The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals.

Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non-inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1-inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti-inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct "lip" overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected children often receive unnecessary anti-inflammatory and immunosuppressive treatments. Increasing awareness of PPRD appears to be essential to allow for a timely diagnosis.

Orthopaedic manifestations of Navajo familial neurogenic arthropathy.

BACKGROUND: Navajo Familial Neurogenic Arthropathy is a disease identified in Navajo children, primarily residing in Arizona, New Mexico, and Utah. To date, there are no reports in the orthopaedic literature regarding this disorder, particularly the clinical manifestations and treatment considerations. METHODS: We carried out a retrospective chart and radiographic review of 2 patients with Navajo familial neurogenic arthropathy. We present these 2 patients as representative of the orthopaedic manifestations of Navajo familial neurogenic arthropathy. RESULTS: Both patients have significant axial and appendicular bone abnormalities, Charcot-type arthopathy, heat intolerance and also anhidrosis. They have normal intelligence. Both patients underwent surgical interventions, with recurrent deformity and infection being the most common complications. CONCLUSIONS: Navajo familial neurogenic arthropathy is a rare clinical entity, seen most commonly in the southwestern regions of the United States. Patients are found to have a myriad of orthopaedic abnormalities, and surgical intervention, while sometimes indicated, can be fraught with complications. LEVEL OF EVIDENCE: Level IV, case series.

Charcot foot in a Hong Kong Chinese diabetic population.

OBJECTIVES: To delineate the epidemiology of Charcot foot in Hong Kong Chinese diabetic patients, and to provide baseline data for benchmarking the clinic service for this special group of patients. DESIGN: Retrospective cohort study. SETTING: Regional hospital, Hong Kong. PATIENTS: Diabetic patients with Charcot foot and age- and sex-matched diabetic foot clinic attendees between 1995 and 2007. MAIN OUTCOME MEASURES: Clinical presentations were compared in patients with Charcot foot and the controls. RESULTS: Twenty-five patients were diagnosed with Charcot foot over 12 years; 60% were male. At the time of diagnosis, the mean age was 59 (standard deviation, 14; range, 38-85) years, with diabetes being diagnosed for a mean of 11 (standard deviation, 8; range, 0-30) years. Retinopathy was noted in 36% (n=9) and nephropathy in 20% (n=5) of the Charcot foot patients. No patient had peripheral vascular disease. This finding was statistically significant. Delayed presentation occurred in 11 patients. Presentation was usually unilateral. In the minority (n=3, 12%) with bilateral involvement, presentation was sequential. Charcot arthropathy affected the mid-foot in 64% of the patients. Superimposed infection was common (61%). Recurrent ulceration occurred in 11%, all of whom presented late. Only one patient underwent major amputation, but the 5-year mortality of Charcot foot patients could be up to 33%. CONCLUSION: Charcot foot was uncommon in this population. Late presentation was common and might be related to superimposed infection; such patients were prone to recurrent ulcers.

Mortality in Asian Indians with Charcot's neuroarthropathy: a nested cohort prospective study.

AIMS: We studied mortality in individuals of diabetes with or without Charcot neuroarthropathy (CN). METHODS: People attending diabetic foot care facility with CN of foot (Cohort 1) were prospectively evaluated. Details pertaining to the duration of diabetes, microvascular and macrovascular complications, foot ulcer, amputation and mortality outcomes were recorded and compared with those without foot complications (Cohort 2) by multivariate logistic regression. RESULTS: Data for 260 individuals of diabetes with CN and 520 individuals without CN were analysed. Mean age at presentation with CN was 55.8 ± 9.1 years, and duration of diabetes was 12.9 ± 7.8 years. 39.8% individuals with CN had foot ulcer, and 15.3% had amputation. People with CN were younger (55 ± 9.1 vs. 59.9 ± 8.1 years, p < 0.001) and had higher prevalence of microvascular complications. A total of 39 (15%) individuals with CN and 50 (9.8%) (p = 0.03) individuals without CN died during median follow-up of 40(24-51) months. People with CN had 2.7 times (OR 2.72, 95% CI 1.4-5.2, p = 0.003) increased mortality risk when matched for potential confounders. Prevalent CAD and low eGFR predicted higher mortality in people with CN. CONCLUSIONS: People with Charcot neuroarthropathy have almost three times increased risk of mortality despite being younger at presentation.

RANKL Gene Polymorphism as a Potential Biomarker to Identify Acute Charcot Foot Among Indian Population With Type 2 Diabetes: A Preliminary Report.

Studies addressing the link between gene polymorphism and Charcot neuropathic osteoarthopathy (CN) have been limited to analyse osteoprotegerin gene. Aim is to understand the association of RANKL gene variants on the susceptibility of diabetic neuropathy and CN and to measure the serum levels of sRANKL among Indian population with type 2 diabetes. 77 subjects (48 males: 29 females) were recruited and divided into 3 groups. Group 1 Control: normal glucose tolerance (NGT). Group 2: Type 2 diabetes mellitus and neuropathy (DPN). Group 3: Established type 2 diabetes mellitus, DPN, and CN. Subjects were genotyped for RANKL SNP 693 C/G and 643 C/T using polymerase chain reaction-restriction fragment length polymorphism. sRANKL levels were measured using ELISA (enzyme-linked immunosorbent assay). The serum levels of sRANKL were significantly different between the 3 groups. In RANKL -643 C/T the frequency of "CT" genotype and the minor allele "T" was greater among the DPN and CN group compared with the NGT. Further statistical analysis found a significant difference in genotypic frequencies between DPN and NGT subjects with CT genotype. In RANK L -693 C/G the frequency of homozygote mutant "GG" and the minor allele "G" was greater among the DPN and CN group compared with the NGT. Significant differences in genomic frequencies were observed among "GG" genotype. RANKL -643 C/T was significantly associated with DPN alone while -693 C/G was significantly associated with both DPN and CN. Thus, the study suggests RANKL polymorphism might be considered as an independent risk factor for the development of CN.

Aspectos epidemiológicos das lesões no pé e tornozelo do paciente diabético / Epidemiological aspects of foot and ankle injury in the diabetic patient

OBJETIVO: Identificar o perfil epidemiológico dos pacientes que procuram tratamento ortopédico das complicações nos pés e tornozelos relacionadas ao diabetes, além de correlacionar à sequência de eventos que culminam na amputação da extremidade. MÉTODO: analisamos os dados de prontuário de 300 pacientes no período compreendido entre março de 1997 a julho de 2006. RESULTADOS: A média de idade foi 61 anos, destes, duzentos e setenta e três pacientes (91 por cento) apresentavam diagnóstico de diabetes do tipo II, onde somente 49 (16,3 por cento) faziam controle regular da glicemia. Quatrocentos e cinco extremidades apresentavam problemas afetando a função do pé ou tornozelo, detacando-se: 102 extremidades (34 por cento) com lesões osteoarticulares relacionadas a neuroartropatia de Charcot; 181 extremidades (60,4 por cento) com ulceração crônica e 97 extremidades (32,4 por cento) com infecção. Após tempo médio de seguimento 14 pacientes (4,6 por cento) foram a óbito. CONCLUSÃO: A ulceração na planta dos pés foi a complicação mais frequente na nossa série de pacientes que, estavam na sétima década de vida, apresentavam diabetes do tipo II, faziam uso irregular de insulina e não realizavam controle adequado da glicemia. A perda da sensibilidade protetora nos pés, em associação com deformidade pré-existente, foi identificada como a principal causa das infecções secundárias culminando com a amputação da extremidade.

OBJECTIVE: To identify the epidemiological profile of patients undergoing orthopedic treatment for complications of the feet and ankles due to diabetes, and to try to establish the sequence of events that led to amputation of the limb. METHOD: The medical records of 300 diabetic patients treated from March, 1997 to July, 2006 were systematically reviewed. RESULTS: The mean age of the patients was 61 years. Of these, two hundred and seventy three (91 percent) were diagnosed with type II diabetes, but only 49 (16.3 percent) had proper medical supervision and control of their glycemia levels. Problems affecting the function of the foot and ankle were found in 405 limbs, with: 102 osteoarticular deformities associated with Charcot's neuroarthropathy (34 percent); 181 chronic ulcers (60.4 percent); and 97 infected limbs (32.4 percent). After the average follow-up time, 14 patients (4.6 percent) died. CONCLUSION: Ulceration of the sole of the foot was the most common complication in our series of patients, the majority of whom were in their seventies, presented type II diabetes, were insulin dependent, and did not have adequate control of glycemia. Loss of sensitivity of the foot, associated with pre-existing deformities, were identified as the main causes of secondary infections culminating in amputation of the limb.