P12.12: Skeletal dysplasias: is it possible the diagnosis before the delivery?

Skeletal dysplasias are a group of heterogeneous disorders affecting growth and morphology of the various segments of the skeleton1-4, with an estimated prevalence of 2–5/10 000 at birth5. Despite recent advances in imaging modalities and molecular genetics6, accurate prenatal diagnosis of skeletal dysplasias remains a clinical challenge7. The difficulties in prenatal diagnosis result from the large number of disorders, their phenotypic variability with overlapping features and the lack of a precise molecular diagnosis for many disorders8. Over the past 30 years, the classification of skeletal dysplasias has evolved from one based upon clinical/radiological/pathological descriptions to one that also includes the underlying molecular abnormality for a few conditions in which the defect is known9. The last version of the International Nosology and Classification of Constitutional Disorders of Bone was published in 200210 and included approximately 300 conditions, of which approximately 50 are apparent and identifiable at birth11. These conditions are relevant to the maternal–fetal medicine specialist as they constitute the group which may be detected before birth. Prenatal diagnosis is easier in the presence of a positive family history and a precise description of the phenotype since many disorders are inherited as autosomal dominant or recessive disorders6. However, it is not unusual that skeletal dysplasias are first suspected during routine sonographic examination after a shortened long bone or other abnormal skeletal finding is observed7. Sonographic evaluation requires a detailed examination of the fetal skeleton, which is described in Table 1. The sonologist must determine if the anomaly is lethal, either by establishing the precise diagnosis of uniformly lethal conditions (Table 2)6 or assessing the risk of pulmonary hypoplasia6, 12-35. Several parameters have been proposed to estimate the risk of pulmonary hypoplasia (see Table 3)6, 12-47. 2.Compare with other segments and classify the limb shortening as: Rhizomelia Mesomelia Acromelia Severe micromelia 3.Qualitative assessment of long bones: Bowing Demineralization Fractures Metaphyseal flaring Absence of bones 5.Evaluate hands and feet Digits (polydactyly/syndactyly) Positional deformities 6.Evaluate the cranium Macrocrania Frontal bossing Cloverleaf skull Hypertelorism/hypotelorism 8.Examination of the spine Platyspondyly Demineralization Hemivertebrae Coronal clefts Vertebral disorganization With the identification of a growing number of mutations responsible for skeletal dysplasias48-50, it is hoped that eventually a specific diagnosis will be possible during the prenatal period51-55. A classification of genetic disorders of the skeleton based on the structure and function of implicated genes and proteins has been proposed recently50, complementing the existing International Nosology and Classification of Constitutional Disorders of Bone10. Accurate diagnosis is important for both proper management of the index case and for genetic counseling56. Moreover, if patients resort to pregnancy termination, molecular diagnostic methods may be the only way to establish the final diagnosis5. For detailed and up-to-date information regarding molecular tests available for the diagnosis of skeletal dysplasias the reader is referred to the web pages of GeneTests (a comprehensive source of information on genetic testing funded by the National Institutes of Health of the USA: http://genetests.org), the European Skeletal Dysplasia Network (http://www.esdn.org/diagnosis.html), the Division of Molecular Pediatrics of the University of Lausanne, Switzerland (http://www.pediatrics.ch/Frames.html) or the International Skeletal Dysplasia Registry at Cedars-Sinai Hospital, Los Angeles, USA (http://www.cedars-sinai.edu/3810.html). The reader is referred to a recent novel article describing how phenotypic relationships could be exploited to find new disease genes and provide clues to gene interactions, pathways and functions57. Despite the increasing availability of molecular testing, a comprehensive molecular diagnostic search for all skeletal dysplasias is not possible at this time. Therefore, the role of imaging is to narrow the differential diagnosis so that specific biochemical and molecular tests can be performed to confirm or exclude a potential diagnosis8, 58-60. Ultrasound is the primary imaging modality used for the initial diagnostic evaluation of an affected fetus. Table 4 summarizes the diagnostic accuracy of two-dimensional ultrasound (2D-US) for prenatal diagnosis of skeletal dysplasias7, 61-64. A precise diagnosis has been reported in 31–65% of cases. The introduction of 3D-US and rendering algorithms to reconstruct the fetal skeleton can improve diagnostic accuracy because additional phenotypic features not detectable by 2D-US may be identified65-77. For example, Garjian et al.68 and Krakow et al.75 reported the diagnosis of additional facial68, 75, scapular anomalies68 and abnormal calcification patterns75 in fetuses with skeletal dysplasias, whereas Moeglin and Benoit71 used the multiplanar visualization method to demonstrate the ‘pointed appearance’ of the upper femoral diaphysis in a case of achondroplasia. Three-dimensional reconstruction of the fetal bones is best performed using the ‘maximum intensity projection’ mode, a rendering algorithm that prioritizes the display of the highest gray levels contained within a region of interest selected by the operator68, 71. If the fetus is examined early enough during pregnancy, the entire skeleton can be included within the region of interest of the three-dimensional volume dataset and, therefore, a panoramic visualization can be achieved68. However, the diagnosis may be missed, as the phenotypic characteristics of some skeletal dysplasias do not manifest until later in pregnancy. Case reports and small series of several skeletal dysplasias have been published describing phenotypic characteristics or skeletal features that were best demonstrated by 3D-US (Table 5)66, 68-71, 73-76. In this issue of the Journal, Ruano et al.78 explore for the first time the use of three-dimensional helical computerized tomography (3D-HCT) as an adjunctive imaging modality for prenatal diagnosis of skeletal dysplasias in six cases: achondroplasia (n = 3), osteogenesis imperfecta (n = 2), and chondrodysplasia punctata (n = 1). This technique consists of fast and continuous acquisition of images as the X-ray source and detector perform ‘spiral’ or ‘helical’ movements with respect to the patient, who is moving in a linear fashion through the gantry79, 80. Helical CT allows fast and continuous acquisition of a volume dataset containing the structures of interest, usually within one breathhold (20–25 s), minimizing motion artifacts79-82. Fast acquisition allows improvement in multiplanar reformatting and three-dimensional reconstruction capabilities over what is feasible with conventional CT. Similarly to 3D-US, postprocessing techniques such as ‘maximum intensity projection’, ‘surface rendering’ and ‘volume rendering’ can be used for three-dimensional reconstruction79, 81, 82. In addition, faster image acquisition with 3D-HCT when compared with conventional CT has the potential to decrease radiation exposure80-82. 3D-HCT has been previously used as an adjunctive diagnostic imaging modality for prenatal diagnosis of congenital anomalies in isolated cases of trisomy 18, cystic hygroma, congenital diaphragmatic hernia and agnathia-holoprosencephaly80, 83, 84. Long bone measurements obtained by postmortem helical CT studies have been compared with those obtained within 24 h of delivery by ultrasound, and a significant correlation between the two methods was observed85. In the study of Ruano et al.78, excellent panoramic images of the fetal skeleton were obtained by 3D-HCT without superimposition of the maternal skeleton, which occurs with radiography. Deformation of the fetal pelvis and an increase in the intervertebral space of the lumbar vertebrae were diagnosed more often using 3D-HCT when compared with 2D-US and 3D-US. In contrast, some phenotypic characteristics of fetuses with skeletal dysplasias were demonstrated only by ultrasound: phalangeal hypoplasia (by both 2D-US and 3D-US), facial dysmorphism (by 3D-US only) and point-calcified epiphysis (by both 2D-US and 3D-US). The overall count of correct phenotypic characteristics detected prenatally favored 3D-HCT over 3D-US (94.3% (33/35) vs. 77.1% (27/35), P = 0.03, McNemar's test for correlated samples). Of interest, however, was the observation that the diagnostic performance of 3D-HCT was not superior to that of 3D-US, as the correct prenatal diagnosis was established by both modalities in all cases. Provided that the two diagnostic methods have comparable diagnostic accuracy, 3D-US has two important advantages over 3D-HCT, namely, lack of radiation exposure and wider availability in the clinical setting. It is also noteworthy that the overall experience with 3D-US for the diagnosis of skeletal dysplasias is still limited65-77. Nevertheless, even in this study, 3D-US performed better than did 2D-US, both in the identification of phenotypic characteristics (77.1% (27/35) vs. 51.4% (18/35), P = 0.004, McNemar's test for correlated samples) and in establishing an accurate diagnosis. Ruano et al.78 proposed that the improved performance in detection of some features of skeletal dysplasias by 3D-HCT when compared with ultrasound could be attributed to 3D-HCT images being examined by both a radiologist and a geneticist, whereas ultrasound examinations were performed and analyzed essentially by a sonologist. It remains to be determined if the type of technology, the team approach, the difference in clinical skills, or a combination of all these factors, are ultimately responsible for the differences observed. Regardless of the cause, one way to minimize biases in the interpretation of cases of skeletal dysplasias examined by ultrasound would be to take advantage of 3D-US and information technology (e.g. acquisition and storage of volumes and the possibility of transmitting the files remotely using a fast Internet connection) to have cases re-examined at centers specialized in the diagnosis of skeletal dysplasias. This approach would maximize the diagnostic potential of 3D-US in the clinical setting by ensuring that physicians skilled in the differential diagnosis of skeletal dysplasias can examine the volume datasets. In addition, referral of cases to institutions appropriately equipped and with expertise in prenatal diagnosis would allow studies to be conducted to answer the very questions raised by the current study. It is expected that, as more prenatal diagnostic centers incorporate 3D-US into clinical practice, proficiency in the reconstruction of skeletal structures, as well as the diagnostic accuracy, are likely to improve. Before embracing the use of 3D-HCT, one must have a clear understanding of the goals of diagnostic imaging in the prenatal investigation of skeletal dysplasias: 1) to narrow the differential diagnosis of skeletal dysplasias so that appropriate confirmatory molecular tests can be selected; 2) to predict lethality; and 3) to identify the fetus with a skeletal dysplasia early enough in pregnancy so that the diagnostic workup can be completed before the limit of fetal viability. 3D-HCT will expose the fetus to some degree of radiation, with the potential for long-term harmful effects86, 87. As the number of centers using 3D-US increases, we look forward to the publication of larger series reporting on the accuracy of the combination of 2D-US and 3D-US for the diagnosis of skeletal dysplasias. In our opinion, ultrasound will remain the primary modality for evaluation of the fetus affected by skeletal dysplasias, and 3D-HCT could have a role in cases where the information provided by 3D-US is insufficient for counseling and management. The final diagnoses in the study of Ruano et al.78 were established by postnatal clinical and radiological findings. While this is the standard today, a definitive diagnosis can be established for a growing number of skeletal dysplasias, including the ones described in this study, using molecular and/or biochemical tests. For example, the differential diagnosis of achondroplasia at birth includes severe hypochondroplasia, cartilage hair hypoplasia (metaphyseal chondrodysplasia, McKusick type), and pseudoachondroplasia88. As more than 99% of the patients with achondroplasia have either a Gly380Arg substitution, resulting from a G to A point mutation at nucleotide 1138 of the fibroblast growth factor receptor 3 (FGFR3) gene, or a G to C point mutation at nucleotide 113889, a definitive molecular diagnosis is possible in the majority of cases90. Osteogenesis imperfecta type II is caused by mutations in either the COL1A1 or COL1A2 gene, resulting in abnormal molecular constitution of pro-collagen type I91-93. Diagnosis can be confirmed by biochemical analysis of collagen (collagen screening) and, if the results are equivocal, DNA sequencing of COL1A1 and COL1A294. Rhizomelic chondrodysplasia punctata (RCDP) is a genetically heterogeneous disorder, with three types (types 1, 2 and 3) and an extensive differential diagnosis, including X-linked recessive chondrodysplasia punctata 1 (CDPX1), warfarin embryopathy, X-linked dominant chondrodysplasia punctata (CDPX2), and chondrodysplasia punctata tibial-metacarpal type95. The most common form is type 1, which is caused by mutations in the PEX7 gene (L292X, G217R, and A218V)95-98. These three mutations can be detected in 60% of the cases, whereas 95% of the mutations can be identified by DNA sequencing of the entire PEX7 gene. RCDP types 2 and 3 are inherited in an autosomal recessive manner and are rarer than RCDP type 1. RCDP type 2 is caused by deficiency of the enzyme dihydroxyacetone phosphate acyltransferase, whereas type 3 is caused by deficiency of the peroxysomal enzyme alkyl-dihydroxyacetone phosphate synthase. In both cases, the diagnosis can be confirmed by measurement of the specific enzyme activity in cultured skin fibroblasts95. For a more detailed list of biochemical and molecular tests for the various forms of chondrodysplasia punctata, the reader is referred to the GeneReviews website (http://www.genetests.org/profiles/rcdp). Thus, we suggest that future studies of skeletal dysplasias by 3D-US or other diagnostic imaging modalities include a combination of imaging, histology and molecular techniques for final diagnosis75, whenever the molecular basis for the disorder is known.

Objective: To determine the accuracy and usefulness of prenatal ultrasonographic and molecular genetic diagnosis in detection of skeletal dysplasia.Methods: This study was based upon data of the 17 cases of skeletal dysplasia diagnosed by prenatal ultrasound and 7 cases by molecular diagnosis performed among the 17 cases and the 2 cases who has familial skeletal dysplasia by molecular diagnosis during the first trimester at Ewha and Eulji University from March 1998 to August 2005.A final diagnosis was sought on the basis of radiographic studies, molecular testing, or both. Results:The mean gestational age at diagnosis was 24.9 weeks (range, 17 to 35 weeks).Nine cases were diagnosed before 24 weeks.A final diagnosis was obtained in 16 cases (94.1%).There was 1 false-positive diagnosis.The antenatal diagnosis was correct in 14 cases (82.4%).The 8 cases were prenatally confirmed and 1 case was postpartum confirmed using molecular genetic testing and accurate antenatal diagnosis and prediction was done.We were able to rule out skeletal dysplasia through chorionic villus sampling during the first trimester in the 2 cases with the family history with skeletal dysplasia.Conclusion: Prenatal diagnosis of skeletal dysplasia can be a considerable diagnostic challenge.However, skeletal dysplasia is correctly diagnosed on the basis of prenatal meticulous ultrasound and antenatal prediction of lethality was highly accurate.Using prenatal molecular diagnosis, skeletal dysplasia can be diagnosed at first trimester of pregnancy and nonlethal skeletal dysplasia can be confirmed when prenatal ultrasound was nonspecific.

To assess the types and numbers of cases, gestational age at specific prenatal diagnosis and diagnostic accuracy of the diagnosis of skeletal dysplasias in a prenatal population from a single tertiary center. This was a retrospective database review of type, prenatal and definitive postnatal diagnoses and gestational age at specific prenatal diagnosis of all cases of skeletal dysplasias from a mixed referral and screening population between 1985 and 2007. Prenatal diagnoses were grouped into 'correct ultrasound diagnosis' (complete concordance with postnatal pediatric or pathological findings) or 'partially correct ultrasound diagnosis' (skeletal dysplasias found postnatally to be a different one from that diagnosed prenatally). We included 178 fetuses in this study, of which 176 had a prenatal ultrasound diagnosis of 'skeletal dysplasia'. In 160 cases the prenatal diagnosis of a skeletal dysplasia was confirmed; two cases with skeletal dysplasias identified postnatally had not been diagnosed prenatally, giving 162 fetuses with skeletal dysplasias in total. There were 23 different classifiable types of skeletal dysplasia. The specific diagnoses based on prenatal ultrasound examination alone were correct in 110/162 (67.9%) cases and partially correct in 50/162 (30.9%) cases, (160/162 overall, 98.8%). In 16 cases, skeletal dysplasia was diagnosed prenatally, but was not confirmed postnatally (n = 12 false positives) or the case was lost to follow-up (n = 4). The following skeletal dysplasias were recorded: thanatophoric dysplasia (35 diagnosed correctly prenatally of 40 overall), osteogenesis imperfecta (lethal and non-lethal, 31/35), short-rib dysplasias (5/10), chondroectodermal dysplasia Ellis-van Creveld (4/9), achondroplasia (7/9), achondrogenesis (7/8), campomelic dysplasia (6/8), asphyxiating thoracic dysplasia Jeune (3/7), hypochondrogenesis (1/6), diastrophic dysplasia (2/5), chondrodysplasia punctata (2/2), hypophosphatasia (0/2) as well as a further 7/21 cases with rare or unclassifiable skeletal dysplasias. Prenatal diagnosis of skeletal dysplasias can present a considerable diagnostic challenge. However, a meticulous sonographic examination yields high overall detection. In the two most common disorders, thanatophoric dysplasia and osteogenesis imperfecta (25% and 22% of all cases, respectively), typical sonomorphology accounts for the high rates of completely correct prenatal diagnosis (88% and 89%, respectively) at the first diagnostic examination.

Prenatal Diagnosis of a Lethal Skeletal Dysplasia.

BackgroundSince the discovery of cell-free foetal DNA in the plasma of pregnant women, many non-invasive prenatal testing assays have been developed. In the area of skeletal dysplasia diagnosis, some PCR-based non-invasive prenatal testing assays have been developed to facilitate the ultrasound diagnosis of skeletal dysplasias that are caused by de novo mutations. However, skeletal dysplasias are a group of heterogeneous genetic diseases, the PCR-based method is hard to detect multiple gene or loci simultaneously, and the diagnosis rate is highly dependent on the accuracy of the ultrasound diagnosis. In this study, we investigated the feasibility of using targeted capture sequencing to detect foetal de novo pathogenic mutations responsible for skeletal dysplasia.Methodology/Principal FindingsThree families whose foetuses were affected by skeletal dysplasia and two control families whose foetuses were affected by other single gene diseases were included in this study. Sixteen genes related to some common lethal skeletal dysplasias were selected for analysis, and probes were designed to capture the coding regions of these genes. Targeted capture sequencing was performed on the maternal plasma DNA, the maternal genomic DNA, and the paternal genomic DNA. The de novo pathogenic variants in the plasma DNA data were identified using a bioinformatical process developed for low frequency mutation detection and a strict variant interpretation strategy. The causal variants could be specifically identified in the plasma, and the results were identical to those obtained by sequencing amniotic fluid samples. Furthermore, a mean of 97% foetal specific alleles, which are alleles that are not shared by maternal genomic DNA and amniotic fluid DNA, were identified successfully in plasma samples.Conclusions/SignificanceOur study shows that capture sequencing of maternal plasma DNA can be used to non-invasive detection of de novo pathogenic variants. This method has the potential to be used to facilitate the prenatal diagnosis of skeletal dysplasia.

Skeletal dysplasias (SDs) are a heterogeneous group of heritable disorders that affect development of bone and cartilage. Because each SD is individually rare and because of the heterogeneity within and among disorders, prenatal diagnosis of a specific SD remains challenging. Molecular genetic diagnosis involves invasive testing, which some patients are not amenable to. Further, genetic analysis is time consuming, and results may not become available in time to make pregnancy management decisions. Low-dose fetal CT can aid in the prenatal evaluation of SDs. The main downside is the low but true risk of fetal radiation exposure. As such, fetal CT should only be performed when there is concern for a severe skeletal dysplasia and the diagnosis is in question after a detailed ultrasound or if molecular genetic testing is unavailable and when prenatal diagnosis may affect management or counseling. Fetal CT should be obtained after consultation with geneticists, maternal-fetal medicine specialists, and fetal radiologists, and sometimes orthopedic surgeons or neonatologists. The purpose of this study was to review the technique of and indications for fetal CT, as well as discuss fetal radiation risk. Illustrative cases will demonstrate when and how CT may be helpful in the diagnosis of SDs.

To assess the accuracy of the prenatal diagnosis of skeletal dysplasias. All antenatally detected anomalies are coded in our ultrasound database, which is linked with a genetics database that includes outcomes. A final diagnosis is sought on the basis of radiographic studies, molecular testing, or both. Our ultrasound and genetics databases were queried for "skeletal dysplasias." All cases were reviewed specifically for the degree of bone shortening and other distinguishing characteristics on antenatal sonography. Thirty-seven cases of skeletal dysplasia were antenatally diagnosed over an 8-year period. Complete follow-up was available in 31 cases. The mean gestational age at diagnosis was 22.7 weeks (range, 14-32.3 weeks). Twenty-one cases were diagnosed before 24 weeks. A final diagnosis was obtained in 80% of cases. The antenatal diagnosis was correct in 20 (65%) of 31 cases. There were 2 false-positive diagnoses. Specific final diagnoses included thanatophoric dysplasia (8), osteogenesis imperfecta (6), Roberts syndrome (2), achondroplasia (3), Ellis-van Creveld syndrome (1), metaphyseal dysplasia (1), spondyloepiphyseal dysplasia (1), distal arthrogryposis (1), caudal regression (1), and glycogen storage disorder (1). The condition was correctly thought to be lethal in 16 of the fetuses on the basis of early severe long bone shortening (13), femur length-abdominal circumference ratio of less than 0.16 (12), hypoplastic thorax (10), marked bowing or fractures (4), short ribs (4), caudal regression (1), and cloverleaf skull (1). The ability to predict lethality was 100%. There were no false-positive findings with respect to lethality. Accurate antenatal diagnosis of skeletal dysplasias is problematic; in this series, only 20 of 31 cases were correctly diagnosed. However, the antenatal prediction of lethality was highly accurate. The most common predictors of lethal skeletal dysplasias included early and severe shortening of the long bones, femur length-abdominal circumference ratio of less than 0.16, hypoplastic thorax, and certain distinguishing characteristics.

Background: Fetal skeletal dysplasias are a group of skeletal dysplasias occurring during the fetal stage. As the use of fetal ultrasonography has become widespread, the rate of prenatal diagnosis of skeletal dysplasias has increased. However, many fetal skeletal dysplasia phenotypes have indistinct definitions, making definitive prenatal diagnosis difficult. Fetal imaging methods that are the basis of diagnosing fetal skeletal dysplasias include ultrasonography and three-dimensional computed tomography. The use of three-dimensional computed tomography requires specific imaging techniques and cannot easily be performed at all facilities. In the present study, we propose to conduct a survey for the preparation of a protocol with a low risk, and a high diagnostic accuracy. Methods: In total, 50 pregnant women who undergo three-dimensional computed tomography for the diagnosis of fetal skeletal dysplasias will be included. The primary outcome is prenatal diagnostic accuracy for fetuses with skeletal dysplasias. The secondary outcome is the safety from radiation exposure. Results and conclusion: Three-dimensional computed tomography should be considered for the prenatal diagnosis of fetal skeletal dysplasias, as it is important to judge whether the prognosis is favorable or lethal. When considering the risk of radiation exposure, high quality images that are adequate for a diagnosis have been obtained using low-dose three-dimensional computed tomography scans. This approach reduces the level of radiation to which the pregnant woman and fetus are exposed. Trial registration: University hospital Medical Information Network (UMIN) Center: Trial registration number is UMIN000034744. Data of registration is October 01, 2018. (URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039610)

The Utah Birth Defect Network (UBDN) collects population-based data for Utah on births from all resident women. The prevalence of skeletal dysplasias and epidemiologic characteristics/outcomes were evaluated. Cases categorized as a skeletal dysplasia from all live births, stillbirths, and pregnancy terminations (TAB) between 1999 and 2008 were reviewed by three clinical geneticists. After case review, 153 were included for analysis (88% live births, 3% stillborn, 9% TAB), and categorized by groupings defined by molecular, biochemical, and/or radiographic criteria as outlined in the 2010 Nosology and Classification of Genetic Skeletal Disorders. The overall prevalence for skeletal dysplasias was 3.0 per 10,000 births, and 20.0 per 10,000 stillbirths. The most common diagnostic groups were osteogenesis imperfecta (OI; n = 40; 0.79 per 10,000), thanatophoric dysplasia (n = 22; 0.43 per 10,000), achondroplasia (n = 18; 0.35 per 10,000), and cleidocranial dysplasia (n = 6; 0.12 per 10,000). The most common groups based on the 2010 Nosology and Classification of Genetic Skeletal Disorders were the FGFR3 chondrodysplasia group (n = 41; 0.81 per 10,000), the OI/decreased bone density group (n = 40; 0.79 per 10,000), and the type 2 collagen group (n = 10; 0.2 per 10,000). Median age of postnatal diagnosis was 30 days (range 1-2,162). Of those deceased, 88% were prenatally suspected; of those alive 29% prenatally suspected. Median age of death for live born individuals was 1 day (range 1-1,450 days). Previously reported prevalence rates vary, but our data provide a population-based approach not limited to the perinatal/neonatal period. Understanding the range for survival within each group/diagnosis is beneficial for health care providers when counseling families.

Cartilage-hair hypoplasia is a rare autosomal recessive skeletal dysplasia. It is particularly prevalent in the Finnish and Amish populations but increasing reports have been documented worldwide. It is caused by pathogenic variants in the RMRP gene. The clinical presentation is highly variable and may include short-limbed short stature, metaphyseal abnormalities, hypotrichosis, and immune deficiency, among other features. Some of the manifestations may present early in the prenatal period and ultrasound assessment is often the tool that raises suspicion for this condition. This review aims to summarize the current knowledge regarding the prenatal diagnosis of cartilage-hair hypoplasia, focusing on its molecular basis and the role of imaging and genetic testing. A comprehensive literature search was conducted in the PubMed/MEDLINE database using the terms 'Prenatal diagnosis', 'Cartilage-hair hypoplasia', 'Skeletal dysplasias', 'Osteochondrodysplasias' and 'RMRP mutation'. Prenatal diagnosis of this condition remains challenging, as ultrasound findings may overlap with other skeletal dysplasias, including lethal forms. Lethality predictors and the potential of molecular testing are also explored. A structured prenatal approach, combined with timely genetic counselling, may allow for an earlier diagnosis and support informed reproductive decisions. Given the recent advances in reproductive technologies and the potential impact of cartilage-hair hypoplasia on affected individuals, this condition should be actively considered in future studies addressing the prenatal diagnosis of skeletal dysplasias.

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

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.

The lamin B receptor (LBR) gene is located in chromosome 1q42.12 and encodes the lamin B receptor, an intracellular protein that binds to lamin B. LBR mutations are associated with a broad phenotypic spectrum ranging from non-lethal to lethal skeletal dysplasias. The typical phenotypes include the Pelger−Huet anomaly (PHA) and embryonic lethal Greenberg dysplasia (GRBGD). With the further study of this gene, other phenotypes have been found in different individuals. This retrospective study analyzed recurrent prenatal moderate skeletal dysplasias in Chinese fetuses. Nothing malformed was detected in the fetal karyotype and microarray, while the whole-exome sequencing identified a homozygous variant (NM_002296.4:c.1757G>A, NP_002287.2:p.Arg586His) in exon 14 of the LBR gene in both fetuses. Mutation analysis in the parents confirmed that the c.1757G>A variation is heterozygous by Sanger sequencing. Intensive analysis on bioinformatics and familial co-segregation suggest that the homozygous variation in the LBR gene is responsible for this recurrent prenatal moderate skeletal dysplasia. Moreover, moderate skeletal dysplasias differ from typical GRBGD phenotypes. Our findings are based on the DNA base test and the prenatal diagnosis of skeletal dysplasia, which can be helpful in proper phenotyping and contribute to a better understanding of the correlation between the phenotype and genotype.

The skeletal dysplasias are a large, heterogeneous group of genetic conditions characterized by abnormal development, growth and maintenance of the elements (bones) comprised in the human skeleton [1]. In the 2010 revision of nosology and classification of genetic skeletal disorders, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes [2], and are present in about 5% of children with birth defects [3]. About 100 skeletal dysplasias have prenatal onset [4] with ultrasound findings particularly in the second trimester [5]. The first step for an accurate diagnosis is a detailed clinical-radiographic evaluation [4]. In fact, because of clinical and genetic heterogeneity of these diseases, with partial clinical overlap, diagnosis is difficult with a consequent delay in specific follow-up and management. Clinical and molecular characterization of a large patients series is the first step that leads to an improvement in knowledge about natural history, epidemiology and pathogenesis of this disease. These advancements are promoted by expertise centres where patients can be followed-up by multidisciplinary teams, required for syndromic nature or different skeletal segments involvement in the most of cases. To improve skeletal disease knowledge, often lacking, it is essential to analyze and integrate available clinical and genetic data; to this purpose, the design and development of disease-specific registries [5] is essential, as well as the presence of a Biobank for the collection of biospecimens. Our experience as Reference Centre for Skeletal Dysplasias led us to activate specific diseases registries, as Multiple Osteochondromas Registry (REM), using an HL7 compliant platform, GePhCARD (Genotype-Phenotype Correlation, Analyses and Research Database) that can encompass clinical, genetic, genealogical and imaging data [6]. This web-application is protected by an authentication system, a relief tool articulated in multilevel access profile for data legal protection and patients’ privacy. GePhCARD will be soon interfaced with BIOGEN (Genetic Biobank) and together will contribute to improve diagnosis and clinical and molecular characterization of rare diseases, allowing to collect high quality biological materials of skeletal dysplasias patients [7]. In this presentation we focus on our experience on a specific skeletal disease, Hereditary Multiple Osteochondromas (MO), and demonstrate how a systematic integration of clinical and molecular data is focal to increase the knowledge on MO natural history and epidemiology [8], contributing also to define personalized and appropriate follow-up and to hypothesize research studies.

To investigate the incidence and outcome of antenatally diagnosed skeletal dysplasia We investigated all cases of fetal skeletal dysplasia referred to a tertiary Fetal Medicine unit between 2002 and 2008. The ultrasound findings, concordance between antenatal and final diagnosis as well as pregnancy outcome were analyzed. Data were collected from the Fetal Medicine database and computerized records supplemented by individual chart reviews. Thirty three cases of skeletal dysplasia were identified. The median maternal age was 30 years (range 18–40) and the median gestational age at referral was 21 weeks (range 11–35 weeks). A provisional ultrasound diagnosis was possible in 21/33 (65%) cases. This diagnosis was however confirmed postnatally or after molecular testing in only half of the cases. The commonest skeletal dysplasia were thanatophoric dysplasia (n = 7) and osteogenesis imperfecta (n = 4). The perinatal outcome in this series was very poor with 64% pregnancies terminated (21/33), 9% (3/33) stillborn, 9% (3/33) died in early neonatal period and only 18% (6/33) alive after the neonatal period. Making a precise prenatal diagnosis of skeletal dysplasia is frequently difficult and often inaccurate. Prediction of lethality is however much easier and is often possible depending on thoracic circumference, degree of limb shortening or the presence of other abnormalities. Parents need to be aware that the outcome of many skeletal dysplasias is poor. Although a precise diagnosis is frequently not possible antenatally, the ultrasound findings usually allow an assessment of perinatal outcome. Decisions about termination of pregnancy can therefore be made with some confidence.