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.

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).
METHODS: 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.
CONCLUSIONS: 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.

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.

BACKGROUND: Osteoarthritis of the hand joints in systemic sclerosis (SSc) patients might be an independent manifestation leading to limitation of upper extremity function. There is no publication quantitatively assessing the thickness of articular cartilage within the hand joints of SSc patients by MRI. The purpose of our study was to quantify the condition and thickness of hand joints cartilage with three-dimensional quantitative MRI (3D q-MRI).
METHODS: The study was conducted in twenty people: ten patients with SSc and ten healthy individuals. All participants were examined with the 3D q-MRI with 3T scanner. The cartilage thickness of proximal (PIP) and distal interphalangeal (DIP) joints as well as metacarpophalangeal joints was measured.
RESULTS: There was no significant difference in cartilage thickness between both groups. However, the joint cartilage was thinner in fingers with acro-osteolysis. In PIP joint of the fingers with acro-osteolysis, the mean cartilage thickness was 0.5 mm (p = 0.0043) and 0.4 mm (p = 0.0034) in DIP joints.
CONCLUSIONS: Quantitative MRI analysis of the joints of the hands of SSc patients does not indicate changes in thickness of the articular cartilage. A significant reduction in the articular cartilage thickness of the fingers with acro-osteolysis indicates the potential of an ischemic basis of articular cartilage destruction in SSc patients.

OBJECTIVE: Systemic sclerosis (SSc) is a rare autoimmune disorder characterized by vascular and fibrosing involvement of the skin and internal organs. In this study, we determined the prevalence and characteristics of radiological hands and feet involvements in Iranian SSc patients to identify the associations between clinical features and radiologic findings.
METHODS: 43 SSc patients (41 women and 2 men), with a median age of 44.8 years (ranges 26-70 years) and a mean disease duration of 11.8 years (ranges 2-28 years) were studied in this cross-sectional study.
RESULTS: 42 patients had radiological changes both in their hands and feet. Only one patient had alteration just in hand. The most frequent changes that we found in hand were Juxta-articular Osteoporosis (93%), Acro-osteolysis (58.2%), and Joint Space Narrowing (55.8%). The prevalence of joint space narrowing or acro-osteolysis was higher in subjects with active skin involvement [modified Rodnan skin score (mRSS) > 14] [16/21 vs. 4/16 for patients with inactive skin involvement (mRSS < 14); p = 0.002]. The most frequent changes that we found in the foot were Juxta-articular Osteoporosis (93%), Acro-osteolysis (46.5%), Joint Space Narrowing (58.1%), and subluxation (44.2%). The presence of anti-ccp antibody was detected in 4 (9.3%), while positive rheumatoid factor was found in 13 (30.2%) of SSc patients.
CONCLUSIONS: This study corroborates that arthropathy is common in SSc patients. The introduction of the specific radiological involvements of SSc needs to be confirmed by further studies, in order to define the appropriate prognosis and treatment of patients.

Frank-Ter Haar syndrome (FTHS), Winchester syndrome (WS), Torg syndrome (TS) and Multicentric Osteolysis Nodulosis and Arthropathy (MONA) are progressive skeletal dysplasia consisting of acro-osteolysis. Mutation in Matrix Metalloproteinase 2 (MMP2), Matrix Metalloproteinase 14 (MMP14) and SH3PXD2B are known genetic defects in these disorders. We hereby report a 5 years and 9 months old girl suffering from progressive limb deformity. She is the first child of a relative couple, who was referred to metabolic disorders\' clinic due to poor growth and bone pain. On physical examination, minor facial dysmorphism, hypertrichosis, severe hand deformity with limitation in range of motion in carpal, metacarpal and phalangeal joints, hallux valgus deformity of feet, soft tissue hypertrophy and nodule formation in palmoplantar areas were detected. Her past history indicated a cardiac defect resulting in open heart surgery at 8 months of age. Genetic study revealed a new homozygote nonsense mutation in MMP2 gene explaining her clinical manifestations. We recommend careful evaluation and follow-up of patients with congenital heart disease, as it may be the first presentation of a genetic multisystem disorder. Early differentiation of the disease from other skeletal dysplasia and rheumatologic disorders could prevent unnecessary management.

UNASSIGNED: To perform molecular genetic analysis of a patient diagnosed with primary hypertrophic osteoarthropathy (PHO) with malnourishment, intussusception, and acro-osteolysis.
UNASSIGNED: At the age of 7 years, a boy born to a consanguineous couple was diagnosed with PHO attributed to delayed closure of the cranial suture, eczema, clubbing of fingers, and swelling of the knee and ankle. Clinical characteristics and follow-up data for 3 years were collected and analyzed. Trio whole-exome sequencing (WES) and copy number variant sequencing were used to screen for causative genetic variants. Candidate variants of the patient and his parents were confirmed by Sanger sequencing. When he was 7 years old, trio WES found that he had biallelic novel variants c.498 + 1G > A, inherited from his parents, in the HPGD gene. The patient was markedly malnourished. Ultrasonography and computed tomography showed intussusception with a gradual expansion of the duodenum, localized intestinal wall thickening, and acro-osteolysis. Cross-sectional blood tests showed that the patient had continuously decreased levels of serum 25-hydroxy vitamin D and serum ferritin at the age of 7and 10 years.
UNASSIGNED: PHO due to HPGD defects is rare in pediatric patients, and finding homozygous novel c.498 + 1G > A has expanded the spectrum of causative variants of HPGD and provided a clue for genotype-phenotype correlation analysis. Similar to mouse model results, human HPGD deficiency may also cause abnormal digestive tract development, and related secondary vitamin D deficiency and acro-osteolysis should be considered in HPGD-related PHO.

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.

Hereditary Sensory and Autonomic Neuropathy (HSAN) Type II is an autosomal recessive genetic disease which presents predominantly with sensory neuropathy and neuropathic ulcers. HSAN Type II is a rare disease, and in the few cases that have been reported, the focus has been on identifying genetic markers of the disease. Orthopaedic conditions may be a major presentation of the disease, and the prevention of superficial trauma and foot care is the only definitive management.

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.
METHODS: 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.