Clinical course and factors associated with progressive acro-osteolysis in early systemic sclerosis: a retrospective cohort study.

To examine clinical course of early systemic sclerosis (SSc) and identify factors for progression of acro-osteolysis by a retrospective cohort study. Dual time-point hand radiography was performed at median interval (range 3.0 ± 0.4 years) in 64 recruited patients. Progressive acro-osteolysis was defined as the worsening of severity of acro-osteolysis according to rating scale (normal, mild, moderate, and severe). Incidence of the progression was determined. Cox regression was analyzed for the predictors. A total of 193.6 per 100 person-years, 19/64 patients had progressive acro-osteolysis with incidence of 9.8 per 100-person-years (95% CI 6.3-15.4). The median time of progressive acro-osteolysis was 3.5 years. Rate of progression increased from 1st to 3rd years follow-up with the progression rate at 1-, 2- and 3-years were 0, 2.0 and 18.3%, respectively. Patients with positive anti-topoisomerase I tended to have more progressive acro-osteolysis but no significant predictors on Cox regression. 44%, 18%, and 33% of who had no, mild, and moderate acro-osteolysis previously developed progression and 10 turned to be severe acro-osteolysis. In conclusion, the incidence of progressive acro-osteolysis was uncommon in early SSc but the rate of progression was pronouncedly increasing after three years follow-up. A half of the patients progressed to severe acro-osteolysis.

Acroosteolysis and facial dysmorphia: a new case of Hajdu-Cheney syndrome.

Hajdu-Cheney syndrome or acro-dento-osteo-dysplasia syndrome is a rare disease characterized by band osteolysis of distal phalanges and facial dysmorphia, among other manifestations. We present the case of a 45-year-old male who consulted for mechanical joint pain of both hands, facial dysmorphism, cranio-facial alterations, and digital telescoping with acroosteolysis.

Acro-osteolysis: imaging, differential diagnosis, and disposition review.

Acro-osteolysis is the osseous destruction of the hand or foot distal phalanges. The categories of the disease include terminal tuft, midshaft, or mixed types. Recognition of acro-osteolysis is straightforward on radiographs, but providing an accurate differential diagnosis and appropriately recommending advanced imaging or invasive tissue diagnosis can be more elusive. A radiologist's ability to provide advanced assessment can greatly aid clinicians in expedient diagnosis and management of the array of diseases presenting with acro-osteolysis.

Is an association of acro-osteolysis, bone fragility, and enchondromatosis a newfound disease caused by an amplification of PTHLH? A case report.

BACKGROUND: Acro-osteolysis (AO) refers to resorption of the distal finger and toe phalanges. It displays two patterns: (i) diffuse AO and (ii) transverse or bandlike AO. AO can be a sign of local distress (e.g. of toxic origin), but is very often a sign of a constitutional or systemic acquired disorder. CASE PRESENTATION: A 15-year-old girl was referred to a paediatric rheumatologist for recurrent pain in her fingertips. She presented a particular cross-sectional AO associated with the presence of intraosseous cysts and bone fragility with atypical fractures. Initial laboratory tests and radiological examination did not allow an etiological diagnosis. Genetic studies revealed a 12p11.22-p11.23 microduplication of 900 kb including the PTHLH (parathyroid hormone-like hormone) gene, which encodes for a hormone involved in the regulation of endochondral ossification and differentiation of chondrocytes, via its PTHLH receptor. CONCLUSIONS: To date, 12p11.22-p11.23 duplications have been reported in five families with skeletal abnormalities, and in particular AO and enchondromatosis associated with bone fragility. This new observation, added to the other reported cases, suggests a close relationship between the presence of this microduplication and the skeletal abnormalities found in the patient. We suggest the descriptive name ABES (acro-osteolysis, bone fragility and enchondromatosis syndrome) to designate this disorder.

Hajdu-Cheney Syndrome: A Report on Successful Halting of Acro-osteolysis.

CASE: The phenomenon of acro-osteolysis often intrigues clinicians and patients alike, as it causes bone resorption. One such condition is Hajdu-Cheney syndrome. We report our experience in identifying and halting the active bone resorption in a patient and his father with 2-year follow-up results. CONCLUSION: Management included identification of the NOTCH2 mutation and treatment with antiresorptive measures. In addition, genetic counseling and antenatal counseling are recommended to explain the risk of inheritance.

Prevalence and clinical association with acro-osteolysis in early systemic sclerosis.

OBJECTIVES: Acro-osteolysis is often associated with systemic sclerosis (SSc). However, the severity of acro-osteolysis and its clinical association among SSc patients is limited. Our aims were to assess the prevalence of acro-osteolysis and the clinical association with acro-osteolysis among SSc patients at early onset of the disease. METHODS: A cross-sectional study of 120 newly diagnosed SSc patients with the onset of less than 4 years were evaluated on clinical characteristics and hand radiographs. Acro-osteolysis was graded on a 0-4-point scale based on the severity and the patients were subdivided into mild, moderate and severe. RESULTS: Among all SSc patients enrolled, 62.5% were females, 56.1% dcSSc and the vast majority of them (84.1%) were positive for anti-topoisomerase I antibody (anti-topo I). The mean disease duration was 2.0±1.3 years. Acro-osteolysis was noted in 77 patients with a prevalence of 64.1% (95%CI 54.9-72.7), of which 16.7% were defined as severe acro-osteolysis. Logistic regression analysis revealed that acro-osteolysis was positively associated with anti-topo I (OR 13.96), hand deformity (OR 3.81) and dysphagia (OR 6.66), but negatively associated with oedematous skin (OR 0.05). Analysis stratified by severity of acro-osteolysis showed significant differences between subgroup in terms of the presence of digital gangrene (p=0.02), ischaemic ulcer (p=0.001), oedematous skin (p=0.001), and hand deformities (p=0.01). CONCLUSIONS: Acro-osteolysis was common in SSc at the early onset of disease. While the presence of anti-topo I, hand deformity and esophageal involvement were strongly associated with acro-osteolysis, oedematous skin was the protective factor for acro-osteolysis.

Temperature-dependent autoactivation associated with clinical variability of PDGFRB Asn666 substitutions.

Ocular pterygium-digital keloid dysplasia (OPDKD) presents in childhood with ingrowth of vascularized connective tissue on the cornea leading to severely reduced vision. Later the patients develop keloids on digits but are otherwise healthy. The overgrowth in OPDKD affects body parts that typically have lower temperature than 37°C. We present evidence that OPDKD is associated with a temperature sensitive, activating substitution, p.(Asn666Tyr), in PDGFRB. Phosphorylation levels of PDGFRB and downstream targets were higher in OPDKD fibroblasts at 37°C but were further greatly increased at the average corneal temperature of 32°C. This suggests that the substitution cause significant constitutive autoactivation mainly at lower temperature. In contrast, a different substitution in the same codon, p.(Asn666Ser), is associated with Penttinen type of premature aging syndrome. This devastating condition is characterized by widespread tissue degeneration, including pronounced chronic ulcers and osteolytic resorption in distal limbs. In Penttinen syndrome fibroblasts, equal and high levels of phosphorylated PDGFRB was present at both 32°C and 37°C. This indicates that this substitution causes severe constitutive autoactivation of PDGFRB regardless of temperature. In line with this, most downstream targets were not affected by lower temperature. However, STAT1, important for tissue wasting, did show further increased phosphorylation at 32°C. Temperature-dependent autoactivation offers an explanation to the strikingly different clinical outcomes of substitutions in the Asn666 codon of PDGFRB.

Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology.

Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients' primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.

Phenotypic presentations of Hajdu-Cheney syndrome according to age - 5 distinct clinical presentations.

We present five Danish individuals with Hajdu-Cheney syndrome (HJCYS) (OMIM #102500), a rare multisystem skeletal disorder with distinctive facies, generalised osteoporosis and progressive focal bone destruction. In four cases positive genetic screening of exon 34 of NOTCH2 supported the clinical diagnosis; in one of these cases, mosaicism was demonstrated, which, to our knowledge, has not previously been reported. In one case no genetic testing was performed since the phenotype was definite, and the diagnosis in the mother was genetically confirmed. The age of the patients differs widely from ten to 57 years, allowing a natural history description of the phenotype associated with this ultra-rare condition. The evolution of the condition is most apparent in the incremental bone loss leading to osteoporosis and the acro-osteolysis, both of which contribute significantly to disease burden.

Association of radiographic findings in hand X-ray with clinical features and autoantibodies in patients with systemic sclerosis.

Musculoskeletal involvement is one of the major causes of impairment in daily life of patients with systemic sclerosis (SSc). Several hand radiographic findings can be seen in SSc patients; however, their association with clinical features and autoantibodies remains unclear. Here, we analyzed 124 SSc patients with their hand X-rays and clinical and serological features. Abnormal findings in hand X-rays including acro-osteolysis, calcinosis, flexion contracture, erosive change, joint space narrowing, and subluxation were observed in 110 patients (68%). These X-ray findings were more prevalent in patients with longer disease duration and digital ischemic changes. The majority of erosions were typical for erosive hand osteoarthritis, which was seen in 19% of patients. Hand X-ray findings were associated with involved organs; acro-osteolysis with interstitial lung disease, calcinosis with pulmonary arterial hypertension and gastrointestinal tract involvement, and flexion contracture with gastrointestinal tract involvement. Those findings were also relevant to autoantibodies; acro-osteolysis was more common in SSc patients with anti-Scl70 antibody but less in patients with anticentromere antibody. Calcinosis was more prevalent in patient with anticentromere antibody. In our study, organ involvements and SSc-associated autoantibodies showed associations with hand radiographic abnormalities. Hand X-ray findings might reflect underlying pathogenesis and autoantibody profiles in SSc patients.Key Points• Hand X-ray abnormalities were observed in approximately two-thirds of patients with SSc.• Erosive osteoarthritis was more prevalent in SSc patients than general population.• Hand X-ray findings were associated with disease duration, organ involvements, and SSc-associated autoantibodies, reflecting underlying pathogenesis.

Palmoplantar keratoderma, oral involvement, and homozygous CTSC mutation in two brothers from Cambodia.

Haim-Munk syndrome (HMS) and Papillon-Lefevre syndrome (PLS) are phenotypic variants of palmoplantar keratoderma (PPK) with progressive early-onset periodontitis and dental caries. HMS and PLS have been associated with homozygous or compound heterozygous mutations in the lysosomal protease gene Cathepsin C (CTSC). There have been only a few documented cases of CTSC mutations in patients from South-East Asia. We report the clinical findings of two Cambodian brothers who presented with diffuse, demarcated PPK with transgrediens extending to the elbows and knees, as well as pachyonychia and dental caries. Arachnodactyly and periodontitis were also found in the older brother. Next-generation sequencing unveiled a homozygous missense variant in CTSC (NM_001814.5: c.1337AC: p.(Asp446Ala)) in both brothers. Both parents were heterozygous for the variant, while an unaffected older brother was homozygous for the wild-type allele. Our study adds to the spectrum of mutations and associated clinical presentations for this rare genodermatosis.