To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.

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A copy number variation morbidity map of developmental delay

British authors are the natural heirs to Charles Dickens and Graham Greene.) Nevertheless there are advantages to British readers in a British book especially, for instance, in the chapter on social paediatrics and occasionally as regards therapeutics. The new Forfar and Arneil is, like its predecessors, a good book. There are many new authors and much of it has been completely rewritten. Each chapter has a long list of references, many of them to further reading in books and important 'landmark' papers rather than to very recent original work, and that seems appropriate for a textbook of this nature. It is up to date, including references to topics such as oesophageal pH monitoring in gastrooesophageal reflux, the value of steroids in bacterial meningitis, a full account of the peroxisomal disorders, the significance of dystrophin in muscular dystrophy, the importance of vitamin A in reducing mortality in third world countries, and the use of sumatriptan in migraine and of vigabatrin and lamotrigine in epilepsy. Surprisingly, neither in this nor in Nelson's textbook could I find any reference to Angelman's syndrome. Some topics chosen at random such as Prader-Willi syndrome or haemolytic uraemic syndrome were discussed more fully in the British textbook. There is a surprising omission, however, and that is the chapter on disorders ofear, nose, and throat. Adenoids, glue ear or secretory otitis media, tonsillitis, and tonsillectomy have all been dropped from the index and deafness is dealt with in the chapter on neurology. If you look up 'tonsils' you will be referred to any entry which reads: 'Tonsils: size, presence of infection, exudate, pitting, peritonsillar swelling?'. The index entry 'ear, nose and throat problems' refers to a brief account of such problems in children with cleft palate. It is one of those crazy facts of modern life that the American book costs £60, the British £125. Who will read this new edition? I shall, and I suppose many other consultant paediatricians will also use it as a standard reference book. Undergraduate students will need a more compact text for their basic reading but should use it to look up specific topics, and doctors studying for the MRCP in paediatrics should make a systematic assault on it to provide them with a personal database to be supplemented by journals and monographs. As a textbook of British paediatrics it has no competition and it remains an excellent work of reference which must be available in all paediatric departments in Britain, but the absence of the chapter on ear, nose, and throat disorders must surely be an error and there is clearly a marketing problem for British publishers faced with American competition. If we want British textbooks, and I would not like to think that the time will be forced upon us when we shall have no choice, then it looks as if we must be prepared to pay for the privilege. DOUG ADDY Consultant paediatrician

https://adc.bmj.com/content/archdischild/68/3/435.2.full.pdf

Syndromes of the Head and Neck

Rheological and Physiological Consequences of Conversion of the Maternal Spiral Arteries for Uteroplacental Blood Flow during Human Pregnancy

Congenital diaphragmatic hernia. Epidemiology and outcome

Central nervous system (CNS) malformations are some of the most common of all congenital abnormalities. Neural tube defects are the most frequent CNS malformations and amount to about 1–2 cases per 1000 births. The incidence of intracranial abnormalities with an intact neural tube is uncertain as probably most of these escape detection at birth and only become manifest in later life. Long-term follow-up studies suggest however that the incidence may be as high as one in 100 births1. Ultrasound has been used for nearly 30 years as the main modality to help diagnose fetal CNS anomalies. The scope of these guidelines is to review the technical aspects of an optimized approach to the evaluation of the fetal brain in surveys of fetal anatomy, that will be referred to in this document as a basic examination. Detailed evaluation of the fetal CNS (fetal neurosonogram) is also possible but requires specific expertise and sophisticated ultrasound machines. This type of examination, at times complemented by three-dimensional ultrasound, is indicated in pregnancies at increased risk of CNS anomalies. In recent years fetal magnetic resonance imaging (MRI) has emerged as a promising new technique that may add important information in selected cases and mainly after 20–22 weeks2,3, although its advantage over ultrasound remains debated4,5.

Sonographic examination of the fetal central nervous system: Guidelines for performing the 'basic examination' and the 'fetal neurosonogram'

Objectives

A retrospective analysis of the prognostic significance of the lung-to-head ratio (LHR) and other prenatal parameters on the outcome of fetuses with left-sided congenital diaphragmatic hernia (CDH).



Methods

A total of 26 fetuses with isolated left CDH without chromosomal abnormalities were included. Twenty-one LHR measurements could retrospectively be calculated from the last available ultrasonographic recordings before birth. The relationship between LHR and fetal outcome and the gestational age dependency of this relation was tested. Cutoff levels as previously published were applied to determine their predictive value in this population. The association between other prenatal predictive variables and fetal outcome was also determined. Survival was defined as discharge from the hospital.



Results

The overall survival rate was 50%. There was a statistically significant difference between the mean LHR of the survivors compared to the mean LHR of the nonsurvivors (1.78 vs 1.02), whereas the mean gestational age of these two groups did not differ. LHR was not gestational age dependent in the prediction of fetal outcome. The cutoff levels LHR 1.4 showed a good applicability in the prediction of fetal outcome within the present study population with a 100% survival if LHR >1.4 and a 100% mortality if LHR <1. An intrathoracic position of the stomach, mediastinal shift, polyhydramnios as individual variables and early diagnosis (<25 weeks' gestation) revealed to be poor sonographic predictors for fetal outcome.



Conclusion

LHR proved to be a good predictor for fetal outcome, independent of gestational age at the time of the measurement. To substantiate our observation, a prospective multicenter study is warranted. Copyright © 2003 John Wiley & Sons, Ltd.

Congenital diaphragmatic hernia: an evaluation of the prognostic value of the lung-to-head ratio and other prenatal parameters

This review describes the pathogenesis of pulmonary hypoplasia and highlights its clinical, radiological and pathologic features, with emphasis on oligohydramnios-related pulmonary hypoplasia. Since pulmonary hypoplasia may lead to severe respiratory distress immediately after birth and even to neonatal death, an accurate and patient-friendly prenatal test for early detection and distinction between lethal and non-lethal pulmonary hypoplasia is still highly desirable. An extended overview of the proposed methods for the prenatal prediction of pulmonary hypoplasia is presented.

/pdf/the-fetal-lung-2-pulmonary-hypoplasia-5c93myy1vc.pdf

The fetal lung 2: pulmonary hypoplasia

Fetal supraventricular tachycardia (SVT) can be successfully treated transplacentally, but in cases where fetal hydrops develops there is considerable morbidity and mortality. The present study was carried out to establish whether the introduction of flecainide altered obstetric management and fetal outcome. A retrospective analysis took place of 51 singleton pregnancies which were referred to the division of prenatal diagnosis because of fetal tachycardia between 1982 and 1993. SVT was documented in 50 out of 51 fetuses, one of which displayed a combination of extensive rhabdomyomas and severe hydrops and died shortly after referral. In the other fetus ventricular tachycardia was diagnosed. Of the remaining 49 fetuses, 14 did not receive any prenatal treatment, but nine needed postnatal treatment. Transplacental treatment of SVT took place in 35 fetuses, of which 22 presented without hydrops and 13 with hydrops. These subsets differed significantly with respect to restoration of normal sinus rhythm (73% vs. 30%; p < 0.001) and mortality (0% vs. 46%; p < 0.001). Digoxin was effective in restoring sinus rhythm in 55 per cent of the non-hydropic fetuses but in only eight per cent of the hydropic fetuses. Flecainide was effective in restoring sinus rhythm in all non-hydropic fetuses where digoxin treatment failed, and in 43 per cent of hydropic fetuses. Administration of flecainide resulted in a significantly reduced mortality (p < 0.001) compared with digoxin treatment. No adverse effects were seen. Postnatal anti-arrhythmic treatment was necessary in 23 infants. Treatment could be withdrawn within one year in all cases but one.

/pdf/the-efficacy-of-flecainide-versus-digoxin-in-the-management-38ck5wzi38.pdf

The efficacy of flecainide versus digoxin in the management of fetal supraventricular tachycardia

Successful human fetal ductus venosus flow velocity waveform recording was achieved cross sectionally in 48 out of 60 women at 19–22, 27–30 and 36–39 weeks of gestation. The ductus venosus shows a pulsatile flow pattern consisting of a systolic and diastolic forward component without a late diastolic reverse component as demonstrated in the inferior vena cava. Peak systolic velocities as high as 40–80 cm/s were observed. A statistically significant increase in time-averaged velocity, peak systolic and peak diastolic velocity with advancing gestational age was established.

Ductus venosus blood flow velocity waveforms in the human fetus--a Doppler study.

A literature survey is presented on normal fetal development during the embryonic, pseudoglandular, canalicular, saccular and alveolar stages in the human fetus. Normal anatomical and physiological aspects of fetal lung development including the fetal pulmonary circulation are described. Factors which may influence fetal lung growth and consequently may play a role in the development of pulmonary hypoplasia are discussed, such as intrauterine and intrathoracic space, lung fluid, fetal breathing movements, normal balance of volume and pressure in the lung and interference with the blood supply.

/pdf/the-fetal-lung-1-developmental-aspects-ndcoljyr04.pdf

J. W. Wladimiroff

Papers

Congenital diaphragmatic hernia: an evaluation of the prognostic value of the lung-to-head ratio and other prenatal parameters

The fetal lung 2: pulmonary hypoplasia

The efficacy of flecainide versus digoxin in the management of fetal supraventricular tachycardia

Ductus venosus blood flow velocity waveforms in the human fetus--a Doppler study.

The fetal lung. 1: Developmental aspects.