Diagnosis Of Skeletal Dysplasias Research Articles

Comprehensive genetic exploration of skeletal dysplasia using targeted exome sequencing.

The purpose of this study was to evaluate the clinical utility of targeted exome sequencing (TES) as a molecular diagnostic tool for patients with skeletal dysplasia. A total of 185 patients either diagnosed with or suspected to have skeletal dysplasia were recruited over a period of 3 years. TES was performed for 255 genes associated with the pathogenesis of skeletal dysplasia, and candidate variants were selected using a bioinformatics analysis. All candidate variants were confirmed by Sanger sequencing, correlation with the phenotype, and a cosegregation study in the family. TES detected "confirmed" or "highly likely" pathogenic sequence variants in 74% (71 of 96) of cases in the assured clinical diagnosis category and 20.3% (13 of 64 cases) of cases in the uncertain clinical diagnosis category. TES successfully detected pathogenic variants in all 25 cases of previously known genotypes. The data also suggested a copy-number variation that led to a molecular diagnosis. This study demonstrates the feasibility of TES for the molecular diagnosis of skeletal dysplasia. However, further confirmation is needed for a final molecular diagnosis, including Sanger sequencing of candidate variants with suspected, poorly captured exons.Genet Med 18 6, 563-569.

Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations

Skeletal dysplasias are highly variable Mendelian phenotypes. Molecular diagnosis of skeletal dysplasias is complicated by their extreme clinical and genetic heterogeneity. We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family, comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability. Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay. Using a gene-centric "matchmaking" system, we were able to identify a Peruvian simplex case subject whose phenotype is strikingly similar to the original Saudi family and whose exome sequencing had revealed a likely pathogenic homozygous missense variant in the same gene. RSPRY1 encodes a hypothetical RING and SPRY domain-containing protein of unknown physiological function. However, we detect strong RSPRY1 protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, consistent with a role in bone development. This study highlights the role of gene-centric matchmaking tools to establish causal links to genes, especially for rare or previously undescribed clinical entities.

A review of imaging protocols for suspected skeletal dysplasia and a proposal for standardisation.

Expert radiology opinions are often requested to aid diagnosis of skeletal dysplasias or dysostoses, but due to variability in the imaging protocols used at different centres the views presented may be considered inadequate or incomplete resulting in diagnostic delays and increased patient and family anxiety. We propose the introduction of a standardised protocol that may be adapted in certain specific situations.

Skeletal dysplasias from an endocrine point of view

Skeletal dysplasias are complex group of diseases with different clinical and radiologic findings involving bone, and/or cartilage. Although skeletal dysplasias are rarely seen when considered individually, general incidence in the population is 1/3000-5000. Skeletal dysplasias are classified in 40 main groups on the basis of clinical, laboratory, radiological and molecular evaluations, and congenital malformations, spinal abnormalities, short extremities, and disproportionate short stature are seen in sekondereletal dysplasias. In addition to bone abnormalities, endocrine problems including hyperglycemia, hypo/hypercalcemia, adrenal failure, pubertal alterations, and disorders of sexual development which are mostly due to genetic disorders may accompany skeletal dysplasias. Differential diagnosis of skeletal dysplasias requires detailed history and physical examination, skeletal X-rays, genetic analysis, some advanced laboratory methods, and multidisciplinary aproach. In this review, it is aimed to present a general approach to skeletal dysplasias, endocrine abnormalities that may accompany, and the most recent classification published in 2010.

Radiation dose reduction at MDCT with iterative reconstruction for prenatal diagnosis of skeletal dysplasia: preliminary study using normal fetal specimens.

The purpose of this study was to investigate to what degree the radiation dose can be reduced without affecting the ability to evaluate normal fetal bones at MDCT with iterative reconstruction. Fifteen normal fetal specimens immersed in containers (30- and 35-cm diameter) were scanned with a 64-MDCT scanner, with tube voltage of 100 kVp and tube current of 600, 300, 150, 100, and 50 mA. Images were subjected to adaptive statistical iterative reconstruction (ASIR). The fetal dose was measured using glass dosimeters. We calculated the relative ratio of the dose at 600 mA. Image quality was evaluated on maximum-intensity-projection and volume-rendering images. Two radiologists recorded the visualization scores of five regions. Images at 600 mA were considered to be standard. With the 30-cm-diameter container, the fetal dose was 10.15 mGy (relative ratio, 100%) at a tube current of 600, 51% at 300, 25% at 150, 17% at 100, and 9% at 50 mA. With the 35-cm-diameter container the fetal dose was 10.01 mGy (relative ratio, 100%) at 600, 47% at 300, 24% at 150, 17% at 100, and 8% at 50 mA. Visual evaluation showed that in both containers, with ASIR 90%, there was a statistically significant difference between 50-and 600-mA images (p<0.01) but not between 600-mA images and those acquired at 100, 150, and 300 mA (p=0.08-1.00). The fetal radiation dose for the evaluation of normal fetal bones can be reduced by 83% with ASIR 90%.

Foetal radiography for suspected skeletal dysplasia: technique, normal appearances, diagnostic approach.

Despite advances in antenatal imaging and genetic techniques, post-delivery post-mortem foetal radiography remains the key investigation in accurate diagnosis of skeletal dysplasia manifesting in the foetus. Foetal radiography is best performed using pathology-specimen radiography equipment and is often carried out in the pathology department without involvement of the radiology unit. However, paediatric radiologists may be asked to interpret post-mortem foetal radiographs when an abnormality is suspected. Many foetal radiographs are carried out before 20weeks' gestation, and the interpreting radiologist needs to be familiar with the range of normal post-mortem foetal appearances at different gestational ages, as well as the appearances of some of the more commonly presenting skeletal dysplasias, and will benefit from a systematic approach when assessing more challenging cases. In this pictorial essay, we illustrate various normal post-mortem foetal radiographic appearances, give examples of commonly occurring skeletal dysplasias, and describe an approach to establishing more difficult diagnoses.

Predictive value of fetal lung volume in prenatally diagnosed skeletal dysplasia.

Pulmonary hypoplasia is a major cause of death in lethal skeletal dysplasias. We hypothesize that in fetuses with prenatally diagnosed skeletal dysplasia, comparison of observed-to-expected (O/E) lung volume will help predict lethality. We conducted a retrospective chart review of patients referred for evaluation of suspected fetal skeletal anomalies. Twenty-three pregnancies were identified with confirmed fetal diagnosis of skeletal dysplasia for which fetal magnetic resonance imaging (MRI) was performed between 21 and 38 weeks of gestation and ultrasound biometry data were available. Femur length to abdominal circumference ratio (FL/AC) and O/E lung volumes were calculated. The association between O/E lung volume, FL/AC, and lethality was measured using logistic regression. Lethality was significantly associated with O/E lung volume (p = 0.002) and FL/AC (p = 0.0476). Analysis with receiver-operating characteristic curves suggested that O/E lung volume of 47.9% or FL/AC of 0.124 could be useful clinical cutoffs in the prediction of lethality. In fetuses with skeletal dysplasia, fetal MRI-derived O/E lung volume was predictive of lethality. When evaluating a fetal skeletal dysplasia, fetal MRI may be considered in cases for which ultrasound-based lethality prediction is ambiguous or uncertain in order to provide families with the most complete and accurate information.

Novel c.358C&gt;T mutation of SOX9 gene in prenatal diagnosis of campomelic dysplasia

Novel c.358<scp>C</scp>&gt;<scp>T</scp> mutation of <i><scp>SOX</scp>9</i> gene in prenatal diagnosis of campomelic dysplasia

Atelosteogenesis Type 2/Diastrophic Dysplasia Phenotypic Spectrum: From Prenatal to Preimplantation Genetic Diagnosis

Atelosteogenesis type II (AO2) and diastrophic dysplasia (DTD) are two recessively inherited, severe skeletal dysplasias caused by mutations in the SLC26A2 gene. AO2 is an invariably lethal condition, while DTD patients may reach adult life, although both diseases have overlapping diagnostic features. Here we report a patient with an intermediate phenotype between AO2 and DTD and present the successful application of preimplantation genetic diagnosis (PGD) in this situation. Sequencing of SLC26A2 alleles in the infant identified two compound heterozygous mutations, p.Arg178Ter and p.Arg279Trp, of paternal and maternal origin, respectively. At request from the parents, PGD was developed by haplotype mapping of parental SLC26A2 alleles in eleven five-day embryos. Transference to the mother was attempted twice, finally resulting in pregnancy and delivery of a healthy baby. This exemplifies the utility of PGD for inherited lethal conditions with a significant risk of recurrence, and highlights the importance of accurate diagnosis of skeletal dysplasias with prenatal manifestation.

Low-Dose Fetal CT in the Prenatal Evaluation of Skeletal Dysplasias and Other Severe Skeletal Abnormalities

Prenatal diagnosis of skeletal dysplasia is often difficult and based on findings with ultrasound, a technique with 40-60% sensitivity. The purpose of this study was to evaluate a preliminary experience in assessing severe prenatal osseous abnormalities with low-dose fetal CT. The hypothesis was that use of CT may improve the prenatal diagnosis of skeletal dysplasia beyond the available capabilities of ultrasound. Retrospective search of a radiology database (July 2008-February 2011) yielded the records of unenhanced CT examinations of patients referred because of abnormal fetal bones. The original ultrasound and CT reports as interpreted at image acquisition were independently analyzed by two radiologists blinded to the final diagnosis and to the findings of the opposing imaging modality. Blinded review of the images was also performed. Correlation was made with the postmortem and postnatal findings. According to the reports of the studies, 5 of 21 cases were interpreted correctly with CT and incorrectly with ultrasound. In 17 cases, CT revealed additional osseous findings not in the ultrasound report. There were no cases in which ultrasound findings were correct and CT findings were incorrect. Blinded review of the images revealed that CT outperformed ultrasound (p < 0.001). There were a total of four CT errors among 218 total measures recorded and a total of 19 ultrasound errors among 218 total measures. Although low-dose fetal CT should never be used as the initial diagnostic modality in cases of suspected skeletal dysplasia, it is a powerful imaging adjunct that depicts the fetal bones in exquisite detail. Use of CT of fetuses at risk of skeletal dysplasia may provide clinicians with more accurate information for counseling of families regarding neonatal morbidity and mortality.

Decision support methods for finding phenotype--disorder associations in the bone dysplasia domain.

A lack of mature domain knowledge and well established guidelines makes the medical diagnosis of skeletal dysplasias (a group of rare genetic disorders) a very complex process. Machine learning techniques can facilitate objective interpretation of medical observations for the purposes of decision support. However, building decision support models using such techniques is highly problematic in the context of rare genetic disorders, because it depends on access to mature domain knowledge. This paper describes an approach for developing a decision support model in medical domains that are underpinned by relatively sparse knowledge bases. We propose a solution that combines association rule mining with the Dempster-Shafer theory (DST) to compute probabilistic associations between sets of clinical features and disorders, which can then serve as support for medical decision making (e.g., diagnosis). We show, via experimental results, that our approach is able to provide meaningful outcomes even on small datasets with sparse distributions, in addition to outperforming other Machine Learning techniques and behaving slightly better than an initial diagnosis by a clinician.

Prenatal diagnosis of osteogenesis imperfecta type II by three‐dimensional computed tomography: The current state of fetal computed tomography

We report a case of osteogenesis imperfecta (OI) (OMIM166210) type II, in which a prenatal diagnosis was made by three-dimensional computed tomography (3D-CT). Subsequent molecular analysis revealed a recurrent, heterozygous mutation in COL1A2. Fetal CT is a powerful tool for visualizing the fetal skeleton and can provide a definitive diagnosis of fetal skeletal dysplasias; however, whether or not its employment for prenatal diagnosis is warranted in terms of fetal radiation risks remains controversial, both medically and ethically. Based on our experience, we review the current state of fetal CT for the diagnosis of skeletal dysplasias, with a discussion of the relevant literature.

FGFR3 related skeletal dysplasias diagnosed prenatally by ultrasonography and molecular analysis: Presentation of 17 cases

Fibroblast Growth Factor Receptor 3 (FGFR3) related skeletal dysplasias are caused by mutations in the FGFR3 gene that result in increased activation of the receptors causing alterations in the process of endochondral ossification in all long bones, and include achondroplasia, hypochondroplasia, thanatophoric dysplasia, and SADDAN. Reports of prenatal diagnosis of FGFR3 related skeletal dysplasias are not rare; however, the correlation between 2nd trimester ultrasonographic findings and underlying molecular defect in these cases is relatively poor. There is a need for specific ultrasound (U/S) predictors than can distinguish lethal from non-lethal cases and aid an earlier prenatal diagnosis. Here we present one familial and 16 sporadic cases with FGFR3 related skeletal dysplasia, and we evaluate biometric parameters and U/S findings consistent with the diagnosis of skeletal dysplasia. U/S scan performed even at the 18th week of gestation can indicate a decreased rate of development of the femora (femur length (FL) <5th centile), while the mean gestational age at diagnosis is still around the 26th week. The utility of other biometric parameters and ratios is discussed (foot length, BPD, HC, FL/foot, and FL/AC). Prenatal cytogenetic and molecular genetic analyses were performed. A final diagnosis was reached by molecular analysis. In two cases of discontinued pregnancy, fetal autopsy led to a phenotypic diagnosis and confirmed the prenatal prediction of lethality. We conclude that the combination of U/S and molecular genetic approach is helpful for establishing an accurate diagnosis of FGFR3-related skeletal dysplasias in utero and subsequently for appropriate genetic counselling and perinatal management.

Genetic diseases of bones and joints

Genetic factors play roles in many diseases. Often these factors are ill defined and unpredictable. Other diseases are caused by specific single gene mutations and are passed to offspring in Mendelian inheritance patterns. There are over 5000 documented Mendelian disorders; over 500 of these affect bones and joints. Some of these single gene disorders affect many tissues, and the skeletal system is one of many organ systems involved. The surgical pathologist must often diagnose these disorders. Important examples are neurofibromatosis, Gaucher's disease, and alkaptonuria. Other single gene disorders almost exclusively affect the skeleton. These disorders are the skeletal dysplasias and 372 have been documented. These disorders are classified using radiographic, clinical, and molecular data. The most common dysplasias are osteogenesis imperfecta, achondroplasia, and osteopetrosis. The surgical pathologist usually does not play a role in the diagnosis of skeletal dysplasias. However, histologic studies often elucidate the pathophysiologic basis of these diseases and proper collection of tissues is important for the evolving understanding of the molecular basis of these disorders.

Ultrasound and autoptic diagnosis of asphyxiating thoracic dysplasia

Background . The skeletal system develops from mesoderm. In most bones (e.g., the long bones), ossification is preceded by cartilage (endochondral ossification). In other cases, such as flat bones, ossification develops directly in the mesenchyme without cartilage formation (intramembranous ossification). Skeletal dysplasias are a heterogeneous group of more disorders associated with developmental abnormalities of bone and cartilage. The modes of transmission are similar: autosomal dominant and recessive and X-linked dominant and recessive. Despite the potential advantages of 3-dimensional ultrasound (3D-US), antenatal diagnosis of skeletal dysplasia is difficult, given the large variety and complexity of these disorders: their phenotypes are variables and their features are overlapping. We present a case report of a woman with prenatal diagnosis of skeletal thoracic dysplasia, confirmed by postnatal radiography and fetal autopsy. Case report . A 26-year-old woman, primigravida, was referred for routine ultrasonic examination during her second trimester of pregnancy. Ultrasonography (USG) showed a single live foetus of a gestational age of 20+3 weeks; biparietal diameter and head circumference were adequate for the week of gestation. There was a polyhydramnios. The fetal thorax was extremely narrow. The thoracic circumference (TC) measured 100 mm (< 5th percentile), the abdominal circumference (AC) measured 157 mm (50th percentile), and the TC/AC ratio was 0.64 (normal range: 0.77–1.01). The long-bone lengths measured < 5th percentile, especially the proximal part of the upper limbs. Ultrasound scans of fetal abdomen revealed bilateral slight increase in the size of kidneys. There were no neural tube defects, and the fetal stomach and urinary bladder were normal. Fetal echocardiography revealed mild ventricular septal defect with good hemodynamic effect. Based on these findings, the diagnosis postulated as possible was asphyxiating thorax dysplasia (ATD). After genetic counseling, the patient decided for an elective termination of the pregnancy. A stillborn male fetus was delivered with a weight of 470 g. Infantogram and gross autopsy findings (narrow thorax, short upper limb bones, poor definition of pyramids of kidneys) supported the diagnosis made. Conclusion . Although skeletal anomalies are difficult to diagnose antenatally, a detailed scan of fetal anatomy between 20 and 32 gestational weeks exclude majority of major skeletal dysplasias. Termination of pregnancy is indicated and must be followed by genetic counseling for recurrence risk.

Early prenatal diagnosis of skeletal anomalies

To review experience of early prenatal diagnosis of skeletal dysplasias, and to explore diagnostic accuracy and improve management. A retrospective review of fetal medicine unit (FMU) records was performed to identify cases where a skeletal dysplasia was suspected by 14 weeks' gestation. A literature review was undertaken to ascertain cases with a diagnosis of a skeletal dysplasia in the late first or early second trimester. Fifteen cases were identified from review of FMU records, including ten different dysplasias with a variety of inheritance patterns. Accurate prenatal diagnosis was made only in cases with a positive family history, and in one case each of thanatophoric dysplasia and Roberts syndrome. Review of the literature identified further cases. Increased nuchal translucency was reported in other cases subsequently diagnosed as having a skeletal dysplasia. In early pregnancy, common presenting features included short femora, abnormal skull shape and mineralisation, profile or chest. Increasing use of first-trimester combined screening for Down's syndrome, with or without detailed anomaly scanning, will result in early detection of more skeletal dysplasias. Parents must be made aware that detailed postnatal pathological and radiological examination is usually required for accurate diagnosis and prediction of recurrence risks.

Prenatal diagnosis of short-rib polydactyly syndrome type 3 (Verma-Naumoff type) by three-dimensional helical computed tomography

We present a case of short-rib polydactyly syndrome (SRPs) type 3 in which accurate prenatal diagnosis was feasible using both ultrasonography and 3D-CT. SRP encompass a heterogeneous group of lethal skeletal dysplasias. However, the phenotypes overlap with those of nonlethal skeletal dysplasias (i.e. Ellis-van Creveld syndrome and Jeune syndrome). As accurate prenatal diagnosis of SRP is helpful for parents, we used 3D-CT in the early third trimester to examine a fetus suggested to have phenotypes of 'short-rib dysplasia group' on ultrasonography. 3D-CT showed mild modification of the vertebral bodies, small ilia with horizontal acetabula and triangular partial ossification defects, and subtle metaphyseal irregularities of the femora. These CT findings and an extensive literature search regarding the phenotypes of various diseases categorized as short-rib dysplasia group led to a correct prenatal diagnosis of SRP type 3. This case exemplified the usefulness of 3D-CT for the precise prenatal diagnosis of skeletal dysplasias.

Bone and joint diseases in children. Skeletal dysplasia in children--unrecognized cases in daily practice

Skeletal dysplasia is a group of diseases caused by aberration of growth, development and differentiation of skeletal tissues including bone and cartilage. Most of the diseases that belong to skeletal dysplasia are monogenic diseases. Diagnosis of skeletal dysplasia during childhood is easier than those in other period of life ; usually we can diagnose them clinically by their characteristic radiographic features and confirm the diagnosis by genetic test when the disease genes are known. However, some skeletal dysplasias may escape from detection because of their mild phenotypes and lack of diagnostic complications, and may be diagnosed as common orthopedic diseases. Here, we present several cases of such skeletal dysplasia that we experienced in our daily practice and highlight diagnostic problems. For correct diagnosis of skeletal dysplasia, it is important to consider its possibility always in the clinical practice and to collect clinical information appropriately, including those regarding family history. The collect diagnosis would lead to better treatment and care for patients and families.

Pattern and prenatal diagnosis of skeletal dysplasias in Qatar population

Objective. To determine the pattern of skeletal dysplasias in Qatar population and to assess the accuracy of prenatal diagnosis and prognosis.Methods. This was a retrospective descriptive study of 30 women with high risk for skeletal dysplasias. The recruited women were submitted to clinical assessment, ultrasound scanning using 2-dimensional, 3-dimensional/4-dimensional and colour Doppler technique with possible molecular diagnosis. The findings were compared with the postnatal or postmortem assessments. Final diagnosis was based on clinical examination, skeletal survey, autopsy and molecular testing as deemed necessary.Results. Thirty cases of skeletal dysplasia were antenatally diagnosed over 4-year period with family history in few cases. Among many entities thanatophoric dysplasia showed largest prevalence [7(23%)]. Prenatal diagnosis was accurate in 76% of foetuses while the first indicator of abnormality was a suspected anomaly found during routine ultrasound assessment in most cases [17(56%)]. Prediction of lethality based on ultrasound findings was 100% accurate.Conclusions. This study confirmed the possibility of good prenatal diagnosis of skeletal dysplasias present among Qatar population. Diagnosis based on ultrasound assessment will improve by adding molecular techniques with positive impact on prenatal care.

A recurrence of a hydrop lethal skeletal dysplasia showing similarity to Desbuquois dysplasia and a proposed new sign: The Upsilon sign

We report on a recurrence of a lethal skeletal dysplasia with features similar to Desbuquois dysplasia (DD) to expand the phenotypic spectrum of DD-like conditions, to increase awareness of DD-like phenotypes in the differential diagnosis of prenatal onset skeletal dysplasias, and to suggest a new sign, the Upsilon sign, to aid in the differential diagnosis of skeletal dysplasias with an extra ossification centre distal to second metacarpal.