Nonsyndromic brachydactyly type D and type E mapped to 7p15 in healthy children and adults from the Jirel ethnic group in eastern Nepal.

OBJECTIVES: There is phenotypic overlap between Brachydactyly Type D (BDD) and Brachydactyly Type E (BDE) that suggests a possible common underlying etiology. We seek to understand the genetic underpinnings of, and relationship between, these skeletal anomalies. METHODS: The Jirel ethnic group of eastern Nepal participates in various genetic epidemiologic studies, including those in which hand-wrist radiographs have been taken to examine skeletal development. Nearly 2,130 individuals (969 males; 1,161 females) were phenotyped for BDD/BDE. Of these, 1,722 individuals (773 males; 949 females) were genotyped for 371 STR markers spanning the autosomal genome. Variance components-based linkage analysis was used to conduct a genome-wide linkage scan for QTL influencing the BDD/BDE phenotype. RESULTS: BDD was present in 3.55%, and BDE was present in 0.39%, of the study sample. Because of the phenotypic overlap between two traits, affecteds of either type were considered as affected by a single combined phenotype (BDD/BDE) having a prevalence of 3.94%. The additive genetic heritability of BDD/BDE was highly significant (h(2) ± SE = 0.89 ± 0.13; P = 1.7 × 10(-11) ). Significant linkage of BDD/BDE was found to markers on chromosome 7p21-7p14 (peak LOD score = 3.74 at 7p15 between markers D7S493 and D7S516). CONCLUSIONS: Possible positional candidate genes in the one-lod support interval of this QTL include TWIST and the HOXA1-A13 cluster. This is the first study to report significant linkage results for BDD/BDE using a large extended pedigree, and the first to suggest that mutations in TWIST and/or the HOXA1-A13 cluster may contribute to these specific skeletal anomalies.

Does brachydactyly have a protective effect on the erosive changes in rheumatoid arthritis?

OBJECTIVE: Brachydactyly (BD) is a general term for inappropriately short fingers and/or toes. The author previously reported that a short metacarpal bone had a protective effect on the metacarpophalangeal joint of the same finger in rheumatoid arthritis (RA). The objective was to investigate the prevalence of BD in patients with RA and its potential effect on the phenotype, especially erosive changes. METHODS: A total of 1524 Korean patients with RA were recruited. The presence of BD on hand radiographs, rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (anti-CCP), HLA-DRB1 shared epitopes (SE), risk haplotypes of peptidyl deiminase type IV (PADI4) and erosive joint stage, and smoking status, were determined. RESULTS: The prevalence of BD was 7.9% (n=120) in our RA cohort. The types of BD were type A3 (79.2%), type D (15.0%), Kirner deformity (14.2%), and type E (6.7%). RA patients with BD had reduced erosion on hand radiographs (OR=0.57, 95% CI: 0.34-0.95, p=0.029) adjusted for age, sex, disease duration, smoking, RF, anti-CCP, SE, and PADI4. CONCLUSION: BD is more common in RA patients than might be expected. BD may have a protective effect on erosive changes in RA independent of previously well-established risk factors such as seropositivity, SE, PADI4, and smoking.

Unilateral congenital terminal finger absences: a condition that differs from symbrachydactyly.

PURPOSE: To describe a type of nonhereditary unilateral transverse deficiency, which we have named hypodactyly, that is distinct from symbrachydactyly or amniotic disruption sequence. METHODS: We identified 19 patients with unilateral congenital anomalies consisting of absent or short bulbous fingers that lack terminal ectodermal elements. Medical records and radiographs were retrospectively reviewed and contrasted with the typical findings of symbrachydactyly and amniotic disruption sequence. RESULTS: No associated syndromes or potentially causative diagnoses were identified in the hypodactyly patients. The digital absences were of a truncated pattern with thickened, tubular soft tissue coverage. Radiographs revealed a pattern of severity progression that is different from that of symbrachydactyly. Distal phalanges were the bony elements absent most frequently, followed sequentially by the middle phalanx and proximal phalanx. In all cases, metacarpals were present. Unlike symbrachydactyly, the ulnar 2 digits were more involved than the index and long fingers, and the thumb was the least involved digit. CONCLUSIONS: Hypodactyly appears to be a congenital hand anomaly that is clinically and radiographically different from symbrachydactyly or amniotic disruption sequence and is presumed to be caused by a distinct pathomechanism. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Evaluation of qualitative methods for phenotyping brachymesophalangia-V from radiographs of children.

OBJECTIVE: Brachymesophalangia-V (BMP-V), the general term for a short and broad middle phalanx of the 5th digit, presents both alone and in a large number of complex brachydactylies and developmental disorders. Past anthropological and epidemiological studies of growth and development have examined the prevalence of BMP-V because small developmental disorders may signal more complex disruptions of skeletal growth and development. Historically, however, consensus on qualitative phenotype methodology has not been established. In large-scale, non-clinical studies such as the Fels Longitudinal Study and the Jiri Growth Study, quantitative assessment of the hand is not always the most efficient manner of screening for skeletal dysmorphologies. The current study evaluates qualitative phenotyping techniques for BMP-V used in past anthropological studies of growth and development to establish a useful and reliable screening method for large study samples. METHODS: A total of 1,360 radiographs from Jiri Growth Study participants aged 3-18 years were evaluated. BMP-V was assessed using three methods: (1) subjective evaluation of length and width of the bone; (2) comparison with skeletal age-matched radiographs; and (3) subjective evaluation of the length of the middle 4th and 5th phalanges. RESULTS: We found that the method that uses skeletal age-matched reference radiographs is the better tool for assessing BMP-V because it considers the shape, rather than solely the length and width of the bone, which can be difficult to judge accurately without measurement. This study highlights the complexity of phenotypic assessment of BMP-V and by extension other brachydactylies.