Case report 373
Potocki–Lupski syndrome in conjunction with bilateral clubfoot Dinesh Dhanaraja, Alice Chub, John G. Pappasc, Ellen Moranb and Wallace B. Lehmanb Potocki–Lupski syndrome (PTLS) is a rare chromosomal microduplication syndrome resulting in multiple congenital abnormalities including developmental delays, autistic features, and certain structural anomalies, with cardiovascular being the most common. The phenotype of this contiguous gene duplication syndrome is quite variable and may include musculoskeletal abnormalities. Given the infrequency and novelty of this disorder, full phenotypic characterization of PTLS has not yet been fully elucidated. We present a case of severe bilateral clubfoot in a patient with PTLS. Diagnosis was made by array-based comparative genomic hybridization and confirmed by fluorescence in-situ hybridization. Because clubfoot was also present in an apparently unaffected brother, the presence of PTLS may have acted as a modifier of the phenotype. This report highlights the complex interaction of
chromosomal and familial factors that contribute to musculoskeletal birth defects. J Pediatr Orthop B 24:373–376 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
We present a male infant with bilateral clubfeet and PTLS (17p microduplication) diagnosed by chromosome microarray. Our case has a chromosomally normal sibling with clubfeet. The treatment of clubfeet in our case and in his sibling offers first insights into the differences and similarities in treating children with genomic copy number variations (microdeletion or microduplication syndromes).
Potocki–Lupski syndrome (PTLS) is a rare genetic disorder that involves a microduplication of band 11.2 on chromosome 17 (dup(17)(p11.2p11.2)) [1]. The typical manifestations of PTLS are those of developmental delays, cognitive and communicative impairment, and autism spectrum disorder. Other clinical features include poor feeding and failure to thrive during infancy, dysmorphic facial features such as high forehead, long triangular face, and long tip of the nose, and cardiovascular abnormalities such as hypoplastic left heart [2–4]. The duplication occurs de novo and it does not have a preferential parental origin [1]. Three previous studies have described orthopaedic manifestations in conjunction with PTLS. The first case presented with thoracic kyphosis, global ligamentous laxity, and flat feet [5]. The second was a case of teratologic dislocation of bilateral hips which required open reduction [6]. A PTLS patient with clubfeet was also previously described in the medical literature [7]. Conversely, clubfoot is one of the most common congenital orthopaedic deformities. Formally known as congenital talipes equinovarus, the disorder occurs in approximately one in 1000 live births, depending upon the population [8]. The etiology remains unclear. The historic perspective proposed by Hippocrates suggesting intrauterine pressure as causative has fallen out of favor [9] and today, emerging theories postulate that the cause is likely multifactorial, including both environmental and genetic factors [10].
Journal of Pediatric Orthopaedics B 2015, 24:373–376 Keywords: chromosomal microduplication syndrome, clubfoot, neuromuscular disease, Ponseti method, Potocki–Lupski syndrome a
Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, Department of Pediatric Orthopaedic Surgery, Center for Children, NYU Hospital for Joint Diseases and cNYU Department of Pediatrics, Human Genetics Division b
Correspondence to Wallace B. Lehman, MD, Department of Pediatric Orthopaedic Surgery, Center for Children, NYU Hospital for Joint Diseases, 301 E. 17th Street, New York, NY 10003, USA Tel: + 1 212 598 6403; fax: + 1 646 794 1201; e-mail: [email protected]
Case report The patient presented to our institution as an 11-day-old male infant with bilateral clubfoot deformity (Fig. 1). The patient was born at 38-weeks gestation by induced vaginal delivery to a 42-year-old mother who had 12 other children (gravida 13, para 12). The pregnancy was complicated by maternal hypertension 1 week before delivery. The patient’s birth weight was 6 lb 7 oz, and he measured 19 inches. The parents were of Ashkenazi Jewish ancestry and nonconsanguineous. He had one other sibling with clubfeet treated with casting, percutaneous tenotomy, and anterior tibial tendon transfer, and another sibling with metatarsus adductus that was resolved with conservative treatment. Ultrasounds during pregnancy were normal other than the clubfoot deformity. On physical exam, the patient was noted to have dysmorphic features including a large anterior fontanelle, moderate bilateral epicanthal folding, downslanting palpebral fissures, low-set posteriorly rotated ears, and a long
1060-152X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/BPB.0000000000000131
374 Journal of Pediatric Orthopaedics B 2015, Vol 24 No 4
Fig. 1
Bilateral clubfoot deformities before Ponseti casting seen in an 11-day-old male infant.
narrow face with a triangular appearance (Fig. 2). His generalized motor tone was normal. Examination of the spine revealed no curvature, tufts of hair, or sacral dimpling. There were no skin lesions or discolorations. Hip range of motion was symmetrical and full. The Ortolani and Barlow exams were negative. Examination of the feet revealed bilateral clubfeet with a Dimeglio score of 19 and Pirani score of 6 [11]. The patient was treated with serial Ponseti casting, bilateral tendo-Achilles lengthening, and bracing. His feet corrected well with a final Dimeglio score of 4 and Pirani score of 0 (Figs 3 and 4); however, it was noted that his feet were significantly stiffer than usual successfully treated clubfeet. At about 6 weeks of age, the infant was noted to have temporal wasting and poor weight gain. It was revealed that the patient had been a poor feeder since birth, with a disorganized suck/swallow reflex and an inability to breast or bottle feed. The mother had been feeding the patient with an eyedropper. A work-up for failure to thrive was initiated without yielding significant findings. A gastroenterology consultation produced a normal barium swallow study. Referral to a pediatric geneticist finally revealed the diagnosis of PTLS by CGH microarray. The patient had a 4.74 Mb pathogenic duplication of chromosome 17p12-p11.2 [arr17p12p11.2 (15,757,617–20,501,923) × 3 in GRCH37/hg19], which was larger than the usual 3.7 Mb duplication. Genetic testing was also offered to the parents but was declined. An echocardiogram was performed which showed a patent ductus arteriosus and foramen ovale. Early intervention therapy and genetic counseling were initiated and the patient’s clinical status improved gradually with time.
Fig. 2
Picture of a 20-month-old child. Dysmorphic features such as large anterior fontanelle, moderate bilateral epicanthal folding, downslanting palpebral fissures, low-set posteriorly rotated ears, and long narrow face with a triangular appearance can be seen.
Discussion Chromosome microarray is the first-tier test for the diagnostic evaluation of children with congenital anomalies [12]. This test reveals constitutional genomic copy number variations (chromosome deletions or duplications) with a resolution (50 kb) that greatly
exceeds that of the conventional karyotype (5 Mb). The deletions and duplications that are below the resolution of the karyotype (microdeletions and microduplications) are the cause of intellectual disability, autism, and multiple congenital anomalies in about 15–20% of children
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Potocki–Lupski syndrome with bilateral clubfoot Dhanaraj et al. 375
Fig. 3
emerged that describe PTLS in conjunction with pathologies other than the original infantile hypotonia, cognitive deficits, and cardiovascular anomalies. As mentioned previously, three other case reports in the literature have proposed that PTLS may be linked to an underlying connective tissue disorder resulting in musculoskeletal manifestations. In general, the 17p11.2 genomic region is an area prone to rearrangements. For instance, Charcot–Marie–Tooth disease type 1A (CMT1A) arises from a microduplication of a locus nearby to PTLS and has distinct musculoskeletal manifestations including cavovarus foot. Also the reciprocal deletion to the PTLS duplication (del17p11.2) is responsible for Smith–Magenis syndrome, a mental retardation syndrome characterized by insomnia disorder and increased frequency of severe scoliosis often requiring surgery [16].
Right foot after Ponseti casting at 20 months.
The patient in our case had a 4.7 Mb duplication, which is larger than the usual 3.7 Mb duplication typically seen in PTLS. The duplicated area was analyzed and found to not include the PMP22 gene associated with CMT1A although it did contain the RAI1 critical region consistent with PTLS. The significance of the larger duplication in our patient is yet to be determined. It could be postulated that the additional regions duplicated may have a role in the accompanying pathology of clubfeet.
Fig. 4
Left foot after Ponseti casting at 20 months.
affected with any of these abnormalities. Many children with congenital anomalies need orthopaedic care and the pediatric orthopaedic surgeon will be confronted frequently with a child diagnosed with a genomic copy number variation (microdeletion or microduplication syndrome). Furthermore, the microdeletion or microduplication diagnosis has frequent implications for clinical care [13]. The identification of Potocki–Lupski as a distinct clinical entity has been fairly recent: the first descriptions of the 17p11.2 duplication were published by Brown et al. in 1996 [14] and Potocki et al. in 2000 [15] and the subsequent full characterization of PTLS was published in 2007 by Potocki et al. [1]. Since then, a few cases have
As mentioned previously, the patient did have an older male sibling with bilateral clubfoot deformity that was treated successfully with Ponseti casting, percutaneous tendo-Achilles lengthening, and anterior tibial tendon transfers. The patient’s sibling was also treated at our institution and he had normal development with no features of any recognizable genetic syndrome including PTLS; he had no genetic tests. It was noted that his PTLS-affected sibling did have significantly stiffer feet throughout his treatment similar to the ‘atypical’ clubfeet seen with certain neuromuscular disorders such as arthrogryposis and cerebral palsy. The PTLS patient also required more casts and had a relapse of his deformity at about the sixth week of his treatment. This, however, may have been due to the additional ailments the patient was experiencing at that time and lapses in his clubfoot treatments that occurred secondary to his complex medical situation. Regardless, his final outcome did demonstrate successful but unusual results. It is possible that clubfoot coupled with PTLS may yield a phenotype that more closely resembles a neuromuscular picture. We recognize that the combination of clubfeet and PTLS may be entirely coincidental in this patient, especially being that the patient had an unaffected sibling with clubfeet. Inversely, the occurrence of clubfeet in the sibling could be coincidental. However, previous seemingly unrelated entities have been found to be related through common genetic pathways, for example clubfoot and autism by the PITX1 gene [10,17]. Despite the
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
376
Journal of Pediatric Orthopaedics B 2015, Vol 24 No 4
possibility of random association, we still find the reporting of this patient to be important in the contribution to the ever-growing database of phenotypes seen with PTLS. Further investigations into the genetic source of various conditions will hopefully lead to improved treatments and recognition of potential associated pathologies. In summary, this case raises the awareness and reinforces the possibility of multiple and sometimes systemic causes of clubfeet.
5
6
7
8
9
Acknowledgements The authors would like to thank Drs Martin Bialer, Ira Parness, and Gregory Tayrose for their assistance and collaboration.
10 11
12
Conflicts of interest
There are no conflicts of interest. 13
References 1
2
3
4
Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM, et al. Characterization of Potocki–Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 2007; 80:633–649. Soler-Alfonso C, Motil KJ, Turk CL, Robbins-Furman P, Friedman EM, Zhang F, et al. Potocki–Lupski syndrome: a microduplication syndrome associated with oropharyngeal dysphagia and failure to thrive. J Pediatr 2011; 158:655–659, e2. Yusupov R, Roberts AE, Lacro RV, Sandstrom M, Ligon AH. Potocki–Lupski syndrome: an inherited dup(17)(p11.2p11.2) with hypoplastic left heart. Am J Med Genet A 2011; 155A:367–371. Jefferies JL, Pignatelli RH, Martinez HR, Robbins-Furman PJ, Liu P, Gu W, et al. Cardiovascular findings in duplication 17p11.2 syndrome. Genet Med 2012; 14:90–94.
14
15
16 17
Martin J, Knight SJ, Sharp AJ, Eichler EE, Hurst J, Kini U. Potocki–Lupski syndrome mimicking a connective tissue disorder. Clin Dysmorphol 2008; 17:211–213. Kuo CC, Chang CC, Hsu HC, Lu TW, Tsai NY. Potocki–Lupski syndrome with teratologic dislocation of the hip: a case report. J Pediatr Orthop B 2013; 22:42–44. Magoulas PL, Liu P, Gelowani V, Soler-Alfonso C, Kivuva EC, Lupski JR, Potocki L. Inherited dup(17)(p11.2p11.2): expanding the phenotype of the Potocki–Lupski syndrome. Am J Med Genet A 2014; 164A:500–504. Barker S, Chesney D, Miedzybrodzka Z, Maffulli N. Genetics and epidemiology of idiopathic congenital talipes equinovarus. J Pediatr Orthop 2003; 23:265–272. Roye DP Jr, Roye BD. Idiopathic congenital talipes equinovarus. J Am Acad Orthop Surg 2002; 10:239–248. Dobbs MB, Gurnett CA. Genetics of clubfoot. J Pediatr Orthop B 2012; 21:7–9. Chu A, Labar AS, Sala DA, van Bosse HJ, Lehman WB. Clubfoot classification: correlation with Ponseti cast treatment. J Pediatr Orthop 2010; 30:695–699. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86:749–764. Henderson LB, Applegate CD, Wohler E, Sheridan MB, Hoover-Fong J, Batista DA. The impact of chromosomal microarray on clinical management: a retrospective analysis. Genet Med 2014; 16:657–664. Brown A, Phelan MC, Patil S, Crawford E, Rogers RC, Schwartz C. Two patients with duplication of 17p11.2: the reciprocal of the Smith-Magenis syndrome deletion? Am J Med Genet 1996; 63:373–377. Potocki L, Chen KS, Park SS, Osterholm DE, Withers MA, Kimonis V, et al. Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 2000; 24:84–87. Spilsbury J, Mohanty K. The orthopaedic manifestations of Smith-Magenis syndrome. J Pediatr Orthop B 2003; 12:22–26. Philippi A, Tores F, Carayol J, Rousseau F, Letexier M, Roschmann E, et al. Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 (PITX1) on chromosome 5q31: a candidate gene analysis. BMC Med Genet 2007; 8:74.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Potocki–Lupski syndrome in conjunction with bilateral clubfoot Dinesh Dhanaraja, Alice Chub, John G. Pappasc, Ellen Moranb and Wallace B. Lehmanb Potocki–Lupski syndrome (PTLS) is a rare chromosomal microduplication syndrome resulting in multiple congenital abnormalities including developmental delays, autistic features, and certain structural anomalies, with cardiovascular being the most common. The phenotype of this contiguous gene duplication syndrome is quite variable and may include musculoskeletal abnormalities. Given the infrequency and novelty of this disorder, full phenotypic characterization of PTLS has not yet been fully elucidated. We present a case of severe bilateral clubfoot in a patient with PTLS. Diagnosis was made by array-based comparative genomic hybridization and confirmed by fluorescence in-situ hybridization. Because clubfoot was also present in an apparently unaffected brother, the presence of PTLS may have acted as a modifier of the phenotype. This report highlights the complex interaction of
chromosomal and familial factors that contribute to musculoskeletal birth defects. J Pediatr Orthop B 24:373–376 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
We present a male infant with bilateral clubfeet and PTLS (17p microduplication) diagnosed by chromosome microarray. Our case has a chromosomally normal sibling with clubfeet. The treatment of clubfeet in our case and in his sibling offers first insights into the differences and similarities in treating children with genomic copy number variations (microdeletion or microduplication syndromes).
Potocki–Lupski syndrome (PTLS) is a rare genetic disorder that involves a microduplication of band 11.2 on chromosome 17 (dup(17)(p11.2p11.2)) [1]. The typical manifestations of PTLS are those of developmental delays, cognitive and communicative impairment, and autism spectrum disorder. Other clinical features include poor feeding and failure to thrive during infancy, dysmorphic facial features such as high forehead, long triangular face, and long tip of the nose, and cardiovascular abnormalities such as hypoplastic left heart [2–4]. The duplication occurs de novo and it does not have a preferential parental origin [1]. Three previous studies have described orthopaedic manifestations in conjunction with PTLS. The first case presented with thoracic kyphosis, global ligamentous laxity, and flat feet [5]. The second was a case of teratologic dislocation of bilateral hips which required open reduction [6]. A PTLS patient with clubfeet was also previously described in the medical literature [7]. Conversely, clubfoot is one of the most common congenital orthopaedic deformities. Formally known as congenital talipes equinovarus, the disorder occurs in approximately one in 1000 live births, depending upon the population [8]. The etiology remains unclear. The historic perspective proposed by Hippocrates suggesting intrauterine pressure as causative has fallen out of favor [9] and today, emerging theories postulate that the cause is likely multifactorial, including both environmental and genetic factors [10].
Journal of Pediatric Orthopaedics B 2015, 24:373–376 Keywords: chromosomal microduplication syndrome, clubfoot, neuromuscular disease, Ponseti method, Potocki–Lupski syndrome a
Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, Department of Pediatric Orthopaedic Surgery, Center for Children, NYU Hospital for Joint Diseases and cNYU Department of Pediatrics, Human Genetics Division b
Correspondence to Wallace B. Lehman, MD, Department of Pediatric Orthopaedic Surgery, Center for Children, NYU Hospital for Joint Diseases, 301 E. 17th Street, New York, NY 10003, USA Tel: + 1 212 598 6403; fax: + 1 646 794 1201; e-mail: [email protected]
Case report The patient presented to our institution as an 11-day-old male infant with bilateral clubfoot deformity (Fig. 1). The patient was born at 38-weeks gestation by induced vaginal delivery to a 42-year-old mother who had 12 other children (gravida 13, para 12). The pregnancy was complicated by maternal hypertension 1 week before delivery. The patient’s birth weight was 6 lb 7 oz, and he measured 19 inches. The parents were of Ashkenazi Jewish ancestry and nonconsanguineous. He had one other sibling with clubfeet treated with casting, percutaneous tenotomy, and anterior tibial tendon transfer, and another sibling with metatarsus adductus that was resolved with conservative treatment. Ultrasounds during pregnancy were normal other than the clubfoot deformity. On physical exam, the patient was noted to have dysmorphic features including a large anterior fontanelle, moderate bilateral epicanthal folding, downslanting palpebral fissures, low-set posteriorly rotated ears, and a long
1060-152X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/BPB.0000000000000131
374 Journal of Pediatric Orthopaedics B 2015, Vol 24 No 4
Fig. 1
Bilateral clubfoot deformities before Ponseti casting seen in an 11-day-old male infant.
narrow face with a triangular appearance (Fig. 2). His generalized motor tone was normal. Examination of the spine revealed no curvature, tufts of hair, or sacral dimpling. There were no skin lesions or discolorations. Hip range of motion was symmetrical and full. The Ortolani and Barlow exams were negative. Examination of the feet revealed bilateral clubfeet with a Dimeglio score of 19 and Pirani score of 6 [11]. The patient was treated with serial Ponseti casting, bilateral tendo-Achilles lengthening, and bracing. His feet corrected well with a final Dimeglio score of 4 and Pirani score of 0 (Figs 3 and 4); however, it was noted that his feet were significantly stiffer than usual successfully treated clubfeet. At about 6 weeks of age, the infant was noted to have temporal wasting and poor weight gain. It was revealed that the patient had been a poor feeder since birth, with a disorganized suck/swallow reflex and an inability to breast or bottle feed. The mother had been feeding the patient with an eyedropper. A work-up for failure to thrive was initiated without yielding significant findings. A gastroenterology consultation produced a normal barium swallow study. Referral to a pediatric geneticist finally revealed the diagnosis of PTLS by CGH microarray. The patient had a 4.74 Mb pathogenic duplication of chromosome 17p12-p11.2 [arr17p12p11.2 (15,757,617–20,501,923) × 3 in GRCH37/hg19], which was larger than the usual 3.7 Mb duplication. Genetic testing was also offered to the parents but was declined. An echocardiogram was performed which showed a patent ductus arteriosus and foramen ovale. Early intervention therapy and genetic counseling were initiated and the patient’s clinical status improved gradually with time.
Fig. 2
Picture of a 20-month-old child. Dysmorphic features such as large anterior fontanelle, moderate bilateral epicanthal folding, downslanting palpebral fissures, low-set posteriorly rotated ears, and long narrow face with a triangular appearance can be seen.
Discussion Chromosome microarray is the first-tier test for the diagnostic evaluation of children with congenital anomalies [12]. This test reveals constitutional genomic copy number variations (chromosome deletions or duplications) with a resolution (50 kb) that greatly
exceeds that of the conventional karyotype (5 Mb). The deletions and duplications that are below the resolution of the karyotype (microdeletions and microduplications) are the cause of intellectual disability, autism, and multiple congenital anomalies in about 15–20% of children
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Potocki–Lupski syndrome with bilateral clubfoot Dhanaraj et al. 375
Fig. 3
emerged that describe PTLS in conjunction with pathologies other than the original infantile hypotonia, cognitive deficits, and cardiovascular anomalies. As mentioned previously, three other case reports in the literature have proposed that PTLS may be linked to an underlying connective tissue disorder resulting in musculoskeletal manifestations. In general, the 17p11.2 genomic region is an area prone to rearrangements. For instance, Charcot–Marie–Tooth disease type 1A (CMT1A) arises from a microduplication of a locus nearby to PTLS and has distinct musculoskeletal manifestations including cavovarus foot. Also the reciprocal deletion to the PTLS duplication (del17p11.2) is responsible for Smith–Magenis syndrome, a mental retardation syndrome characterized by insomnia disorder and increased frequency of severe scoliosis often requiring surgery [16].
Right foot after Ponseti casting at 20 months.
The patient in our case had a 4.7 Mb duplication, which is larger than the usual 3.7 Mb duplication typically seen in PTLS. The duplicated area was analyzed and found to not include the PMP22 gene associated with CMT1A although it did contain the RAI1 critical region consistent with PTLS. The significance of the larger duplication in our patient is yet to be determined. It could be postulated that the additional regions duplicated may have a role in the accompanying pathology of clubfeet.
Fig. 4
Left foot after Ponseti casting at 20 months.
affected with any of these abnormalities. Many children with congenital anomalies need orthopaedic care and the pediatric orthopaedic surgeon will be confronted frequently with a child diagnosed with a genomic copy number variation (microdeletion or microduplication syndrome). Furthermore, the microdeletion or microduplication diagnosis has frequent implications for clinical care [13]. The identification of Potocki–Lupski as a distinct clinical entity has been fairly recent: the first descriptions of the 17p11.2 duplication were published by Brown et al. in 1996 [14] and Potocki et al. in 2000 [15] and the subsequent full characterization of PTLS was published in 2007 by Potocki et al. [1]. Since then, a few cases have
As mentioned previously, the patient did have an older male sibling with bilateral clubfoot deformity that was treated successfully with Ponseti casting, percutaneous tendo-Achilles lengthening, and anterior tibial tendon transfers. The patient’s sibling was also treated at our institution and he had normal development with no features of any recognizable genetic syndrome including PTLS; he had no genetic tests. It was noted that his PTLS-affected sibling did have significantly stiffer feet throughout his treatment similar to the ‘atypical’ clubfeet seen with certain neuromuscular disorders such as arthrogryposis and cerebral palsy. The PTLS patient also required more casts and had a relapse of his deformity at about the sixth week of his treatment. This, however, may have been due to the additional ailments the patient was experiencing at that time and lapses in his clubfoot treatments that occurred secondary to his complex medical situation. Regardless, his final outcome did demonstrate successful but unusual results. It is possible that clubfoot coupled with PTLS may yield a phenotype that more closely resembles a neuromuscular picture. We recognize that the combination of clubfeet and PTLS may be entirely coincidental in this patient, especially being that the patient had an unaffected sibling with clubfeet. Inversely, the occurrence of clubfeet in the sibling could be coincidental. However, previous seemingly unrelated entities have been found to be related through common genetic pathways, for example clubfoot and autism by the PITX1 gene [10,17]. Despite the
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
376
Journal of Pediatric Orthopaedics B 2015, Vol 24 No 4
possibility of random association, we still find the reporting of this patient to be important in the contribution to the ever-growing database of phenotypes seen with PTLS. Further investigations into the genetic source of various conditions will hopefully lead to improved treatments and recognition of potential associated pathologies. In summary, this case raises the awareness and reinforces the possibility of multiple and sometimes systemic causes of clubfeet.
5
6
7
8
9
Acknowledgements The authors would like to thank Drs Martin Bialer, Ira Parness, and Gregory Tayrose for their assistance and collaboration.
10 11
12
Conflicts of interest
There are no conflicts of interest. 13
References 1
2
3
4
Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM, et al. Characterization of Potocki–Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 2007; 80:633–649. Soler-Alfonso C, Motil KJ, Turk CL, Robbins-Furman P, Friedman EM, Zhang F, et al. Potocki–Lupski syndrome: a microduplication syndrome associated with oropharyngeal dysphagia and failure to thrive. J Pediatr 2011; 158:655–659, e2. Yusupov R, Roberts AE, Lacro RV, Sandstrom M, Ligon AH. Potocki–Lupski syndrome: an inherited dup(17)(p11.2p11.2) with hypoplastic left heart. Am J Med Genet A 2011; 155A:367–371. Jefferies JL, Pignatelli RH, Martinez HR, Robbins-Furman PJ, Liu P, Gu W, et al. Cardiovascular findings in duplication 17p11.2 syndrome. Genet Med 2012; 14:90–94.
14
15
16 17
Martin J, Knight SJ, Sharp AJ, Eichler EE, Hurst J, Kini U. Potocki–Lupski syndrome mimicking a connective tissue disorder. Clin Dysmorphol 2008; 17:211–213. Kuo CC, Chang CC, Hsu HC, Lu TW, Tsai NY. Potocki–Lupski syndrome with teratologic dislocation of the hip: a case report. J Pediatr Orthop B 2013; 22:42–44. Magoulas PL, Liu P, Gelowani V, Soler-Alfonso C, Kivuva EC, Lupski JR, Potocki L. Inherited dup(17)(p11.2p11.2): expanding the phenotype of the Potocki–Lupski syndrome. Am J Med Genet A 2014; 164A:500–504. Barker S, Chesney D, Miedzybrodzka Z, Maffulli N. Genetics and epidemiology of idiopathic congenital talipes equinovarus. J Pediatr Orthop 2003; 23:265–272. Roye DP Jr, Roye BD. Idiopathic congenital talipes equinovarus. J Am Acad Orthop Surg 2002; 10:239–248. Dobbs MB, Gurnett CA. Genetics of clubfoot. J Pediatr Orthop B 2012; 21:7–9. Chu A, Labar AS, Sala DA, van Bosse HJ, Lehman WB. Clubfoot classification: correlation with Ponseti cast treatment. J Pediatr Orthop 2010; 30:695–699. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86:749–764. Henderson LB, Applegate CD, Wohler E, Sheridan MB, Hoover-Fong J, Batista DA. The impact of chromosomal microarray on clinical management: a retrospective analysis. Genet Med 2014; 16:657–664. Brown A, Phelan MC, Patil S, Crawford E, Rogers RC, Schwartz C. Two patients with duplication of 17p11.2: the reciprocal of the Smith-Magenis syndrome deletion? Am J Med Genet 1996; 63:373–377. Potocki L, Chen KS, Park SS, Osterholm DE, Withers MA, Kimonis V, et al. Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 2000; 24:84–87. Spilsbury J, Mohanty K. The orthopaedic manifestations of Smith-Magenis syndrome. J Pediatr Orthop B 2003; 12:22–26. Philippi A, Tores F, Carayol J, Rousseau F, Letexier M, Roschmann E, et al. Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 (PITX1) on chromosome 5q31: a candidate gene analysis. BMC Med Genet 2007; 8:74.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
