Clinical utility of comprehensive gene panel testing for common and rare causes of skeletal dysplasia and other skeletal disorders: Results from the largest cohort to date.

Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019-April 2022). Median (range) age was 8 (0-90) years, 70.5% had short stature and/or disproportionate growth, 27.4% had a positive molecular diagnosis (MDx), and 30 individuals received two MDx. Genes most commonly contributing to MDx were FGFR3 (16.9%), ALPL (13.0%), and COL1A1 (10.3%). Most of the 112 genes associated with ≥1 MDx were primarily involved in signal transduction (n = 35), metabolism (n = 23), or extracellular matrix organization (n = 17). There were implications associated with specific care/treatment options for 84.4% (1158/1372) of MDx-positive individuals; >50% were linked to conditions with targeted therapy approved or in clinical development, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and mucopolysaccharidosis. Forty individuals with initially inconclusive results became MDx-positive following family testing. Follow-up mucopolysaccharidosis enzyme activity testing was positive in 14 individuals (10 of these were not MDx-positive). Our findings showed that inclusion of metabolic genes associated with SD increased the clinical utility of a gene panel and confirmed that integrated use of comprehensive gene panel testing with orthogonal testing reduced the burden of inconclusive results.

Imaging in osteogenesis imperfecta: Where we are and where we are going.

Osteogenesis imperfecta (OI) is a rare phenotypically and genetically heterogeneous group of inherited skeletal dysplasias. The hallmark features of OI include bone fragility and susceptibility to fractures, bone deformity, and diminished growth, along with a plethora of associated secondary features (both skeletal and extraskeletal). The diagnosis of OI is currently made on clinical grounds and may be confirmed by genetic testing. However, imaging remains pivotal in the evaluation of this disease. The aim of this article is to review the current role played by the various radiologic techniques in the diagnosis and monitoring of OI in the postnatal setting as well as to discuss recent advances and future perspectives in OI imaging. Conventional Radiography and Dual-energy X-ray Absorptiometry (DXA) are currently the two most used imaging modalities in OI. The cardinal radiographic features of OI include generalized osteopenia/osteoporosis, bone deformities, and fractures. DXA is currently the most available technique to assess Bone Mineral Density (BMD), specifically areal BMD (aBMD). However, DXA has important limitations and cannot fully characterize bone fragility in OI based on aBMD. Novel DXA-derived parameters, such as Trabecular Bone Score (TBS), may provide further insight into skeletal changes induced by OI, but evidence is still limited. Techniques like Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) can be useful as problem-solvers or in specific settings, including the evaluation of cranio-cervical abnormalities. Recent evidence supports the use of High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) as a promising tool to improve the characterization of bone fragility in OI. However, HR-pQCT remains a primarily research technique at present. Quantitative Computed Tomography (QCT) is an alternative to DXA for the determination of BMD at central sites, with distinct advantages but considerably higher radiation exposure. Quantitative Ultrasound (QUS) is a portable, inexpensive, and radiation-free modality that may complement DXA evaluation, providing information on bone quality. However, evidence of usefulness of QUS in OI is poor. Radiofrequency Echographic Multi Spectrometry (REMS) is an emerging non-ionizing imaging method that holds promise for the diagnosis of low BMD and for the prediction of fracture risk, but so far only one published study has investigated its role in OI. To conclude, several different radiologic techniques have proven to be effective in the diagnosis and monitoring of OI, each with their own specificities and peculiarities. Clinicians should be aware of the strategic role of the various modalities in the different phases of the patient care process. In this scenario, the development of international guidelines including recommendations on the role of imaging in the diagnosis and monitoring of OI, accompanied by continuous active research in the field, could significantly improve the standardization of patient care.

Using MRI-derived observed-to-expected total fetal lung volume to predict lethality in fetal skeletal dysplasia.

BACKGROUND: Pulmonary hypoplasia is the primary cause of perinatal death in lethal skeletal dysplasias. The antenatal ultrasound correlates for lethality are indirect, measuring the thorax (thoracic circumference, TC) or femur compared to the abdomen (TC/AC, FL/AC). A single study has correlated lethality with the observed-to-expected total lung volume (O/E-TFLV) on fetal MRI in 23 patients. OBJECTIVE: Our aim was to define a cutoff value to predict lethality more specifically using MRI-derived O/E-TFLV. MATERIALS AND METHODS: Two large fetal center databases were searched for fetuses with skeletal dysplasia and MRI; O/E-TFLV was calculated. Ultrasound measures were included when available. Each was evaluated as a continuous variable against lethality (stillbirth or death in the first month of life). Logistic regression and receiver operating characteristic (ROC) curve analyses evaluated the prediction ability. AUC, sensitivity, and specificity were calculated. P < 0.05 was considered statistically significant. RESULTS: A total of 80 fetuses met inclusion criteria. O/E-TFLV < 0.49 was a significant risk factor in predicting lethality, with sensitivity and specificity of 0.63 and 0.93, respectively, and an AUC of 0.81 (P < 0.001). FL/AC < 0.129 was also a strong variable with sensitivity, specificity, and AUC of 0.73, 0.88, and 0.78, respectively (P < 0.001). TC/AC and TC percentile were not significant risk factors for lethality. An O/E-TFLV of < 0.38 defines a specificity for lethality at 1.00. CONCLUSION: MRI-derived O/E-TFLV and US-derived FL/AC are significant predictors of lethality in fetuses with skeletal dysplasia. When prognosis is uncertain after ultrasound, calculation of MRI-derived O/E-TFLV may provide additional useful information for prognosis and delivery planning.

A new case of Melnick-Needles syndrome with skeletal manifestations: A case report.

INTRODUCTION AND IMPORTANCE: Melnick-Needles syndrome (MNS) is a rare skeletal dysplasia that affects skeletal and connective tissue. Less than 70 cases of MNS reported in the literature. MNS had various clinical manifestations such as skeletal deformity, cortical bony sclerosis, facial abnormality, and urogenital symptoms. CASE PRESENTATION: We presented a 5-year-old girl who referred to our orthopedic clinic with knee valgus deformity, spinal kyphoscoliosis, bilateral coxa valga, and humerus cortical irregularity. Based on some facial and skeletal feature, MNS was confirmed with genetic evaluation (heterozygote Filamin A genome). CLINICAL DISCUSSION: The diagnosis of MNS requires a thorough medical and family history, physical examination, and radiographic evaluation. Differential diagnoses for patients with skeletal and facial deformities like MNS include Camurati-Engelmann disease, cystinuria, Galloway-Mowat syndrome, Joubert syndrome, and mucopolysaccharidosis. Treatment for MNS patients with bony deformities without lethal conditions can be conservative, but corrective surgery may be necessary in some cases. CONCLUSIONS: MNS was a rare syndrome with common clinical manifestations such as limb and spine deformity. It is important to conduct a careful examination of any patient who presents with limb and skeletal deformity to the orthopedic clinic, as the disease may have some lethal clinical implications.

Frequency of skeletal dysplasia in children with short stature presenting to endocrine clinic: An observational study.

Objective: To determine the frequency of skeletal dysplasia in children with short stature presenting to the endocrine clinic of a tertiary care hospital. Methods: This descriptive cross-sectional study was performed in the Outpatient Department of Endocrinology of National Institute of Child Health, Karachi, for 6 months of duration. A total of 200 children coming to endocrine OPD of NICH of either gender, having the age less than 14 years and height more than -2.5 SD below the mean (<3rd percentile), and growth failure (<4 cm/yr) were enrolled. A complete general physical examination including height, weight, fronto-occipital circumference (FOC), arm span, and U/L (upper/lower) segment ratio (using SI units and SDS) was performed. Results: Out of 200 children with short stature, skeletal dysplasia was diagnosed in 23 (11.5%) children with the mean age of 4.7 (±3.7) years. Proportion of skeletal dysplasia among short stature was high in females. Out of 75 girls, skeletal dysplasia was diagnosed in 10 (13.3%) girls, while out of 125 boys, skeletal dysplasia was diagnosed in 13 (10.4%) boys, whereas when we see proportion among skeletal dysplasia out of 23 children of skeletal dysplasia, 13 (56.5%) were boys, while 10 (43.5%) were girls. Conclusion: In this study, skeletal dysplasia was diagnosed in 11.5% children with short stature with the mean age of 4.7 years. It is concluded that the frequency of skeletal dysplasia in this institute is fairly high.

Displasia tanatofórica tipo II, una entidad congénita inusual. Reporte de caso / Thanatophoric dysplasia type 2, an unusual congenital disease - Case Report

Resumen La displasia tanatofórica es un defecto congènito inusual y esporádico cuyo desenlace es la muerte intrauterina o pocos días después del nacimiento. Su aparición se ha descrito en 0,2-0,5 casos de cada 10.000 nacidos vivos, y depende de la mutación del receptor del factor de crecimiento fibroblasto-3. Cuenta con dos presentaciones clínicas: tipo I y tipo II; esta última es menos frecuente y se caracteriza por el hallazgo de cráneo en hoja de trébol y micromelia con fémures rectos. A continuación, se presenta el caso de una joven multípara con hallazgo en la primera ecografía del embarazo de feto con acortamiento general de las extremidades y disminución de la osificación general, sugestiva de displasia tanatofórica tipo II, que resultó en la interrupción voluntaria del embarazo. El diagnóstico temprano en la gestación es importante para orientar la práctica médica con base en el mal pronóstico del padecimiento de esta patología.

Abstract Thanatophoric dysplasia is an unusual and sporadic congenital defect whose outcome is intrauterine death or a few days after birth. Its appearance has been described in 0.2-0.5 cases of every 10,000 live births and depends on the mutation of the fibroblast growth factor receptor-3. It exhibits two clinical presentations, of these, the so-called type II is less frequent and is characterized by the finding of a cloverleaf skull and micromelia with straight femurs. The following is the case of a young multiparous pregnant woman with a finding in her first ultrasound of fetus pregnancy with general shortening of the limbs and decreased general ossification, suggestive of thanatophoric dysplasia type II, which resulted in the voluntary termination of pregnancy. Early diagnosis in pregnancy is important in order to guide medical practice based on the poor prognosis of suffering from this pathology.

Genetic analysis of a pedigree of DYNC2H1 gene variation-caused short rib polydactyly syndrome type Ⅲ / 中华围产医学杂志

This paper reported the genetic analysis of a pedigree in which three affected fetuses with short limbs were revealed by first-trimester ultrasonography in three consecutive pregnancies. Tissues of the second aborted fetus were collected and analyzed by chromosome karyotype analysis and whole exome sequencing. The results indicated compound heterozygous mutations of EX64-EX83 Del and c.8190G>T in the DYNC2H1 gene. Real-time fluorescence quantitative polymerase chain reaction and Sanger sequencing further confirmed that the two variants were inherited from the father and the mother with normal phenotypes, respectively. EX64-EX83 Del was a likely pathogenic variant and c.8190G>T was a variant of uncertain significance. Based on the above results and the medical history, it was highly suspected that the fetus had autosomal recessive short rib polydactyly syndrome type Ⅲ caused by compound heterozygous variants. Real-time fluorescent quantitative polymerase chain reaction and Sanger sequencing results of the third aborted fetus were consistent with the second fetus. Given the same phenotypes of fetuses in the second and third pregnancy, it was strongly suggested that the heterozygous variations of EX64-EX83 Del and c.8190G>T in the DYNC2H1 gene were the pathogenic variants in this pedigree.

Prenatal diagnosis of diastrophic dysplasia in the second trimester of pregnancy: Two- and three- dimensional ultrasonographic findings

To present a prenatal diagnosis of diastrophic dysplasia in the second trimester of pregnancy using two- (2D) and three-dimensional (3D) ultrasonography. The mother was primigravida and aged 12 years. She underwent the first 2D obstetric ultrasound examination at 27 weeks, showing bilaterally upper and lower limb micromelia, thumb and hallux in bilateral abduction, bilateral talipes equinovarus; hyperlordosis of the lumbar spine, cervical, lumbar, and sacral scoliosis; cervical hyperkyphosis with the misalignment of cervical vertebrae, and straight clavicles. 3D ultrasonography in conventional and HDlive rendering modes confirmed the changes observed in 2D ultrasonography and allowed improved understanding by the parents. At birth, the newborn presented transient respiratory distress and neonatal sepsis. At the time of writing, the child is aged 31 months and under follow-up by the pediatrics department. 3D ultrasound allowed the parents to understand the fetal malformations better, and they received adequate counseling.

Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara / Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology

La acrodisostosis es una displasia esquelética rara, de herencia autosómica dominante, que se caracteriza por la presencia de disostosis facial y periférica, talla baja y diferentes grados de obesidad. La acrodisostosis de tipo 1, secundaria a la mutación heterocigota en el gen PRKAR1A (17q24.2), se caracteriza por la asociación de resistencia hormonal múltiple con anomalías esqueléticas. Su incidencia está infradiagnosticada debido a que comparte rasgos clínicos y de laboratorio con otras entidades como el seudohipoparatiroidismo. Presentamos el caso de una niña de 8 años, con acrodisostosis tipo 1, confirmada mediante estudio genético. Además del fenotipo característico descrito, la talla baja y la resistencia hormonal, la paciente presentó una afectación progresiva de la función pulmonar: un patrón pulmonar obstructivo no reversible. En la literatura revisada, no se han encontrado otros casos que describan esta asociación entre acrodisostosis y afectación respiratoria.

Acrodysostosis is a rare skeletal displasia, of autosomal dominant inheritance, characterized by the presence of facial and peripheral dysostosis, short stature and obesity. Type 1 acrodysostosis is secondary to a mutation in the PRKAR1A (17q24.2) gene, which results in multi hormonal resistance and skeletal anomalities. This syndrome is under-diagnosed as it shares analytical and clinical characteristics with other entities, such as pseudohypoparathyroidism. We report the case of an eight-year-old girl with genetically confirmed type 1 acrodysostosis. In addition to the characteristic phenotype described, the short stature and the hormonal resistance, the patient suffered a progressive lung function deterioration: an irreversible pulmonary obstructive pattern. We have not found in previous literature cases reporting an association between acrodysostosis and lung function impairement.

Cervical Disorders in Mucopolysaccharidosis IVA-Morquio disease.

Morquio disease or mucopolysaccharidosis type IVA (Online Mendelian Inheritance in Man No. 253000) is a rare autosomal recessive disease classified in the group of metabolism inborn errors. The glycosaminoglycans accumulate in chondrocytes, which disturbs bone growth and leads to skeletal manifestations, such as skeletal dysplasia and a short stature. In addition, the disproportionate growth of the trachea can lead to airway insufficiency. We report the case of a 27-year-old man with dwarfism due to Morquio disease, which had resulted in quadriparesis, hyperreflexia, and dyspnea, requiring a "look up to the sky" compensatory position. Imaging studies of the neck showed tracheal tortuosity, spinal stenosis, myelopathy, and neurogenic arthropathy (Charcot joint). The patient was treated with occipital-cervical-thoracic instrumentation. However, postoperative tracheal correction was required. Considering the wide spectrum of clinical features in those with mucopolysaccharidosis type IVA, individualized multidisciplinary treatment is recommended.

[Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology]. / Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara.

Acrodysostosis is a rare skeletal displasia, of autosomal dominant inheritance, characterized by the presence of facial and peripheral dysostosis, short stature and obesity. Type 1 acrodysostosis is secondary to a mutation in the PRKAR1A (17q24.2) gene, which results in multi hormonal resistance and skeletal anomalities. This syndrome is under-diagnosed as it shares analytical and clinical characteristics with other entities, such as pseudohypoparathyroidism. We report the case of an eight-year-old girl with genetically confirmed type 1 acrodysostosis. In addition to the characteristic phenotype described, the short stature and the hormonal resistance, the Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology patient suffered a progressive lung function deterioration: an irreversible pulmonary obstructive pattern. We have not found in previous literature cases reporting an association between acrodysostosis and lung function impairement.

La acrodisostosis es una displasia esquelética rara, de herencia autosómica dominante, que se caracteriza por la presencia de disostosis facial y periférica, talla baja y diferentes grados de obesidad. La acrodisostosis de tipo 1, secundaria a la mutación heterocigota en el gen PRKAR1A (17q24.2), se caracteriza por la asociación de resistencia hormonal múltiple con anomalías esqueléticas. Su incidencia está infradiagnosticada debido a que comparte rasgos clínicos y de laboratorio con otras entidades como el seudohipoparatiroidismo. Presentamos el caso de una niña de 8 años, con acrodisostosis tipo 1, confirmada mediante estudio genético. Además del fenotipo característico descrito, la talla baja y la resistencia hormonal, la paciente presentó una afectación progresiva de la función pulmonar: un patrón pulmonar obstructivo no reversible. En la literatura revisada, no se han encontrado otros casos que describan esta asociación entre acrodisostosis y afectación respiratoria.

Spinal anesthesia in a patient with Schwartz-Jampel syndrome.

BACKGROUND: Schwartz-Jampel syndrome (SJS) is a very rare inherited disorder characterized by multiple skeletal deformities, limited joint mobility, micrognathia, blepharophimosis, myotonia, and growth retardation. SJS is caused by mutations in the gene encoding perlecan (heparan sulfate proteoglycan). Anesthetic management of these patients is challenging. The use of spinal anesthesia in these patients has not been reported. CASE PRESENTATION: A 14-year-old boy was scheduled for inguinal hernia and hydrocele repair. The diagnosis of SJS was based on his dysmorphic features, electromyographic (EMG) pattern and genetic testing. General anesthesia may encounter difficult airway management, resistance to muscle relaxants, or possibility of malignant hyperthermia. Regional anesthesia may be difficult or even harmful due to skeletal deformities. We report successful management of spinal anesthesia and surgery was done. The patient had an uneventful recovery and was discharged home. We describe the special precautions against pitfalls for using this technique in patients with SJS. CONCLUSION: Spinal anesthesia may be an effective and safe technique for patients with SJS and it may.

Joint Replacements in Individuals With Skeletal Dysplasias: One Institution's Experience and Response to Operative Complications.

BACKGROUND: Skeletal dysplasias are a heterogeneous group of >400 genetic disorders characterized by abnormal bone growth. Many individuals experience joint pain and limitation, coming to require joint replacement much earlier than the average-statured population. In addition, prosthesis survival rate is less in the dysplastic population. The purpose of this study is to identify risk factors for surgery and provide recommendations to improve surgical outcomes. METHODS: This a retrospective review of 29 individuals with a skeletal dysplasia who had 64 joint replacements between April 1985 and January 2019 at a single institution. We collected demographics, physical examination, medical history, imaging studies, surgical indication, and complications. RESULTS: Spondyloepiphyseal dysplasia was the most common skeletal dysplasia (7), followed by pseudoachondroplasia (4) and multiple epiphyseal dysplasia (4). Average age of the cohort was 40.6 years (range 14-64). Hip arthroplasty (34) was the most commonly performed surgery. The majority of arthroplasties (75%) required custom components. Complication rate was 37.3%, most commonly pulmonary embolism (3) and pneumonia (3). Most complications (81.8%) occurred in individuals with either a pre-existing cardiopulmonary comorbidity or lumbar/sacral deformity. Body mass index did not correlate with complication severity (R = -0.042, P = .752) or rate (R = 0.006, P = .963). CONCLUSION: Surgical complications are highest in patients with pre-existing cardiopulmonary conditions. Body mass index does not predict complications in this cohort. Preoperative evaluations for individuals with skeletal dysplasias should include comprehensive work-up of spine issues and extraskeletal systems that present an operative risk. Intraoperative protocol should include special consideration for placement on the table, airway maintenance, and spinal cord monitoring in select cases.

Manejo quirúrgico de la duplicación patelar bilateral en displasia epifisiaria múltiple recesiva. Reporte de caso / Surgical management of bilateral duplication of the patella in multiple recessive epiphyseal dysplasia. A case report

Introducción La displasia epifisiaria múltiple (DEM) es una enfermedad poco frecuente y con gran variedad clínica y se caracteriza por deformidades en las articulaciones, dolor, y trastornos de la marcha. La duplicación patelar se asocia con DEM recesiva y consiste en dos segmentos patelares escalonados separados por tejido blando entre ellos. Caso clínico Paciente masculino de 30 años con cuadro clínico de DEM recesiva con duplicación patelar, presenta dolor crónico bilateral de cadera y rodilla, y trastorno de la marcha. Tras el examen físico, se evidenció derrame articular, dificultad para la flexión de las rodillas y un cuerpo libre intra-articular bilateral. Se identificaron dos segmentos patelares, displasia acetabular y de cabeza femoral bilateral con imágenes diagnósticas. El manejo quirúrgico de la duplicación patelar fue resección de los segmentos óseos accesorios, conduciendo a un resultado clínico satisfactorio al año de seguimiento. Discusión Aunque no se realiza el diagnóstico genético de la DEM, nuestro paciente presenta las características fenotípicas y radiológicas de esta entidad. Para la duplicación patelar, se realizó la resección de las patelas accesorias, considerando el alto riesgo de no unión. Sin embargo, existen varios reportes donde unieron los dos segmentos patelares, pero principalmente en niños. Este es el primer reporte publicado sobre el manejo quirúrgico de esta patología en Colombia. La duplicación patelar puede manejarse con éxito mediante la resección de la patela accesoria en adultos. Aunque los hallazgos imagenológicos son muy sugestivos de esta patología, se requiere un adecuado examen físico para evitar un diagnóstico equivoco y tardío.

Background Multiple epiphyseal dysplasia (MED) is a rare disease with a great clinical variation, and is characterised by deformities in the joints, pain, and gait disorders. Duplication of the patella is associated with recessive MED, and consists of two staggered patellar segments separated by soft tissue between them. Clinical case A 30-years-old male patient with a clinical manifestation of recessive MED with duplication of the patella, chronic bilateral hip and knee pain, as well as gait disorder. After the physical examination, joint effusion, difficulty in flexing the knees, and a bilateral intra-articular free body were evident. Two patellar segments, acetabular dysplasia and bilateral femoral head, were identified with diagnostic imaging. The surgical management of duplication of the patella was resection of the accessory bone segments, leading to a satisfactory clinical result at one year of follow-up. Discussion Although the genetic diagnosis of the MED was not made, our patient presented with the phenotypic and radiological characteristics of this disease. For duplication of the patella, the accessory patella resection was performed, considering the high risk of non-union. However, there are several reports where the two patellar segments are joined; but mainly in children. This is the first report published about the surgical management of this pathology in Colombia. Duplication of the patella can be managed successfully by resecting accessory patella in adults. Although the imaging findings are very suggestive of this pathology, an adequate physical examination is required to avoid a false and late diagnosis.

Clinical characteristics and pathogenic gene analysis in a large pedigree with multiple epiphyseal dysplasia / 中华骨科杂志

Objective@#To provide experimental evidence for genetic counseling and prenatal molecular diagnosis by analyzing the clinical characteristics and screening for pathogenic genes of a five-generation suspected multiple epiphyseal dysplasia (MED) family (17 patients).@*Methods@#The family members' medical history, general physical examination and hip joint X-ray examination were collected. Peripheral blood samples of the family members were collected and DNA were extracted from these samples. The exons of clinical genes from probands' DNA were sequenced by High throughput sequencing method. Next Gene software was used to compare and analyze the sequence and INGENUITY software was further used to annotate the mutations in order to find the pathogenic mutations in probands. The suspicious mutations were confirmed in pedigree members by PCR and Sanger sequencing.@*Results@#The family consisted of 5 generations and 38 members. Pedigree analysis was consistent with autosomal dominant inheritance. There were 17 patients in the family, and their clinical manifestations showed abnormal walking posture in childhood, pain in hip and knee joints, and typical pathological changes of epiphyseal dysplasia on X-ray. Cartilage oligomeric matrix protein (COMP) gene c.1153G>A (p.Asp385Asn) missense heterozygous mutation was screened in proband, which was genotypically and phenotypically segregated in the pedigree.@*Conclusion@#A missense mutation of the comp gene has been identified in a pedigree affected with MED which was the first reported in a big family. Our result is conducive to the further diagnosis and treatment and also provides a molecular basisfor the future prenatal diagnosis.

Clinical characteristics and pathogenic gene analysis in a large pedigree with multiple epiphyseal dysplasia / 中华骨科杂志

Objective To provide experimental evidence for genetic counseling and prenatal molecular diagnosis by analyzing the clinical characteristics and screening for pathogenic genes of a five-generation suspected multiple epiphyseal dysplasia (MED) family (17 patients).Methods The family members' medical history,general physical examination and hip joint X-ray examination were collected.Peripheral blood samples of the family members were collected and DNA were extracted from these samples.The exons of clinical genes from probands' DNA were sequenced by High throughput sequencing method.Next Gene software was used to compare and analyze the sequence and INGENUITY software was further used to annotate the mutations in order to find the pathogenic mutations in probands.The suspicious mutations were confirmed in pedigree members by PCR and Sanger sequencing.Results The family consisted of 5 generations and 38 members.Pedigree analysis was consistent with autosomal dominant inheritance.There were 17 patients in the family,and their clinical manifestations showed abnormal walking posture in childhood,pain in hip and knee joints,and typical pathological changes of epiphyseal dysplasia on X-ray.Cartilage oligomeric matrix protein (COMP) gene c.1153G ＞ A (p.Asp385Asn) missense heterozygous mutation was screened in proband,which was genotypically and phenotypically segregated in the pedigree.Conclusion A missense mutation of the comp gene has been identified in a pedigree affected with MED which was the first reported in a big family.Our result is conducive to the further diagnosis and treatment and also provides a molecular basisfor the future prenatal diagnosis.

Bone dysplasias in 1.6 million births in Argentina.

Currently accepted birth prevalence for osteochondrodysplasias (OCDs) is about 2 per 10,000 births. Our main goal is to estimate the prevalence of OCDs in Argentina and compare it with other surveillance systems. We examined 1,663,610 births among 160 hospitals of RENAC (Red Nacional de Anomalías Congénitas - National Network of Congenital Anomalies) between November 2009 and December 2016. Cases were detected and registered according to a pre-established protocol, ranked in three diagnostic evidence levels according to available clinical documentation, and categorized according to the 9th edition of the nosology and classification of genetic skeletal disorders. Within our dataset, the most frequent groups were Group-1 (FGFR3, chondrodysplasia) and Group-25 (Osteogenesis Imperfecta and decreased bone density). Birth prevalence per 10,000 for the main OCD types, were: Achondroplasia 0.47 (95% CI: 0.38-0.59), Thanatophoric Dysplasia 0.37 (95% CI: 0.29-0.48), and the Osteogenesis Imperfecta group 0.34 (95% CI: 0.26-0.44). For total OCD, birth prevalence was 2.20 per 10.000 births (95% CI: 1.98-2.44). RENAC prevalence of total OCDs was found to be lower than that reported by the Latin-American Study of Congenital Malformations (ECLAMC) and Utah Birth Defect Network but higher than EUROCAT. Our investigation is the first study of OCD prevalence in Argentina using data from every jurisdiction of the country.

Prenatal diagnosis of three cases of fetal skeletal dysplasia resulting from loss of heterozigosity of short stature homeobox gene / 中华围产医学杂志

Objective To analyze the genotype-phenotype correlation in fetal skeletal dysplasia,and to investigate the methods of prenatal diagnosis and genetic counseling.Methods From May 2016 to November 2017,three gravidas whose fetuses were diagnosed with short stature homeobox (SHOX) gene deficiency were recruited from those receiving invasive prenatal diagnosis and single nucleotide polymorphismarray (SNP-array) due to fetal structural abnormalities detected by prenatal ultrasound scan in Shanghai First Maternity and Infant Hospital,Tongji University School of Medicine.Fetus 1 and 3 were singleton pregnancies and fetus 2 was twin pregnancy.Amniotic fluid cells were isolated and analyzed by karyotyping and SNP-array.Peripheral blood samples were collected from their parents and also analyzed by SNP-array.Results All three fetuses were diagnosed with fetal skeletal dysplasia based on second trimester ultrasound findings showing the lengths of femora,humeri,tibiae,fibulae,ulnae and radii length below the 5th percentile of corresponding gestational age.Karyotypes of the three fetuses were normal.SNP-array examination showed that each case had 1 to 2.5 Mb deletion in the pseudoautosomal region of the short arms of sex chromosomes,including SHOX gene.Their skeletal dysplasia were all caused by SHOX haploinsufficiency.Microdeletions of fetus 1 and 3 were inherited from their mothers,while that of fetus 2 was inherited from the father.After genetic counseling,two singleton gravidas decided to terminate their pregnancies and the twin pregnant one underwent selective reduction.Conclusion Prenatal ultrasound,in combination with SNP-array,offers fast and efficient detection of fetal skeletal dysplasia due to SHOX gene deficiency.