HAND SURGERY
Discordant Type I Preaxial Polydactyly in Monozygotic Twins on the Same Hand A Case Report Zhi Yang Ng, MRCS,* Po Yi Sau, MBChB,Þ and Gale Jue-Shuang Lim, FAMS (Plast Surg)*þ Abstract: There are 4 types of preaxial polydactyly (PPD), and type I (PPD-I), also known as thumb duplication, is the most common. This frequently encountered condition has since been further described and classified by Wassel based on the level of duplication of skeletal anatomy. Genetic studies have localized possible candidate gene(s) for PPD types II to IV to the chromosomal region 7q36 but the current literature attributes PPD-I to isolated, spontaneous mutations typically with unilateral involvement only. Recent epidemiological studies have also suggested nongenetic causes for PPD-I including social and environmental factors. Herein, we would like to present a case of discordant PPD-I expression affecting the same hand in a pair of monozygotic twins and suggest possible reasons for this presentation because previous similar reports only had involvement of 1 child. Key Words: preaxial polydactyly, thumb duplication, monozygotic twins (Ann Plast Surg 2015;75: 398Y400)
P
reaxial polydactyly (PPD) has a reported incidence of up to 1 in 3000 births1 with thumb duplication (PPD-I) comprising most of these cases, especially in the Asian population.2 Although PPD-II, III, and IV have been linked to allelic or locus heterogeneity at chromosome 7q36,3 the etiopathogenesis of PPD-I remains unknown despite its frequent occurrence. Epidemiological studies on PPD-I have described a possible contribution from environmental inf luences such as socioeconomic circumstances and upper respiratory tract infections.4 Analysis of monozygotic twins with PPD-I by Peterson and Rayan5 (1 Wassel IV, 1 normal) has suggested the potentially teratogenic inf luence of in utero exposure to drugs such as methamphetamine, whereas Lajeunie et al6 described a similar case of discordant PPD-I expression (also 1 Wassel IV, 1 normal) in a pair of monozygotic twins for Crouzon syndrome but with an otherwise uneventful antenatal period and suggested postfertilization events such as abnormal separation to be responsible. A recent review by Al-Qattan7 also concluded that the various forms of PPD were due to a spectrum of embryonic insults (with PPD-I the mildest) due to genetic aberrations with a consequent increase in sonic hedgehog (SHH) protein expression and thus that of other gene products acting on the anterior limb bud, leading to maldevelopment of the radius and the first digit. The current literature considers the etiology of PPD-I to be multifactorial with various possible causative factors proffered including differences in placental vascular supply8 as well as the various genetic events described previously. Herein, we would like to Received June 6, 2014, and accepted for publication, after revision, July 23, 2014. From the Departments of *Plastic Reconstructive and Aesthetic Surgery, †Obstetrics and Gynecology, and ‡Orthopedic Surgery, KK Women’s and Children’s Hospital, Singapore, Singapore. Conflicts of interest and sources of funding: none declared. Reprints: Zhi Yang Ng, MRCS, Department of Plastic Reconstructive and Aesthetic Surgery, KK Women’s and Children’s Hospital, 100 Bukit Timah Rd, Singapore 229899, Singapore. E-mail: [email protected]. Copyright * 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0148-7043/15/7504-0398 DOI: 10.1097/SAP.0000000000000336
398
www.annalsplasticsurgery.com
report a case of discordant thumb duplication (1 Wassel IV, 1 Wassel V) in a pair of monozygotic twins to further support the multifactorial hypothesis with an underlying genetic component for PPD-I causality.
CASE REPORT The patients were both girls of 3 years and 4 months of age when they presented for evaluation of right thumb polydactyly for surgical correction. They were both products of a monochorionic, diamniotic pregnancy delivered prematurely at 31-week gestation and the mother’s pregnancy was otherwise uneventful with no reports of antenatal illnesses or maternal drug usage. Of note, both dating and subsequent growth scans did not detect any upper limb skeletal malformations or significant difference in umbilical artery f low. Family history of limb malformations was also absent. On physical examination, no syndromic features were detected. In twin A, there was a size mismatch between the radial and ulnar duplicates and the former was stiff and nonfunctional; in twin B, the proximal phalanx of the radial duplicate was hypoplastic, smaller, and nonfunctional. Both larger duplicates were a good match for size with the contralateral, normal thumb and had functioning joints and tendons. Further radiographic evaluation confirmed Wassel IV in twin A (Fig. 1) and Wassel V in twin B (Fig. 2). This was consistent with intraoperative findings. The radial duplicates were then excised and thumb reconstruction was performed. Upon institutional review board approval and parental consent, cheek swabs were performed on the patients and DNA was analyzed using a commercial detection kit based on the quantitativef luorescent polymerase chain reaction method. This allowed the rapid detection of common chromosomal aneuploidies by analyzing more than 20 short tandem repeat makers on 3 autosomes (chromosomes 13, 18, and 21) and the sex chromosomes. Results showed complete concordance and confirmed monozygosity of the twins.
DISCUSSION To the best of our knowledge, this is the first report in the English literature to describe discordant phenotypic expression for PPD-I in both monozygotic twin subjects on the same hand after they had been subjected to the same antenatal physiological influences, rather than the involvement of 1 child only as reported previously.5,6 Our case invokes several interesting considerations. First, differential placental blood supply was previously thought to be accountable for phenotypic discordance in monozygotic twin pairs.8 Advances in technology have now enabled the placental vasculature to be quantified using 3-dimensional sonography9 but this remains largely within the realm of research. In contrast, conventional 2-dimensional umbilical artery Doppler waveforms have been reported to provide a good estimate of downstream vascular resistance and thus placental blood f low.10 In our case, prepartum umbilical arterial Doppler assessments were not suggestive of differential placental blood supply. Second, an unremarkable antenatal period certainly does not rule out the potential influence of occult infection(s) as epidemiological studies of isolated PPD-I have suggested that maternal upper respiratory tract infections during the first trimester is a significant Annals of Plastic Surgery
&
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Volume 75, Number 4, October 2015
Annals of Plastic Surgery
& Volume 75, Number 4, October 2015
risk factor for the development of this condition.4 Regardless of the insult, the physiological ‘‘damage’’ to both twins should be similar given that there was no significant difference in umbilical artery flow between the twins. This lends credence to our hypothesis of a multifactorial causation with involvement of the same genetic loci for PPD-I. At the molecular level, Lajeunie et al highlighted the presence of a FGFR2 mutation, which causes Pfeiffer syndrome11 with concurrent malformations of the upper and lower limbs, and in turn, hint at its possible involvement in PPD-I.6 Basic science studies in mice have also shown a vital role of FGFR2 in maintenance of the apical ectodermal ridge and thus the proper development and apoptosis of a growing limb bud. Moreover, FGFR2 is believed to act upstream of and inhibit SHH and FGF4 activation.12 Therefore, it can be appreciated that a FGFR2 mutation can lead to increased expression of SHH and FGF4 which in turn sets up the SHH-FGF4 feedback loop13 with the consequence of aberrant limb development and thus PPD of various severities as postulated by Al-Qattan.7 It should be noted that another modulator of SHH activity is the zone of polarizing activity (ZPA) regulatory sequence (ZRS) located on chromosome 7q36 which is involved in various phenotypes of upper limb formations, notably PPD types II, III, and IV. It is likely then that the candidate gene for PPD-I lies within the ZRS region upstream of SHH. Unfortunately, we were only able to confirm genetic concordance in our twin subjects and were unable to perform a functional study to elucidate the differences, if any, within the chromosomal region of interest or in gene expression. It might, therefore, be possible that the various clinical presentations of PPD-I as popularized by Wassel represent a spectrum of severity in apoptosis of the duplicated digit not dissimilar to that for PPD as described by AlQattan7 due to interactions between FGFR2 and SHH. In short, perhaps the ‘‘damage’’ to each twin in this report varied because of a difference in placental blood f low that could not be quantified with conventional sonography techniques. The twins therefore each presented with PPD-I of a different severity as we have suggested.
PPD-I on the Same Hand in Monozygotic Twins
FIGURE 2. Radiographic evaluation revealed a Wassel type V thumb duplication in twin B.
In summary, we support the current belief that the cause of PPD-I is multifactorial in origin, but there is likely to be an underlying genetic component. In this case, a genetic insult, most probably due to a subclinical infection, led to mutation(s) in the chromosomal region 7q36 with the consequence of differential genetic expression of SHH and FGF4 and related gene product(s) which then manifested as different forms of PPD-I in a pair of monozygotic twins.
ACKNOWLEDGMENTS The authors thank Dr Hai Yang Law, DPhil, for performing the DNA analysis.
REFERENCES 1. Naasan A, Page RE. Duplication of the thumb. A 20-year retrospective review. J Hand Surg Br. 1994;19:355Y360. 2. Leung PC, Chan KM, Cheng JC. Congenital anomalies of the upper limb among the Chinese population in Hong Kong. J Hand Surg Am. 1982;7:563Y565. 3. Zguricas J, Bakker WF, Heus H, et al. Genetics of limb development and congenital hand malformations. Plast Reconstr Surg. 1998;101:1126Y1135. 4. Materna-Kiryluk A, Jamsheer A, Wisniewska K, et al. Epidemiology of isolated preaxial polydactyly type I: data from the Polish Registry of Congenital Malformations (PRCM). BMC Pediatr. 2013;13:26. 5. Peterson SL, Rayan GM. Monozygotic twins discordant for thumb polydactyly. Plast Reconstr Surg. 2004;113:449Y451.
FIGURE 1. Radiographic evaluation confirmed a Wassel type IV thumb duplication in twin A. * 2015 Wolters Kluwer Health, Inc. All rights reserved.
6. Lajeunie E, Bonaventure J, El Ghouzzi V, et al. Monozygotic twins with Crouzon syndrome: concordance for craniosynostosis and discordance for thumb duplication. Am J Med Genet. 2000;91:159Y160.
www.annalsplasticsurgery.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
399
Annals of Plastic Surgery
Ng et al
7. Al-Qattan MM. Preaxial polydactyly of the upper limb viewed as a spectrum of severity of embryonic events. Ann Plast Surg. 2013;71:118Y124. 8. Machin GA. Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. Am J Med Genet. 1996;61:216Y228. 9. Pomorski M, Zimmer M, Fuchs T, et al. Quantitative assessment of placental vasculature and placental volume in normal pregnancies with the use of 3D Power Doppler. Adv Med Sci. 2014;59:23Y27. 10. Giles WB, Trudinger BJ, Baird PJ. Fetal umbilical artery flow velocity waveforms and placental resistance: pathological correlation. Br J Obstet Gynaecol. 1985;92:31Y38.
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& Volume 75, Number 4, October 2015
11. Rutland P, Pulleyn LJ, Reardon W, et al. Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. Nat Genet. 1995;9: 173Y176. 12. Revest JM, Spencer-Dene B, Kerr K, et al. Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Dev Biol. 2001;231:47Y62. 13. Laufer E, Nelson CE, Johnson RL, et al. Sonic hedgehog and FGF4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell. 1994;79:993Y1003.
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Discordant Type I Preaxial Polydactyly in Monozygotic Twins on the Same Hand A Case Report Zhi Yang Ng, MRCS,* Po Yi Sau, MBChB,Þ and Gale Jue-Shuang Lim, FAMS (Plast Surg)*þ Abstract: There are 4 types of preaxial polydactyly (PPD), and type I (PPD-I), also known as thumb duplication, is the most common. This frequently encountered condition has since been further described and classified by Wassel based on the level of duplication of skeletal anatomy. Genetic studies have localized possible candidate gene(s) for PPD types II to IV to the chromosomal region 7q36 but the current literature attributes PPD-I to isolated, spontaneous mutations typically with unilateral involvement only. Recent epidemiological studies have also suggested nongenetic causes for PPD-I including social and environmental factors. Herein, we would like to present a case of discordant PPD-I expression affecting the same hand in a pair of monozygotic twins and suggest possible reasons for this presentation because previous similar reports only had involvement of 1 child. Key Words: preaxial polydactyly, thumb duplication, monozygotic twins (Ann Plast Surg 2015;75: 398Y400)
P
reaxial polydactyly (PPD) has a reported incidence of up to 1 in 3000 births1 with thumb duplication (PPD-I) comprising most of these cases, especially in the Asian population.2 Although PPD-II, III, and IV have been linked to allelic or locus heterogeneity at chromosome 7q36,3 the etiopathogenesis of PPD-I remains unknown despite its frequent occurrence. Epidemiological studies on PPD-I have described a possible contribution from environmental inf luences such as socioeconomic circumstances and upper respiratory tract infections.4 Analysis of monozygotic twins with PPD-I by Peterson and Rayan5 (1 Wassel IV, 1 normal) has suggested the potentially teratogenic inf luence of in utero exposure to drugs such as methamphetamine, whereas Lajeunie et al6 described a similar case of discordant PPD-I expression (also 1 Wassel IV, 1 normal) in a pair of monozygotic twins for Crouzon syndrome but with an otherwise uneventful antenatal period and suggested postfertilization events such as abnormal separation to be responsible. A recent review by Al-Qattan7 also concluded that the various forms of PPD were due to a spectrum of embryonic insults (with PPD-I the mildest) due to genetic aberrations with a consequent increase in sonic hedgehog (SHH) protein expression and thus that of other gene products acting on the anterior limb bud, leading to maldevelopment of the radius and the first digit. The current literature considers the etiology of PPD-I to be multifactorial with various possible causative factors proffered including differences in placental vascular supply8 as well as the various genetic events described previously. Herein, we would like to Received June 6, 2014, and accepted for publication, after revision, July 23, 2014. From the Departments of *Plastic Reconstructive and Aesthetic Surgery, †Obstetrics and Gynecology, and ‡Orthopedic Surgery, KK Women’s and Children’s Hospital, Singapore, Singapore. Conflicts of interest and sources of funding: none declared. Reprints: Zhi Yang Ng, MRCS, Department of Plastic Reconstructive and Aesthetic Surgery, KK Women’s and Children’s Hospital, 100 Bukit Timah Rd, Singapore 229899, Singapore. E-mail: [email protected]. Copyright * 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0148-7043/15/7504-0398 DOI: 10.1097/SAP.0000000000000336
398
www.annalsplasticsurgery.com
report a case of discordant thumb duplication (1 Wassel IV, 1 Wassel V) in a pair of monozygotic twins to further support the multifactorial hypothesis with an underlying genetic component for PPD-I causality.
CASE REPORT The patients were both girls of 3 years and 4 months of age when they presented for evaluation of right thumb polydactyly for surgical correction. They were both products of a monochorionic, diamniotic pregnancy delivered prematurely at 31-week gestation and the mother’s pregnancy was otherwise uneventful with no reports of antenatal illnesses or maternal drug usage. Of note, both dating and subsequent growth scans did not detect any upper limb skeletal malformations or significant difference in umbilical artery f low. Family history of limb malformations was also absent. On physical examination, no syndromic features were detected. In twin A, there was a size mismatch between the radial and ulnar duplicates and the former was stiff and nonfunctional; in twin B, the proximal phalanx of the radial duplicate was hypoplastic, smaller, and nonfunctional. Both larger duplicates were a good match for size with the contralateral, normal thumb and had functioning joints and tendons. Further radiographic evaluation confirmed Wassel IV in twin A (Fig. 1) and Wassel V in twin B (Fig. 2). This was consistent with intraoperative findings. The radial duplicates were then excised and thumb reconstruction was performed. Upon institutional review board approval and parental consent, cheek swabs were performed on the patients and DNA was analyzed using a commercial detection kit based on the quantitativef luorescent polymerase chain reaction method. This allowed the rapid detection of common chromosomal aneuploidies by analyzing more than 20 short tandem repeat makers on 3 autosomes (chromosomes 13, 18, and 21) and the sex chromosomes. Results showed complete concordance and confirmed monozygosity of the twins.
DISCUSSION To the best of our knowledge, this is the first report in the English literature to describe discordant phenotypic expression for PPD-I in both monozygotic twin subjects on the same hand after they had been subjected to the same antenatal physiological influences, rather than the involvement of 1 child only as reported previously.5,6 Our case invokes several interesting considerations. First, differential placental blood supply was previously thought to be accountable for phenotypic discordance in monozygotic twin pairs.8 Advances in technology have now enabled the placental vasculature to be quantified using 3-dimensional sonography9 but this remains largely within the realm of research. In contrast, conventional 2-dimensional umbilical artery Doppler waveforms have been reported to provide a good estimate of downstream vascular resistance and thus placental blood f low.10 In our case, prepartum umbilical arterial Doppler assessments were not suggestive of differential placental blood supply. Second, an unremarkable antenatal period certainly does not rule out the potential influence of occult infection(s) as epidemiological studies of isolated PPD-I have suggested that maternal upper respiratory tract infections during the first trimester is a significant Annals of Plastic Surgery
&
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Volume 75, Number 4, October 2015
Annals of Plastic Surgery
& Volume 75, Number 4, October 2015
risk factor for the development of this condition.4 Regardless of the insult, the physiological ‘‘damage’’ to both twins should be similar given that there was no significant difference in umbilical artery flow between the twins. This lends credence to our hypothesis of a multifactorial causation with involvement of the same genetic loci for PPD-I. At the molecular level, Lajeunie et al highlighted the presence of a FGFR2 mutation, which causes Pfeiffer syndrome11 with concurrent malformations of the upper and lower limbs, and in turn, hint at its possible involvement in PPD-I.6 Basic science studies in mice have also shown a vital role of FGFR2 in maintenance of the apical ectodermal ridge and thus the proper development and apoptosis of a growing limb bud. Moreover, FGFR2 is believed to act upstream of and inhibit SHH and FGF4 activation.12 Therefore, it can be appreciated that a FGFR2 mutation can lead to increased expression of SHH and FGF4 which in turn sets up the SHH-FGF4 feedback loop13 with the consequence of aberrant limb development and thus PPD of various severities as postulated by Al-Qattan.7 It should be noted that another modulator of SHH activity is the zone of polarizing activity (ZPA) regulatory sequence (ZRS) located on chromosome 7q36 which is involved in various phenotypes of upper limb formations, notably PPD types II, III, and IV. It is likely then that the candidate gene for PPD-I lies within the ZRS region upstream of SHH. Unfortunately, we were only able to confirm genetic concordance in our twin subjects and were unable to perform a functional study to elucidate the differences, if any, within the chromosomal region of interest or in gene expression. It might, therefore, be possible that the various clinical presentations of PPD-I as popularized by Wassel represent a spectrum of severity in apoptosis of the duplicated digit not dissimilar to that for PPD as described by AlQattan7 due to interactions between FGFR2 and SHH. In short, perhaps the ‘‘damage’’ to each twin in this report varied because of a difference in placental blood f low that could not be quantified with conventional sonography techniques. The twins therefore each presented with PPD-I of a different severity as we have suggested.
PPD-I on the Same Hand in Monozygotic Twins
FIGURE 2. Radiographic evaluation revealed a Wassel type V thumb duplication in twin B.
In summary, we support the current belief that the cause of PPD-I is multifactorial in origin, but there is likely to be an underlying genetic component. In this case, a genetic insult, most probably due to a subclinical infection, led to mutation(s) in the chromosomal region 7q36 with the consequence of differential genetic expression of SHH and FGF4 and related gene product(s) which then manifested as different forms of PPD-I in a pair of monozygotic twins.
ACKNOWLEDGMENTS The authors thank Dr Hai Yang Law, DPhil, for performing the DNA analysis.
REFERENCES 1. Naasan A, Page RE. Duplication of the thumb. A 20-year retrospective review. J Hand Surg Br. 1994;19:355Y360. 2. Leung PC, Chan KM, Cheng JC. Congenital anomalies of the upper limb among the Chinese population in Hong Kong. J Hand Surg Am. 1982;7:563Y565. 3. Zguricas J, Bakker WF, Heus H, et al. Genetics of limb development and congenital hand malformations. Plast Reconstr Surg. 1998;101:1126Y1135. 4. Materna-Kiryluk A, Jamsheer A, Wisniewska K, et al. Epidemiology of isolated preaxial polydactyly type I: data from the Polish Registry of Congenital Malformations (PRCM). BMC Pediatr. 2013;13:26. 5. Peterson SL, Rayan GM. Monozygotic twins discordant for thumb polydactyly. Plast Reconstr Surg. 2004;113:449Y451.
FIGURE 1. Radiographic evaluation confirmed a Wassel type IV thumb duplication in twin A. * 2015 Wolters Kluwer Health, Inc. All rights reserved.
6. Lajeunie E, Bonaventure J, El Ghouzzi V, et al. Monozygotic twins with Crouzon syndrome: concordance for craniosynostosis and discordance for thumb duplication. Am J Med Genet. 2000;91:159Y160.
www.annalsplasticsurgery.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
399
Annals of Plastic Surgery
Ng et al
7. Al-Qattan MM. Preaxial polydactyly of the upper limb viewed as a spectrum of severity of embryonic events. Ann Plast Surg. 2013;71:118Y124. 8. Machin GA. Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. Am J Med Genet. 1996;61:216Y228. 9. Pomorski M, Zimmer M, Fuchs T, et al. Quantitative assessment of placental vasculature and placental volume in normal pregnancies with the use of 3D Power Doppler. Adv Med Sci. 2014;59:23Y27. 10. Giles WB, Trudinger BJ, Baird PJ. Fetal umbilical artery flow velocity waveforms and placental resistance: pathological correlation. Br J Obstet Gynaecol. 1985;92:31Y38.
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www.annalsplasticsurgery.com
& Volume 75, Number 4, October 2015
11. Rutland P, Pulleyn LJ, Reardon W, et al. Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. Nat Genet. 1995;9: 173Y176. 12. Revest JM, Spencer-Dene B, Kerr K, et al. Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Dev Biol. 2001;231:47Y62. 13. Laufer E, Nelson CE, Johnson RL, et al. Sonic hedgehog and FGF4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell. 1994;79:993Y1003.
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
