Yunlan Xu

Effect of Variation of ABCB1 and ABCC3 Genotypes on the Survival of Bone Tumor Cases after Chemotherapy

We conducted a comprehensive study to investigate the role of genes involved in transport pathways in response to chemotherapy and clinical outcome of osteosarcoma cases. Genotyping of six SNPs was performed in a 384-well plate format on the Sequenom MassARRAY platform for 208 osteosarcoma patients to reveal any correlations of the six SNPs with response to chemotherapy and clinical outcome. Individuals with the ABCB1 rs1128503 TT and ABCC3 rs4148416 TT genotypes had a higher probability of responding poorly to chemotherapy, indicated by odds ratios (ORs) of 2.46 (95%CI, 1.21-5.74) and 3.78 (95% CI, 1.20-13.85), respectively. Moreover, the ABCB1 rs1128503 TT and ABCC3 rs4148416 TT genotypes were significantly associated with shorter disease- free survival (DFS) and overall survival (OS). Our study found the two SNPs in two transporter genes and one phase II metabolism enzyme to be associated with response to chemotherapy and overall survival in osteosarcoma patients, suggesting potential prognostic biomarker applications of the two SNPs.

Exome sequencing reveals a novel PTHLH mutation in a Chinese pedigree with brachydactyly type E and short stature.

Brachydactyly includes shortening of digits due to abnormal development of phalanges, metacarpals, or both. It can occur either as an isolated malformation or with other anomalies as part of many congenital syndromes. It is included as one of the dysostosis groups affecting the limbs in the nosology and classification of genetic skeletal disorders. However, brachydactyly usually shows a high degree of phenotypic variability. In this study, we successfully identified a novel heterozygous mutation of the parathyroid hormone-like hormone (PTHLH) gene by exome sequencing in a Chinese pedigree with brachydactyly and short stature. The PTHLH gene encodes a parathyroid hormone-related protein (PTHrP) that is involved in the regulation of endochondral bone development, and mutations in this gene cause the type E form of brachydactyly. The mutation p.L15R occurs at a hydrophobic core region of the signal peptide, suggesting that this variation probably changes the signal peptide cleavage site at the in silico prediction. Further in vitro functional analysis showed that this mutation can lead to the retention of an N-terminal signal peptide fragment after the nascent proteins are translated.

Novel frame-shift mutations of GLI3 gene in non-syndromic postaxial polydactyly patients

Polydactyly is a common congenital limb deformity. This anomaly may occur in isolation (non-syndromic) or as part of a syndrome. The glioma-associated oncogene family zinc finger 3 (GLI3) is known to be associated with both syndromic and non-syndromic polydactyly. GLI3 plays a predominant role in the pathogenesis of syndromic polydactyly: mutations have been identified in 68% of patients with Greig cephalopolysyndactyly syndrome and 91% of patients with Pallister-Hall syndrome. The knowledge regarding the contribution of GLI3 in non-syndromic polydactyly is currently very limited. In this study, we assembled a cohort of individuals of Chinese ethnicity with non-syndromic postaxial polydactyly. We presented the clinical features and molecular evaluations of 19 probands. GLI3 mutations were identified in 15.8% of probands (3/19) including two novel frame-shift mutations c.3855dupC (p.Met1286HisfsTer18) and c.4141delA (p.Arg1381GlyfsTer38) detected in sporadic cases and one previously reported nonsense mutation (c.1927C>T/p.Arg643Ter) in a familial case. Of note, GLI3 mutations were exclusively detected in patients with bilateral polydactyly affecting both hands and feet. Three out of five (60%) probands with bilateral polydactyly on both hands and feet carried pathogenic mutations in GLI3. Our study demonstrated the role of GLI3 in a significant fraction of patients with non-syndromic bilateral polydactyly affecting both hands and feet.

A New Subtype of Multiple‐Synostoses Syndrome is Caused by a Mutation in GDF6 that Decreases its Sensitivity to Noggin and Enhances its Potency as a BMP Signal

Growth and differentiation factors (GDFs) are secreted signaling molecules within the BMP family that have critical roles in joint morphogenesis during skeletal development in mice and humans. Using genetic data obtained from a six‐generation Chinese family, we identified a missense variant in GDF6 (NP_001001557.1; p.Y444N) that fully segregates with a novel autosomal dominant synostoses (SYNS) phenotype, which we designate as SYNS4. Affected individuals display bilateral wrist and ankle deformities at birth and progressive conductive deafness after age 40 years. We find that the Y444N variant affects a highly conserved residue of GDF6 in a region critical for binding of GDF6 to its receptor(s) and to the BMP antagonist NOG, and show that this mutant GDF6 is a more potent stimulator of the canonical BMP signaling pathway compared with wild‐type GDF6. Further, we determine that the enhanced BMP activity exhibited by mutant GDF6 is attributable to resistance to NOG‐mediated antagonism. Collectively, our findings indicate that increased BMP signaling owing to a GDF6 gain‐of‐function mutation is responsible for loss of joint formation and profound functional impairment in patients with SYNS4. More broadly, our study highlights the delicate balance of BMP signaling required for proper joint morphogenesis and reinforces the critical role of BMP signaling in skeletal development.

Mutational screening of GLI3, SHH, preZRS, and ZRS in 102 Chinese children with nonsyndromic polydactyly

Background: Polydactyly is a group of congenital limb malformations that show high degree of phenotypic variability and genetic heterogeneity. Results: In the present study, four genomic regions (exons of GLI3, SHH, and noncoding sequences of preZRS and ZRS) involved in hedgehog (Hh) signaling pathway were sequenced for 102 unrelated Chinese children with nonsyndromic polydactyly. Two GLI3 variants (c.2844 G > G/A; c.1486C > C/T) and four preZRS variants (chr7:156585336 A>G; chr7:156585421 C>A; chr7: 156585247 G>C; chr7:156585420 A > C) were observed in 2(2.0%) and 6(5.9%) patients, respectively. These variants are not over‐represented in the Chinese healthy population. All the 8 cases showed preaxial polydactyly in hands. Additionally, no specific patterns of malformation predicted mutations in other candidate genes or sequences. Conclusions: This is the first report of the assessment of the frequency of GLI3/SHH/preZRS/ZRS in Chinese patients to show any higher possibility of mutations or variants for the 4 genes or sequences in China. Developmental Dynamics 246:392–402, 2017.

Elastic stable intramedullary nailing for severely displaced distal tibial fractures in children.

AbstractElastic stable intramedullary nailing (ESIN) has became a well-accepted method of osteosynthesis of diaphyseal fractures in the skeletally immature patient for many advantages, the purpose of this study is to evaluate the preliminary results of this minimally invasive treatment for severely displaced distal tibial diaphyseal metaphyseal junction (DTDMJ) fractures.This study was carried out over a 6-year period. Twenty-one severely displaced DTDMJ fractures treated using ESIN were evaluated clinically and radiographically. Complications were assessed: the patients were evaluated with regard to nonunion, malunion, infection, growth arrest, leg length discrepancy, implant irritation, and joint function.Mean age at the time of surgery was 7.8 years (range between 5.3 and 14.8 years), mean body weight 34.1 kg, all fractures were transverse or mild oblique type, including 3 open fractures, 5 multifragmented fractures, and 4 fractures associated with polytrauma; 6 cases were treated with antegrade ESIN of tibia while 15 cases need combined retrograde fibula and antegrade tibia fixation treatments. Follow-ups were ranging from 11 to 36 months, 19 fractures showed both clinical and radiographic evidence of healing within 5 months; all cases had full range motion of knee and ankle with symmetrical foot progress angle. Nail removal was at a mean 7.1 months, at final follow-up, no growth arrest or disturbances occurred. Five patients had complications; leg length discrepancy had decreased yet affected 2 patients, 2 cases showed delayed union, and 1 case developed restricted dorsal extension at the metatarsophalangeal joint of the hallux.ESIN is the treatment of choice for pediatric severely displaced DTDMJ fractures that cannot be reduced by closed reduction or ones that cannot be casted. The advantages include faster fracture healing, excellent functional and cosmetic results, safe and reliable surgical technique, and lower severe complication rate.

Clinical study of 459 polydactyly cases in China, 2010 to 2014.

Polydactyly is one of the most common hereditary limb malformations, involving additional digits on the hands and/or feet, which is a very attractive model to appreciate clinical and genetic heterogeneity. A high level of heterogeneity in polydactyly has been identified in different regions. However, such data of the medical literatures for Asian populations are relatively limited. This study was intended to shed light on the phenotypic manifestations of polydactyly in the recruited Chinese population and to characterize the medical literature on this condition. A total of 459 well‐characterized polydactyly cases from Shanghai Childrens Medical Center were recruited. Their phenotypes, inheritance patterns, and clinical heterogeneity were obtained from clinical medical records. It was found that 4.8% of cases were familial and 95.2% were sporadic. The proportions of preaxial and postaxial polydactyly types were 74.7% and 25.3%, respectively. In preaxial polydactyly, type I formed the overwhelming majority (95.9%). Among the postaxial polydactyly cases, type A was most prevalent at 69.8% and type B was witnessed in 30.2% of cases. Familial and sporadic polydactyly patients mainly had unilateral presentations. A total of 583 limbs with additional digits were recorded in the 459 subjects. Upper limb involvement was more common than lower, and right hand involvement was more common than left for preaxial polydactyly, and lower limb involvement was more common than upper in postaxial polydactyly. This cohort added useful clinical/epidemiological information to the polydactyly literature in the Chinese population and highlighted its marked clinical heterogeneity.

Pre-bent elastic stable intramedullary nail fixation for distal radial shaft fractures in children

Objective:  To investigate the functional and radiographic outcomes of pre‐bent elastic stable intramedullary nail in treatment of distal radial shaft fractures in children.

Exome sequencing identifies a novel nonsense mutation of HOXD13 in a Chinese family with synpolydactyly.

Synpolydactyly (SPD) is an autosomal dominant limb malformation with a distinctive combination of syndactyly and polydactyly. SPD is clinically heterogeneous and could be genetically classified into three types. The clinical phenotype of SPD is complicated by its variable expressivity. In the present study, whole exome sequencing (WES) was used to identify the affected gene(s) in a Chinese family with atypical SPD phenotype. Our results showed that a novel heterogenous nonsense mutation (c.556C > T, p.R186X) in HOXD13 was associated with this SPD case. Due to variable expressivity, the diagnosis of a clinical heterogenous disease such as SPD is usually difficult. Our results also suggested that WES is an efficient tool to assist with these diagnoses.

Soft tissue Rosai-Dorfman disease in child: A case report and literature review.

Background:Rosai–Dorfman disease was commonly characterized as massive, painless, bilateral, symmetric cervical lymphadenopathy, with fever, leukocytosis, and elevated sedimentation rate. However, soft tissue Rosai–Dorfman disease (STRDD) is a rare benign tumor. Methods:We hereby present 1 case of a 17-month-old girl, an isolated subcutaneous mass was detected on her right forearm, and no signs of pain, swelling, or erythema were observed at the site. Results:The patient underwent an excisional biopsy for the mass. Immunohistochemistry results showed that it was positive for S-100 protein and CD68, whereas negative for CD1a, which supported the diagnosis of STRDD. Conclusions: The patient showed no evidence of recurrence or metastasis 2 years after the surgery.Some multifocal masses were reported to be much more prone to recurrence. Further follow-up of STRDD is necessary.