Serum osteocalcin level is associated with the mortality in Chinese patients with Fibrodysplasia ossificans progressiva aged ≤18 years at diagnosis.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by extraskeletal heterotopic ossification. It is well recognized that FOP can lead to a devastating condition of disability. However, the mortality rate of FOP patients in China and risk factors for mortality are still largely unclear. METHODS: We conducted a retrospective research on a cohort of 65 cases of FOP patients in China from 2008 to 2018. We reviewed medical records of these FOP patients to retrieve information such as date of birth/death, gender, clinical features, genotypes and biochemical parameters and analyze the correlation of these parameters with the mortality. RESULTS: 92.3% (60/65 cases) patients were classic FOP patients, 3.1% (2/65 cases) were FOP-plus and 4.6% (3/65 cases) were FOP variants. 9 cases of this cohort were dead during the ten-year period, and the overall mortality rate was 13.8%. c.617G > A mutation was confirmed in all non-survivors. In FOP patients≤18 years at diagnosis, non-survivors demonstrated significantly lower blood osteocalcin and alkaline phosphatase levels compared with survivors (P < 0.05), and spearman correlation and logistic regression analysis indicated that serum osteocalcin and alkaline phosphatase levels were negatively correlated with the mortality. Furthermore, the receiver-operating characteristic curve analysis showed serum osteocalcin had the largest area under the curve of 0.855 among four biochemical parameters, and serum osteocalcin < 65.9 ng/ml displayed a good capacity to discriminate the non-survivors from survivors in FOP patients aged 18 years and younger at diagnosis. CONCLUSIONS: Our findings showed that the mortality rate of FOP was 13.8% in China. Serum OC level was negatively correlated with the mortality in Chinese FOP patients ≤18 years at diagnosis.

A rare fatality due to calcified stylohyoid ligament (Eagle syndrome).

The elongation or calcification of the stylohyoid ligament that leads to pressure symptoms, or entrapment of nearby glossopharyngeal nerve or carotid artery, is known as Eagle syndrome. A PubMed search leads to finding of rare fatality among the 49 reported cases. In the present case, the deceased was a 40-year-old male who choked on his food. We hypothesise that the impaction of food in the upper respiratory tract, as well as the inability to intubate the person, were both the result of the calcified stylohyoid ligament.

Mutations in the T (brachyury) gene cause a novel syndrome consisting of sacral agenesis, abnormal ossification of the vertebral bodies and a persistent notochordal canal.

BACKGROUND: The T gene (brachyury gene) is the founding member of the T-box family of transcription factors and is vital for the formation and differentiation of the mesoderm and the axial development of all vertebrates. RESULTS: We report here on four patients from three consanguineous families exhibiting sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies, and the identification and characterisation of their underlying genetic defect. Given the consanguineous nature and the similarity of the phenotypes between the three families, we performed homozygosity mapping and identified a common 4.1 Mb homozygous region on chromosome 6q27, containing T, brachyury homologue (mouse) or T. Sequencing of T in the affected individuals led to the identification of a homozygous missense mutation, p.H171R, in the highly conserved T-box. The homozygous mutation results in diminished DNA binding, increased cell growth, and interferes with the normal expression of genes involved in ossification, notochord maintenance and axial mesoderm development. CONCLUSIONS: We have identified a shared homozygous mutation in three families in T and linked it to a novel syndrome consisting of sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies. We suggest that screening for the ossification of the vertebrae is warranted in patients with sacral agenesis to evaluate the possible causal involvement of T.

Uncovertebral hypertrophy is a significant risk factor for the occurrence of heterotopic ossification after cervical disc replacement: survivorship analysis of Bryan disc for single-level cervical arthroplasty.

OBJECTIVES: The purpose of this study is to investigate the incidence of heterotopic ossification (HO) in the Bryan cervical arthroplasty group and to identify associations between preoperative factors and the development of HO. METHODS: We performed a retrospective review of clinical and radiological data on patients who underwent single-level cervical arthroplasty with Bryan prosthesis between January 2005 and September 2007. Patients were postoperatively followed-up at 1, 3, 6, 12 months and every year thereafter. The clinical assessment was conducted using Odom's criteria. The presence of HO was evaluated on the basis of X-ray at each time-point according to the McAfee classification. In this study, we focused on survivorship of Bryan prosthesis for single-level arthroplasty. The occurrence of ROM-affecting HO was defined as a functional failure and was used as an endpoint for determining survivorship. RESULTS: Through the analysis of 19 cases of Bryan disc arthroplasty for cervical radiculopathy and/or myelopathy, we revealed that ROM-affecting HO occurs in as many as 36.8% of cases and found that 37% of patients had ROM-affecting HO within 24 months following surgery. The overall survival time to the occurrence of ROM-affecting HO was 36.4 ± 4.4 months. Survival time of the prosthesis in the patient group without preoperative uncovertebral hypertrophy was significantly longer than that in the patient group with preoperative uncovertebral hypertrophy (47.2 months vs 25.5 months, p = 0.02). Cox regression proportional hazard analysis illustrated that preoperative uncovertebral hypertrophy was determined as a significant risk factor for the occurrence of ROM-affecting HO (hazard ratio = 12.30; 95% confidential interval = 1.10-137.03; p = 0.04). CONCLUSION: These findings suggest that the condition of the uncovertebral joint must be evaluated in preoperative planning for Bryan cervical arthroplasty.

Neural crest-specific loss of Prkar1a causes perinatal lethality resulting from defects in intramembranous ossification.

The cranial neural crest (CNC) undergoes complex molecular and morphological changes during embryogenesis in order to form the vertebrate skull, and nearly three quarters of all birth defects result from defects in craniofacial development. The molecular events leading to CNC differentiation have been extensively studied; however, the role of the cAMP-dependent protein kinase [protein kinase A (PKA)] during craniofacial development has only been described in palate formation. Here, we provide evidence that strict PKA regulation in postmigratory CNC cells is essential during craniofacial bone development. Selective inactivation of Prkar1a, a regulatory subunit of the PKA holoenzyme, in the CNC results in perinatal lethality caused by dysmorphic craniofacial development and subsequent asphyxiation. Additionally, aberrant differentiation of CNC mesenchymal cells results in anomalous intramembranous ossification characterized by formation of cartilaginous islands in some areas and osteolysis of bony trabeculae with fibrous connective tissue stabilization in others. Genetic interaction studies revealed that genetic reduction of the PKA catalytic subunit C(alpha) was able to rescue the phenotype, whereas reduction in Cbeta had no effect. Overall, these observations provide evidence of the essential role of proper regulation of PKA during the ossification of the bones of the skull. This knowledge may have implications for the understanding and treatment of craniofacial birth defects.

Clinicopathological analysis of primary lung carcinoma with heterotopic ossification.

Pulmonary heterotopic ossification is an unusual event. The relationship between ossification and lung carcinoma is unclear. The present study analyzed clinicopathological features of primary lung carcinoma with heterotopic ossification. We reviewed 2269 surgically resected primary lung carcinomas and identified 33 with heterotopic ossification, including 15 cases with intratumoral heterotopic ossification (IHO) and 18 cases with extratumoral heterotopic ossification (EHO). All cases with IHO were adenocarcinomas and 10 of 15 (66.6%) cases had confirmed positive mucin staining in the tumor cells. Cases with EHO could be divided into three patterns, and each pattern is potentially associated with the background conditions of lung parenchyma. Immunohistochemistry, BMP-2 production was present in 13 of 15 (86.7%) cases with IHO, although, only 4 of 17 (23.5%) cases with EHO. A prognostic analysis revealed no statistically significant difference to be observed between adenocarcinomas with IHO and without IHO. The present study suggested that IHO associated with adenocarcinomas and BMP-2 production in the tumor cells, whereas EHO was not associated with the biology of the carcinoma.

Osificación parenquimatosa difusa del pulmón: prersentación de un caso

Presentamos el caso de un hombre de 49 años con osificación parenquimatosa difusa del pulmón. Los hallazgos clínicos y radiológicos orientaron el diagnóstico hacia una enfermedad intersticial. La biopsia pulmonar a cielo abierto fue requerida para el diagnóstico. Ninguna de las entidades relacionadas conla osificación pulmonar fue encontrada en este paciente.