Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. OBJECTIVE: The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. METHODS: SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. RESULTS: Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. CONCLUSION: Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.

TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia.

OBJECTIVE: The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. METHODOLOGY: We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. CASES: Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. CONCLUSION: TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered.

Fetal home monitoring for the prenatal management of gastroschisis.

BACKGROUND: Fetal distress is a frequent complication of gastroschisis, and could be screened for by home monitoring, as many pregnant women expecting an affected child live far away from a specialized perinatal center. This study was undertaken to audit a policy of fetal home monitoring (FHM) to achieve early detection of fetal heart rate (FHR) abnormalities in gastroschisis. METHODS: Daily FHM was started at a median age of 30 weeks in 31 pregnant women referred following prenatal diagnosis of isolated gastroschisis. Monitoring was considered abnormal in cases with decelerations, tachycardia, bradycardia, decreased baseline variability or absence of accelerations. When an ominous FHR was detected and confirmed by in-hospital monitoring, an emergency cesarean section (C-section) was indicated. Otherwise, an elective C-section was planned. RESULTS: In 20 cases FHM remained normal. There were 16 elective C-sections, two emergency C-sections for FHR abnormalities detected by in-hospital monitoring, and two spontaneous premature vaginal deliveries. In 11 cases, an abnormal FHM was detected. There was one intrauterine death with acute ischemic necrosis of the large bowel. The other abnormalities consisted of decreased baseline variability with tachycardia (n = 7) or without tachycardia (n = 3) and were confirmed by in-hospital follow-up in nine cases, leading to emergency C-section. CONCLUSION: The high rate of abnormal FHR patterns picked up by FHM in gastroschisis led to a rate of emergency C-sections of 9/31. However, this strategy failed to prevent one intrauterine death due to acute bowel necrosis.

Sonography in prenatal diagnosis of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder with an incidence of 1/15 000. More than 90% of CAH cases result from mutations of CYP21, leading to 21-hydroxylase deficiency. In its classical form, CAH is severe and consists of the virilizing (increase of androgens) and salt-wasting (lack of aldosterone) phenotype. When a proband exists, early prenatal diagnosis for CAH can be performed by direct molecular analysis in the first trimester. We describe herein two cases suggesting that the prenatal diagnosis of CAH can be initiated by the sonographic appearance of the adrenal gland at the second-trimester scan in the absence of a family history.

A novel PCR approach for prenatal detection of the common NEMO rearrangement in incontinentia pigmenti.

OBJECTIVES: Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that is usually lethal in males in the prenatal period. Largely 80% of cases are accounted for by a large-scale deletion encompassing exons 4 to 10 of the NEMO gene. The aim of this work was to facilitate prenatal diagnosis of IP by devising a novel test for detection of the prevalent NEMO deletion. METHODS: We devised a sensitive and reproducible multiplex PCR test enabling simultaneous amplification of the deleted and wild-type NEMO genes in IP female individuals. RESULTS: Combination of this DNA test, with Xq28 linkage analysis and X-inactivation pattern study enabled us to offer an IP prenatal diagnosis in 15 of the 16 couples at a 50% risk to have an affected offspring. CONCLUSION: A current approach to IP prenatal diagnosis is proposed on the basis of the previously mentioned molecular tools.

Can three-dimensional ultrasound be used for the assessment of the fetal lung volume in cases of congenital diaphragmatic hernia?

We report on 2 fetuses with congenital diaphragmatic hernia (CDH) in whom the fetal lung volumes were estimated by three-dimensional ultrasound and the results compared with the postmortem lung volume measurements. Both examiners (sonographer and pathologist) were blinded to each other's results. The 1st case was a right CDH diagnosed at 20 weeks of gestation. The 2nd case was a left CDH diagnosed at 22 weeks of gestation. Both pregnancies were terminated upon request of the parents. Three-dimensional ultrasound estimation of the fetal lung volume was performed 1 day before termination of pregnancy using the technique of rotation of the three perpendicular planes. The left and right lung volumes estimated by three-dimensional ultrasound were 3.88 and 1.87 cm(3), respectively, in the 1st case and 0 and 5.52 cm(3), respectively, in the 2nd case. On postmortem examination, the left and right lung volumes were 3.0 and 2.2 cm(3), respectively, in case 1 and 1.1 and 5.6 cm(3), respectively, in case 2. This suggests that a three-dimensional estimation of pulmonary volumes may be correlated with postmortem findings in cases with CDH.

First-trimester diagnosis of osteogenesis imperfecta associated with encephalocele by conventional and three-dimensional ultrasound.

To illustrate the three-dimensional sonographic features of a rare genetic disorder, we report on prenatal diagnosis of osteogenesis imperfecta congenita associated with encephalocele at 13 weeks of gestation, using conventional and three-dimensional ultrasound. Because the parents were first-degree cousins and on the basis of the family history, a recessive autosomal inheritance was suspected. Of seven previous pregnancies, five were unaffected and two had been terminated in the second trimester owing to a similar abnormality (one affected boy and one affected girl). In the case we present, the diagnosis was made on the basis of two-dimensional ultrasound performed by physicians aware of the history; the quality of three-dimensional ultrasound imaging suggests that this technique might have contributed toward establishing a precise diagnosis in the absence of a positive family history. Besides, the global view provided by three-dimensional surface-rendering images made the parents more confident of the accuracy of the diagnosis. Although osteogenesis imperfecta congenita is generally considered as autosomal dominant, the case we report suggests that it may be inherited in a recessive autosomal fashion at least when associated with encephalocele. Three-dimensional ultrasound confirmed the conventional two-dimensional examination and was helpful in convincing the parents of the accuracy of the diagnosis.