Difficulties In Prenatal Diagnosis Research Articles

Rare clinical case of harlequin ichthyosis: opportunities and difficulties of prenatal diagnosis

Rare clinical case of harlequin ichthyosis: opportunities and difficulties of prenatal diagnosis

Small size, big problems: insights and difficulties in prenatal diagnosis of fetal microcephaly.

Microcephaly is a sign, not a diagnosis. Its incidence varies widely due to the differences in the definition and the population being studied. It is strongly related to neurodevelopmental disorders. Differences in definitions and measurement techniques between fetuses and newborns pose a great challenge for the diagnosis and prognostication of fetal microcephaly. A false positive diagnosis can result (in countries where it is legal) in erroneous termination of pregnancy, where a false negative diagnosis might lead to the birth of a microcephalic newborn. Microcephaly in growth restricted fetuses deserves special attention and separate evaluation as it is an important prognostic factor, and not necessarily part of the general growth retardation. Several genetic syndromes incorporating microcephaly and intrauterine growth retardation (IUGR) are discussed. Deceleration of the head circumference (HC) growth rate even when the HC is still within normal limits might be the only clue for developing microcephaly and should be considered during fetal head growth follow up. Combining additional parameters such as a positive family history, associated anomalies, and new measurement parameters can improve prediction in about 50% of cases, and thus should be part of the prenatal workup. Advances in imaging modalities and in prenatal genetic investigation along with the emergence of new growth charts can also improve diagnostic accuracy. In this article, we review the different definitions and etiologies of fetal microcephaly, discuss difficulties in diagnosis, investigate the reasons for the low yield of prenatal diagnosis, and provide improvement suggestions. Finally, we suggest an updated algorithm that will aid in the diagnosis and management of fetal microcephaly.

Diagnostic challenges in Goldenhar syndrome – a case report

Goldenhar syndrome, also known as oculo-auriculo-vertebral syndrome, represents a rare congenital complex of anomalies, involving the development of the first and second brachial arches during the first embryonary stage. In addition to the craniofacial disorders, Goldenhar syndrome can include central nervous system, heart, skeleton or kidneys pathologies as well as vertebral defects. We present the case of a Goldenhar syndrome whose first pathologic sign was tetralogy of Fallot, with associated cardiovascular disorders (atrial septal defect type ostium secundum, and single umbilical artery) and bilateral microtia, with malformation of auditory canal, mandibular hypoplasia and a single epibulbar dermoid. The Goldenhar syndrome was diagnosed after birth, the article emphasizing the difficulties of prenatal diagnosis.

Spotlight on … infection in obstetrics and gynaecology

In 1847, Ignaz Phillip Semmelweis proposed hand washing with chlorinated lime solution as a method of hand disinfection to reduce the incidence of puerperal fever. Obstetricians should feel part of this legacy because Semmelweis made this suggestion while working in an obstetric clinic in Vienna. At the time, Semmelweis could not explain the mechanism of his proposal and understandably it created much controversy and conflict. Over a century later, we continue to reap the benefits of Semmelweis's pioneering thinking. In the early 1860s, Louis Pasteur, the French biologist and chemist, became one of the pioneers of the germ theory of disease and a founder of bacteriology. Soon after, Joseph Lister at the University of Glasgow produced his pioneering work on antiseptic surgery and went on to promote hand washing and sterilisation of surgical instruments. After 150 years we continue to audit our practice of ‘bare below the elbows’ and hand washing before contact with our patients. Over the last two decades, The Obstetrician & Gynaecologist (TOG) has contributed to upholding the legacy of these pioneers and maintaining interest and awareness in managing infection in obstetrics and gynaecology. Nunns and Scott (TOG 2001;3:32–5) described the differential diagnoses of ulcers and erosions of the vulva. For readers in the Western world, it is important to remember that primary infective ulcers of the vulva can appear in the form of lymphogranuloma venereum or chancroid, or be caused by Donovanosis, amoebiasis and, of course, syphilis. One of the most common infections is caused by Candida, and group B streptococcus is a common resident in cervicovaginal secretions. Although Higgins (TOG 2001;4:184–8) writes under the heading of recurrent vulvovaginal candidiasis, he also informs us about the characteristics and management of other genital infections. Many of the infective diseases are sexually transmitted, where confidentiality forms an important part of management. Kausar and Bradbeer (TOG 2006;8:240–4) wrote about patient confidentiality in sexually transmitted infections (STIs). They refer to the guidance by the General Medical Council on this matter and also provide guidance on when confidential information can be disclosed. Sinha and Otiffy (TOG 2012;14:106–14) highlighted the role of sepsis in maternal deaths, reviewed the risk factors and described the features of septicaemic shock. They also recommended the use of a modified obstetric early warning scoring system for the early recognition of serious illness. During in vitro fertilisation, both males and females are prone to infection. Although such infection is rare, when it occurs it can have devastating effects. Sowerby and Parsons (TOG 2006;8:159–63) provide an eloquent review of methods of reducing the risk of such infection. Genital tuberculosis (TB) may be asymptomatic, go unrecognised or masquerade as other gynaecological conditions. In their review of genital TB, Gatongi et al. (TOG 2005;7:75–9) discussed the diagnosis, investigation and management of the condition. Five years later, Mahendru and colleagues (TOG 2010;12:163–71) wrote on the difficulties of diagnosing and managing TB in pregnancy. In 2007, Harris et al. (TOG 2008;10:17–21) described the investigation and treatment of recurrent urinary tract infection (UTI). In the same year, McCormick et al. (TOG 2008;10:156–62) highlighted the importance of diagnosing and treating UTIs in pregnancy, as they can be asymptomatic and are associated with significant maternal and perinatal morbidity and mortality. Moore and colleagues (TOG 2002;4:197–200) reviewed HIV in pregnancy. We learned that the incidence of heterosexually acquired HIV infection was rising and that HIV disease progression is monitored by serum viral count and T-helper cell (CD4) count. The authors also covered the risk factors that increased mother-to-child transmission (MTCT). Six years later, Kelly et al. (TOG 2008;10:42–8) presented a review of the drug treatment of HIV and outlined the impact of the virus on gynaecological practice. Although treatments are available for HIV, they are not curative and there is no guarantee against MTCT. Another 4 years later, Byrne, Fakoya and Harding (TOG 2012;14:17–24) provided an international perspective on HIV infection. They mentioned that MTCT accounted for 90% of HIV infection in childhood and that in the developing world, prevention of MTCT was limited by resources, lack of infrastructure and stigma. Infections in pregnancy that affect the fetus have arguably remained somewhat of an enigma. Cytomegalovirus (CMV) is one of them. In their 2009 paper, McCarthy et al. (TOG 2009;11:96–100) comprehensively reviewed CMV infection in pregnancy, which serves as a useful guide for those involved in caring for this group of women. More recently, Navti et al. (TOG 2016;18:301–7) provided an update on CMV in pregnancy and discussed the difficulties in prenatal diagnosis and options for management. It is important to remember that CMV is the most common cause of congenital viral infection and up to 90% of CMV infections remain asymptomatic at birth. A very useful and easily readable article was authored by To et al. (TOG 2009;11:108–16). It deals with CMV, parvovirus, toxoplasmosis, varicella-zoster virus and rubella infection in pregnancy. We learn that detection of virus alone is not synonymous with fetal damage, and that a negative result does not completely exclude the possibility of fetal infection. Human parvovirus infection in pregnancy was reviewed by Ismail and Kilby (TOG 2003;5:4-9). Among other important information in this review, we get to know that transplacental transmission occurs in approximately one-third of cases of maternal infection. Malaria in pregnancy has serious maternal and fetal complications. Pregnant women who are not immune and who plan to travel to areas with malaria should be warned of the risks. If such travel is inevitable, appropriate prophylactic measures should be advised. Gitau and Eldred (TOG 2005;7:5–11) highlight aspects of diagnosis, treatment and prophylaxis of malaria in pregnancy. Genital tract sepsis is one of the leading causes of maternal death in the UK. A significant proportion of these are due to community acquired group A streptococcal (GAS) infection. GAS infection is a life-threatening cause of puerperal sepsis. Palaniappan et al.'s (TOG 2012;14:9–16) review of GAS infection is a very useful reminder of this serious infection. Group B streptococcal (GBS) disease in pregnancy can be transmitted from mother to fetus and may lead to neonatal sepsis, pneumonia, meningitis or even death. To screen or not to screen is a trending question in the minds of many. In 2005, Abd El Malek and colleagues (TOG 2005;7:34–9) presented an update to this commonly encountered problem. Cockell et al. (TOG 2008;10:171–6) reminded us of the importance of women's views in the production of the Royal College of Obstetricians and Gynaecologists’ patient information leaflets on GBS infection in babies. Muggleston et al. (TOG 2014;16:87–92) presented a useful summary of the National Institute for Health and Care Excellence 2012 guideline on the use of antibiotics in early onset infection (arising within 72 hours of birth) of the neonate. An online collection of all TOG articles on infection in obstetrics and gynaecology is available at onlinetog.org.

Sensibilité du diagnostic échographique des malformations de la main. À propos de 80 cas

During pregnancy, the Haute Autorité de santé (HAS) recommends to realize three ultrasonographic evaluations, notably for the early detection of congenital malformations. Yet, in our experience, ultrasonographic antenatal diagnoses of hand malformations are rare. This is both a retrospective (years 2003-2008) and a prospective study (2009-2012). It quantifies the sensibility of hand malformations ultrasonographic diagnosis. Questionnaires have been sent or given during consultations to parents of children with upper limb malformation. The parents' acceptance of diagnosis and their anxiety have been evaluated. Eighty-eight malformations have been recruited for our series. Only 11 antenatal diagnoses have been made. Thus, sonographic diagnosis sensibility is 12.5% in our series. Thirty-nine percent of the parents have been shocked by the absence of diagnosis at birth. The sensibility of hand malformation ultrasonographic diagnosis is rarely documented in literature. It is generally low. This diagnosis may raise concerns about eugenism and legal issues. However, congenital malformations, even in the absence of a diagnosis, must be taken care of by a clearly determined network. Our results highlight difficulties of prenatal diagnosis of upper limb malformations. A lot of questions arise: what information should be delivered to the parents? Should antenatal ultrasonographic diagnosis be legislated? "Minor" malformations are often well managed by the parents, but "major" malformations ignored often raise legal issues.

Application of spatio-temporal image correlation technology in the diagnosis of fetal cardiac abnormalities

Congenital heart disease is the birth defect with the highest incidence in China. Its timely and accurate prenatal diagnosis is critical for appropriate perinatal and postnatal management and salvage treatment. With improvements in the diagnostic capabilities of ultrasound and clinical manipulation techniques, prenatal diagnosis is conducted increasingly early and with greater accuracy. However, the representations of tiny blood vessels and the determination of abnormal spatial structures in the fetal period continue to cause difficulties in prenatal diagnosis. In theory, spatio-temporal image correlation (STIC) technology is able to compensate for the defects of previous traditional two-dimensional (2D) ultrasound and improve the diagnostic accuracy. The aim of the present study was to investigate the clinical application value of STIC technology combined with traditional 2D ultrasound in the diagnosis of fetal cardiac abnormalities. A total of 1,286 fetuses were subjected to sequential echocardiographic examination, during which STIC technology was used to collect heart volume data and carry out image post-processing and off-line analysis. In addition, the prenatal and postnatal echocardiography results were compared with the pathology results following the induced labor of fetuses with cardiac abnormalities. The sensitivity, specificity, misdiagnosis rate and rate of missed diagnosis for the STIC technology in the diagnosis of prenatal fetal cardiac abnormalities were 97.4, 99.6, 0.4 and 2.6%, respectively. The total coincidence rate was 99.2% and the positive and negative predictive values were 97.9 and 99.4%, respectively; the statistics for the consistency check of the STIC technology in the diagnosis of fetal cardiac abnormalities are κ=0.991, P=0.000. STIC technology combined with fetal echocardiography may be used for the definite diagnosis of fetal heart malformations, with high sensitivity and specificity.

P24.09: The role of computed tomography in the investigation of stillbirth due to congenital malformation

Cystic hygromas are considered a form of vascular malformations of the lymphatic system, with an estimated incidence of 1 in 12,000 births (Fonkalsrud). They are fluid-filled sacs consisting of single or multiple cysts, that result from a blockage in the lymphatic system, mostly at the neck. They occur in approximately 1% of fetuses and have a high mortality rate when diagnosed prior to 30 weeks, because they can progress to hydrops and fetal death, or evolve to webbed neck, edema and lymphangioma. They may be an isolated finding or part of a syndrome such as Turner, Noonan and some trissomies. The success of the pregnancy depends on several factors, and the birth is a critical moment for the life of the patient. Primigesta, young Eastern European women, where a left cystic cervical hygroma was detected at 27 weeks of gestation in routine ultrasound. A medical interruption of pregnancy was proposed but refused and the pregnancy was carried out until full term. A thorough study was performed, with ultrasound scans and MRI, and no other congenital anomalies detected. Delivery was by a planned cesarean at full term, with Apgar scores 9 and 10 at first and five minutes, respectively, and the weight, height and head circumference were appropriate for gestational age. As shown by previous imaging studies, there was a clear airway and neither respiratory distress nor trouble feeding was observed. The karyotype was 46, XY and on day 16, he had surgical removal of the hygroma, which occurred without incidents. This case exemplifies the difficulty of pre-natal diagnosis and advising parents of a potential deadly condition. Even though this case was a surgical success, pre-natal findings of cystic hygroma are generally associated with a poor prognosis, especially when diagnosed prior to 30 weeks. The MRI assisted us in the decision taking process by reassuring a non-obstructed airway and normal fetal anatomy.

Bilateral Absence of Adrenal Glands: A Case Series that Expands the Spectrum of Associations and Highlights the Difficulties in Prenatal Diagnosis

Adrenal agenesis (AA) defined by the complete absence of development of adrenals is a rare anomaly, which is documented mainly in experimental animals and less frequently in human subjects in the literature. This study was aimed at describing the varied phenotype of this condition in two stillborn and one termination of pregnancy fetuses and two neonates, the associated abnormalities and the difficulties encountered to achieve the prenatal diagnosis. Five cases with AA diagnosed at post-mortem examination were selected and their characteristics were analyzed. The detection of this unusual condition has usually been made as an incidental discovery at post-mortem examination. None of the cases described in this series had been diagnosed at prenatal ultrasonography. Respiratory distress was the commonest clinical presentation in the liveborn. Maternal diabetes was associated with one case. Anomalies of kidneys, lungs, spleen, and blood vessels were associated with two of the cases. No gonadal abnormalities were detected in any of the cases. These cases illustrate the varied clinical presentation of this rare condition and confirm the difficulty in achieving a prenatal diagnosis.

EM.P.2.12 Walker-Warburg syndrome: LARGE mutation in two sibs. The difficulty of prenatal diagnosis

EM.P.2.12 Walker-Warburg syndrome: LARGE mutation in two sibs. The difficulty of prenatal diagnosis

Tetrasomy 12p (Pallister-Killian syndrome): difficulties in prenatal diagnosis

We report a rare case of Pallister-Killian syndrome diagnosed prenatally with increased nuchal translucency during screening for trisomy 21. Echografic and postmortem examination of the fetus, G-banded chromosome and FISH analysis on short- and long-term chorion villous sampling (CVS) culture. Cytogenetic analysis revealed a supernumerary isochromosome 12p after long-term culture whereas a normal cell line was detected in short-term culture only. Sonografic examination in 17-weeks' gestation showed further increase of the NT and the additional presence of brachymelia, diaphragmatic hernia and a marked dextroposition of the heart. Termination of the pregnancy was performed. The cases of PKS karyotypically confirmed on CVS are reviewed, and cytogenetic and sonographic aspects of the prenatal diagnosis of PKS are discussed.

Harlequin ichthyosis — difficulties in prenatal diagnosis

Ichthyoses belong to the group of genodermatoses, characterized by hyperkeratosis and desquamation of the epidermis. Clinical manifestation is heterogeneous and depends on the type of the disease. Harlequin foetus is the most severe form of congenital ichtyosis, inherited as an autosomal recessive trait. The disfunction of the epidermis begins prenatally. Neonates are often born prematurely, in severe condition. At present better care and treatment prolong the length and quality of children's life. We report a case of harlequin ichthyosis. Parents were healthy and there was no history of ichthyosis or other congenital anomalies in the family. Sonography at the 26th week of gestation revealed anomalies of the fetal face; however, the diagnosis of harlequin ichthyosis was not established prenatally. The male child was born alive at the 37th week of the third pregnancy, with birth weight of 2900 g. Typical features of harlequin ichthyosis were present at birth. Intensive neonatological care was necessary. The child survived and at the time of the report was 6 months old and in good condition.

Cardiac screening examination of the fetus: guidelines for performing the ‘basic’ and ‘extended basic’ cardiac scan

Ultrasound in Obstetrics & GynecologyVolume 27, Issue 1 p. 107-113 ISUOG GuidelineFree Access Cardiac screening examination of the fetus: guidelines for performing the ‘basic’ and ‘extended basic’ cardiac scan First published: 22 December 2005 https://doi.org/10.1002/uog.2677Citations: 160 You are viewing the old version of these guidelines. Click here to read the updated guidelines AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Introduction Congenital heart disease (CHD) is a leading cause of infant mortality, with an estimated incidence of about 4–13 per 1000 live births1-3. Between 1950 and 1994, 42% of infant deaths reported to the World Health Organization were attributable to cardiac defects4. Structural cardiac anomalies were also among the most frequently missed abnormalities by prenatal ultrasonography5, 6. Prenatal detection of CHD may improve the pregnancy outcome of fetuses with specific types of cardiac lesions7-11. Prenatal detection rates have varied widely for CHD12. Some of this variation can be attributed to examiner experience, maternal obesity, transducer frequency, abdominal scars, gestational age, amniotic fluid volume, and fetal position13, 14. Continuous training of health-care professionals based on feedback, a low threshold for echocardiography referrals and convenient access to fetal heart specialists are particularly important factors that can improve the effectiveness of a screening program3, 15. As one example, the major cardiac anomaly detection rate doubled after implementing a two-year training program at a medical facility in Northern England16. The ‘basic’ and ‘extended basic’ cardiac ultrasound examinations are designed to maximize the detection of heart anomalies during a second-trimester scan17. These guidelines can be used for evaluating low-risk fetuses that are examined as a part of routine prenatal care18-20. This approach helps to identify fetuses at risk for genetic syndromes and provides useful information for patient counseling, obstetrical management and multidisciplinary care. Suspected heart anomalies will require more comprehensive evaluation using fetal echocardiography. General Considerations Gestational age The fetal cardiac examination is optimally performed between 18 and 22 weeks' menstrual age. Some anomalies may be identified during the late first and early second trimesters of pregnancy, especially when increased nuchal translucency is identified21-26. Some countries, however, do not offer a medical insurance system for financial reimbursement of earlier scans at a time when more subtle cardiac defects may be undetectable or not present. Subsequent screening at 20–22 weeks' gestation is less likely to require an additional scan for completion of this evaluation, although many patients would prefer knowing about major defects at an earlier stage of pregnancy27. Many anatomic structures can still be satisfactorily visualized beyond 22 weeks, especially if the fetus is not prone. Despite the well-documented utility of a four-chamber view, one should be aware of potential diagnostic pitfalls that can prevent timely detection of CHD28-30. Detection rates can be optimized by performing a thorough examination of the heart, recognizing that the four-chamber view is much more than a simple count of cardiac chambers, understanding that some lesions are not discovered until later pregnancy, and being aware that specific types of abnormalities (e.g. transposition of the great arteries or aortic coarctation) may not be evident from this scanning plane alone. Technical factors Ultrasound transducer Higher-frequency probes will improve the likelihood of detecting subtle defects at the expense of reduced acoustic penetration. The highest possible transducer frequency should be used for all examinations, recognizing the trade-off between penetration and resolution. Harmonic imaging may provide improved images especially for patients with increased maternal abdominal wall thickness during the third trimester of pregnancy.31 Imaging parameters Gray scale is still the basis of a reliable fetal cardiac scan. System settings should emphasize a high frame rate with increased contrast resolution. Low frame persistence, a single acoustic focal zone, and a relatively narrow image field should also be used for this purpose. Zoom and cine-loop Images should be magnified until the heart fills at least a third to one half of the display screen. If available, a cine-loop feature can be used to assist the evaluation of ventricular septal defects and heart valve leaflets throughout the cardiac cycle. Basic Cardiac Examination The basic cardiac screening examination relies on a four-chamber view of the fetal heart32, 33. This view should not be mistaken for a simple chamber count because it involves a careful evaluation of specific criteria (Figure 1). Major elements for a basic examination of the fetal heart are shown in Table 1. A normal heart is usually no larger than one-third the area of the chest. Some views may reveal a small hypoechogenic rim around the fetal heart that can be mistaken for a pericardial effusion. An isolated finding of this type usually represents a normal variation34, 35. Figure 1Open in figure viewerPowerPoint Four-chamber view of the fetal heart. Key components of a normal four-chamber view include an intact interventricular septum and atrial septum primum. There is no disproportion between the left (LV) and right (RV) ventricles. A moderator band helps to identify the morphologic right ventricle. Note how the ‘offset’ atrioventricular septal valve leaflets insert into the crux. Reproduced with permission from: Lee W. American Institute of Ultrasound in Medicine. Performance of the basic fetal cardiac ultrasound examination. J Ultrasound Med 1998; 17: 601–607. Table 1. Basic cardiac screening examination. Adapted with permission from: Lee W. American Institute of Ultrasound in Medicine. Performance of the basic fetal cardiac ultrasound examination. J Ultrasound Med 1998; 17: 601–607 General Normal cardiac situs, axis and position Heart occupies a third of thoracic area Majority of heart in left chest Four cardiac chambers present No pericardial effusion or hypertrophy Atria Atria approximately equal in size Foramen ovale flap in left atrium Atrial septum primum present Ventricles Ventricles about equal in size No cardiac wall hypertrophy Moderator band at right ventricular apex Ventricular septum intact (apex to crux) Atrioventricular valves Both atrioventricular valves open and move freely Tricuspid valve leaflet inserts on ventricular septum closer to the cardiac apex than to the mitral valve Cardiac rate and regular rhythm should be confirmed. The normal rate ranges from 120 to 160 beats per minute. Mild bradycardia is transiently observed in normal second-trimester fetuses. Fixed bradycardia, especially heart rates that remain below 110 beats per minute, requires timely evaluation for possible heart block. Repetitive heart rate decelerations during the third trimester can be caused by fetal distress. Occasional skipped beats are typically not associated with an increased risk of structural fetal heart disease. However, this finding may occur with clinically significant cardiac rate or rhythm disturbances as an indication for fetal echocardiography36. Mild tachycardia (> 160 beats per minute) can occur as a normal variant during fetal movement. Persistent tachycardia, however, should be further evaluated for possible fetal distress or more serious tachydysrhythmias. The heart is normally deviated about 45 ± 20° (2 standard deviations (SD)) toward the left side of the fetus (Figure 2)37. Careful attention should be given to cardiac axis and position because they can be easily evaluated even if the four-chamber view is not satisfactorily visualized38. Situs abnormalities should be suspected when the fetal heart and/or stomach is/are not found on the left side as well. Abnormal axis increases the risk of a cardiac malformation, especially involving the outflow tracts. This finding may be associated with a chromosomal anomaly. Some hearts are abnormally displaced from their usual position in the anterior left central chest. Abnormal cardiac position can be caused by a diaphragmatic hernia or space-occupying lesion, such as cystic adenomatoid malformation. Position abnormalities can also be secondary to fetal lung hypoplasia or agenesis. Figure 2Open in figure viewerPowerPoint Fetal cardiac axis and position. The cardiac axis can be measured from a four-chamber view of the fetal heart. A line through the interventricular axis is extended to the posterior border of the heart to produce point P, the location of which can be used to define fetal cardiac position. LA, left atrium; LV, left ventricle; RA, right atium; RV, right ventricle. Adapted with permission from: Comstock CH. Normal fetal heart axis and position. Obstet Gynecol 1987; 70: 255–259. Both atrial chambers normally appear similar in size and the foramen ovale flap should open into the left atrium. Pulmonary veins can often be seen entering the left atrium. However, their identification should not be considered a mandatory part of a basic cardiac screening examination. The lower rim of atrial septal tissue, called the septum primum, should be present. A moderator band helps to identify the morphologic right ventricle. Both ventricles should also appear similar in size without evidence for thickened walls. Although mild ventricular disproportion can occur as a normal variant, hypoplastic left heart syndrome and aortic coarctation are important causes of this disparity39, 40. The ventricular septum should be carefully examined for cardiac wall defects from the apex to the crux. Septal wall defects may be difficult to detect when the transducer's angle of insonation is directly parallel to the ventricular wall. Under these circumstances, a defect may be falsely suspected because of acoustic ‘drop-out’ artifact. Small septal defects (1–2 mm) can be very difficult to confirm if the ultrasound imaging system fails to provide a sufficient degree of lateral resolution, especially if fetal size and position are unfavorable. Two distinct atrioventricular valves (right-sided, tricuspid and left-sided, mitral) should be seen to open separately and freely. The septal leaflet of the tricuspid valve is inserted to the septum closer to the apex when compared to the mitral valve (i.e. normal offset). Abnormal alignment of the atrioventricular valves can be a key sonographic finding for cardiac anomalies such as atrioventricular septal defect. Extended Basic Cardiac Examination If technically feasible, routine views of the outflow tracts should be attempted as part of an ‘extended basic’ cardiac screening examination. Evaluation of outflow tracts can increase the detection rates for major cardiac malformations above those achievable by the four-chamber view alone41, 42. Additional views to the basic cardiac examination are more likely to identify conotruncal anomalies such as tetralogy of Fallot, transposition of the great arteries, double outlet right ventricle, and truncus arteriosus. An extended basic examination minimally requires that normal great vessels are approximately equal in size and that they cross each other at right angles from their origins as they exit from their respective ventricular chambers. Failure to confirm these findings in a well-visualized study warrants further evaluation. Sonographic technique The outflow tracts are usually obtained by angling the transducer toward the fetal head from a four-chamber view when the interventricular septum is tangential to the ultrasound beam (Figure 3). Another method for evaluating the outflow tracts has also been described for the fetus when the interventricular septum is perpendicular to the ultrasound beam43. This approach requires a four-chamber view of the heart where the probe is rotated until the left ventricular outflow tract is seen. Once this view is obtained, the transducer is rocked cephalad until the pulmonary arterial outflow tract is observed in a plane that is perpendicular to the aorta. Figure 3Open in figure viewerPowerPoint Fetal heart scanning technique. The four-chamber view of the heart is obtained from an axial scanning plane across the fetal thorax. Corresponding views of the left (LVOT) and right (RVOT) ventricular outflow tracts are found by angling the transducer toward the fetal head. Reproduced with permission from: Lee W. American Institute of Ultrasound in Medicine. Performance of the basic fetal cardiac ultrasound examination. J Ultrasound Med 1998; 17: 601–607. Yoo et al. have also described a ‘three-vessel view’ to evaluate the pulmonary artery, ascending aorta, and superior vena cava in relation to their relative sizes and relationships (Figure 4)44, 45. Others have used this view to emphasize vascular relationships to the fetal trachea as well46, 47. Figure 4Open in figure viewerPowerPoint Three-vessel view of the fetal heart. This view demonstrates the relationship of the pulmonary artery (PA), aorta (Ao) and superior vena cava (SVC) in the upper mediastinum. Note the alignment as well as the relative sizes of the three vessels. The pulmonary artery has the largest diameter and is the most anterior vessel while the superior vena cava is the smallest and the most posterior. ant, anterior; Lt, left; post, posterior; Rt, right. Image courtesy of Dr J. S. Carvalho. Left ventricular outflow tract The left ventricular outflow tract (LVOT) view confirms the presence of a great vessel originating from the left ventricle (Figure 5). Continuity should be documented between the anterior aortic wall and ventricular septum. The aortic valve moves freely and should not be thickened. When the LVOT is truly the aorta, it should even be possible to trace the vessel into its arch, from which three arteries originate into the neck. However, identification of these aortic arch vessels should not be considered as a routine part of the extended basic cardiac examination. The LVOT view may help to identify ventricular septal defects and conotruncal abnormalities that are not seen during the basic cardiac examination alone. Figure 5Open in figure viewerPowerPoint Left ventricular outflow tract (LVOT). This view demonstrates a great artery that exits the left ventricle. The aortic valve leaflets should be freely moving and not thickened. LV, left ventricle; RV, right ventricle. Reproduced with permission from: Lee W. American Institute of Ultrasound in Medicine. Performance of the basic fetal cardiac ultrasound examination. J Ultrasound Med 1998; 17: 601–607. Right ventricular outflow tract A view of the right ventricular outflow tract (RVOT) documents the presence of a great vessel from a morphologic right ventricle with a moderator band (Figure 6). The pulmonary artery normally arises from the right ventricle and courses toward the left of the more posterior ascending aorta. It is usually slightly larger than the aortic root during fetal life and crosses the ascending aorta at about a 70° angle just above its origin. Figure 6Open in figure viewerPowerPoint Right ventricular outflow tract (RVOT). This view emphasizes that a great vessel can be seen exiting the morphologic right ventricle (RV). The bifurcation is not always clearly seen in this manner. Note that the RVOT exits the ventricle at about 70° to the aortic outflow tract. Occasionally, the right superior vena cava (SVC) will be seen as the most posterior vessel. Adapted with permission from: Lee W. American Institute of Ultrasound in Medicine. Performance of the basic fetal cardiac ultrasound examination. J Ultrasound Med 1998; 17: 601–607. The pulmonary arterial valves move freely and should not be thickened. The RVOT can be confirmed as a pulmonary artery only if its distal end appears bifurcated, although this division cannot always be seen owing to fetal position. The distal pulmonary artery normally divides toward the left side into a ductus arteriosus that continues into the descending aorta. The right side branches into the right pulmonary artery. A large obstetrical ultrasound survey of over 18 000 fetuses examined the standardized practice of incorporating a basic cardiac examination into the routine 30 minutes48. When technically feasible, an extended basic evaluation of the outflow tracts was also attempted. Of the studies that included an adequate four-chamber view, most of them (93%) were associated with satisfactory evaluation of the outflow tracts. Non-visualization rates were: left ventricular outflow tract, 4.2%; right ventricular outflow tract, 1.6%; both outflow tracts, 1.3%. Fetal Echocardiogram A fetal echocardiogram should be performed if recognized risk factors raise the likelihood of congenital heart disease beyond what would be expected for a low-risk screening population. Unfortunately, a high proportion of prenatally detectable cases of congenital heart disease occurs in patients without any risk factors or extra-cardiac anomalies49. Specific details of this specialized procedure are not within the scope of this article. Health-care practitioners, however, should be familiar with some of the reasons why patients could be referred for this comprehensive evaluation (Table 2)50. As an example, increased nuchal translucency of greater than 3.5 mm at 11–14 weeks' gestation, is an indication for a detailed cardiac evaluation even if this measurement subsequently falls into the normal range later in pregnancy51-54. Table 2. Common indications for fetal echocardiography Maternal indications Family history First-degree relative of proband Pre-existing metabolic disease Diabetes Phenylketonuria Maternal infections Parvovirus B19 Rubella Coxsackie Cardiac teratogen exposure Retinoids Phenytoin Carbamazepine Lithium carbonate Valproic acid Maternal antibodies Anti-Ro (SSA) Anti-La (SSB) Fetal indications Suspected fetal heart anomaly Abnormal fetal karyotype Major extracardiac anomaly Abnormal nuchal translucency ≥ 3.5 mm before 14 weeks' gestation Fetal cardiac rate or rhythm disturbances Persistent bradycardia Persistent tachycardia Persistent irregular heart rhythm Fetal echocardiography should be performed by specialists who are familiar with the prenatal diagnosis of congenital heart disease. In addition to information provided by the basic screening examination, a detailed analysis of cardiac structure and function may further characterize visceroatrial situs, systemic and pulmonary venous connections, foramen ovale mechanism, atrioventricular connections, ventriculoarterial connections, great vessel relationships and sagittal views of the aortic and ductal arches. Advanced sonographic techniques can be used to study the heart. For example, Doppler ultrasonography can measure blood flow velocity or identify abnormal flow patterns across valves and within heart chambers. M-mode echocardiography also offers an important method for analyzing cardiac dysrhythmias, suspected ventricular dysfunction, and abnormal wall thickness. Acknowledgements These guidelines were developed under the auspices of the ISUOG Education Committee. Chair: Professor Sturla Eik-Nes, National Center for Fetal Medicine, Trondheim, Norway. Appreciation is particularly extended to specialty consultants who contributed to this project: Dr W. Lee, Task Force Chair William Beaumont Hospital, Royal Oak, MI, USA Dr J. S. Carvalho Royal Brompton and St. George's Hospitals, London, UK Professor R. Chaoui Center for Prenatal Diagnosis and Human Genetics, Berlin, Germany Dr J. Copel Yale University School of Medicine, New Haven, CT, USA Professor K. Hecher University Medical Centre, Hamburg-Eppendorf, Germany Professor D. Paladini University Federico II, Naples, Italy Copies of this document will be available at:http://www.isuog.org ISUOG Secretariat Unit 4, Blythe Mews Blythe Road London W14 0HW, UK e-mail: [email protected] References 1Ferencz C, Rubin JD, McCarter RJ, Brenner JI, Neill CA, Perry LW, Hepner SI, Downing JW. Congenital heart disease: prevalence at livebirth. The Baltimore–Washington infant study. Am J Epidemiol 1985; 121: 31– 36. 2Meberg A, Otterstad JE, Froland G, Lindberg H, Sorland SJ. Outcome of congenital heart defects—a population-based study. Acta Paediatr 2000; 89: 1344– 1351. 3Cuneo BF, Curran LF, Davis N, Elrad H. Trends in prenatal diagnosis of critical cardiac defects in an integrated obstetric and pediatric cardiac imaging center. J Perinatol 2004; 24: 674– 678. 4Rosano A, Botto LD, Botting B, Mastroiacovo P. Infant mortality and congenital anomalies from 1950 to 1994: an international perspective. J Epidemiol Community Health 2000; 54: 660– 666. 5Crane JP, LeFevre ML, Winborn RC, Evans JK, Ewigman BG, Bain RP, Frigoletto FD, McNellis D. A randomized trial of prenatal ultrasonographic screening: impact on the detection, management, and outcome of anomalous fetuses. The RADIUS Study Group. Am J Obstet Gynecol 1994; 171: 392– 399. 6Abu-Harb M, Hey E, Wren C. Death in infancy from unrecognized congenital heart disease. Arch Dis Child 1994; 71: 3– 7. 7Bonnet D, Coltri A, Butera G, Fermont L, Le Bidois J, Kachaner J, Sidi D. Detection of transposition of the great arteries in fetuses reduces neonatal morbidity and mortality. Circulation 1999; 99: 916– 918. 8Tworetzky W, McElhinney DB, Reddy VM, Brook MM, Hanley FL, Silverman NH. Improved surgical outcome after fetal diagnosis of hypoplastic left heart syndrome. Circulation 2001; 103: 1269– 1273. 9Andrews R, Tulloh R, Sharland G, Simpson J, Rollings S, Baker E, Qureshi S, Rosenthal E, Austin C, Anderson D. Outcome of staged reconstructive surgery for hypoplastic left heart syndrome following antenatal diagnosis. Arch Dis Child 2001; 85: 474– 477. Erratum in Arch Dis Child 2002; 86: 313. 10Franklin O, Burch M, Manning N, Sleeman K, Gould S, Archer N. Prenatal diagnosis of coarctation of the aorta improves survival and reduces morbidity. Heart 2002; 87: 67– 69. 11Tworetzky W, Wilkins-Haug L, Jennings RW, van der Velde ME, Marshall AC, Marx GR, Colan SD, Benson CB, Lock JE, Perry SB. Balloon dilation of severe aortic stenosis in the fetus: potential for prevention of hypoplastic left heart syndrome: candidate selection, technique, and results of successful intervention. Circulation 2004; 110: 2125– 2131. 12Simpson LL. Screening for congenital heart disease. Obstet Gynecol Clin North Am 2004; 31: 51– 59. 13DeVore G, Medearis AL, Bear MB, Horenstein J, Platt LD. Fetal echocardiography: factors that influence imaging of the fetal heart during the second trimester of pregnancy. J Ultrasound Med 1993; 12: 659– 663. 14Sharland GK, Allan LD. Screening for congenital heart disease prenatally. Results of a 2 1/2-year study in the South East Thames Region. Br J Obstet Gynaecol 1992; 99: 220– 225. 15Carvalho JS, Mavrides E, Shinebourne EA, Campbell S, Thilaganathan B. Improving the effectiveness of routine prenatal screening for major congenital heart defects. Heart 2002; 88: 387– 391. 16Hunter S, Heads A, Wyllie J, Robson S. 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First-trimester diagnosis of fetal congenital heart disease by transvaginal ultrasonography. Obstet Gynecol 1994; 84: 69– 72. 22Yagel S, Weissman A, Rotstein Z, Manor M, Hegesh J, Anteby E, Lipitz S, Achiron R. Congenital heart defects: natural course and in utero development. Circulation 1997; 96: 550– 555. 23Rustico MA, Benettoni A, D'Ottavio G, Fischer-Tamaro L, Conoscenti GC, Meir Y, Natale R, Bussani R, Mandruzzato GP. Early screening for fetal cardiac anomalies by transvaginal echocardiography in an unselected population: the role of operator experience. Ultrasound Obstet Gynecol 2000; 16: 614– 619. 24Carvalho JS. Fetal heart scanning in the first trimester. Prenat Diagn 2004; 24: 1060– 1067. 25Carvalho JS, Moscoso G, Tekay A, Campbell S, Thilganathan B, Shinebourne EA. Clinical impact of first and early second trimester fetal echocardiography on high risk pregnancies. Heart 2004; 90: 921– 926. 26Huggon IC, Ghi T, Cook AC, Zosmer N, Allan LD, Nicolaides KH. Fetal cardiac abnormalities identified prior to 14 weeks' gestation. Ultrasound Obstet Gynecol 2002; 20: 22– 29. 27Schwarzler P, Senat MV, Holden D, Bernard JP, Masroor T, Ville Y. Feasibility of the second-trimester fetal ultrasound examination in an unselected population at 18, 20 or 22 weeks of pregnancy: a randomized trial. Ultrasound Obstet Gynecol 1999; 14: 92– 97. 28Tegnander E, Eik-Nes SH, Johansen OJ, Linker DT. Prenatal detection of heart defects at the routine fetal examination at 18 weeks in a non-selected population. Utrasound Obstet Gynecol 1995; 5: 372– 380. 29Chaoui R. The four-chamber view: four reasons why it seems to fail in screening for cardiac abnormalities and suggestions to improve detection rate. Ultrasound Obstet Gynecol 2003; 22: 3– 10. 30Tegnander E, Eik-Nes SH, Linker DT. Incorporating the four-chamber view of the fetal heart into the second-trimester routine fetal examination. Ultrasound Obstet Gynecol 1994; 4: 24– 28. 31Paladini D, Vassallo M, Tartaglione A, Lapadula C, Martinelli P. The role of tissue harmonic imaging in fetal echocardiography. Ultrasound Obstet Gynecol 2004; 23: 159– 164. 32Allan LD, Crawford DC, Chita SK, Tynan MJ. Prenatal screening for congenital heart disease. Br Med J 1986; 292: 1717– 1719. 33Copel JA, Pilu G, Green J, Hobbins JC, Kleinman CS. Fetal echocardiographic screening for congenital heart disease: the importance of the four-chamber view. Am J Obstet Gynecol 1987; 157: 648– 655. 34Di Salvo DN, Brown DL, Doubilet PM, Benson CB, Frates MC. Clinical significance of isolated fetal pericardial effusion. J Ultrasound Med 1994; 13: 291– 293. 35Yoo SJ, Min JY, Lee YH. Normal pericardial fluid in the fetus: color and spectral Doppler analysis. Ultrasound Obstet Gynecol 2001; 18: 248– 252. 36Copel JA, Liang RI, Demasio K, Ozeren S, Kleinman CS. The clinical significance of the irregular fetal heart rhythm. Am J Obstet Gynecol 2000; 182: 813– 817. 37Comstock CH. Normal fetal heart axis and position. Obstet Gynecol 1987; 70: 255– 259. 38Smith RS, Comstock CH, Kirk JS, Lee W. Ultrasonographic left cardiac axis deviation: a marker for fetal anomalies. Obstet Gynecol 1995; 85: 187– 191. 39Sharland GK, Chan KY, Allan LD. Coarctation of the aorta: difficulties in prenatal diagnosis. Br Heart J 1994; 71: 70– 75. 40Kirk JS, Comstock CH, Lee W, Smith RS, Riggs TW, Weinhouse E. Fetal cardiac asymmetry: a marker for congenital heart disease. Obstet Gynecol 1999; 93: 189– 192. 41Bromley B, Estroff JA, Sanders SP, Parad R, Roberts D, Frigoletto FD Jr, Benacerraf BR. Fetal echocardiography: accuracy and limitations in a population at high and low risk for heart defects. Am J Obstet Gynecol 1992; 166: 1473– 1481. 42Yoo S-J, Lee Y-H, Kim ES, Ryu HM, Kim MY, Choi H-K, Cho KS, Kim A. Three-vessel view of the fetal upper mediastinum: an easy means of detecting abnormalities of the ventricular outflow tracts and great arteries during obstetric screening. Ultrasound Obstet Gynecol 1997; 9: 173– 182. 43Yoo S-J, Lee Y-H, Cho KS. Abnormal three-vessel view on sonography: a clue to the diagnosis of congenital heart disease in the fetus. AJR Am J Roentgenol 1999; 172: 825– 830. 44Kirk JS, Riggs TW, Comstock CH, Lee W, Yang SS, Weinhouse E. Prenatal screening for cardiac anomalies: the value of routine addition of the aortic root to the four-chamber view. Obstet Gynecol 1994; 84: 427– 431. 45DeVore G. The aortic and pulmonary outflow tract screening examination in the human fetus. J Ultrasound Med 1992; 11: 345– 348. 46Vinals F, Heredia F, Giuliano A. The role of the three vessels and trachea view (3VT) in the diagnosis of congenital heart defects. Ultrasound Obstet Gynecol 2003; 22: 358– 367. 47Yagel S, Arbel R, Anteby EY, Raveh D, Achiron R. The three vessels and trachea view (3VT) in fetal cardiac scanning. Ultrasound Obstet Gynecol 2002; 20: 340– 345. 48Vettraino IM, Lee W, Bronsteen RA, Comstock CH. Sonographic evaluation of the ventricular cardiac outflow tracts. Letter to the Editor. J Ultrasound Med 2005; 24: 566. 49Stumpflen I, Stumpflen A, Wimmer M, Bernaschek G. Effect of detailed fetal echocardiography as part of routine prenatal ultrasonographic screening on detection of congenital heart disease. Lancet 1996; 348: 854– 857. 50Small M, Copel JA. Indications for fetal echocardiography. Pediatr Cardiol 2004; 25: 210– 222. 51Hyett J, Moscoso G, Papapanagiotou G, Perdu M, Nicolaides KH. Abnormalities of the heart and great arteries in chromosomally normal fetuses with increased nuchal translucency thickness at 11–13 weeks of gestation. Ultrasound Obstet Gynecol 1996; 7: 245– 250. 52Hyett JA, Perdu M, Sharland GK, Snijders RS, Nicolaides KH. Increased nuchal translucency at 10–14 weeks of gestation as a marker for major cardiac defects. Ultrasound Obstet Gynecol 1997; 10: 242– 246. 53Mavrides E, Cobian-Sanchez F, Tekay A, Moscoso G, Campbell S, Thilaganathan B, Carvalho JS. Limitations of using first-trimester nuchal translucency measurement in routine screening for major congenital heart defects. Ultrasound Obstet Gynecol 2001; 17: 106– 110. 54Ghi T, Huggon IC, Zosmer N, Nicolaides KH. Incidence of major structural cardiac defects associated with increased nuchal translucency but normal karyotype. Ultrasound Obstet Gynecol 2001; 18: 610– 614. Citing Literature Volume27, Issue1January 2006Pages 107-113 FiguresReferencesRelatedInformation

Newer imaging modalities in the prenatal diagnosis of skeletal dysplasias

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.

MRX42: Two linkage intervals, one in the pericentromeric region and one in Xq26, and the impact for carrier risk estimation

A nonspecific X-linked mental retardation (MRX) family is reported with four mild to moderately affected males and no intellectual impairment in their obligate carrier mothers. Linkage analysis obtained the same multipoint lod score of 2.08 for two intervals on the X chromosome already reported to be linked to other MRX and syndromic X-linked mental retardation (XLMR) families: one pericentromeric and the other at Xq26. Since the responsible gene is not yet characterized, haplotyping is presently the only means available for carrier and prenatal testing for this form of MRX. Carrier risk estimation using pedigree and haplotype data for five females at risk is presented, and the difficulties of prenatal diagnosis given linkage to two different regions is discussed.

Methylenetetrahydrofolate reductase deficiency in four siblings: a clinical, biochemical, and molecular study of the family.

A diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency was made in four sibs at different ages. The first three, including a pair of twins, had retarded psychomotor development, poor social contact, and seizures. Biologically, hyperhomocysteinemia and hypomethioninemia were found associated with low folate levels in serum and red cells, especially undetectable methyltetrahydrofolate in red cells. In the fourth child, prenatal diagnosis was not conclusive because of moderate decrease of enzymatic activity in chorionic villi and trophoblast. The girl was also affected, as shown by hyperhomocysteinemia and low folate levels found several days after birth. A 677C-->T (Ala-->Val) mutation was found in a homozygous state in the four children and in the father. Additionally, a second homozygous mutation, 1081C-->T, changing an arginine to cysteine also was identified in all of the children, whereas the distantly consanguineous parents were heterozygous. This amino acid substitution affecting an arginine residue in a sequence located at the end of catalytic domain seems critical for the function of the enzyme. The difficulty of prenatal diagnosis is discussed given the variability found in enzymatic activity and in the clinical phenotypes.

Coarctation of the aorta: difficulties in prenatal diagnosis.

To formulate echocardiographic criteria for the prenatal diagnosis of coarctation of the aorta. A retrospective study examining the echocardiograms of fetuses with a verified aortic arch abnormality and those in whom the diagnosis was suspected prenatally but was not subsequently confirmed. Tertiary referral centre for fetal echocardiography. 87 fetuses in whom the diagnosis of coarctation was correctly made in 54, suspected but unproved in 24, and overlooked prenatally in nine. Measurements of left and right ventricular size, the diameters of the great arteries, the diameters of the left and right atrioventricular valvar orifices, the appearance of the aortic arch, and the direction of the flow of blood across the foramen ovale. Measurements of the ventricular widths, diameters of the great arteries, or the diameters of the atrioventricular valvar orifices, did not allow clear distinction between cases that definitely had a coarctation and those in whom the diagnosis was unproved. The appearance of the aortic arch, particularly in the horizontal projection, was more helpful in distinguishing cases of coarctation, although this also was not always diagnostic. A predominantly left to right shunt across the foramen ovale was detected more often in cases with a substantiated coarctation (58%) than in those with an unproved diagnosis (12%). The most severe forms of coarctation are associated with relative hypoplasia of the left heart structures compared with the right and a correct diagnosis can be made in early pregnancy. The milder forms of coarctation, however, are consistent with a normal early fetal echocardiogram. In late pregnancy it may be impossible to exclude coarctation categorically as the right heart structures may appear larger than the left in the normal fetus. Thus although a combination of echocardiographic features can correctly identify aortic arch anomalies in the fetus, none either alone or in combination, could clearly distinguish between real and false positive cases, particularly in late gestation.

Fetal Hydronephrosis: Problems in Diagnosis and Management

Experience with the prenatal diagnosis and management of four cases of congenital renal abnormalities is presented. Neither prenatal intervention nor early delivery was indicated in any of these patients. The current enthusiasm for aggressive management of fetal renal abnormalities may underestimate difficulties in prenatal diagnosis and overestimate the potential benefits of early intervention.

Fetal hydronephrosis: Problems in diagnosis and management

Experience with the prenatal diagnosis and management of four cases of congenital renal abnormalities is presented. Neither prenatal intervention nor early delivery was indicated in any of these patients. The current enthusiasm for aggressive management of fetal renal abnormalities may underestimate difficulties in prenatal diagnosis and overestimate the potential benefits of early intervention.