HAND/PERIPHERAL NERVE Upper Extremity Anomalies in Pfeiffer Syndrome and Mutational Correlations Felecia E. Cerrato, M.P.H. Laura C. Nuzzi, B.A. Todd A. Theman, M.D. Amir Taghinia, M.D. Joseph Upton, M.D. Brian I. Labow, M.D. Boston, Mass.
Background: Pfeiffer syndrome is characterized by craniosynostosis and a variety of associated upper and lower extremity anomalies. The authors reviewed presentation and treatment of upper extremity anomalies in a series of genotyped patients with Pfeiffer syndrome. Methods: Medical records of patients with Pfeiffer syndrome seen at the authors’ institution over a 16-year period were reviewed. Data on clinical presentation, genetic testing, and treatment were collected. The upper extremity anomalies were documented using plain radiographs and physical examinations by a multidisciplinary craniofacial team. Results: Of 15 patients identified as having FGFR1- or FGFR2-confirmed Pfeiffer syndrome, 12 (80 percent) presented with upper extremity anomalies, most commonly broad thumbs [n = 10 (83 percent)], radial clinodactyly (thumbs) [n = 7 (58 percent)], and symphalangism [n = 7 each (58 percent)]. All patients with upper extremity anomalies had lower extremity anomalies. Six of the 12 patients (50 percent) with upper extremity findings underwent surgical correction. FGFR1 or FGFR2 genotype did not correlate with upper extremity phenotype. Conclusions: Although broad thumbs are common, patients with Pfeiffer syndrome often present with other upper extremity anomalies that may not require surgical intervention. Genetic and allelic heterogeneity may explain phenotypic variability in these upper extremity anomalies. Characterization of these limb differences should be made by pediatric hand surgeons as part of a craniofacial team. Treatment decisions should be individualized and dictated by the type and severity of clinical presentation. (Plast. Reconstr. Surg. 133: 654e, 2014.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV.
P
feiffer syndrome is a rare genetic disorder caused by autosomal dominant mutations in FGFR1 or FGFR2. Patients traditionally present with craniosynostosis and may be clinically categorized into types I, II, and III. Type I Pfeiffer syndrome typically presents with broad thumbs and great toes, moderate midfacial hypoplasia, and normal intellect. Type II is more severe, presenting with developmental delay and mental retardation, hydrocephalus, risk of early death, and a cloverleaf cranial deformity. Type III is similar to type II but lacks the presence of cloverleaf deformity.1 Patients may present with multiple upper extremity anomalies or normal upper extremities From the Department of Plastic and Oral Surgery, Boston Children’s Hospital and Harvard Medical School. Received for publication October 10, 2013; accepted November 4, 2013. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000000107
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with or without lower extremity involvement.1 The most commonly associated upper extremity anomalies are broad thumbs (Fig. 1). However, other upper extremity anomalies affecting the elbow, wrist, and hand have been observed (Table 1 and Fig. 2).2–6 These limb differences may also be observed in patients with other syndromic and nonsyndromic types of craniosynostosis. The frequency of these anomalies in Pfeiffer syndrome patients remains unknown, as previous studies have been limited to case reports or small case series encompassing other craniosynostosis syndromes.6–8 Unlike Apert syndrome, for which detailed descriptions exist, there are no studies solely concerning the spectrum of upper extremity anomalies associated with Pfeiffer syndrome. Although patients with Apert syndrome invariably require Disclosures: The authors have no financial interest to declare in relation to the content of this article.
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Volume 133, Number 5 • Upper Extremities in Pfeiffer Syndrome
Fig. 1. The “broad” thumb classically associated with Pfeiffer syndrome. (Left) Abnormal insertions of the extensor pollicis longus and abductor pollicis brevis in conjunction with a longitudinally bracketed epiphysis of the proximal phalanx can lead to radial clinodactyly. (Center) The broad nail plate and radially deviated thumb commonly seen in Pfeiffer syndrome patients. (Right) Plain radiograph of the thumb of a Pfeiffer syndrome patient demonstrating the abnormally wide distal phalanx and C-shaped epiphysis of the wedge-shaped proximal phalanx.
surgery to manage complex syndactyly,9 patients with Pfeiffer syndrome may or may not require surgical intervention. We reviewed records of patients with Pfeiffer syndrome seen in our craniofacial center and characterized the upper extremity anomalies, genetic variants, and corrective procedures. Genotype-phenotype correlations and lower extremity anomalies were documented.
diagnosis of Pfeiffer syndrome (variant in FGFR1 or FGFR2). Extremities were examined by craniofacial surgeons, hand surgeons, and geneticists. Medical records were reviewed for demographics, clinical presentation, presence and type of upper and lower extremity anomalies, upper extremity corrective procedures, and genetic testing results. Radiographs or photographs were reviewed to confirm the type of upper extremity anomaly.
PATIENTS AND METHODS After approval from the Boston Children’s Hospital Committee on Clinical Investigation, the medical records of patients with Pfeiffer syndrome treated between 1994 and 2010 were reviewed. Patients were identified by International Classification of Diseases, Ninth Revision diagnosis codes 755.55 (acrocephalosyndactyly) and 756.0 (congenital anomalies of skull and face bones). Inclusion criteria included a clinical and molecular Table 1. Upper Extremity Anomalies in Pfeiffer Syndrome Location Elbow Wrist Hand Thumb Fingers
Anomaly Humeroulnar synostosis; radioulnar synostosis; radial head dislocation; ankylosis Carpal coalitions; “Madelung-like” deformity of the distal radius Metacarpal synostosis (partial greater than complete) Broad, short thumbs; radial clinodactyly Syndactyly (simple, incomplete); polydactyly; symphalangism; brachydactyly; clinodactyly (border digits more frequently affected)
RESULTS Fifteen patients with FGFR-confirmed Pfeiffer syndrome were identified (Table 2). Thirteen patients presented with type I Pfeiffer syndrome, and two patients were diagnosed with type II Pfeif fer syndrome. Radiographs were available for 12 patients, and one patient underwent ultrasonography of the upper extremities. Twelve patients (80 percent) presented with upper extremity anomalies, most commonly broad thumbs [n = 10 (83 percent)], radial clinodactyly of the thumbs [n = 7 (58 percent)], and symphalangism [n = 7 (58 percent)] (Table 3). All patients with broad thumbs had other bilateral upper extremity anomalies. Of the two patients without broad thumbs, one presented with elbow ankylosis (patient 14), and the other presented with several upper extremity anomalies, including radial clinodactyly of the thumbs, syndactyly, clinodactyly of other fingers, and postaxial polydactyly (patient 7). All of the patients with upper extremity anomalies also had lower
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Fig. 2. A variety of hand anomalies in a patient with Pfeiffer syndrome. (Left) Plain anteroposterior radiograph demonstrating symphalangism in the index, middle, ring, and small fingers. Also note the clinodactyly of the index and small fingers and carpal coalitions that are present. (Center and right) The same patient also had numerous soft-tissue syndactylies.
extremity anomalies, most commonly broad great toes [n = 8 (67 percent)]. Of the three patients who did not have upper extremity anomalies, only one had broad great toes. Of the 12 patients with upper extremity anomalies, one had a coding sequence mutation in FGFR1, and 11 (92 percent) had mutations in FGFR2, of which five were splice-site mutations, five were altered amino acid sequence, and one was not specified. The same mutations were detected in patients 5 and 6 and patients 14 and 15, respectively, all of whom were unrelated. Patients 7, 8, and 10 also shared the same mutation; patients 7 and 8 were the children of patient 10. The majority of patients did not have any corrective upper extremity surgery. Six of the 12 patients (50 percent) with anomalies did undergo operative treatment (Table 4). Five patients underwent procedures to correct thumb deformities, including opening wedge osteotomies of the proximal phalanx and Z-plasty along the radial border of the thumb (Fig. 3). Two patients had procedures to correct simple polydactyly and one patient underwent multiple procedures to excise a recurrent metacarpal synostosis between the ring and little finger metacarpals to facilitate palmar pinch.
DISCUSSION We report a series of 15 patients with a clinical and confirmed molecular diagnosis of Pfeif fer syndrome and characterize their upper extremity anomalies. Although broad thumbs
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are historically associated with Pfeiffer syndrome, these are not uniformly seen in our series. Furthermore, not all Pfeiffer syndrome patients presented with an extremity anomaly. A spectrum of upper extremity anomalies was found, most often with corresponding lower extremity involvement. These anomalies did not uniformly require surgical treatment. Patients had either an FGFR1 or FGFR2 mutation, the majority of which have been reported previously. Even patients with an identical mutation exhibited variable type and severity of upper extremity anomaly. These observations speak to the genetic, allelic, and phenotypic heterogeneity of this condition. Three types of Pfeiffer syndrome have been described. Patients with type I Pfeiffer syndrome traditionally present with craniosynostosis, broad thumbs and great toes, moderate to severe midfacial hypoplasia, and normal intellect. Type II is usually accompanied by severe forms of developmental delay and mental retardation, in addition to proptosis, hydrocephalus, risk of early death, and a cloverleaf cranial deformity. Type III Pfeif fer syndrome, not observed in this case series, is similar to type II but without the cloverleaf deformity.4,10 Other reported associated anomalies include impaired hearing,11–13 cleft palate,14 lower extremity anomalies,15 and ocular problems.16 We observed heterogeneity in the presentation of upper extremity anomalies. The majority of patients had broad thumbs, but all patients with broad thumbs also had other various upper extremity anomalies. Only patient 14 presented with isolated bilateral elbow ankylosis. Previous
Volume 133, Number 5 • Upper Extremities in Pfeiffer Syndrome Table 2. Presentation of Upper and Lower Extremities in a Series of Patients with Pfeiffer Syndrome* Age at Presentation (yr)
Patient
Sex
1
Male
2 3
Female Male
1.4 1.03‡
4 5
Male Female
6.5 0.2
6
Female
2.7‡
7§
Female
0.3‡
8§
Male
0.7‡
9
Male
6.1‡
10§
Female
7.0‡
11
Male
0.1‡
12 13
Female Female
11.5‡ 0.01
14 15
Female Male
0.3 0.3
0.2
Upper Extremity Anomaly† Broad thumbs; radial clinodactyly of thumbs; clinodactyly and brachydactyly (mild) of middle, ring, and small fingers Broad thumbs; radial head dislocation Broad thumbs; radial clinodactyly of thumbs; symphalangism index fingers; simple ulnar polydactyly None Broad thumbs; radial clinodactyly of thumbs; radioulnar synostosis; symphalangism all fingers Broad thumbs; symphalangism index fingers Radial clinodactyly of thumbs; syndactyly middle and ring fingers; symphalangism index finger; clinodactyly index, middle, ring, and small fingers; simple ulnar polydactyly Broad thumbs; radial clinodactyly of thumbs; symphalangism (fingers not specified); simple ulnar polydactyly None Broad thumbs; radial clinodactyly of thumbs; symphalangism index fingers; clinodactyly middle fingers; b rachydactyly small fingers; radiohumeral synostosis; simple ulnar polydactyly Broad thumbs; radial clinodactyly of thumbs; metacarpal synostosis; clinodactyly small fingers None Broad thumbs; symphalangism; clinodactyly small fingers; elbow ankylosis Elbow ankylosis Broad thumbs (mild); radioulnar synostosis
Lower Extremity Anomaly†
Genetic Variant Detected
Broad toes; syndactyly second FGFR1: Pro252Arg and third toes; brachydactyly fourth and fifth toes No foot anomalies Syndactyly first and second toes; aberrant bony formation of phalanges of first toe None Broad toes; syndactyly all toes
FGFR2: Cys342Ser FGFR2: unspecified mutation FGFR2: Ser347Cys FGFR2: c.1119-1 G-to-C
Hallux varus; duplication bone FGFR2: c.1119-1 of first toes (not specified) G-to-C Broad toes; syndactyly FGFR2: c.940-1 third and fourth toes; G-to-A symphalangism Syndactyly; symphalangism
FGFR2: c.940-1 G-to-A
Broad toes
FGFR2: unspecified splice site mutation FGFR2: c.940-1 G-to-A
Broad toes; syndactyly third and fourth toes; symphalangism
Broad toes; syndactyly second, third, fourth toes; clinodactyly great toes None Broad toes; symphalangism
FGFR2: Ala314Ser
Broad toes Broad toes
FGFR2: Cys342Arg FGFR2: Cys342Arg
FGFR2: Ser354Cys FGFR2: Trp290Cys
*All patients were diagnosed with type I Pfeiffer syndrome except patients 2 and 13, who were diagnosed with type II. †Anomalies are bilateral unless specified. ‡Reported age is at first corrective procedure related to Pfeiffer syndrome at our institution. These patients had previous procedures to treat Pfeiffer syndrome performed at outside institutions. §Patients 7 and 8 were the children of patient 10.
Table 3. Distribution of Upper Extremity Anomalies in Patients with Pfeiffer Syndrome Type of Upper Extremity Anomaly (n = 12)
No.
% of All Patients (n = 15)
% of Patients with Upper Extremity Anomalies (n = 12)
Broad thumbs Radial clinodactyly (thumbs) Symphalangism Elbow anomaly Clinodactyly (other fingers) Polydactyly Brachydactyly Metacarpal synostosis Broad fingers Syndactyly
10 7 7 6 5 4 2 2 1 1
67 47 47 40 33 27 13 13 7 7
83 58 58 50 42 33 17 17 8 8
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Plastic and Reconstructive Surgery • May 2014 Table 4. Surgical Procedures on Upper Extremity Anomalies in Patients with Pfeiffer Syndrome Patient
Total No. of Operations
Corrective Procedures
3
3
5
2
6 8 10 11
1 1 3 6
Excision ulnar polydactyly removal*; Z-plasty radial border of thumb and opening wedge osteotomy right thumb; and Z-plasty radial border of thumb and opening wedge osteotomy left thumb Z-plasty, full-thickness skin graft of radial border of thumb, and opening wedge osteotomy right thumb; and Z-plasty radial border of thumb and opening wedge osteotomy left thumb Surgical procedure to narrow/straighten* Excision ulnar polydactyly Correction of radial clinodactyly of thumbs (three times)* Z-plasty radial border of thumb and opening wedge osteotomy left thumb, and excision of left ring and small finger metacarpal synostosis; Z-plasty radial border of thumb and opening wedge osteotomy right thumb, and excision of right ring and small finger metacarpal synostosis; reexcision of right ring and small finger metacarpal synostosis with fascia lata implant right hand; reexcision of left ring and small finger metacarpal synostosis with fascia lata implant left hand, and opening wedge osteotomy and bone graft left small finger; reexcision of metacarpal synostosis, right ring and small finger metacarpal synostosis, and implantation of fascia lata, right hand; and scar revision and advancement flap right thumb
*Procedure performed at outside institution; details not available.
studies have reported a prevalence of elbow abnormalities as high as 68 percent in Pfeiffer syndrome patients with affected upper extremities.6,17 Although only six of our 15 patients (40 percent) had anomalies of the elbows, this finding still supports the current literature that elbow involvement is common in these patients (Fig. 4). A variety of mutations in FGFR1 and FGFR2 have been shown to cause Pfeiffer syndrome. As in prior studies, genotypic, allelic, and phenotypic variability was observed in our series. In FGFR1, only one mutation, Pro252Arg, has been reported.18–21 The one patient in our series with this mutation (patient 1) presented with the broad, deviated thumbs; brachydactyly and clinodactyly of fingers; in addition to broad great toes, syndactyly, and brachydactyly of the toes that have previously been reported in patients with this mutation.21 Although these patients may not have craniosynostosis,18,21 patient 1 did present with craniosynostosis. Most patients in our study harbored FGFR2 mutations, which account for 95 percent of the mutations that cause Pfeiffer syndrome.10,22–24 Patient 13 had the Trp290Cys mutation that has been associated with the more severe type II Pfeif fer syndrome, including cloverleaf deformity, ocular proptosis, radioulnar synostosis, and broad thumbs and great toes.25–27 Patient 13 did in fact demonstrate characteristics of type II Pfeiffer syndrome, supporting prior assertions that this mutation leads to a more severe craniofacial presentation and multiple extremity involvement. Other mutations may also lead to a more severe presentation. Patient 2, who also carried a diagnosis of type II Pfeiffer syndrome, presented
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with craniosynostosis, broad thumbs, and dislocation of the radial head. The FGFR2 variant found in this patient was Cys342Ser. This mutation has been previously reported in Pfeiffer syndrome and in Crouzon syndrome, although other mutations at this site have been found in patients with Jackson-Weiss syndrome.22,27–30 Two unrelated patients in our series with a different mutation at the Cys342 site, Cys342Arg, presented with the milder type I Pfeiffer syndrome; both patients had elbow anomalies, and one had
Fig. 3. A series of radiographs demonstrating the treatment of thumb radial clinodactyly in a patient with Pfeiffer syndrome. (Left) Plain radiograph of the thumb before correction at 1 year of age. (Center) Plain radiograph 1 year after Z-plasty and opening wedge osteotomy with bone grafting of the proximal phalanx (white arrow). (Right) Three years later, the bone graft is well incorporated and the thumb remains straight.
Volume 133, Number 5 • Upper Extremities in Pfeiffer Syndrome
Fig. 4. Examples of wrist and elbow anomalies in two patients with Pfeiffer syndrome. (Left) Plain anteroposterior radiograph demonstrating congenital radial head dislocation and abnormal humeroulnar articulation. The articular surface of the distal radius is also abnormally canted similar to a Madelung-type deformity. (Right) Plain anteroposterior radiograph of another Pfeiffer syndrome patient with radioulnar synostosis.
minimally broadened thumbs. These limb differences have been described previously in patients with this mutation.20 Another example of phenotypic heterogeneity is demonstrated by the three patients from the same family reported in this study. All harbored a splice-site mutation, a G-to-A transition outside exon IIIc (c.940-1 G-to-A). It has been reported that mutations at this site lead to broad, radially deviated thumbs.20,27 Interestingly, only two members of this family had broad thumbs, and only one member had clinodactyly and brachydactyly in other digits. Similarly, patient 4 carried the Ser347Cys mutation that has been reported in the most severe type of Pfeiffer syndrome including multiple extremity anomalies.31 However, our patient had no upper or lower extremity anomalies. Other FGFR2 coding sequence mutations observed in our series, Ala314Ser and Ser354Cys, have been reported in patients with isolated bilateral coronal synostosis and Crouzon syndrome, respectively.30 In addition, unrelated patients with the same splice-site mutation (c.1119-1 G-to-C) exhibited different types of upper extremity anomalies. Although
approximate genotype-phenotype correlations are suggested by our data and the observations of others, no precise upper extremity phenotype can be assumed in Pfeiffer syndrome even among patients with seemingly identical mutations. Unknown secondary mutations or epigenetic influences may underlie these subtle differences. Apert syndrome, the most common FGFR-mediated acrocephalosyndactyly, stands in contrast to Pfeiffer syndrome in a number of ways. Apert syndrome is caused primarily by only two mutations in FGFR2, Ser252Trp or Pro253Arg,32 although Ser252Phe has also been reported.33,34 All Apert syndrome patients present with either the type I, type II, or type III hand anomaly, characterized by increasingly severe complex syndactyly.35–39 Invariably, all four extremities are involved. Unlike the variable Pfeiffer limb findings, the relatively consistent “Apert hand” has been well-studied, and treatment algorithms have been published.9,35,39–42 Although the overlapping features between the two syndromes such as short, radially deviated thumbs, symphalangism, and metacarpal synostosis have been emphasized, our series demonstrates the marked differences in incidence, severity, and limb involvement between these syndromes. It is possible that the genetic and allelic heterogeneity observed in Pfeiffer syndrome may contribute to the variable presentations of upper extremity anomalies in these patients. Another important distinction between Pfeif fer and Apert syndromes relates to treatment. Although all Apert syndrome patients typically undergo multiple syndactyly releases within the first 2 years of life, not all Pfeiffer syndrome patients require hand surgery. In our series, only 50 percent of patients with upper extremity anomalies underwent surgical treatment early in life. As elsewhere, the extremities of Pfeiffer syndrome patients were evaluated by plain radiographs and detailed physical examinations by a multidisciplinary craniofacial team, including hand surgeons.9 Although isolated broad thumbs may not require surgical correction, operations to lengthen and straighten severely deviated or short thumbs may improve hand function. Limb differences such as polydactyly and syndactyly are managed as in other conditions.9 Metacarpal synostosis between the fourth and fifth metacarpals can limit palmar grasp and in some instances may warrant correction (Fig. 5). As with Apert hands that lack interphalangeal motion, Pfeiffer syndrome patients with symphalangism may benefit functionally from resection of these synostoses
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Fig. 5. Synostosis of the fourth and fifth metacarpals in a patient with Pfeiffer syndrome. (Left) Abducted small finger with flattening of the hypothenar eminence and loss of “palmar pinch.” (Center) Intraoperative view with extensor tendons retracted laterally and periosteum stripped away. (Right) Plain radiograph showing the synostosis. As in Apert syndrome, loss of palmar pinch may compromise hand function in Pfeiffer syndrome patients, especially those with concurrent symphalangism.
and interpositional arthroplasty, although recurrent synostosis can occur. Diagnoses such as symphalangism, elbow ankylosis, and radiohumeral synostosis were not managed surgically in our series. As with Apert syndrome patients, functional and aesthetic outcomes of hand operations should be reassessed alongside craniofacial evaluations as the patient grows. There are several important limitations to our study. The total number of patients included in our study is small, and only patients with mutations in FGFR1 or FGFR2 were included. Patients with a clinical diagnosis of only Pfeiffer syndrome were excluded based on the phenotypic overlap between Pfeiffer syndrome and forms of syndromic craniosynostosis. Upper extremity anomalies could not always be confirmed by radiographs, and in some cases we relied on clinical descriptions to characterize these anomalies. It is also possible that not all upper extremity anomalies were included. The exact mutation was not available for two patients. These limitations contribute to difficulties in correlating specific mutations with the type or severity of upper extremity anomalies in Pfeiffer syndrome patients. The classic association between Pfeiffer syndrome and broad thumbs belies the variable upper extremity findings seen in these patients. Unlike Apert syndrome, Pfeiffer syndrome patients may possess a variety of FGFR mutations and may exhibit normal extremities or a wide array of limb differences. The genotypic and phenotypic heterogeneity observed in this syndrome makes it difficult to correlate genetic variants and extremity
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findings. Surgery may improve hand function in some but is not required for all Pfeiffer syndrome patients. Regardless, early evaluation of limb differences should involve a pediatric hand surgeon as part of the craniofacial team. Brian I. Labow, M.D. Department of Plastic and Oral Surgery Boston Children’s Hospital and Harvard Medical School 300 Longwood Avenue Hunnewell-1 Boston, Mass. 02115 [email protected]
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factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome. Hum Genet. 1997;99:602–606. 27. Cornejo-Roldan LR, Roessler E, Muenke M. Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome. Hum Genet. 1999;104:425–431. 28. Meyers GA, Day D, Goldberg R, et al. FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: Evidence for missense changes, insertions, and a deletion due to alternative RNA splicing. Am J Hum Genet. 1996;58:491–498. 29. Tartaglia M, Di Rocco C, Lajeunie E, Valeri S, Velardi F, Battaglia PA. Jackson-Weiss syndrome: Identification of two novel FGFR2 missense mutations shared with Crouzon and Pfeiffer craniosynostotic disorders. Hum Genet. 1997;101:47–50. 30. Robson CD, Mulliken JB, Robertson RL, et al. Prominent basal emissary foramina in syndromic craniosynostosis: Correlation with phenotypic and molecular diagnoses. AJNR Am J Neuroradiol. 2000;21:1707–1717. 31. Chokdeemboon C, Mahatumarat C, Rojvachiranonda N, Tongkobpetch S, Suphapeetiporn K, Shotelersuk V. FGFR1 and FGFR2 mutations in Pfeiffer syndrome. J Craniofac Surg. 2013;24:150–152. 32. Wilkie AO, Slaney SF, Oldridge M, et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;9:165–172. 33. Oldridge M, Lunt PW, Zackai EH, et al. Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2. Hum Mol Genet. 1997;6:137–143. 34. Lajeunie E, Cameron R, El Ghouzzi V, et al. Clinical variability in patients with Apert’s syndrome. J Neurosurg. 1999;90:443–447. 35. Upton J. Apert syndrome. Classification and pathologic anatomy of limb anomalies. Clin Plast Surg. 1991;18:321–355. 36. Kasser J, Upton J. The shoulder, elbow, and forearm in Apert syndrome. Clin Plast Surg. 1991;18:381–389. 37. Cohen MM Jr, Kreiborg S. Hands and feet in the Apert syndrome. Am J Med Genet. 1995;57:82–96. 38. Holten IW, Smith AW, Bourne AJ, David DJ. The Apert syndrome hand: Pathologic anatomy and clinical manifestations. Plast Reconstr Surg. 1997;99:1681–1687. 39. Fearon JA. Treatment of the hands and feet in Apert syndrome: An evolution in management. Plast Reconstr Surg. 2003;112:1–12; discussion 13–19. 40. Chang J, Danton TK, Ladd AL, Hentz VR. Reconstruction of the hand in Apert syndrome: A simplified approach. Plast Reconstr Surg. 2002;109:465–470; discussion 471. 41. Guero S, Vassia L, Renier D, Glorion C. Surgical management of the hand in Apert syndrome. Handchir Mikrochir Plast Chir. 2004;36:179–185. 42. Guero SJ. Algorithm for treatment of Apert hand. Tech Hand Up Extrem Surg. 2005;9:126–133.
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Background: Pfeiffer syndrome is characterized by craniosynostosis and a variety of associated upper and lower extremity anomalies. The authors reviewed presentation and treatment of upper extremity anomalies in a series of genotyped patients with Pfeiffer syndrome. Methods: Medical records of patients with Pfeiffer syndrome seen at the authors’ institution over a 16-year period were reviewed. Data on clinical presentation, genetic testing, and treatment were collected. The upper extremity anomalies were documented using plain radiographs and physical examinations by a multidisciplinary craniofacial team. Results: Of 15 patients identified as having FGFR1- or FGFR2-confirmed Pfeiffer syndrome, 12 (80 percent) presented with upper extremity anomalies, most commonly broad thumbs [n = 10 (83 percent)], radial clinodactyly (thumbs) [n = 7 (58 percent)], and symphalangism [n = 7 each (58 percent)]. All patients with upper extremity anomalies had lower extremity anomalies. Six of the 12 patients (50 percent) with upper extremity findings underwent surgical correction. FGFR1 or FGFR2 genotype did not correlate with upper extremity phenotype. Conclusions: Although broad thumbs are common, patients with Pfeiffer syndrome often present with other upper extremity anomalies that may not require surgical intervention. Genetic and allelic heterogeneity may explain phenotypic variability in these upper extremity anomalies. Characterization of these limb differences should be made by pediatric hand surgeons as part of a craniofacial team. Treatment decisions should be individualized and dictated by the type and severity of clinical presentation. (Plast. Reconstr. Surg. 133: 654e, 2014.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV.
P
feiffer syndrome is a rare genetic disorder caused by autosomal dominant mutations in FGFR1 or FGFR2. Patients traditionally present with craniosynostosis and may be clinically categorized into types I, II, and III. Type I Pfeiffer syndrome typically presents with broad thumbs and great toes, moderate midfacial hypoplasia, and normal intellect. Type II is more severe, presenting with developmental delay and mental retardation, hydrocephalus, risk of early death, and a cloverleaf cranial deformity. Type III is similar to type II but lacks the presence of cloverleaf deformity.1 Patients may present with multiple upper extremity anomalies or normal upper extremities From the Department of Plastic and Oral Surgery, Boston Children’s Hospital and Harvard Medical School. Received for publication October 10, 2013; accepted November 4, 2013. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000000107
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with or without lower extremity involvement.1 The most commonly associated upper extremity anomalies are broad thumbs (Fig. 1). However, other upper extremity anomalies affecting the elbow, wrist, and hand have been observed (Table 1 and Fig. 2).2–6 These limb differences may also be observed in patients with other syndromic and nonsyndromic types of craniosynostosis. The frequency of these anomalies in Pfeiffer syndrome patients remains unknown, as previous studies have been limited to case reports or small case series encompassing other craniosynostosis syndromes.6–8 Unlike Apert syndrome, for which detailed descriptions exist, there are no studies solely concerning the spectrum of upper extremity anomalies associated with Pfeiffer syndrome. Although patients with Apert syndrome invariably require Disclosures: The authors have no financial interest to declare in relation to the content of this article.
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Volume 133, Number 5 • Upper Extremities in Pfeiffer Syndrome
Fig. 1. The “broad” thumb classically associated with Pfeiffer syndrome. (Left) Abnormal insertions of the extensor pollicis longus and abductor pollicis brevis in conjunction with a longitudinally bracketed epiphysis of the proximal phalanx can lead to radial clinodactyly. (Center) The broad nail plate and radially deviated thumb commonly seen in Pfeiffer syndrome patients. (Right) Plain radiograph of the thumb of a Pfeiffer syndrome patient demonstrating the abnormally wide distal phalanx and C-shaped epiphysis of the wedge-shaped proximal phalanx.
surgery to manage complex syndactyly,9 patients with Pfeiffer syndrome may or may not require surgical intervention. We reviewed records of patients with Pfeiffer syndrome seen in our craniofacial center and characterized the upper extremity anomalies, genetic variants, and corrective procedures. Genotype-phenotype correlations and lower extremity anomalies were documented.
diagnosis of Pfeiffer syndrome (variant in FGFR1 or FGFR2). Extremities were examined by craniofacial surgeons, hand surgeons, and geneticists. Medical records were reviewed for demographics, clinical presentation, presence and type of upper and lower extremity anomalies, upper extremity corrective procedures, and genetic testing results. Radiographs or photographs were reviewed to confirm the type of upper extremity anomaly.
PATIENTS AND METHODS After approval from the Boston Children’s Hospital Committee on Clinical Investigation, the medical records of patients with Pfeiffer syndrome treated between 1994 and 2010 were reviewed. Patients were identified by International Classification of Diseases, Ninth Revision diagnosis codes 755.55 (acrocephalosyndactyly) and 756.0 (congenital anomalies of skull and face bones). Inclusion criteria included a clinical and molecular Table 1. Upper Extremity Anomalies in Pfeiffer Syndrome Location Elbow Wrist Hand Thumb Fingers
Anomaly Humeroulnar synostosis; radioulnar synostosis; radial head dislocation; ankylosis Carpal coalitions; “Madelung-like” deformity of the distal radius Metacarpal synostosis (partial greater than complete) Broad, short thumbs; radial clinodactyly Syndactyly (simple, incomplete); polydactyly; symphalangism; brachydactyly; clinodactyly (border digits more frequently affected)
RESULTS Fifteen patients with FGFR-confirmed Pfeiffer syndrome were identified (Table 2). Thirteen patients presented with type I Pfeiffer syndrome, and two patients were diagnosed with type II Pfeif fer syndrome. Radiographs were available for 12 patients, and one patient underwent ultrasonography of the upper extremities. Twelve patients (80 percent) presented with upper extremity anomalies, most commonly broad thumbs [n = 10 (83 percent)], radial clinodactyly of the thumbs [n = 7 (58 percent)], and symphalangism [n = 7 (58 percent)] (Table 3). All patients with broad thumbs had other bilateral upper extremity anomalies. Of the two patients without broad thumbs, one presented with elbow ankylosis (patient 14), and the other presented with several upper extremity anomalies, including radial clinodactyly of the thumbs, syndactyly, clinodactyly of other fingers, and postaxial polydactyly (patient 7). All of the patients with upper extremity anomalies also had lower
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Fig. 2. A variety of hand anomalies in a patient with Pfeiffer syndrome. (Left) Plain anteroposterior radiograph demonstrating symphalangism in the index, middle, ring, and small fingers. Also note the clinodactyly of the index and small fingers and carpal coalitions that are present. (Center and right) The same patient also had numerous soft-tissue syndactylies.
extremity anomalies, most commonly broad great toes [n = 8 (67 percent)]. Of the three patients who did not have upper extremity anomalies, only one had broad great toes. Of the 12 patients with upper extremity anomalies, one had a coding sequence mutation in FGFR1, and 11 (92 percent) had mutations in FGFR2, of which five were splice-site mutations, five were altered amino acid sequence, and one was not specified. The same mutations were detected in patients 5 and 6 and patients 14 and 15, respectively, all of whom were unrelated. Patients 7, 8, and 10 also shared the same mutation; patients 7 and 8 were the children of patient 10. The majority of patients did not have any corrective upper extremity surgery. Six of the 12 patients (50 percent) with anomalies did undergo operative treatment (Table 4). Five patients underwent procedures to correct thumb deformities, including opening wedge osteotomies of the proximal phalanx and Z-plasty along the radial border of the thumb (Fig. 3). Two patients had procedures to correct simple polydactyly and one patient underwent multiple procedures to excise a recurrent metacarpal synostosis between the ring and little finger metacarpals to facilitate palmar pinch.
DISCUSSION We report a series of 15 patients with a clinical and confirmed molecular diagnosis of Pfeif fer syndrome and characterize their upper extremity anomalies. Although broad thumbs
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are historically associated with Pfeiffer syndrome, these are not uniformly seen in our series. Furthermore, not all Pfeiffer syndrome patients presented with an extremity anomaly. A spectrum of upper extremity anomalies was found, most often with corresponding lower extremity involvement. These anomalies did not uniformly require surgical treatment. Patients had either an FGFR1 or FGFR2 mutation, the majority of which have been reported previously. Even patients with an identical mutation exhibited variable type and severity of upper extremity anomaly. These observations speak to the genetic, allelic, and phenotypic heterogeneity of this condition. Three types of Pfeiffer syndrome have been described. Patients with type I Pfeiffer syndrome traditionally present with craniosynostosis, broad thumbs and great toes, moderate to severe midfacial hypoplasia, and normal intellect. Type II is usually accompanied by severe forms of developmental delay and mental retardation, in addition to proptosis, hydrocephalus, risk of early death, and a cloverleaf cranial deformity. Type III Pfeif fer syndrome, not observed in this case series, is similar to type II but without the cloverleaf deformity.4,10 Other reported associated anomalies include impaired hearing,11–13 cleft palate,14 lower extremity anomalies,15 and ocular problems.16 We observed heterogeneity in the presentation of upper extremity anomalies. The majority of patients had broad thumbs, but all patients with broad thumbs also had other various upper extremity anomalies. Only patient 14 presented with isolated bilateral elbow ankylosis. Previous
Volume 133, Number 5 • Upper Extremities in Pfeiffer Syndrome Table 2. Presentation of Upper and Lower Extremities in a Series of Patients with Pfeiffer Syndrome* Age at Presentation (yr)
Patient
Sex
1
Male
2 3
Female Male
1.4 1.03‡
4 5
Male Female
6.5 0.2
6
Female
2.7‡
7§
Female
0.3‡
8§
Male
0.7‡
9
Male
6.1‡
10§
Female
7.0‡
11
Male
0.1‡
12 13
Female Female
11.5‡ 0.01
14 15
Female Male
0.3 0.3
0.2
Upper Extremity Anomaly† Broad thumbs; radial clinodactyly of thumbs; clinodactyly and brachydactyly (mild) of middle, ring, and small fingers Broad thumbs; radial head dislocation Broad thumbs; radial clinodactyly of thumbs; symphalangism index fingers; simple ulnar polydactyly None Broad thumbs; radial clinodactyly of thumbs; radioulnar synostosis; symphalangism all fingers Broad thumbs; symphalangism index fingers Radial clinodactyly of thumbs; syndactyly middle and ring fingers; symphalangism index finger; clinodactyly index, middle, ring, and small fingers; simple ulnar polydactyly Broad thumbs; radial clinodactyly of thumbs; symphalangism (fingers not specified); simple ulnar polydactyly None Broad thumbs; radial clinodactyly of thumbs; symphalangism index fingers; clinodactyly middle fingers; b rachydactyly small fingers; radiohumeral synostosis; simple ulnar polydactyly Broad thumbs; radial clinodactyly of thumbs; metacarpal synostosis; clinodactyly small fingers None Broad thumbs; symphalangism; clinodactyly small fingers; elbow ankylosis Elbow ankylosis Broad thumbs (mild); radioulnar synostosis
Lower Extremity Anomaly†
Genetic Variant Detected
Broad toes; syndactyly second FGFR1: Pro252Arg and third toes; brachydactyly fourth and fifth toes No foot anomalies Syndactyly first and second toes; aberrant bony formation of phalanges of first toe None Broad toes; syndactyly all toes
FGFR2: Cys342Ser FGFR2: unspecified mutation FGFR2: Ser347Cys FGFR2: c.1119-1 G-to-C
Hallux varus; duplication bone FGFR2: c.1119-1 of first toes (not specified) G-to-C Broad toes; syndactyly FGFR2: c.940-1 third and fourth toes; G-to-A symphalangism Syndactyly; symphalangism
FGFR2: c.940-1 G-to-A
Broad toes
FGFR2: unspecified splice site mutation FGFR2: c.940-1 G-to-A
Broad toes; syndactyly third and fourth toes; symphalangism
Broad toes; syndactyly second, third, fourth toes; clinodactyly great toes None Broad toes; symphalangism
FGFR2: Ala314Ser
Broad toes Broad toes
FGFR2: Cys342Arg FGFR2: Cys342Arg
FGFR2: Ser354Cys FGFR2: Trp290Cys
*All patients were diagnosed with type I Pfeiffer syndrome except patients 2 and 13, who were diagnosed with type II. †Anomalies are bilateral unless specified. ‡Reported age is at first corrective procedure related to Pfeiffer syndrome at our institution. These patients had previous procedures to treat Pfeiffer syndrome performed at outside institutions. §Patients 7 and 8 were the children of patient 10.
Table 3. Distribution of Upper Extremity Anomalies in Patients with Pfeiffer Syndrome Type of Upper Extremity Anomaly (n = 12)
No.
% of All Patients (n = 15)
% of Patients with Upper Extremity Anomalies (n = 12)
Broad thumbs Radial clinodactyly (thumbs) Symphalangism Elbow anomaly Clinodactyly (other fingers) Polydactyly Brachydactyly Metacarpal synostosis Broad fingers Syndactyly
10 7 7 6 5 4 2 2 1 1
67 47 47 40 33 27 13 13 7 7
83 58 58 50 42 33 17 17 8 8
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Plastic and Reconstructive Surgery • May 2014 Table 4. Surgical Procedures on Upper Extremity Anomalies in Patients with Pfeiffer Syndrome Patient
Total No. of Operations
Corrective Procedures
3
3
5
2
6 8 10 11
1 1 3 6
Excision ulnar polydactyly removal*; Z-plasty radial border of thumb and opening wedge osteotomy right thumb; and Z-plasty radial border of thumb and opening wedge osteotomy left thumb Z-plasty, full-thickness skin graft of radial border of thumb, and opening wedge osteotomy right thumb; and Z-plasty radial border of thumb and opening wedge osteotomy left thumb Surgical procedure to narrow/straighten* Excision ulnar polydactyly Correction of radial clinodactyly of thumbs (three times)* Z-plasty radial border of thumb and opening wedge osteotomy left thumb, and excision of left ring and small finger metacarpal synostosis; Z-plasty radial border of thumb and opening wedge osteotomy right thumb, and excision of right ring and small finger metacarpal synostosis; reexcision of right ring and small finger metacarpal synostosis with fascia lata implant right hand; reexcision of left ring and small finger metacarpal synostosis with fascia lata implant left hand, and opening wedge osteotomy and bone graft left small finger; reexcision of metacarpal synostosis, right ring and small finger metacarpal synostosis, and implantation of fascia lata, right hand; and scar revision and advancement flap right thumb
*Procedure performed at outside institution; details not available.
studies have reported a prevalence of elbow abnormalities as high as 68 percent in Pfeiffer syndrome patients with affected upper extremities.6,17 Although only six of our 15 patients (40 percent) had anomalies of the elbows, this finding still supports the current literature that elbow involvement is common in these patients (Fig. 4). A variety of mutations in FGFR1 and FGFR2 have been shown to cause Pfeiffer syndrome. As in prior studies, genotypic, allelic, and phenotypic variability was observed in our series. In FGFR1, only one mutation, Pro252Arg, has been reported.18–21 The one patient in our series with this mutation (patient 1) presented with the broad, deviated thumbs; brachydactyly and clinodactyly of fingers; in addition to broad great toes, syndactyly, and brachydactyly of the toes that have previously been reported in patients with this mutation.21 Although these patients may not have craniosynostosis,18,21 patient 1 did present with craniosynostosis. Most patients in our study harbored FGFR2 mutations, which account for 95 percent of the mutations that cause Pfeiffer syndrome.10,22–24 Patient 13 had the Trp290Cys mutation that has been associated with the more severe type II Pfeif fer syndrome, including cloverleaf deformity, ocular proptosis, radioulnar synostosis, and broad thumbs and great toes.25–27 Patient 13 did in fact demonstrate characteristics of type II Pfeiffer syndrome, supporting prior assertions that this mutation leads to a more severe craniofacial presentation and multiple extremity involvement. Other mutations may also lead to a more severe presentation. Patient 2, who also carried a diagnosis of type II Pfeiffer syndrome, presented
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with craniosynostosis, broad thumbs, and dislocation of the radial head. The FGFR2 variant found in this patient was Cys342Ser. This mutation has been previously reported in Pfeiffer syndrome and in Crouzon syndrome, although other mutations at this site have been found in patients with Jackson-Weiss syndrome.22,27–30 Two unrelated patients in our series with a different mutation at the Cys342 site, Cys342Arg, presented with the milder type I Pfeiffer syndrome; both patients had elbow anomalies, and one had
Fig. 3. A series of radiographs demonstrating the treatment of thumb radial clinodactyly in a patient with Pfeiffer syndrome. (Left) Plain radiograph of the thumb before correction at 1 year of age. (Center) Plain radiograph 1 year after Z-plasty and opening wedge osteotomy with bone grafting of the proximal phalanx (white arrow). (Right) Three years later, the bone graft is well incorporated and the thumb remains straight.
Volume 133, Number 5 • Upper Extremities in Pfeiffer Syndrome
Fig. 4. Examples of wrist and elbow anomalies in two patients with Pfeiffer syndrome. (Left) Plain anteroposterior radiograph demonstrating congenital radial head dislocation and abnormal humeroulnar articulation. The articular surface of the distal radius is also abnormally canted similar to a Madelung-type deformity. (Right) Plain anteroposterior radiograph of another Pfeiffer syndrome patient with radioulnar synostosis.
minimally broadened thumbs. These limb differences have been described previously in patients with this mutation.20 Another example of phenotypic heterogeneity is demonstrated by the three patients from the same family reported in this study. All harbored a splice-site mutation, a G-to-A transition outside exon IIIc (c.940-1 G-to-A). It has been reported that mutations at this site lead to broad, radially deviated thumbs.20,27 Interestingly, only two members of this family had broad thumbs, and only one member had clinodactyly and brachydactyly in other digits. Similarly, patient 4 carried the Ser347Cys mutation that has been reported in the most severe type of Pfeiffer syndrome including multiple extremity anomalies.31 However, our patient had no upper or lower extremity anomalies. Other FGFR2 coding sequence mutations observed in our series, Ala314Ser and Ser354Cys, have been reported in patients with isolated bilateral coronal synostosis and Crouzon syndrome, respectively.30 In addition, unrelated patients with the same splice-site mutation (c.1119-1 G-to-C) exhibited different types of upper extremity anomalies. Although
approximate genotype-phenotype correlations are suggested by our data and the observations of others, no precise upper extremity phenotype can be assumed in Pfeiffer syndrome even among patients with seemingly identical mutations. Unknown secondary mutations or epigenetic influences may underlie these subtle differences. Apert syndrome, the most common FGFR-mediated acrocephalosyndactyly, stands in contrast to Pfeiffer syndrome in a number of ways. Apert syndrome is caused primarily by only two mutations in FGFR2, Ser252Trp or Pro253Arg,32 although Ser252Phe has also been reported.33,34 All Apert syndrome patients present with either the type I, type II, or type III hand anomaly, characterized by increasingly severe complex syndactyly.35–39 Invariably, all four extremities are involved. Unlike the variable Pfeiffer limb findings, the relatively consistent “Apert hand” has been well-studied, and treatment algorithms have been published.9,35,39–42 Although the overlapping features between the two syndromes such as short, radially deviated thumbs, symphalangism, and metacarpal synostosis have been emphasized, our series demonstrates the marked differences in incidence, severity, and limb involvement between these syndromes. It is possible that the genetic and allelic heterogeneity observed in Pfeiffer syndrome may contribute to the variable presentations of upper extremity anomalies in these patients. Another important distinction between Pfeif fer and Apert syndromes relates to treatment. Although all Apert syndrome patients typically undergo multiple syndactyly releases within the first 2 years of life, not all Pfeiffer syndrome patients require hand surgery. In our series, only 50 percent of patients with upper extremity anomalies underwent surgical treatment early in life. As elsewhere, the extremities of Pfeiffer syndrome patients were evaluated by plain radiographs and detailed physical examinations by a multidisciplinary craniofacial team, including hand surgeons.9 Although isolated broad thumbs may not require surgical correction, operations to lengthen and straighten severely deviated or short thumbs may improve hand function. Limb differences such as polydactyly and syndactyly are managed as in other conditions.9 Metacarpal synostosis between the fourth and fifth metacarpals can limit palmar grasp and in some instances may warrant correction (Fig. 5). As with Apert hands that lack interphalangeal motion, Pfeiffer syndrome patients with symphalangism may benefit functionally from resection of these synostoses
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Fig. 5. Synostosis of the fourth and fifth metacarpals in a patient with Pfeiffer syndrome. (Left) Abducted small finger with flattening of the hypothenar eminence and loss of “palmar pinch.” (Center) Intraoperative view with extensor tendons retracted laterally and periosteum stripped away. (Right) Plain radiograph showing the synostosis. As in Apert syndrome, loss of palmar pinch may compromise hand function in Pfeiffer syndrome patients, especially those with concurrent symphalangism.
and interpositional arthroplasty, although recurrent synostosis can occur. Diagnoses such as symphalangism, elbow ankylosis, and radiohumeral synostosis were not managed surgically in our series. As with Apert syndrome patients, functional and aesthetic outcomes of hand operations should be reassessed alongside craniofacial evaluations as the patient grows. There are several important limitations to our study. The total number of patients included in our study is small, and only patients with mutations in FGFR1 or FGFR2 were included. Patients with a clinical diagnosis of only Pfeiffer syndrome were excluded based on the phenotypic overlap between Pfeiffer syndrome and forms of syndromic craniosynostosis. Upper extremity anomalies could not always be confirmed by radiographs, and in some cases we relied on clinical descriptions to characterize these anomalies. It is also possible that not all upper extremity anomalies were included. The exact mutation was not available for two patients. These limitations contribute to difficulties in correlating specific mutations with the type or severity of upper extremity anomalies in Pfeiffer syndrome patients. The classic association between Pfeiffer syndrome and broad thumbs belies the variable upper extremity findings seen in these patients. Unlike Apert syndrome, Pfeiffer syndrome patients may possess a variety of FGFR mutations and may exhibit normal extremities or a wide array of limb differences. The genotypic and phenotypic heterogeneity observed in this syndrome makes it difficult to correlate genetic variants and extremity
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findings. Surgery may improve hand function in some but is not required for all Pfeiffer syndrome patients. Regardless, early evaluation of limb differences should involve a pediatric hand surgeon as part of the craniofacial team. Brian I. Labow, M.D. Department of Plastic and Oral Surgery Boston Children’s Hospital and Harvard Medical School 300 Longwood Avenue Hunnewell-1 Boston, Mass. 02115 [email protected]
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