Radial Ray Deficiency Research Articles

The Classification of VACTERL Association into 3 Groups According to the Limb Defect.

Summary:The VACTERL association (VA) is defined as the nonrandom co-occurrence of 6 anomalies: vertebral anomalies (V), Anal atresia (A), Cardiac defects (C), Tracheo-esophageal fistula (TE), Renal defects (R), and Limb anomalies (L). The current communication presents an argument that patients with VA should be classified into three district groups based on their limb defects: VACTERL1: patients with normal limbs; VACTERL2: patients with limb anomalies other than radial ray defects of the upper limbs; and VACTERL3: patients with radial ray defects of the upper limbs. The author will demonstrate that the rationale behind the L1-3 classification in patients in VA is based on the embryogenesis of the 6 affected anatomical areas in VA. The pathogenesis of VACTERL1 is secondary to perturbations of Sonic Hedgehog (SHH) interactions. SHH signaling is known to have a major role in the normal development of the vertebrae, ano-rectal area, heart, tracheo-esophageal area, and kidney. However, SHH is not involved in the development of the radial ray; hence, patients present with no limb defects. The pathogenesis of VACTERL2 is variable depending on the type of gene mutation. The pathogenesis of VACTERL3 is related to errors in a group of proteins (namely, the proteins of the TBX5-SALL4-SALL1 loop and the FGF8-FGF10 loop/ pathway). These proteins are essential for the normal development of the radial ray and they interact in the development of the other anatomical areas of VA including the heart and kidney. Hence, VACTERL3 patients present with radial ray deficiency.

Prevalence and risk factors of radial ray deficiencies: A population-based case-control study.

Radial ray deficiency is the most common congenital deficiency of the upper limb. The aim of our study was to investigate maternal risk factors for radial ray deficiencies. We conducted a nationwide population-based case-control study using national registers. All cases with a radial ray deficiency born between 1996 and 2008 were included in the study and compared with five controls without limb deficiency. In total, 115 (10 isolated, 18 with multiple congenital anomalies, and 87 syndromic) cases with radial ray deficiencies were identified and compared with 575 matched controls. The total prevalence in Finland was 1.22 per 10,000 births. No significant risk factors were observed for nonsyndromic cases. In the syndromic group, advanced maternal age (≥35 years) increased the risk of radial aplasia (aOR 2.45, 95% CI 1.37-4.36), and a similar association was observed with multiple pregnancy (aOR 2.97, 1.16-7.62) and male sex (aOR 1.96, 1.18-3.25). Valproic acid was also a risk factor (p = .002). In conclusion, novel associations in the syndromic group of advanced maternal age and multiple pregnancy and increased risk of radial ray deficiencies were observed. Also, early reports on increased risk of RRD associated with valproate and male sex were supported by our results.

Bilateral Radial Club Hands at the Komfo Anokye Teaching Hospital, Kumasi, Ghana: A Case Report.

Radial Club Hand (RCH) is a rare and complex congenital disorder of the pre-axial border of the upper extremity. It is a congenital longitudinal radial ray deficiency which presents as radial deviation of the hand and distal forearm in the shape of a golf club 1, 2. Radial ray deficiency (the most common type of longitudinal failure of formation) is a spectrum of malformations affecting the structures of the radial side of the forearm, including hypoplasia of the bones, joints, muscles, tendons, ligaments, nerves and blood vessels. The thumb dysfunction, wrist instability and short upper extremity that accompany this condition can cause significant functional impairment particularly in patients with bilateral involvement. Thus, the performance of activities of daily living such as accomplishing personal hygiene, fastening buttons and zippers becomes challenging 3.

The Pathogenesis of Radial Ray Deficiency in Thrombocytopenia-Absent Radius (TAR) Syndrome.

The genetic basis of thrombocytopenia-absent radius (TAR) syndrome was recently identified to be related to the RBM8A gene. The encoded protein (known as the Y14 protein) is widely expressed in human cells (including osteoblasts) and plays several essential intracellular functions. Hence, the pathogenesis of radial ray deficiency in thrombocytopeniaabsent radius syndrome remains a mystery. The current paper reviews the pathogenesis of the clinical features of thrombocytopenia-absent radius syndrome and offers a hypothesis of pathogenesis through attenuation of the Fibroblast Growth Factor 8 signal in the mesoderm because of an increased degradation of the Fibroblast Growth Factor Receptor 1.

Genetic heterogeneity in type III familial cutaneous syndactyly and linkage to chromosome 7q36

The ZRS (zone of polarizing activity regulatory sequence) is a long-range limb-specific Sonic Hedgehog (SHH) enhancer. In humans, the ZRS is located in chromosome 7q36 within intron 5 of LMBR1; approximately 1 Mb telomeric of SHH. Point mutations and duplications of the ZRS lead to a variable phenotype of preaxial polydactyly/triphalangeal thumb, tibial hypoplasia, radial ray deficiency, and type IV familial syndactyly (syndactyly of all digits with polydactyly). The ZRS is conserved among mammals and fish and regulates the expression of SHH. In mice, the conserved ZRS within the Lmbr1 gene is found in chromosome 5. The Hammertoe (Hm) mouse mutants have a mutation in the Lmbr1 locus and show syndactyly of digits 2-5 without polydactyly. No previous reports have described isolated syndactyly without polydactyly to be related to the LMBR1 locus in humans. In this report, we describe a family with simple cutaneous syndactyly involving digits 2-5, without polydactyly which is consistent with the phenotype of type III syndactyly. The locus we identified on ch7q36.3 is syntenic to the Hm locus; and affected members of the family had a phenotype analogous to Hm. Hence, the type of syndactyly described in the current report may be equivalent to Hm mice.

The Ubiquitin/SUMO Pathway and Radial Ray Deficiency Syndromes

Protein regulation is the function of several pathways and enzyme systems in the human body. One of these pathways is the ubiquitin/SUMO pathway. The author has noted that almost all known syndromes of radial ray deficiency are related to this pathway. In this article, these syndromes are reviewed with special attention to their relationship with the ubiquitin/SUMO pathway. This opens a new insight into the pathogenesis of radial ray deficiency syndromes.

Characteristics and associated anomalies in radial ray deficiencies in Finland—A population‐based study

Upper-limb defects with deficiencies of the radial ray have varying etiologies, with a low proportion of true Mendelian disorders. We carried out a population-based study to elucidate the birth prevalence and clinical spectrum of radial ray deficiencies in Finland. We identified all births with radial ray deficiency reported to the Finnish Register of Congenital Malformations in 1993-2005. Altogether 138 cases were identified (123 live births), with a birth prevalence of 1.83 per 10,000 births and a live birth prevalence of 1.64 per 10,000 live births. The proportion of infant deaths was as high as 35%. The majority of the cases were associated with known syndromes or multiple anomalies; only 13% were true isolated radial ray deficiencies. The most common syndrome was trisomy 18, and the most common in multiple anomalies was VACTERL association. In 8.7% of cases an association between radial ray deficiency and heart anomaly was observed. The high proportion of cases with associated major anomalies indicates that radial ray deficiency can be regarded isolated only after thorough assessment of the various organ systems in an affected infant.

Complex genetics of radial ray deficiencies: screening of a cohort of 54 patients

Radial ray deficiencies are characterized by unilateral or bilateral absence of varying portions of the radius and thumb. Both isolated and syndromic forms have been described, and although for some of the syndromes the causal gene has been identified, many patients remain without a genetic diagnosis. In this study, a cohort of 54 patients with radial ray deficiencies was screened for genomic aberrations by molecular karyotyping. In 8 of 54 cases, an aberration was detected. Two unrelated patients inherited a 1q21.1 microduplication from a healthy parent, whereas in a third patient, a 16p13.11 microduplication was identified. Two other interesting microdeletions were detected: a 10q24.3 deletion at the split hand-foot malformation (SHFM3) locus and a 7p22.1 deletion including the RAC1 gene. The finding of these microduplications may just be coincidental or, alternatively, they may illustrate the broad phenotypic spectrum of these microduplications. Duplications in the 10q24.3 region result in split hand-foot malformations, and our observation indicates that deletions may cause radial ray defects. Finally, a candidate gene for radial ray deficiencies was detected in the 7p22.1 deletion. RAC1 plays an important role in the canonical Wnt pathway and conditional RAC1 knockout mice exhibit truncated-limb defects.

A novel mutation in the SHH long‐range regulator (ZRS) is associated with preaxial polydactyly, triphalangeal thumb, and severe radial ray deficiency

Sonic Hedgehog (SHH) within the posteriorly located zone of polarizing activity is the main controller of the antero-posterior axis of limb development. The ZRS (zone of polarizing activity regulatory sequence) is a long-range limb-specific SHH enhancer. Several point mutations in the ZRS have been described in humans. These mutations cause enhanced SHH activity and ectopic anterior expression of SHH and a variable phenotype of preaxial polydactyly and triphalangeal thumb. Absent thumb or radius has not been reported with ZRS mutations. Here, we report on a family with a variable phenotype of preaxial polydactyly as well as absent thumb and radius, with kidney and cardiac defects. The family was screened for SALL1, SALL4, and TBX5 mutations, but all were normal. Finally, they were screened for ZRS mutations, which showed a novel point mutation within the ZRS, NG_009240.1: g.106954C>T (traditional nomenclature: ZRS619C>T) in the five affected members. This mutation was not previously reported in any public domain database, and was not found in our healthy and ethnically matched control individuals or unaffected family members. We hypothesize that interactions of SHH and SALL1 explain the overlapping features of the family described here and patients with Townes-Brocks syndrome.

Treatment for Nonunion after Derotational Osteotomy of the Radius Using Vascularized Bone Graft in a Patient with Radial Ray Deficiency

Treatment for Nonunion after Derotational Osteotomy of the Radius Using Vascularized Bone Graft in a Patient with Radial Ray Deficiency

Congenital Upper Limb Deficiencies and Associated Malformations in Finland: A Population-Based Study

To calculate the national incidence of upper limb deficiencies and associated infant mortality in children in Finland using the International Federation of Societies for Surgery of the Hand (IFSSH) classification. Radial ray deficiency, ulnar ray deficiency, central ray deficiency, transverse arrest, phocomelia, undergrowth, and constriction band syndrome with skeletal defects were evaluated. We reviewed upper limb deficiencies among all 753,342 births in Finland during 1993 to 2005 reported to the Finnish Register of Congenital Malformations. Classification of these upper limb deficiencies was done according to a modified IFSSH system. We calculated incidence, gender and side distributions, frequency of associated anomalies, and infant mortality rates in different subtypes of the deficiencies. Familial occurrence of congenital upper limb defects was recorded. A total of 419 cases (234 male, 185 female) of upper limb deficiencies were identified. The national incidence of upper limb deficiencies was 5.56 per 10,000 births and 5.25 per 10,000 live births. The most common upper limb abnormality was radial ray deficiency (138), followed by subgroups of undergrowth (91), upper limb defects due to constriction band syndrome (51), central ray deficiency (41), and ulnar ray deficiency (33). Perinatal mortality was 14%. Infant mortality among children with upper limb deficiencies was 137 per 1,000 live births, compared with an overall infant mortality of 3.7 per 1,000 live births in Finland. Additional birth defects were found in 60% of these children. Prevalence of upper limb defects in relatives of the census population was 2% (11 of 419). The national incidence of upper limb deficiencies is 5.25 per 10,000 live births. Congenital upper limb deficiencies are associated with additional birth defects in two thirds of cases. These children, especially children with radial ray deficiency, have a high perinatal mortality rate. When divided into subgroups using IFSSH classification, differences emerge in both associated anomalies and mortality.

An Autopsy Case of Klippel‐Feil Syndrome with Cardiovascular Anomalies and Upper Limb Anomaly

Abstract An autopsy case of Klippel‐Feil syndrome with the classical triad of short neck, low posterior hairline and limitation of neck movement is reported. The patient died of cardiac failure resulting from complicated serious cardiovascular anomalies such as double outlet right ventricle, congenital mitral valve stenosis and coarctation of aorta. The condition was also complicated by radial ray deficiency of the left arm and asymmetry of the thyroid gland. Narrowing of the left subclavian and axillary arteries was detected by angiography while the patient was alive, a finding which may suggest the etiology of this congenital anomaly complex.

Experimental study of radial ray deficiency

The teratogenic mechanisms of radial ray deficiency were investigated. Radial ray deficiencies were induced in WKAH/Hkm rat foetuses by maternal administration of myleran on day 10, 10.5, or 11 of pregnancy. The skeletal anomalies in rats were similar to those in human beings, suggesting that exposure to some environmental factors at a sensitive period of embryogenesis may cause radial ray deficiency in humans. Ulnar ray deficiency has also been induced in rat foetuses by maternal administration of myleran, so it is suggested that radial deficiency and ulnar deficiency are caused by a common teratogenic mechanism in humans. However, the critical period for radial deficiency is one day later than that for ulnar deficiency in rats, which may contribute to the greater frequency of radial deficiency than ulnar deficiency in clinical cases.

Congenital hand anomalies in Japan: A family study

During the 20-year period from 1968 to 1987, 1024 patients with congenital anomalies of the hand from 1000 Japanese families were examined in our clinic. Of these patients, 204 had relatives with limb anomalies. While postaxial polydactyly showed a 33% level of familial recurrence, symphalangism and Kirner's syndrome showed about 23% recurrence, syndactyly 18%, radioulnar synostosis 9%, radial ray deficiency 8%, cleft hand 7%, and duplicated thumb 5%. None of the relatives had ulnar deficiency or symbrachydactyly.

TERATOGENIC MECHANISM OF DRUG-INDUCED ANOMALIES OF EXTREMITIES IN RATS

In order to clarify the teratogenic mechanism of oligodactyly, we have carried out some experimental studies in rats. In this paper we report the results and discuss the teratogenic mechanism of the anomalies of the extremities. 1. Ulnar ray deficiency, cleft hand, central ray polydactyly, and central ray syndactyly were induced in W: Gun rats, and radial ray deficiency was induced only in W KAH/H km rats. The features of these anomalies in rats were the same as in humans. The critical periods of ulnar ray deficiency and radial ray deficiency seemed to be earlier than those of central polydactyly, syndactyly, and cleft hand. The critical period of cleft hand was identical to those of central polydactyly and central syndactyly, and advanced cases of central polydactyly or syndactyly in which the fusion area extended as far as the proximal phalanx and metacarpus, became identical to the cleft hand. These findings suggest that radial and ulnar ray deficiencies belong to longitudinal ray deficiency, and the central polydactyly, syndactyly, and cleft hand might be formed by the same teratogenic mechanism, that is, failure of separation of finger ray. 2. DNA synthesis and cell condensation in the developing hand plate of normal and preaxial oligodactylic rats treated with myleran on the day of 12.0th gestation were examined using a BrdU/anti-BrdU immunohistochemical study. DAN-synthesizing cells were distributed uniformly in the mesenchyme of the hand on day 12.0 in normal rat embryos. From day 13.0. these cells were distributed in the interdigital mesenchymal areas, leaving rare labeled cells in the sites of cell condensation. When the labeled mesenchymal cells were followed from day 12.0 until day 14.0, they were found to be concentrated in the digital rays. We concluded that cell migration rather than cell proliferation in the digital-ray area could be an initial step in digital-ray formation. In the oligodactylic hand plate, mesenchymal cell condensation was delayed and preaxial digital rays were not formed. On day 13.0 the number of DNA-synthesizing cells was much less than normal in all areas of the hand plate, and cell necrosis of the epidermis and mesenchyme near the epidermis was prominent. On day 14.0, DNA-synthesizing cells decreased in the epidermis rather than in the mesenchyme. From these results, we conclude that the mechanism of this oligodactyly could involve a mesenchymal cell deficit and restriction of migration.

Radial Ray Deficiency

We reviewed thirty-seven hands of 26 patients with radial ray deficiency. Twelve patients (46%) had associated anomalies in extremities and/or other systems. Following Blauth's method, we classified patients into five groups. There was a positive correlation between the severity of the dysplasia of the thumb and the radius. Twelve hands of 10 patients were surgically treated. The mean follow-up time was 45 months. Only six hands had satisfactory cosmesis and function after surgery. We discuss the difficulty of treatment for severe cases.

Ｈｏｌｔ‐Ｏｒａｍ症候群の８例

The autosomal dominant upper extremity skeletal defects with congenital heart disease is known as the Holt-Oram syndrome. From 1964 to 1984, we have experienced 8 cases of the Holt-Oram syndrome among 100 cases of radial ray deficiencies in our hospital. We reviewed these 8 cases and discussed the mechanism of combination of congenital heart disease and upper extremity skeletal defects. We, as orthopedic surgeons, emphasize the importance of paying attention to the congenital heart disease when we treat the upper extremity skeletal defects.

A clinical study of congenital anomalies of the hand

The author has studied the clinical features of split hand, syndactyly, radial and ulnar ray deficiency, and brachydactyly. Many clinical findings make clear that typical split and is not a result of failure of formation but a result of union of digital rays. If we would try to classify congenital anomalies of the hand on the basis of embryological failure, syndactyly and split hand, and webbed and web free brachydactyly are never classified into other categories, just as constriction band syndrome is not divided by the presence of union of the digital rays.