Surgical treatment of osteogenesis imperfecta: a summary of the incidence of femoral implant-related complications in children with Sillence type I, III and IV.

PURPOSE: This study explored the incidence of IRCs used in the procedures of the femur in children with osteogenesis imperfecta (OI) and investigated the independent risk factors of IRCs. METHODS: Three hundred eight-eight cases of surgical data about children with OI were included, who were treated with plate, elastic nail, Kirschner wire and telescopic rod. The choice of different procedures depended on the age of children, the status of femur and the availability of devices. Patient demographics and major IRCs were recorded to compare the outcomes of the four procedures. Then, Cox proportional hazard regression was used to analyse the independent risk factors of IRC, and subgroup analysis was applied to further verify the above results. RESULTS: The total incidence of IRC in the four groups was 90.1% (191/212) for plate, 96.8% (30/31) for Kirschner wire, 87.7% (57/65) for elastic nail and 30.0% (24/80) for telescopic rod. The incidence of IRC in the telescopic rod was lower than that in plate, elastic nail and Kirschner wire (P < 0.001). Cox proportional hazard regression analysis confirmed that procedure was the independent risk factor of IRC (HR, 0.191; 95% CI, 0.126-0.288; P < 0.001), fracture (HR, 0.193; 95% CI, 0.109-0.344; P < 0.001) and deformity (HR, 0.086; 95% CI, 0.027-0.272; P < 0.001). In addition, age of surgery was the independent risk factor of fracture (HR, 0.916; 95% CI, 0.882-0.952; P < 0.001) and deformity (HR, 1.052; 95% CI, 1.008-1.098; P = 0.019). Subgroup analysis confirmed that age of surgery, gender, classification, preoperative state and angle did not affect the effect of telescopic rod on reducing the risk of IRCs. CONCLUSIONS: In our cohort, lower incidence of IRCs was observed in telescopic rod group compared with plate, Kirschner wire and elastic nail. Procedure and age of surgery were independent risk factors of fracture. Likewise, procedure and age of surgery were independent risk factors of deformity, and procedure was independent risk factors of IRC.

The patient-related factors in revision procedures on tibia of patients with osteogenesis imperfecta treated with the Peter-Williams nail.

OBJECTIVE: To investigate the patient-related factors that affect the revision rate for the tibia in patients with osteogenesis imperfecta treated with the Peter-Williams nail, and to explore the relationship between the risk factors and complications postsurgery. METHODS: We retrospectively analysed the data of 211 patients (93 females (44.08%) and 118 males (55.92%)) with osteogenesis imperfecta treated with Peter-Williams. The factors affecting surgical revision were analysed by performing binary logistic regression. Then, a total of 211 patients with type III, type I or type IV OI were divided into five groups according to the results of regression. Statistical comparison of these groups was performed to further investigate the relationship between patient-related factors and revision procedures. Statistical comparison was also performed to analyse the relationship between the classification and postoperative complications. RESULTS: Among the 211 patients who underwent surgery, 40 had type I OI, 109 had type IV OI, and 62 had type III OI. Binary logistic regression revealed that the classification (OR = 3.32, 95% CI 1.06-10.39, P = 0.039) and initial operation age (OR = 0.83, 95% CI 0.76-0.92, P < 0.001) were significantly correlated with revision procedures. In type III patients, the initial operation age was significantly correlated with revision procedures (P < 0.001), and the revision rate was lower in patients aged 9 to12 years (P = 0.001). In type I and IV patients, the initial operation age was not significantly correlated with revision procedures (P = 0.281). Classification had a significant effect on postoperative deformity (P = 0.003). CONCLUSIONS: The study reported that the age of initial surgery and classification were the influencing factors affecting the revision procedures of tibia in patients with osteogenesis imperfecta treated with the Peter-Williams nail. In patients with type III disease, the revision rate was lower individuals aged 9-12 years old, and a higher incidence of postoperative deformity was observed.

Which is the best femoral implant in children with osteogenesis imperfecta? a retrospective cohort study of 783 procedures.

BACKGROUND: Osteogenesis imperfecta (OI) is a hereditary genetic disorder characterized by bone fragility and extremity deformities. The surgical management for long-bone fractures and deformities in OI remains a challenge. We aimed to compare clinical outcomes after femoral surgery splinted with the telescopic rod, the plate and screws, the elastic nail and the non-elongating rod in setting of OI. METHODS:  A retrospective cohort study included 783 femoral procedures (mean age 6.00 (interquartile range (IQR) 5.00) years, 335 (42.8%) females) was conducted, and individuals were categorized into four groups according to implants. After verifying comparability among the groups, revision rate and implant survival period were compared among the Sillence types and the same comparison were made among four groups within each Sillence type. The incidence of refractures, deformities, and implant-related complications were also compared among the four groups. RESULTS: There were no significant differences in demographic information among the four groups in terms of sex (p = 0.101), laterality (p = 0.587), Sillence type (p = 0.122), and postoperative follow-up period (p = 0.214). In total, children with Sillence type III had the highest revision rate and the shortest implant survival period; children with Sillence type I had the lowest revision rate and the longest implant survival period; and children with Sillence type IV had the revision rate and the implant survival period between those observed in Sillence types I and III. In Sillence types III and IV, the telescopic rod had lower revision rate (III 24.8%; IV 20.9%) compared to the plate (III 97.2%, p<0.001; IV 80.3%, p<0.001), the elastic nail (III 100.0%, p=0.019; IV 73.9%, p<0.001) and the non-elongating rod (III 65.0%, p<0.001; IV46.9%, p<0.001); the median implant survival period of the telescopic rod (III 48.00 (IQR 28.50) months; IV 43.00 (33.00) months) is longer than the plate (III 11.00 (9.00) months, p<0.001; IV 19.00 (20.00) months, p<0.001), the elastic nail (III 45.00 (37.75) months, p=1.000; IV 19.00 (35.00) months, p=0.028) and the non-elongating rod (III 39.00 (31.75) months, p=0.473; IV 38.50 (29.75) months, p=1.000).A similar trend was observed in Sillence type I (p = 0.063, p = 0.003; respectively). In addition, the incidence of refracture (15.5%), deformity (2.8%) and implant-related complications (23.1%) were also statistically lower in the telescopic rod group. CONCLUSION: In our cohort, lower revision rate and longer implant survival period were observed in telescopic rod group. This was mainly due to the significant lower incidence of refracture, deformity and implant-related complications with the use of telescopic rod.

CRISPR/Cas9 correction of a dominant cis-double-variant in COL1A1 isolated from a patient with osteogenesis imperfecta increases the osteogenic capacity of induced pluripotent stem cells.

Osteogenesis imperfecta (OI) is a hereditary skeletal disorder that is mainly caused by variants in COL1A1/2. So far, no specific treatment has been developed to correct its underlying etiology. We aimed to gain a better understanding of the pathological mechanisms of OI and develop gene therapies to correct OI-causing variants. A de novel cis-double-variant c.[175C>T; 187T>A] in COL1A1 was identified from a 5-year-old OI patient by whole-exome sequencing (WES). Three peptide nucleic acids (PNAs) were designed and then transfected patient-derived fibroblasts. PNA2 affected the translational strand and induced an optimal interfering effect at 0.25µM concentration, proved by Sanger sequencing, qPCR, Western blot, and immunostaining. Additionally, induced pluripotent stem cells (iPSCs) were cultured from patient-derived fibroblasts. Clones of iPSCs with c.187T>A variant and those with both variants largely restored their osteogenic capacities after CRISPR/Cas9 gene editing, which corrected the variants. Importantly, correcting c.187T>A variant alone in CRISPR-edited iPSCs was sufficient to alleviate OI phenotypes, as indicated by increased levels of COL1A1, COL1A2, ALP mRNAs, and COL1A1 protein. Our findings suggest that c.187T>A is the dominant variant of cis-double-variant in COL1A1 that led to OI, and PNA interference and CRISPR/Cas9 gene editing may be new therapeutic tools for OI treatment. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

[Identification of pathogenic variants in three Chinese patients with McCune-Albright syndrome].

OBJECTIVE: To explore the genetic basis for three Chinese patients with McCune-Albright syndrome (MAS). METHODS: Three children who had respectively presented at Shandong Provincial Hospital in April 2019 and Peking Union Medical College Hospital in August 2020 and May 2021 were selected as the research subjects. Peripheral blood samples of the probands and their family members were taken for the extraction of genomic DNA. Potential variants were screened by whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing of the patients and their family members. RESULTS: The proband from family 1 was found to harbor a heterozygous c.601C>T (p.R201C) missense variant in exon 8 of the GNAS gene, whilst the probands from families 2 and 3 were both found to harbor a heterozygous c.602G>A (p.R201H) missense variant in exon 8 of the GNAS gene. Both variants were known to be pathogenic, and all probands were found to be mosaics for the corresponding variants but with various degrees. CONSLUSION: WES can effectively diagnose MAS and other somatic genetic disorders. In this study, the combined WES and Sanger sequencing have verified the degree of mosaicisms of pathogenic variants in the three MAS patients, albeit no apparent correlation was found between the degree of mosaicisms and the phenotype of patients. Above finding has provided a basis for genetic counseling and prenatal diagnosis for the affected families.

Incidence and prevalence of 121 rare diseases in China: Current status and challenges: 2022 revision.

The current study updated data on the incidence and prevalence of 121 rare diseases listed in China's First List of Rare Diseases to provide rationales and references for the development and promotion of rare-disease-related policies. The National Health Commission of the People's Republic of China issued the Rare Disease Diagnosis and Treatment Guide (2019) (denoted here as China's Rare Disease Diagnosis and Treatment Guide). Then 121 diseases were registered with the national rare disease diagnosis and treatment network. The incidence/prevalence of 121 rare diseases varied from country to country. Data are available for a total of 76 rare diseases (76 of 121 rare diseases, 62.81%) in China, including data on the incidence of 23 rare diseases (19.01%) and data on the prevalence of 66 (54.55%). There are data on the incidence/prevalence of 112 rare diseases (112 of 121 rare diseases, 92.56%) at the global level, including data on the incidence of 86 rare diseases (71.07%) and data on the prevalence of 91 (75.21%). On average, the incidence of progressive muscular dystrophies, hyperphenylalaninemia, citrullinemia, and methylmalonic acidemia is over 1/10,000 in China. The prevalence of coronary artery ectasia, congenital scoliosis, retinitis pigmentosa, severe congenital neutropenia, congenital hyperinsulinemic hypoglycemia, and osteogenesis imperfecta is over 1/10,000 in China. All of these figures are beyond the cut-off of 1/10,000 according to the 2021 definition of rare diseases in China. As registration and investigation of rare diseases continues, the spectrum of rare diseases in some provinces is expanding. Diseases such as idiopathic pulmonary arterial hypertension, hepatolenticular degeneration, hemophilia, amyotrophic lateral sclerosis, idiopathic pulmonary fibrosis, and multiple sclerosis are relatively prevalent in some regions and cities of China. Registration efforts promote the correction of incidence/prevalence data, development of orphan drugs, coverage by medical insurance, and development of clinical and diagnostic pathways.

Identification of six novel variants from nine Chinese families with hypophosphatemic rickets.

BACKGROUND: Hypophosphatemic rickets (HR) is a rare genetic disorder associated with renal phosphate wasting and characterized by bone defects. Inactivating mutations in the phosphate regulating endopeptidase homolog X­linked gene (PHEX) account for most cases of HR. The aim of this study was to identify causative variants in nine unrelated Chinese families associated with HR, and to determine potential pathogenicity of the identified variants. METHODS: Genomic DNA was isolated from the peripheral blood of HR patients and their healthy relatives, followed by next-generation sequencing and/or Sanger sequencing. In silico prediction combined with conservation analysis was performed to assess the effects of the variants, and 3D protein modeling was conducted to predict the functional effects on the encoded protein. RESULTS: All HR patients recruited in this study displayed bone deformities and tooth agenesis, as well as reduced serum phosphate levels and elevated urine phosphate levels. Nine PHEX variants were identified in eight families, including four novel variants (c.1661_1726del, c.980A > G, c.1078A > T, and c.1017_1051dup). Of the nine identified PHEX variants, five caused a truncated protein, two caused an altered amino acid, and the other two were the canonical splicing variants. Novel variants c.1336G > A and c.1364 T > C in SLC34A3 were also found in one family. Conservation analysis showed that all the amino acids corresponding to the missense variants were highly conserved. In silico analysis and 3D protein structure modeling confirmed the pathogenicity of these variants. CONCLUSIONS: This study identified four novel variants in PHEX and two novel variants in SLC34A3 in a Chinese cohort with HR. Our findings highlight the dominant role of PHEX in HR, and expand the genotypic and phenotypic spectra of this disorder.

Current diagnosis and management of rare pediatric diseases in China.

This review categorizes and summarizes the rare pediatric diseases that have been included in the First List of Rare Diseases that was jointly published by the National Health Commission and four other government departments in China in 2018. In total, 58 diseases that develop during childhood are included. These diseases involve nine organ systems, including the musculoskeletal, respiratory, immune, endocrine and metabolic, nervous, cardiovascular, hematological, urinary, and integumentary systems. Affected children often have multiorgan involvement with various presentations. Severe diseases can cause acute symptoms starting in the neonatal period that lead to increased morbidity and mortality without prompt management. Early diagnosis and treatment can significantly change the course of a disease and improve its prognosis. This work systemically reviews the status of rare pediatric diseases with a relatively high incidence in the First List of Rare Diseases.

Genotypic and Phenotypic Analysis in Chinese Cohort With Autosomal Recessive Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a rare heritable skeletal disorder which is mainly caused by defected type I collagen. Autosomal recessive OI (AR-OI) is caused by mutations of genes that are responsible for type I collagen modification and folding, and is often associated with more severe phenotypes. Due to the limited number of recessive OI patients, it has been difficult to study the mutation spectrum as well as the correlation of genotype and phenotype. This study recruited a Chinese cohort of 74 AR-OI families, aiming to establish the mutation spectrum and to examine the genotypic and phenotypic correlation. We identified 82 variants including 25 novel variants and 57 HGMD reported variants in these AR-OI patients, using whole exome sequencing/panel sequencing combined with Sanger sequencing. Pathogenic mutations were found at WNT1 (n = 30, 40.54%), SERPINF1 (n = 22, 29.73%), FKBP10 (n = 10, 13.51%), CRTAP (n = 3, 4.05%), P3H1 (n = 3, 4.05%), SERPINH1 (n = 2, 2.70%), SEC24D (n = 3, 4.05%), and PLOD2 (n = 1, 1.35%) respectively. Thus, WNT1 represents the most frequent pathogenic gene of AR-OI in Chinese population. The most common clinical manifestations of AR-OI patients include walking problem (72.86%), scoliosis (65.28%) and frequent fractures (fractures ≥2/year) (54.05%). Interestingly, ptosis represents a unique phenotype of patients carrying WNT1 variants, and it was rare in patients harboring other pathogenic genes. Our study expanded the mutation spectrum of AR-OI and enriched the knowledge of genotypic and phenotypic correlation in Chinese cohort with AR-OI.

Comprehensive bioinformatic analysis of Wnt1 and Wnt1-associated diseases.

Wnt1 is the first member of the Wnt family that was identified. It is phylogenetically conserved and essential for oncogenesis and multiple developmental processes. This study has summarized diseases and mutations related to Wnt1. Wnt1 is involved in various cancers, genetic type XV osteogenesis imperfecta, osteoporosis, and neurological diseases. The expression of Wnt1 in normal tissues and different types of cancers and the potential survival of cancer were analyzed using experiment-based bioinformatic analysis. Systematic analysis indicated that abnormal expression of Wnt1 is significantly associated with cancers, such as kidney renal carcinoma, hepatocellular carcinoma, thyroid carcinoma, head and neck squamous cell carcinoma, and uterine corpus endometrial carcinoma. GeneMANIA and STRING predicted that 32 proteins were involved with Wnt1 in Wnt signaling pathways and sorting and secretion of Wnts. These interacting molecules significantly co-occurred according to cBioPortal analysis. Thirty-three genes with an alteration frequency of more than 50% were observed in several cancers like esophageal squamous cell carcinoma, melanoma, and non-small cell lung cancer. Functional and experiment-based bioinformatics indicated that Wnt1 may act as a target of a potential biomarker for various types of human cancers. Wnt1 and other Wnt1-related proteins and signaling pathways may be ways to treat osteoporosis.

Mutation spectrum of COL1A1/COL1A2 screening by high-resolution melting analysis of Chinese patients with osteogenesis imperfecta.

High-resolution melting (HRM) analysis has been shown to be a time-saving method for the screening of genetic variants. To increase the precision of the diagnosis of osteogenesis imperfecta (OI), we used HRM to explore COL1A1/COL1A2 mutations in 87 Chinese OI patients and to perform population-based studies of the relationships between their genotypes and phenotypes. Peripheral blood samples were collected from the 87 non-consanguineous probands. The coding regions and exon boundaries of COL1A1/COL1A2 were detected by HRM and confirmed by Sanger sequencing. The functional effects of mutations were predicted through bioinformatic tools. Mutations were detected in 70.3% of familial cases and 40% of sporadic cases (p < 0.01). Compared with COL1A1 mutations, patients with COL1A2 mutations were more prone to severe phenotypes. Helical mutations (caused by substitution of the glycine within the Gly-X-Y triplet domain) were more likely to occur in patients with type III and IV (p < 0.05). Haploinsufficiency mutations (caused by frameshift, nonsense, and splice-site mutations) appeared more frequently in patients with type I (p < 0.05). Compared with the Sanger sequencing and whole exome sequencing (WES), HRM was found to reduce total costs by 78%- 80% in patients who had a positive HRM separate melting curve. Our findings suggest that HRM would greatly benefit small and understaffed hospitals and laboratories, and would facilitate the accurate diagnosis and early treatment of OI in remote and less developed regions.

Validation and Classification of Atypical Splicing Variants Associated With Osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI) is a rare inherited bone dysplasia, which is mainly caused by mutations in genes encoding type I collagen including COL1A1 and COL1A2. It has been well established to identify the classical variants as well as consensus splicing-site-variants in these genes in our previous studies. However, how atypical variants affect splicing in OI patients remains unclear. From a cohort of 867 OI patients, we collected blood samples from 34 probands which contain 29 variants that are located close to splice donor/acceptor sites in either COL1A1 or COL1A2. By conducting minigene assay and sequencing analysis, we found that 17 out of 29 variants led to aberrant splicing effects, while no remarkable aberrant splicing effect was observed in the remaining 12 variants. Among the 17 variants that affect splicing, 14 variants led to single splicing influence: 9 led to exon skipping, 2 resulted in truncated exon, and 3 caused intron retention. There were three complicated cases showing more than one mutant transcript caused by recognition of several different splice sites. This functional study expands our knowledge of atypical splicing variants, and emphasizes the importance of clarifying the splicing effect for variants near exon/intron boundaries in OI.

Molecular mechanisms and clinical manifestations of rare genetic disorders associated with type I collagen.

Type I collagen is an important structural protein of bone, skin, tendon, ligament and other connective tissues. It is initially synthesized as a precursor form, procollagen, consisting of two identical pro-α1(I) and one proα2(I) chains, encoded by COL1A1 and COL1A2, respectively. The N- and C- terminal propeptides of procollagen are cleavage by N-proteinase and C-proteinase correspondingly, to form the central triple helix structure with Gly-X-Y repeat units. Mutations of COL1A1 and COL1A2 genes are associated with osteogenesis imperfecta, some types of Ehlers-Danlos syndrome, Caffey diseases, and osteogenesis imperfect/Ehlers- Danlos syndrome overlapping diseases. Clinical symptoms caused by different variations can be variable or similar, mild to lethal, and vice versa. We reviewed the relationship between clinical manifestations and type I collagen - related rare genetic disorders and their possible molecular mechanisms for different mutations and disorders.

Splice receptor-site mutation c.697-2A>G of the COL1A1 gene in a Chinese family with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and blue sclerae, which are mainly caused by a mutation of the COL1A1 or COL1A2 genes that encode type I procollagen. Mutations in the splice site of type I collagen genes are one of the mutations that cause OI and usually lead to a mild or moderate OI phenotype. A heterozygous A to G point mutation in intron 9 at the -2 position of the splice receptor site of COL1A1 was identified in a family with type I or IV OI. Three affected individuals in four generations of one family all presented with several clinical symptoms. They all had pectus carinatum, flat feet, gray-blue sclerae, and normal stature, teeth, hearing, and vision. Forearm fractures, small joint dislocations, and muscle weakness were all present in the patient's father and grandmother, who presented with a moderate type IV phenotype. The 10-year-old proband with type I OI had suffered a fracture twice, but had no history of joint dislocation or skin hyperextensibility. Charting the family helped to identify clinical symptoms in patients with mutations at the N-terminal of type I collagen genes.

Genotypic and phenotypic characterization of Chinese patients with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a rare hereditary skeletal dysplasia, characterized by recurrent fractures and bone deformity. This study presents a clinical characterization and mutation analysis of 668 patients, aiming to establish the mutation spectrum and to elucidate genotype-phenotype correlations in Chinese OI patients. We identified 274 sequence variants (230 in type I collagen encoding genes and 44 in noncollagen genes), including 102 novel variants, in 340 probands with a detection rate of 90%. Compared with 47 loss-of-function variants detected in COL1A1, neither nonsense nor frameshift variants were found in COL1A2 (p < 0.0001). The major cause of autosomal recessive OI was biallelic variants in WNT1 (56%, 20/36). It is noteworthy that three genomic rearrangements, including one gross deletion and one gross duplication in COL1A1 as well as one gross deletion in FKBP10, were detected in this study. Of ten individuals with glycine substitutions that lie towards the N-terminal end of the triple-helical region of the α1(I) chain, none exhibited hearing loss, suggesting a potential genotype-phenotype correlation. The findings in this study expanded the mutation spectrum and identified novel correlations between genotype and phenotype in Chinese OI patients.

The impact of the intestinal microbiome on bone health.

Intestinal microbial flora, known as the second gene pool of the human body, play an important role in immune function, nutrient uptake, and various activities of host cells, as well as in human disease. Intestinal microorganisms are involved in a variety of mechanisms that affect bone health. Gut microbes are closely related to genetic variation, and gene regulation plays an important part in the development of bone-related diseases such as osteoporosis. Intestinal microorganisms can disrupt the balance between bone formation and resorption by indirectly stimulating or inhibiting osteoblasts and osteoclasts. In addition, intestinal microorganisms affect bone metabolism by regulating growth factors or altering bone immune status and can also alter the metabolism of serotonin, cortisol, and sex hormones, thereby affecting bone mass in mice. Moreover, probiotics, antibiotics, and diet can change the composition of the intestinal microbial flora, thus affecting bone health and also potentially helping to treat bone disease. Studying the relationship between intestinal flora and osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells may provide a basis for preventing and treating bone diseases. This paper reviews recent advances in the study of the relationship between intestinal microflora and bone disease.

Novel WNT1 mutations in children with osteogenesis imperfecta: Clinical and functional characterization.

INTRODUCTION: Biallelic mutations in WNT1 can give rise to a rare form of moderate to severe OI. Here we report on 12 children (age 2 to 16 years; 5 girls) with biallelic WNT1 mutations. METHODS: Genomic DNA was analyzed either by targeted next-generation sequencing or Sanger sequencing. Mutations were modeled on the WNT1 protein structure. The in vitro functional effect of WNT1 mutations on WNT signaling was assessed in HEK293 cells using the topflash reporter assay system. RESULTS: All patients had lower extremity deformities and vertebral compression fractures. Seven individuals had upper extremity deformities. Intellectual development appeared normal in 11 children, but was clearly impaired in a 3-year old boy. Ptosis was noted in 7 patients. Height z-scores varied widely, from -7.2 to +1.5. A total of 11 disease-causing WNT1 variants (7 missense mutations, 4 mutations leading to premature termination codons) were identified, of which 9 were novel. Three-dimensional protein modeling suggested that each of the missense mutations led to structural modifications. Functional in vitro studies revealed that all observed missense mutations led to decreased ability of WNT1 to induce WNT signaling via the canonical WNT pathway. CONCLUSIONS: The reported biallelic WNT1 variants cause loss of WNT1 function and lead to a severe bone fragility phenotype with conspicuous involvement of the spine.

Novel NTRK1 mutations in Chinese patients with congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder, characterized by loss of algesthesis and inability to sweat. CIPA is known to be caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1). However, the details of NTRK1 mutations in Chinese CIPA patients remain unclear. In the present study, we recruited 36 CIPA patients from 34 unrelated families in mainland China. Blood samples from these patients and their available familial members were collected and subjected to genetic analysis. We identified 27 mutations in NTRK1 from this cohort, including 15 novel mutations. Interestingly, we discovered two forms of novel recurrent mutations: the first was a large intragenic deletion c.429-374_717 + 485del mediated by recombination between Alu elements, and the second was a deep intronic substitutions c.[851-798C > T;851-794C > G]. All probands were homozygotes or compound heterozygotes of these mutations. Current findings expand our knowledge about the mutation spectrum of NTRK1 in Chinese CIPA patients and provide more evidence for precise diagnosis of the clinically suspected patients with CIPA.

Circular RNAs and hereditary bone diseases.

Circular RNA (circRNA) is a non-linear form of RNA derived from exonic, intronic, and exon-intron gene regions. circRNAs are characterized by covalent closed loops, highly stable nuclease resistance, and specific expression in species and developmental stages. CircRNA molecules have been identified as playing roles in the regulation of cell transcription, transcriptional expression after translation, interactions with microRNAs, and protein coding. A high stability and tissue- and disease-specific expression allow circRNAs to serve as potential biomarkers both for diseases and prognosis. CircRNAs function in bone remodeling by directly participating in bone-related signaling pathways and by forming the circRNA-miRNA-mRNA axis. Studies have seldom reported on the low incidence of circRNAs in genetic bone disorders. The current study reviews the characteristics of circRNAs and recent research on their role in rare hereditary bone diseases.

Complex heterozygous WNT1 mutation in severe recessive osteogenesis imperfecta of a Chinese patient.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder with a predominately autosomal-dominant inheritance pattern. Recessive forms of OI are rare and involve many different causative genes. WNT1 mutations were found to cause either autosomal-recessive OI or dominantly inherited early-onset osteoporosis. Here we describe a 32-year-old boy with severe osteopenia and deformity of the extremities. The relative long thumb and ring finger are obvious. We identified a novel combination of complex heterozygous WNT1 mutation of c.397 A>T (p.Ala133Thr) and c.506dupG (p.Cys170Leufs*) in the proband, both parents and young brother were shown to be heterozygous asymptomatic carriers of the mutation. This is the eleventh family and the thirteenth patient we have ever found in China. Mutation of c.397 A>T (p.Ala133Thr) was found for the third time following our previous findings in two individual families with four patients in total, and may be a hotspot mutation in Chinese WNT1-related OI patients. In silico programs supported the damaging effects for both mutations. The three-D structure demonstrated the severely destroyed stability of WNT1. Serum levels of WNT1, LRP5, and ß-catenin were decreased, while higher levels of GSK-3ß were detected. The molecular mechanisms of the complex heterozygous mutations need further study.