Homozygosity for a Rare Plec Variant Suggests a Contributory Role in Congenital Insensitivity to Pain.

Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the molecular etiology of congenital insensitivity to pain in two Thai patients. Clinical, radiographic, histopathologic, immunohistochemical, and molecular studies were performed. Patients were found to have congenital insensitivity to pain, self-mutilation, acro-osteolysis, cornea scars, reduced temperature sensation, tooth agenesis, root maldevelopment, and underdeveloped maxilla and mandible. The skin biopsies revealed fewer axons, decreased vimentin expression, and absent neurofilament expression, indicating lack of dermal nerves. Whole exome and Sanger sequencing identified a rare homozygous variant c.4039C>T; p.Arg1347Cys in the plakin domain of Plec, a cytolinker protein. This p.Arg1347Cys variant is in the spectrin repeat 9 region of the plakin domain, a region not previously found to harbor pathogenic missense variants in other plectinopathies. The substitution with a cysteine is expected to decrease the stability of the spectrin repeat 9 unit of the plakin domain. Whole mount in situ hybridization and an immunohistochemical study suggested that Plec is important for the development of maxilla and mandible, cornea, and distal phalanges. Additionally, the presence of dental anomalies in these patients further supports the potential involvement of Plec in tooth development. This is the first report showing the association between the Plec variant and congenital insensitivity to pain in humans.

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.

Severe Acro-osteolysis Mimicking Arthritis Mutilans in a Patient with Primary Hyperparathyroidism: A Case Report.

BACKGROUND: Primary hyperparathyroidism (PHPT) should be considered in the differential diagnosis of a patient with suspected secondary osteoporosis, and severe osteoporosis with multiple fractures is frequently the first clinical manifestation of the disease. CASE PRESENTATION: Mutilating arthritis (arthritis mutilans) can be part of the clinical presentation of a number of rheumatic diseases, most commonly seen in psoriatic arthritis, rheumatoid arthritis, and juvenile idiopathic arthritis, but also in systemic lupus, systemic sclerosis, and multicentric reticulohistiocytosis. Evidence exists that subperiosteal and subchondral bone resorption, seen in PHPT, could induce the so-called 'osteogenic synovitis', which could eventually lead to the development of a secondary osteoarthritis with bone deformities. CONCLUSION: Here, we present a case report of a patient initially diagnosed with PHPT who presented with mutilating arthritis of the finger joints and discuss whether the severe acro-osteolysis is a manifestation of the endocrinopathy or whether there is a co-existing undiagnosed inflammatory joint disease.

A rare LMNA missense mutation causing a severe phenotype of mandibuloacral dysplasia type A: a case report / Uma rara mutação missense no gene LMNA causando um fenótipo grave de displasia mandibuloacral tipo A: relato de caso

ABSTRACT Objective: To report the case of a girl presenting a severe phenotype of mandibuloacral dysplasia type A (MADA) characterized by prominent osteolytic changes and ectodermal defects, associated with a rare homozygous LMNA missense mutation (c.1579C>T). Case description: A 6-year-old girl was evaluated during hospitalization exhibiting the following dysmorphic signs: subtotal alopecia, dysmorphic facies with prominent eyes, marked micrognathia and retrognathia, small beaked nose, teeth crowding and thin lips, generalized lipodystrophy, narrow and sloping shoulders, generalized joint stiffness and bone reabsorption in the terminal phalanges. In dermatological examination, atrophic skin, loss of cutaneous elasticity, hyperkeratosis, dermal calcinosis, and hyperpigmented and hypochromic patches were observed. Radiology exams performed showed bilateral absence of the mandibular condyles, clavicle resorption with local amorphous bone mass confluence with the scapulae, shoulder joints with subluxation and severe bone dysplasia, hip dysplasia, osteopenia and subcutaneous calcifications. Comments: MADA is a rare autosomal recessive disease caused by mutations in LMNA gene. It is characterized by craniofacial deformities, skeletal anomalies, skin alterations, lipodystrophy in certain regions of the body and premature ageing. Typical MADA is caused by the p.R527H mutation in the LMNA gene. However, molecular analysis performed from oral epithelial cells obtained from the patient showed the rare mutation c.1579C>T, p. R527C in the exon 9 of LMNA. This is the sixth family identified with this mutation described in the literature.

RESUMO Objetivo: Relatar o caso de uma jovem que apresentava um fenótipo grave de displasia mandibuloacral tipo A (MADA) caracterizado por alterações osteolíticas proeminentes e defeitos ectodérmicos, associados a uma rara mutação homozigótica missense no gene LMNA (c.1579C>T). Descrição do caso: Uma menina de seis anos foi avaliada durante hospitalização apresentando os seguintes sinais dismórficos: alopecia subtotal, fácies dismórfica com olhos proeminentes, micrognatia e retrognatia acentuada, nariz pequeno e adunco, dentes apinhados e lábios finos, lipodistrofia generalizada, ombros estreitos e inclinados, rigidez articular e reabsorção óssea nas falanges terminais. Ao exame dermatológico, observou-se pele atrófica, perda da elasticidade cutânea, hiperceratose, calcinose dérmica e manchas hiperpigmentadas e hipocrômicas. Exames radiológicos realizados mostraram ausência de côndilos mandibulares bilaterais, reabsorção da clavícula com massa óssea amorfa local confluindo com as escápulas, articulações do ombro com subluxação e displasia óssea severa, com displasia coxofemoral, osteopenia e calcificações subcutâneas. Comentários: MADA é uma doença autossômica recessiva rara causada por mutações no gene LMNA. Caracteriza-se por deformidades craniofaciais, anomalias esqueléticas, alterações cutâneas, lipodistrofia em determinadas regiões do corpo e envelhecimento precoce. MADA típica é causada pela mutação p.R527H no gene LMNA. No entanto, a análise molecular realizada com células epiteliais orais obtidas da paciente mostrou a mutação rara c.1579C>T, p. R527C no exon 9 do gene LMNA. Esta é a sexta família identificada com essa mutação descrita na literatura.

Acro-osteólisis, hallazgos de imagen y posibles diagnósticos etiológicos / Acro-osteolysis, imaging findings and possible aetiological diagnoses

La acro-osteólisis es un hallazgo radiológico infrecuente caracterizado por una reabsorción o destrucción ósea que afecta típicamente a las falanges distales de la mano.Sus causas son múltiples. Puede estar asociada a enfermedades sistémicas, tener un origen familiar, ser idiopática o secundaria a agentes externos, por lo que el patrón radiográfico, la edad del paciente y una buena historia clínica serán claves para llegar a su diagnóstico etiológico.Presentamos el caso de una mujer de 40 años que consulta por dolor de aproximadamente 1 año de evolución a nivel de la región interfalángica distal del primer y segundo dedo de la mano derecha. Entre las pruebas complementarias realizadas durante el estudio, destaca la radiografía simple de la mano, donde se observa una reabsorción parcial en banda de la región media de la falange distal del primer y segundo dedo, compatible con acro-osteólisis.(AU)

Acro-osteolysis is a rare radiological finding characterized by bone resorption or destruction that typically affects the distal phalanges of the hand.There are many causes. The condition can be associated with systemic diseases, have a family origin or be idiopathic or secondary to external agents. Therefore, the radiographic pattern, the patient’s age in addition to a good clinical history will be key to diagnosing its aetiology.We report the case of a 40-year-old woman who consulted for pain of approximately one year clinical course at the level of the distal interphalangeal region of the first and second fingers of the right hand. Among the complementary test performed during the study the x-ray revealed a band-like partial resorption in the middle region of the distal phalanx of the first and second fingers, compatible with acro-osteolysis.(AU)

Acro-osteolysis in a Filipino male with Vinyl chloride exposure: A case report

@#Occupational acro-osteolysis pertains to bone resorption of the distal phalanges of the hands and feet among workers with vinyl chloride exposure. We report the case of a Filipino man with osteolysis of the distal phalanges of the hands initially considered to have systemic sclerosis. The patient had gradual shortening of the fingers, thickening of the skin over the extremities, and hypopigmented patches over a span of more than 20 years. His lower extremities presented with non-pitting edema, skin thickening, and neuropathy, without shortening of the digits. Difficulty of ambulation was apparent due to the development of feet inversion. Radiographic findings of the hands and feet included resorption of distal phalanges, erosive and sclerotic changes, and narrowed joint spaces. Other conditions considered were Hansen’s disease, skeletal tuberculosis, and diabetic neuropathic arthropathy, which were eventually ruled out. The final diagnosis was occupational acro-osteolysis secondary to vinyl chloride exposure. The patient underwent serial total contact casting of the bilateral lower extremities to relieve bipedal edema and to reposition the feet. This case emphasizes the significance of investigating a patient’s occupational history and highlights a rare sequela of exposure to a commonly used chemical agent in the manufacture of polyvinyl chloride products.

Pyknodysostosis: report of a rare case with review of literature

Pyknodysostosis is a rare autosomal recessive disorder characterized by the post natal onset of short limbs, short stature, and generalized hyperostosis along with acro-osteolysis with sclerosis of the terminal phalanges, a feature that is considered essentially pathognomonic. Other features include persistence of fontanelles, delayed closure of sutures, wormian bones, absence of frontal sinuses, and obtuse mandibular gonial angle with relative mandibular prognathism. We report a case of 17-year-old girl who presented with a chief complaint of retention of deciduous teeth. General physical examination demonstrated short stature, frontal and parietal bossing, depressed nasal bridge, beaked nose, hypoplastic midface, wrinkled skin over the finger tips, and nail abnormalities. Radiographs showed multiple impacted permanent and supernumerary teeth, hypoplastic paranasal sinuses with acro-osteolysis of terminal phalanges, and open fontanelles, and sutures along with wormian bones in the lambdoidal region.

A case of acro-osteolysis caused by peripheral neuropathy after minor burn injury / 대한내과학회지

Acro-osteolysis is characterized by bone resorption in the fingers and toes and can occur in several diseases. Occupational exposure to polyvinyl chloride polymers, thermal injury, and repetitive mechanical injury can also cause acro-osteolysis. The pathophysiology of the disease is unknown, but a unifying theme of vascular and mechanical injury is presented. Signs include Raynaud's phenomenon, bone loss in the hand and cold sensitivity. We report the case of a 67-year-old woman who presented with acro-osteolysis after being burned repeatedly.

A case of acro-osteolysis caused by peripheral neuropathy after minor burn injury / 대한내과학회지

Acro-osteolysis is characterized by bone resorption in the fingers and toes and can occur in several diseases. Occupational exposure to polyvinyl chloride polymers, thermal injury, and repetitive mechanical injury can also cause acro-osteolysis. The pathophysiology of the disease is unknown, but a unifying theme of vascular and mechanical injury is presented. Signs include Raynaud's phenomenon, bone loss in the hand and cold sensitivity. We report the case of a 67-year-old woman who presented with acro-osteolysis after being burned repeatedly.