Reconstruction of the hand in Apert syndrome: a simplified approach

Children born with Apert acrocephalosyndactyly pose great challenges to the pediatric hand surgeon. Reconstructive dilemmas consist of shortened, deviated phalanges and extensive skin deficits following syndactyly release. We present a 10-year review of patients with Apert acrocephalosyndactyly who were treated with a simplified surgical approach. Between 1986 and 1996, 10 patients with Apert syndrome underwent reconstructive surgery of their hands. The overall strategy involved early bilateral separation of syndactylous border digits at 1 year of age, followed by sequential unilateral middle syndactyly mass separation with thumb osteotomy and bone grafting as needed. In these 10 patients, a total of 53 web spaces were released, 49 of which involved osteotomies for complex syndactyly. Only local flaps and full-thickness skin grafts from the groin were used in all cases to achieve soft-tissue coverage. To date, seven of the 53 web spaces have needed revision (revision rate, 13 percent). Eleven thumb osteotomies (nine opening wedge and two closing wedge) were performed. Bone grafts from the proximal ulna or from other digits were used in all cases. To date, none of these thumb osteotomies have needed revision. This early, simplified approach to the complex hand anomalies of Apert acrocephalosyndactyly has been successful in achieving low revision rates and excellent functional outcomes as measured by gross grasp and pinch and by patient and parent satisfaction.     

Apert syndrome with preaxial polydactyly showing the typical mutation Ser252Trp in the FGFR2 gene

The Apert syndrome is characterized by craniosynostosis and syndactyly of hands and feet. Although most cases are sporadic, an autosomal dominant mode of inheritance is well documented. Two mutations in the FGFR2 gene (Ser252Trp and Pro253Arg) account for most of the cases. We report a patient with a rare form of Apert syndrome with polydactyly. The proposita has turribrachycephaly. complete syndactyly of 2nd to 5th digits ("mitten hands" and cutaneous fusion of all toes). The X-rays revealed craniosynostosis of the coronal suture and preaxial polydactyly of hands and feet with distal bony fusion. Molecular analysis found a C755G transversion (Ser252Trp) in the FGFR2 gene. Only eight patients with Apert syndrome and preaxial polydactyly have been reported and this is the first case in which molecular diagnosis is available. On the basis of the molecular findings in this patient, polydactyly should be considered part of the spectrum of abnormalities in the Apert syndrome. This assertion would establish the need for a new molecular classification of the acrocephalopolysyndactylies.     

Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.

Apert syndrome is a distinctive human malformation characterized by craniosynostosis and severe syndactyly of the hands and feet. It is caused by specific missense substitutions involving adjacent amino acids (Ser252Trp or Pro253Arg) in the linker between the second and third extracellular immunoglobulin domains of fibroblast growth factor receptor 2 (FGFR2). We have developed a simple PCR assay for these mutations in genomic DNA, based on the creation of novel (SfiI) and (BstUI) restriction sites. Analysis of DNA from 70 unrelated patients with Apert syndrome showed that 45 had the Ser252Trp mutation and 25 had the Pro253Arg mutation. Phenotypic differences between these two groups of patients were investigated. Significant differences were found for severity of syndactyly and presence of cleft palate. The syndactyly was more severe with the Pro253Arg mutation, for both the hands and the feet. In contrast, cleft palate was significantly more common in the Ser252Trp patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. We conclude that, although the phenotype attributable to the two mutations is very similar, there are subtle differences. The opposite trends for severity of syndactyly and cleft palate in relation to the two mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, the ligands for FGFR2.     

A case of symbrachydactyly with oligodactyly

The term symbrachydactyly describes syndactyly accompanied by brachydactyly. Brachydactyly is seen in middle phalanges of both hands and feet and very short in length or absent. As for syndactyly it is a cutaneous type. It has always been observed unilaterally and sporadically. A familial type of this syndrome has also been reported. There have been many classifications of symbrachydactyly. Of these, Blauth classification is the most favored one. Yet these classifications have been inadequate to include many recently discovered other forms of symbrachydactyly. A three month old child was brought to the Istanbul University Genetic Research Center because of his abnormal hands and feet. He was the second child of a couple who had no kinship ties to each other. In the history of the family, there was no mention of any anomaly as such. There was a complete syndactyly involving the 3rd through the 5th fingers, partial syndactyly between the 2nd and 3rd, and the thumb was normal in the right hand. There was only one finger in the left hand. There was total syndactyly in four toes of the right foot with oligodactyly and absence of the big toe. The left foot had five toes with a complete syndactyly between the 2nd and the 3rd. Radiological observation indicated that the middle phalanges of both extremities were rudimentary or never developed. There was no osseous syndactyly. As observed in this case, oligodactylous type that is bilateral and involves both hands and feet together is very unusual. The purpose of this study is to present a rare case of this anomaly that requires a reassessment of symbrachydactyly and its traditional classifications.     

Combined second and third toe transfer

Historically, restoration of hand function following multiple digital amputation has been unsatisfactory. The evolution of digital reconstruction with toe transfer has enabled surgeons to reestablish prehension in these severely injured hands. A 4-year experience with 26 consecutive combined second and third toe transfers to replace missing adjacent fingers was reviewed in order to delineate the indications and technical considerations and to emphasize prevention of donor-site complications. Combined second and third toe transfer is reserved for adjacent finger amputations proximal to the digital web space with remaining fingers no longer than the small finger. Radial amputations are replaced with contralateral combined toe units, while ipsilateral toes are more ideal for ulnar amputations. Limited dorsal and plantar skin flaps extending only to the midpoint of the first and third digital web spaces allow for direct donor-site closure and uncomplicated healing. Maintenance of the plantar metatarsal arch by avoiding metatarsal shaft osteotomies or bone grafting-shortened metatarsals eliminates potential gait disturbances. When properly applied in selected patients, this single-stage microsurgical procedure can restore prehensile function, improve the appearance of the hand with multiple digital amputations, and preserve near-normal donor-foot function.     

Apert syndrome with omphalocele: A case report

Apert syndrome is a genetic disorder known as acrocephalopolysyndactyly type 1 caused by mutations in the fibroblast growth factor receptor 2 and characterized by coronal craniosynostosis, symmetric bone and skin syndactyly of hands and feet, and craniofacial dysmorphic features. The estimated prevalence of this syndrome is 10 to 15.5 cases per 1,000,000 live births. Apert syndrome has considerable clinical variability. We present a case of Apert syndrome and associated features reported to the National Registry of Congenital Anomalies of Argentina (RENAC). The reported case had omphalocele, esophageal atresia, and mega cisterna magna. The last two signs were reported several times as part of the clinical presentation of Apert syndrome. To our knowledge, this is the second reported case diagnosed with Apert syndrome associated with omphalocele. Birth Defects Research (Part A), 100:726–729, 2014. © 2014 Wiley Periodicals, Inc.     

THE COEVOLUTION OF HUMAN HANDS AND FEET

Human hands and feet have longer, more robust first digits, and shorter lateral digits compared to African apes. These similarities are often assumed to be independently evolved adaptations for manipulative activities and bipedalism, respectively. However, hands and feet are serially homologous structures that share virtually identical developmental blueprints, raising the possibility that digital proportions coevolved in human hands and feet because of underlying developmental linkages that increase phenotypic covariation between them. Here we show that phenotypic covariation between serially homologous fingers and toes in Homo and Pan is not only higher than expected, it also causes these digits to evolve along highly parallel trajectories under episodes of simulated directional selection, even when selection pressures push their means in divergent directions. Further, our estimates of the selection pressures required to produce human‐like fingers and toes from an African ape‐like ancestor indicate that selection on the toes was substantially stronger, and likely led to parallel phenotypic changes in the hands. Our data support the hypothesis that human hands and feet coevolved, and suggest that the evolution of long robust big toes and short lateral toes for bipedalism led to changes in hominin fingers that may have facilitated the emergence of stone tool technology.     

Relative lengths of fingers and toes in human males and females

Digital scans of the hands and feet were obtained from 62 heterosexual females and 60 heterosexual males. Scans only of the hands were obtained from 29 homosexual females and 35 homosexual males. The lengths of the individual fingers and toes were estimated from those images by two experienced judges, and length ratios were constructed for all possible pairs of fingers (or toes) on each hand (or foot). Thumbs were not measured, but the great toe was measured and used to construct length ratios. Past research had concentrated on the relative lengths of the index and ring fingers (the 2D:4D ratio). This ratio is close to 1.0 in females and smaller than 1.0 in males. Here 2D:4D did exhibit the largest sex difference, for both hands, followed by 2D:5D and 3D:4D. The sex differences were larger for the right hand than for the left. For both homosexual females and homosexual males, nearly all of the length ratios for fingers were intermediate to those for heterosexual females and heterosexual males; that is, the ratios of homosexual females were masculinized and those of homosexual males were hypomasculinized, but few of these differences were significant. Because many toes were substantially arched, acceptable estimates of length often could not be obtained from the two-dimensional scans, meaning that conclusions about toes are much less certain than those for fingers. Nevertheless, the length ratios were generally larger for toes than for fingers, and the sex differences were generally smaller for toes.     

Apert syndrome with partial preaxial polydactyly.

Acrocephalosyndactyly type I or Apert syndrome is characterized by craniosynostosis, particular dysmorphic features and abnormalities of the hands and feet. Rarely, polydactyly of the toes has been reported, and in this event the diagnosis of Carpenter syndrome must be discussed. A case of atypical Acrocephalosyndactyly type I syndrome with partial preaxial polydactyly is reported. Despite this preaxial polydactyly a diagnosis of Apert syndrome consecutive to a new mutation was made, and the possibility of recurrence considered to be highly improbable.     

De novo alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome.

Apert syndrome, one of five craniosynostosis syndromes caused by allelic mutations of fibroblast growth-factor receptor 2 (FGFR2), is characterized by symmetrical bony syndactyly of the hands and feet. We have analyzed 260 unrelated patients, all but 2 of whom have missense mutations in exon 7, which affect a dipeptide in the linker region between the second and third immunoglobulin-like domains. Hence, the molecular mechanism of Apert syndrome is exquisitely specific. FGFR2 mutations in the remaining two patients are distinct in position and nature. Surprisingly, each patient harbors an Alu-element insertion of approximately 360 bp, in one case just upstream of exon 9 and in the other case within exon 9 itself. The insertions are likely to be pathological, because they have arisen de novo; in both cases this occurred on the paternal chromosome. FGFR2 is present in alternatively spliced isoforms characterized by either the IIIb (exon 8) or IIIc (exon 9) domains (keratinocyte growth-factor receptor [KGFR] and bacterially expressed kinase, respectively), which are differentially expressed in mouse limbs on embryonic day 13. Splicing of exon 9 was examined in RNA extracted from fibroblasts and keratinocytes from one patient with an Alu insertion and two patients with Pfeiffer syndrome who had nucleotide substitutions of the exon 9 acceptor splice site. Ectopic expression of KGFR in the fibroblast lines correlated with the severity of limb abnormalities. This provides the first genetic evidence that signaling through KGFR causes syndactyly in Apert syndrome.     

Analysis of phenotypic features and FGFR2 mutations in Apert syndrome.

A phenotypic and genotypic survey was conducted on 36 Apert syndrome patients. In all but one patient, an FGFR2 mutation, either S252W or P253R, was found in exon IIIa (exon U or 7). The frequency was 71% and 26%, for the mutations S252W and P253R, respectively. These mutations occur in the linker region between immunoglobulin-like domains II and III, which are involved in activation of the receptor by ligand binding and dimerization. The fact that one patient did not have a mutation in the same exon suggests further genetic heterogeneity in Apert syndrome. The frequencies of occurrence or means for measurements of 29 different clinical features (including severity of craniofacial features, syndactyly of the hands and feet, and multisystem involvement) were determined for all patients and for the two subgroups defined by their mutations. Comparison between the subgroups for the different clinical features was performed and suggested no statistically significant differences. These results are not unexpected, because the two common mutations for Apert syndrome alter FGFR2 at adjacent amino acids that are likely to have similar biological, and therefore phenotypic, consequences.     

The Saethre-Chotzen syndrome with partial bifid of the distal phalanges of the great toes

Summary The authors describe three cases of familial acrocephalosyndactyly (ACS) in two boys (9 and 3 years of age) and in their 7.5-year old sister. In addition, irregularities in skull and limbs were found in the 46-year old father as well as in two other children, i.e., two girls, 14 and 4 years of age. The mother (46 years-old) and the remaining four 4 boys (12-, 9-, and 7-years-old), as well as the youngest child, a son, (1-year-old) did not show any deviations.The diagnosis of the Saethre-Chotzen syndrome in six members of one family was based on the finding of a typical skull deformation (oxybrachycephalia), low hairline, flattened nasofrontal angle, lateral deviation of the nasal septum, facial dysmorphy, prolapse of upper eyelids, antomongoloid placement of palpebral fissures, protruding eyes, hypertelorism, dysmorphy of auricles, imperfect hearing, highly arched palate, improper dentition, and characteristic skin syndactyly of hands and feet. In addition, deformed chest, weight and height deficiency, significant mental retardation, as well as, in the boys, true cryptorchidism were found. Radiological examination showed, in all affected members of the family, intensified digitate impressions within the whole fornix of the skull, large and deep sella turcica, underdeveloped frontal bone and upper jaw bone, untypical syndactyly of hands and feet, and the partial bifid of distal phalanges of the great toes, not described previously in the Saethre-Chotzen syndrome. In the differential diagnosis, other forms of ACS, i.e., Apert, Vogt, Pfeiffer, Summitt, and Herrmann-Opitz syndromes, were not found.Manifestation of the described symptoms transferred autosomally, dominantly, and with a similar degree of expression in 6 of 11 members of one family, leads us to think that they are the consequence of a fresh mutation revealed in the father.     

Syndactyly of the toes

The experience gained through the management of 43 patients with syndactyly of the toes is presented. The incidence appears to be similar to that of syndactyly of the fingers. Type 1 syndactyly, or zygodactyly, always presented itself as a cosmetic problem; its correction is occasionally indicated and the procedure used is discussed. Type 2 syndactyly, or polysyndactyly, represents a functional problem and deserves surgical correction. My negative experience with the more complex procedures described for the correction of polysyndactyly is presented as well as my satisfaction with the simpler procedures. Suggestions for management are offered.     

Bartsocas-Papas syndrome with variable expressivity in an Egyptian family

Bartsocas-Papas syndrome (BPS) is an autosomal recessively inherited sublethal popliteal pterygium condition characterized by intrauterine or neonatal death, severe popliteal webbing, oligosyndactyly, ankyloblepharon, orofacial clefts, intraoral filiform bands and genital anomalies. Internal organ involvement has seldom been identified. We report on a 3 years old female patient of healthy first cousin parents with BPS. She presented with orofacial clefting, severe popliteal webs, club feet, oligosyndactyly of the toes, hypogenitalism and normal hands and internal organs. Ankyloblepharon and filiform bands between the alveolar ridges were evident at birth. Pedigree analysis revealed a more severely affected female sib, who died a few minutes after birth with additional manifestations including near complete lip fusion without oral cleft, complete syndactyly in both hands and an omphalocele. Linkage was excluded to the IRF6 gene; a candidate gene implicated in the Van der Woude and popliteal pterygium syndromes, with overlapping features with BPS. To our knowledge, this is the 5th surviving patient with this syndrome in the literature. In this report, we also discuss the proposed pathogenetic mechanisms for BPS and compare our patients with similarly described cases as well as overlapping spectrum of other popliteal pterygium syndromes. Our findings provide further evidence of intrafamilial clinical heterogeneity in families with BPS.     

Minimizing impairment in laborers with finger losses distal to the proximal interphalangeal joint by second toe transfer

Traditionally, toe-to-hand transfers have been reserved for thumb amputations or for use after severe mutilating injuries. The authors report their experience with the use of second toe-for-finger amputations with preserved or reconstructible proximal interphalangeal joints in manual workers. The aim of the procedure was to reduce impairment and to upgrade the hand from a functional and cosmetic standpoint. Fifteen second-toe wrap-around or variations were carried out on 11 adults (18 to 41 years old). Four patients with two or more finger amputations received two sequential second toes; four patients with two finger amputations received one toe; and each of three patients with single-digit amputation received a single toe. All but one amputation were performed less than 3 weeks after the accident. All toes survived. Range of motion at the native proximal interphalangeal joint was more than 90 percent in all patients but one; however, it was minimal at the transplanted joints. Patient satisfaction was high from a cosmetic and functional standpoint. Ten of 11 laborers resumed their previous activity. On the basis of this experience, a classification with aesthetic and functional implications is proposed to help in the decision-making process when dealing with multidigital injuries. It is concluded that second-toe transfer is an excellent choice for finger amputation distal to the proximal interphalangeal joint in laborers. Its prime indication is for amputations of two fingers where at least one toe should be transferred, as required, to achieve an "acceptable hand" (three-fingered hand). Early transfer allows salvage of critical structures from the damaged finger, such as joints, tendons, and bone, that otherwise would be lost. Early transplantation is highly recommended.     

Effects on toes from prenatal exposure to anticonvulsants

BACKGROUND: Changes in the distal phalanges of the fingers, including coned epiphyses and hypoplasia of the phalanges, are recognized teratogenic effects of the anticonvulsant drugs phenytoin and phenobarbital. We hypothesized that the frequency of these changes would also be increased in the toes of children exposed to these drugs in comparison to unexposed children. METHODS: We report on the findings in an analysis of radiographs of the feet of 63 children exposed in utero to either phenytoin alone, phenobarbital alone or both drugs and 56 unexposed comparison children. RESULTS: Only subtle changes were identified. The frequency of coned epiphyses and hypoplasia of phalanges of the toes was the same in both the anticonvulsant and unexposed children. Among the anticonvulsant-exposed children, however, there was a strong association between the presence of coned epiphyses in the feet and in the hands: all five children with coned epiphyses in the hands, as described previously in the same individuals by Lu et al. ([2000] Teratology 61:277-283) had coned epiphyses in their feet (P = 0.0012). Measurements showed a shortening of metatarsals in all three treatment groups, but this was significant only in the phenytoin monotherapy-exposed children. CONCLUSIONS: Subtle changes are present in the phalanges and metatarsals of the feet of anticonvulsant-exposed children, but the overall frequency is much less than occurred in the hands of the same children. We conclude that the presence of either coned epiphyses or hypoplasia of the phalanges of the toes cannot be considered a distinctive feature of the teratogenicity of the anticonvulsant drugs phenytoin and phenobarbital.     

Mohr syndrome in two siblings

The present study reports on two siblings of different sex, affected with a condition corresponding to Mohr syndrome. Characteristic symptoms such as epicanthic folds, a broad and flattened nasal root, a lobulated and hamartomatous tongue, poly- and syndactyly on both hands and feet, doubling of the big toes with less frequent features such as marked psychosomatic retardation and overall hypotony have been observed. All the cited anomalies have been of importance in the differential diagnosis. Difficulties associated with classification of new syndromes and the importance for practical clinical genetics of distinguishing between them are discussed.     

Virus associated papillomas in colobus monkeys (Colobus guereza)

Numerous papillomas ranging in size from 1--10 mm were seen in four colobus monkeys (Colobus guereza). The lesions were confined to the fingers and toes and to the dorsal-lateral aspects of the hands and feet distal to the carpus and tarsus. Electron microscopy of two of the lesions revealed compactly arranged crystalline arrays of intranuclear virus particles in the epidermis. The particles were seen only in cells of the stratum granulosum and stratum corneum. By the negative stain technique, the non-enveloped spherical particles measured 52--58 mm in diameter. The arrangement of the capsomeres was consistent with an icosahedral symmetry. The observations suggested a viral etiology for the cutaneous papillomas similar to that of other mammalian species.     

Simultaneous multiple toe transfers in hand reconstruction

Our experience with simultaneous transfer of two or more toe units to the same hand where multiple digits were missing is presented. Forty-six toes from 38 feet were transferred to reconstruct 19 hands in 19 patients. The transfers consisted of 7 combined second and third toe units and 32 single toes. Three patients had a primary and 16 patients had a secondary reconstruction. There was one complete and one partial failure. The two-point discrimination ranged from 6 mm to protective sensation. Total active movement averaged 57 degrees in the thumb and 127, 93, 71, and 68 degrees, respectively, in the fingers reconstructed at middle phalanx, proximal phalanx, metacarpophalangeal joint, and metacarpal head. Pulp-to-pulp pinch averaged 2.4 kg in patients who had thumbs reconstructed and averaged 3.0 kg in patients who had normal thumbs. There was no cold intolerance, and no significantly disabled foot occurred except one with scissoring deformity. Simultaneous multiple toe transfer in hand reconstruction is feasible without increased complications both in primary and secondary wound conditions. It is time-effective and cost-effective.     

Sixty-four cases of thumb and finger reconstruction using transplantation of the big toe skin-nail flap combined with the second toe or the second and third toes

The purpose of this article is to introduce the results of thumb and finger reconstruction using transplantation of the big toe wraparound flap combined with the second toe or the second and third toes. Between August of 1981 and December of 1998, in a series of 64 cases involving 58 patients with digitless hands, either (1) the thumb and index fingers were reconstructed by transplantation of a big toe wraparound flap combined with the adjacent second toe harvested from the ipsilateral foot; or (2) the thumb, index, and long fingers were reconstructed by transplantation of an ipsilateral big toe wraparound flap combined with the adjacent second and third toes. The phalanx of the new thumb was usually an iliac block. The success rate of this series was 92.2 percent. At long-term follow-up, the average static 2-point discrimination was less than 10 mm. The distance between the tip of the new thumb and the new index finger ranged from 6 to 10 cm (average, 8 cm). Opposition action was nimble and forceful. The patients could lift a 6- to 12-kg weight with their reconstructed digits. All patients were satisfied with their new hands and were able to use them in their daily activities. The transplants for reconstructing the thumb and fingers are harvested from the same foot in a procedure known as one-foot donation. Function of the bilateral digitless hand can be recovered with this procedure.