 17p13.3 (982,034-1,215,203)x3
* Corresponding author. ul. Czerniakowska 231, 00-416, Warsaw, Poland. ska-Chahwan). E-mail address: [email protected] (A. Kucin
https://doi.org/10.1016/j.tjog.2019.05.026 1028-4559/© 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
ska-Chahwan et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 574e576 A. Kucin
575
Fig. 1. Monodactyly of the right hand: (a) ultrasound imaging in 24 weeks of gestation, (b) 3 weeks old neonate. Lower limbs malformation: (c) ultrasound imaging of femur and single bone in lower leg in 24 weeks of gestation, (d) 3 weeks old neonate.
Discussion
Fig. 2. Pedigree: black circle - affected female, circle with smaller black circle inside asymptomatic carrier female, clear circle marked N.E. - asymptomatic female not examined genetically, clear square - not affected male.
containing a part of ABR, TUSC5 and BHLHA9 genes where the last is causative for SHFLD type 3 [1e3]. Patient decided to continue the pregnancy. Baby girl was born at term, in good general condition with monodactyly in right hand, tibial aplasia in both lower legs and deformed both feet with oligodactyly [Fig. 1b and d]. Microarray analysis was carried out also in pregnant patient and her asymptomatic mother and gave positive results on both. In case of patient's 14-years-old healthy sister we advised to wait with testing till her age of consent, while presence of microduplication itself is harmless but may influence on her progeny [Fig. 2].
Ectrodactyly also named as split hand/foot malformation (SHFM) appears as a lack of central rays in hand/foot or as a monodactyly in the most severe cases. Genetic background and inheritance pattern differs. TP63, WNT10B, DLX5 genes mutations, duplications in loci 10q24 and 17p13.3 or deletion in locus 2q31 are well known causes of SHFM identified in about 50% of cases. Inheritance can be autosomal dominant, recessive or X-linked in rare cases. While SHFM have several known causative genetic changes, split hand/foot with long bone deficiency is more homogeneous with 90% of patients possessing 17p13.3 microduplication and forming type 3 of the syndrome also described herein [4]. Type 1 and 2 of the syndrome (SHFLD1, OMIM %119100 and SHFLD2, OMIM %610685) are mapped to chromosome 1 and 6 respectively [5]. Percent sign (%) before OMIM numbers indicates that the entry describes a confirmed mendelian phenotype for which the underlying molecular basis is unknown. SHFLD is characterized by split hand/foot with additional malformations of long bones where tibial aplasia is the most severe. All 3 types of the syndrome are inherited in an autosomal dominant way. Absence of the defect in earlier generations can be misleading that malformation is of de novo origin. In SHFLD reduced penetrance, variable expressivity and anticipation occurs which means that not all carriers are symptomatic, symptoms can be expressed with different severity even in members of the same family and next generations are affected more frequently and more severely than the ancestry [2,6e11]. For these reasons pedigree analysis is essential to indicate at-risk family members and to propose them genetic counsel. Incidence
Table 1 Prenatal cases of SHFLD. Author
Family history
Prenatal findings
Molecular diagnosis
Outcome
Family members testing
Cho IA et al.
negative
none
positive
aCGH; duplication 17p13.3 211 kb; ABR, BHLHA9, TUSC5, YWHAE, CRK genes aCGH; duplication 17p13.3 233 bp; part of ABR, BHLHA9, TUSC5 genes
termination of pregnancy
ska-Chahwan Kucin A et al. (present case)
upper limbs: oligosyndactyly; bilateral lower limbs: agenesis of fibulae, knees flexion, club feet, oligodactyly; bilateral upper limbs: monodactyly; unilateral lower limbs: tibial agenesis, club feet, oligodactyly; bilateral
live birth
mother e duplication 17p13.3; grandmother e duplication 17p13.3 (no clinical findings)
ska-Chahwan et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 574e576 A. Kucin
576
of the syndrome is estimated to be about 1:1.000.000 liveborn [12]. Duplication located at chromosome 17p13.3 as molecular basis of SHFLD3 was firstly described in 2011 by Armour et al. [1]. Since then several postnatal cases of individual patients or series of members of affected families were reported [2,6e11]. Interestingly, only one case report of SHFLD3 prenatal diagnosis with no family members testing was published to date [Table 1] [13]. To conclude in case of split hand/foot prenatal diagnosis careful ultrasound examination of long bones is important. Accompanying long bones deficiency may indicate SHFLD3 and necessity of extended cytogenetic testing with aCGH. Due to reduced penetrance pedigree analysis and genetic counsel is important for whole family and not only for affected members. Advances in genetics may allow to establish diagnosis in previously undiagnosed patients, therefore it is valuable to have contact details noted in medical records. Funding statement Array comparative genomic hybridization examinations were funded by grant from Ministry of Science and Higher Education 3942/E-215/S/2016 to Beata Nowakowska. Conflicts of interest None. Acknowledgments All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments. For this type of study (retrospective, case report) formal consent was not required. Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information (photographs) are included in this article. This article does not contain any studies with animals performed by any of the authors.
References [1] Armour CM, Bulman DE, Jarinova O, Rogers RC, Clarkson KB, DuPont BR, et al. 17p13.3 microduplications are associated with split-hand/foot malformation and long-bone deficiency (SHFLD). Eur J Hum Genet 2011; 19:1144e51. [2] Klopocki E, Lohan S, Doelken SC, Stricker S, Ockeloen CW, Soares Thiele de Aguiar R, et al. Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. J Med Genet 2012;49: 119e25. [3] Lezirovitz K, Maestrelli SR, Cotrim NH, Otto PA, Pearson PL, MingroniNetto RC. A novel locus for split-hand/foot malformation associated with tibial hemimelia (SHFLD syndrome) maps to chromosome region 17p13.1-17p13.3. Hum Genet 2008;123:625e31. ska-Seidler A, Socha M, Jamsheer A. Split-hand/foot malformation [4] Sowin molecular cause and implications in genetic counselling. J Appl Genet 2014;55:105e15. [5] Naveed M, Nath SK, Gaines M, Al-Ali MT, Al-Khaja N, Hutchings D, et al. Genomewide linkage scan for split-hand/foot malformation with longbone deficiency in a large Arab family identifies two novel susceptibility loci on chromosomes 1q42.2-q43 and 6q14.1. Am J Hum Genet 2007;80: 105e11. [6] Petit F, Andrieux J, Demeer B, Collet LM, Copin H, Boudry-Labis E, et al. Splithand/foot malformation with long-bone deficiency and BHLHA9 duplication: two cases and expansion of the phenotype to radial agenesis. Eur J Med Genet 2013;56:88e92. [7] Petit F, Jourdain AS, Andrieux J, Baujat G, Baumann C, Beneteau C, et al. Split hand/foot malformation with long-bone deficiency and BHLHA9 duplication: report of 13 new families. Clin Genet 2014;85:464e9. €tzer KM, Klaushofer K, Grill F. A child with split-hand/ [8] Al Kaissi A, Ganger R, Ro foot associated with tibial hemimelia (SHFLD syndrome) and thrombocytopenia maps to chromosome region 17p13.3. Am J Med Genet 2014;164A: 2338e43. [9] Nagata E, Kano H, Kato F, Yamaguchi R, Nakashima S, Takayama S, et al. Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex. Orphanet J Rare Dis 2014;9: 125. [10] Fusco C, Nittis P, Alfaiz AA, Pellico MT, Augello B, Malerba N, et al. A new split hand/foot malformation with long bone deficiency familial case. J Pediatr Genet 2017;6:98e102. [11] Shen Y, Si N, Liu Z, Liu F, Meng X, Zhang Y, et al. 17p13.3 genomic rearrangement in a Chinese family with split-hand/foot malformation with long bone deficiency: report of a complicated duplication with marked variation in phenotype. Orphanet J Rare Dis 2018;13:106. [12] Fernandez-Palazzi F, Bendahan J, Rivas S. Congenital deficiency of the tibia: a report on 22 cases. J Pediatr Orthop B 1998;7:298e302. [13] Cho IA, Park JK, Baek JC, Ha AN, Kang MY, Lee JI, et al. Split hand/foot malformation with long-bone deficiency and BHLHA9 duplication: a prenatal diagnosis report. J Gene Med 2015;12:123e7.
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Case Report
The role of ultrasound and genetic counsel in prenatal diagnosis of split hand/foot malformation with long bone deficiency ska-Chahwan a, *, Dominika Szcze˛ sniak b, Beata Nowakowska c, Anna Kucin Tomasz Roszkowski a a b c
Clinic of Gynecology Oncology and Obstetrics, Centre of Postgraduate Medical Education, Warsaw, Poland Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 3 January 2019
Objective: The aim of the report is to highlight importance of careful ultrasound examination and genetic counsel in case of split hand/foot prenatal diagnosis. Evaluation of the accompanying long bone deficiency indicates that array comparative genomic hybridization (aCGH) should be used. Case report: We present a prenatal diagnosis of split hand/foot malformation with long bone deficiency type 3 (SHFLD3) in a patient suffering from congenital limb anomalies but without previous molecular diagnosis. Genetic consultation and prenatal testing were offered. While karyotype was normal, aCGH revealed microduplication in locus 17p33.3. Microarray analysis was carried out also in pregnant patient and her asymptomatic mother and gave positive results on both. Conclusion: Prenatal diagnosis of SHFLD3 either imaging or cytogenetic is possible. Both methods should be used to make a correct diagnosis. Due to reduced penetrance of SHFLD3 not all individuals carrying microduplication present clinical findings. Therefore, pedigree analysis and genetic counsel is important for whole family and not only for affected members. Advances in genetics may allow to establish exact diagnosis in previously undiagnosed patients. © 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Ectrodactyly Genetic counsel Microduplication Split hand/foot Tibial aplasia
Introduction
Case report
Major limb anomalies are individually rare, variable and complex, what makes exact diagnosis difficult. It is even more difficult or impossible in the prenatal examination. However, some malformations have a recognizable pattern and correct diagnosis can be established. Genetic counsel is valuable and can bring on a recognition of the syndrome. We present a prenatal diagnosis of split hand/foot malformation with long bone deficiency type 3 (SHFLD3) and prenatal genetic counsel implication for the affected family. The syndrome is designated in Online Mendelian Inheritance in Man database (OMIM) by unique number #612576. Hash tag (#) before a number indicates that molecular basis for phenotype description is known.
A 21-year-old patient presented in 20 weeks of her first pregnancy to our Ultrasound Department for the anomaly scan. The patient was recognized at birth to have a right hand split and major malformation of the left lower leg and foot (medical records were not retained by the patient). For improvement of walking ability by prosthetic the left knee-level amputation was performed at the age of 11 years. Genetic diagnosis was not established as molecular basis of the malformation was not discovered yet at that time. During pregnancy obstetric ultrasound examination revealed monodactyly in one hand, single bones in both lower legs and deformation of both feet in a female fetus [Fig. 1a and c]. Genetic consultation and prenatal testing were offered. Based on clinical presentation in the patient and the fetus a suspicion of split hand/ foot malformation with long bone deficiency (SHFLD) has been raised. Amniocentesis for karyotyping and for array comparative genomic hybridization (aCGH) was performed. While karyotype was normal, aCGH revealed 233 kb microduplication in locus 17p33.3 with coordinates arr [hg19] 17p13.3 (982,034-1,215,203)x3
* Corresponding author. ul. Czerniakowska 231, 00-416, Warsaw, Poland. ska-Chahwan). E-mail address: [email protected] (A. Kucin
https://doi.org/10.1016/j.tjog.2019.05.026 1028-4559/© 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
ska-Chahwan et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 574e576 A. Kucin
575
Fig. 1. Monodactyly of the right hand: (a) ultrasound imaging in 24 weeks of gestation, (b) 3 weeks old neonate. Lower limbs malformation: (c) ultrasound imaging of femur and single bone in lower leg in 24 weeks of gestation, (d) 3 weeks old neonate.
Discussion
Fig. 2. Pedigree: black circle - affected female, circle with smaller black circle inside asymptomatic carrier female, clear circle marked N.E. - asymptomatic female not examined genetically, clear square - not affected male.
containing a part of ABR, TUSC5 and BHLHA9 genes where the last is causative for SHFLD type 3 [1e3]. Patient decided to continue the pregnancy. Baby girl was born at term, in good general condition with monodactyly in right hand, tibial aplasia in both lower legs and deformed both feet with oligodactyly [Fig. 1b and d]. Microarray analysis was carried out also in pregnant patient and her asymptomatic mother and gave positive results on both. In case of patient's 14-years-old healthy sister we advised to wait with testing till her age of consent, while presence of microduplication itself is harmless but may influence on her progeny [Fig. 2].
Ectrodactyly also named as split hand/foot malformation (SHFM) appears as a lack of central rays in hand/foot or as a monodactyly in the most severe cases. Genetic background and inheritance pattern differs. TP63, WNT10B, DLX5 genes mutations, duplications in loci 10q24 and 17p13.3 or deletion in locus 2q31 are well known causes of SHFM identified in about 50% of cases. Inheritance can be autosomal dominant, recessive or X-linked in rare cases. While SHFM have several known causative genetic changes, split hand/foot with long bone deficiency is more homogeneous with 90% of patients possessing 17p13.3 microduplication and forming type 3 of the syndrome also described herein [4]. Type 1 and 2 of the syndrome (SHFLD1, OMIM %119100 and SHFLD2, OMIM %610685) are mapped to chromosome 1 and 6 respectively [5]. Percent sign (%) before OMIM numbers indicates that the entry describes a confirmed mendelian phenotype for which the underlying molecular basis is unknown. SHFLD is characterized by split hand/foot with additional malformations of long bones where tibial aplasia is the most severe. All 3 types of the syndrome are inherited in an autosomal dominant way. Absence of the defect in earlier generations can be misleading that malformation is of de novo origin. In SHFLD reduced penetrance, variable expressivity and anticipation occurs which means that not all carriers are symptomatic, symptoms can be expressed with different severity even in members of the same family and next generations are affected more frequently and more severely than the ancestry [2,6e11]. For these reasons pedigree analysis is essential to indicate at-risk family members and to propose them genetic counsel. Incidence
Table 1 Prenatal cases of SHFLD. Author
Family history
Prenatal findings
Molecular diagnosis
Outcome
Family members testing
Cho IA et al.
negative
none
positive
aCGH; duplication 17p13.3 211 kb; ABR, BHLHA9, TUSC5, YWHAE, CRK genes aCGH; duplication 17p13.3 233 bp; part of ABR, BHLHA9, TUSC5 genes
termination of pregnancy
ska-Chahwan Kucin A et al. (present case)
upper limbs: oligosyndactyly; bilateral lower limbs: agenesis of fibulae, knees flexion, club feet, oligodactyly; bilateral upper limbs: monodactyly; unilateral lower limbs: tibial agenesis, club feet, oligodactyly; bilateral
live birth
mother e duplication 17p13.3; grandmother e duplication 17p13.3 (no clinical findings)
ska-Chahwan et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 574e576 A. Kucin
576
of the syndrome is estimated to be about 1:1.000.000 liveborn [12]. Duplication located at chromosome 17p13.3 as molecular basis of SHFLD3 was firstly described in 2011 by Armour et al. [1]. Since then several postnatal cases of individual patients or series of members of affected families were reported [2,6e11]. Interestingly, only one case report of SHFLD3 prenatal diagnosis with no family members testing was published to date [Table 1] [13]. To conclude in case of split hand/foot prenatal diagnosis careful ultrasound examination of long bones is important. Accompanying long bones deficiency may indicate SHFLD3 and necessity of extended cytogenetic testing with aCGH. Due to reduced penetrance pedigree analysis and genetic counsel is important for whole family and not only for affected members. Advances in genetics may allow to establish diagnosis in previously undiagnosed patients, therefore it is valuable to have contact details noted in medical records. Funding statement Array comparative genomic hybridization examinations were funded by grant from Ministry of Science and Higher Education 3942/E-215/S/2016 to Beata Nowakowska. Conflicts of interest None. Acknowledgments All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments. For this type of study (retrospective, case report) formal consent was not required. Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information (photographs) are included in this article. This article does not contain any studies with animals performed by any of the authors.
References [1] Armour CM, Bulman DE, Jarinova O, Rogers RC, Clarkson KB, DuPont BR, et al. 17p13.3 microduplications are associated with split-hand/foot malformation and long-bone deficiency (SHFLD). Eur J Hum Genet 2011; 19:1144e51. [2] Klopocki E, Lohan S, Doelken SC, Stricker S, Ockeloen CW, Soares Thiele de Aguiar R, et al. Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. J Med Genet 2012;49: 119e25. [3] Lezirovitz K, Maestrelli SR, Cotrim NH, Otto PA, Pearson PL, MingroniNetto RC. A novel locus for split-hand/foot malformation associated with tibial hemimelia (SHFLD syndrome) maps to chromosome region 17p13.1-17p13.3. Hum Genet 2008;123:625e31. ska-Seidler A, Socha M, Jamsheer A. Split-hand/foot malformation [4] Sowin molecular cause and implications in genetic counselling. J Appl Genet 2014;55:105e15. [5] Naveed M, Nath SK, Gaines M, Al-Ali MT, Al-Khaja N, Hutchings D, et al. Genomewide linkage scan for split-hand/foot malformation with longbone deficiency in a large Arab family identifies two novel susceptibility loci on chromosomes 1q42.2-q43 and 6q14.1. Am J Hum Genet 2007;80: 105e11. [6] Petit F, Andrieux J, Demeer B, Collet LM, Copin H, Boudry-Labis E, et al. Splithand/foot malformation with long-bone deficiency and BHLHA9 duplication: two cases and expansion of the phenotype to radial agenesis. Eur J Med Genet 2013;56:88e92. [7] Petit F, Jourdain AS, Andrieux J, Baujat G, Baumann C, Beneteau C, et al. Split hand/foot malformation with long-bone deficiency and BHLHA9 duplication: report of 13 new families. Clin Genet 2014;85:464e9. €tzer KM, Klaushofer K, Grill F. A child with split-hand/ [8] Al Kaissi A, Ganger R, Ro foot associated with tibial hemimelia (SHFLD syndrome) and thrombocytopenia maps to chromosome region 17p13.3. Am J Med Genet 2014;164A: 2338e43. [9] Nagata E, Kano H, Kato F, Yamaguchi R, Nakashima S, Takayama S, et al. Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex. Orphanet J Rare Dis 2014;9: 125. [10] Fusco C, Nittis P, Alfaiz AA, Pellico MT, Augello B, Malerba N, et al. A new split hand/foot malformation with long bone deficiency familial case. J Pediatr Genet 2017;6:98e102. [11] Shen Y, Si N, Liu Z, Liu F, Meng X, Zhang Y, et al. 17p13.3 genomic rearrangement in a Chinese family with split-hand/foot malformation with long bone deficiency: report of a complicated duplication with marked variation in phenotype. Orphanet J Rare Dis 2018;13:106. [12] Fernandez-Palazzi F, Bendahan J, Rivas S. Congenital deficiency of the tibia: a report on 22 cases. J Pediatr Orthop B 1998;7:298e302. [13] Cho IA, Park JK, Baek JC, Ha AN, Kang MY, Lee JI, et al. Split hand/foot malformation with long-bone deficiency and BHLHA9 duplication: a prenatal diagnosis report. J Gene Med 2015;12:123e7.