Prenatal diagnosis of pyloric atresia-junctional epidermolysis bullosa syndrome in a fetus not known to be at risk

Junctional epidermolysis bullosa with pyloric atresia (PA-JEB) is a highly lethal, inherited, autosomal recessive disease. Thus far, prenatal diagnosis of this syndrome was only realized on pregnancies at risk for recurrence. We report the case of a 26-year-old woman, first cousin to her husband, who had undergone amniocentesis for polyhydramnios. The karyotype was normal but the amniotic fluid contained acetylcholinesterase. A targeted scan at 25 weeks' gestation did not find spina bifida, but polyhydramnios with a dilated stomach, and several other anomalies: echogenic particles in the amniotic fluid, a thin skin which closely adhered to the nasal bones, narrow nostrils, abnormal ears, fisted hands, malposition of both first toes, and kidney malformation. Despite no previous case in the family, it was thought that sonographic findings were suggestive of the PA-JEB syndrome. A fetal skin biopsy was carried out at 28 weeks' gestation. The ultrastructural examination of fetal skin displayed JEB. Genetic analysis detected a homozygous mutation in the gene encoding integrin alpha 6. Termination of pregnancy was carried out at 29 weeks' gestation. These results illustrate that in the case of a fetus not known to be at risk, diagnosis of PA-JEB can be achieved by ultrasound findings leading to fetal skin biopsy and ultrastructural examination of blistered epidermis. Some new sonographic signs should raise the possibility of significant cutaneous desquamation and blister formation in a fetus, especially when there is positive amniotic acetylcholinesterase coupled with elevated alpha-fetoprotein or suspected pyloric atresia.     

Mohr syndrome in two sisters: prenatal diagnosis in a 22-week-old fetus with post-mortem findings in both.

Oral-facial digital syndrome type II (OFP syndrome II; orofaciodigital syndrome II) is a rare autosomal recessive syndrome, first described by Mohr (1941). We present two sisters with Mohr syndrome from a consanguineous family. One is a three-day-old female patient, the other is 22-week-old fetus. Polydactyly with bifid thumbs in both hands, bilateral polysyndactyly of halluces, lateral polysyndactyly and bilateral pes equinovarus were demonstrated in the fetus sonographically. Corpus callosum agenesis, congenital heart disease, bilateral bifid thumbs and halluces and polydactyly were seen in both patients. In addition, post-mortem findings showed absence of olfactory nerve, single atrium. VSD, abnormal lung lobulation and natal teeth in the fetus. Absence of olfactory nerve and natal teeth have not been reported previously in Mohr syndrome.     

Conceiving a fetus for bone marrow donation: an ethical problem in prenatal diagnosis

We present a family who sought prenatal diagnosis in order to bear a healthy child to serve as an HLA-identical bone marrow donor for their son affected with Wiskott-Aldrich syndrome. They intended to abort HLA-incompatible fetuses who would have been unsuitable bone marrow donors. This case led us to conclude that prenatal diagnosis should not be used to benefit a third party or facilitate the conception or abortion of a fetus for the purpose of generating an organ for transplantation. The limits of parental autonomy and physician responsibility are discussed.     

First-trimester prenatal diagnosis of homozygous (14;21) translocation in a fetus with 44 chromosomes

A (14;21) homozygous Robertsonian translocation was detected by first-trimester prenatal diagnosis. The related parents were heterozygous for the same translocation. At birth the baby was physically normal and had a normal psychomotor development. Together with a few previous observations in living homozygotes for (13;14) translocations, this case corroborates the idea that these subjects with 44 chromosomes are healthy without dysmorphic features.     

Aplasia cutis congenita associated with epidermolysis bullosa and pyloric atresia: the diagnostic role of prenatal ultrasonography.

Aplasia cutis congenita associated with epidermolysis bullosa and pyloric atresia is a rare congenital disease in which localized or widespread areas of skin are absent at birth. Alphafetoprotein (AFP) and skin biopsy have been used for prenatal diagnosis of this condition. A patient in whom normal levels of amniotic AFP at 16 weeks' gestation presumably excluded the disease and who was at risk for aplasia cutis congenita associated with epidermolysis bullosa and pyloric atresia is described. However, 10 weeks later, ultrasonographic examination revealed hydramnios, a dilated stomach, a deformed external ear, and a contracted fisted hand. All signs were confirmed postnatally. The role of ultrasonography and the value of other diagnostic methods in this congenital disease are discussed.     

Sudden unexpected death of a term fetus in an anticardiolipin-positive mother

A term male fetus suddenly and unexpectedly died in utero at the 40th week of gestation. The mother had a regular and unremarkable pregnancy except for an anticardiolipin antibodies positivity. The histological examination of the cardiac conduction system showed islands of conduction tissue in the central fibrous body, known as persistent fetal dispersion. The brainstem examination revealed a severe bilateral hypoplasia of the arcuate nucleus. This morphological finding has been described in more than 35% of our stillborn as well as sudden infant death syndrome (SIDS) cases, independently from the presence of anticardiolipin antibodies. Some authors have given emphasis to the possible lethal association of maternal autoantibodies and QT prolongation. Our findings emphasize the need of an accurate postmortem examination including the study of brainstem and cardiac conduction system in every case of unexpected late intrauterine death, following the same standardized autopsy protocol adopted in SIDS cases.     

Molecular and fetal tissue biopsy capabilities are needed to maximize prenatal diagnosis of junctional epidermolysis bullosa: fetal skin biopsy using a 1-mm microendoscope

OBJECTIVE: To describe a minimally invasive micro-endoscopic technique for fetal skin biopsy and direct examination for a lethal skin condition. MATERIALS AND METHODS: Direct fetoscopic examination of a fetus was undertaken along with full thickness skin biopsies at 19 weeks' gestation. RESULTS: No phenotypic expressions of the lethal condition were visualized and six full thickness skin biopsies were collected. Pathological examination revealed normal skin structures not consistent with junctional epidermolysis bullosa (JEB). CONCLUSION: Minimally invasive examination with the 1 mm endoscope allows direct fetal phenotypic evaluation, full thickness skin biopsies, with risks similar to amniocentesis.     

Consequences of prenatal diagnosis of cystic fibrosis on the reproductive attitudes of parents of affected children.

Three hundred and twenty-six French families with a cystic fibrosis-affected child who were referred for prenatal diagnosis were analysed by sibship size: 74.2 per cent of the couples had no further pregnancies to term after the affected child, who was deceased in 34.6 per cent of cases. These couples were followed prospectively after prenatal diagnosis and 77 had two or more consecutive pregnancies with prenatal diagnosis. The aim of these couples was to succeed in constituting a family with two normal children.     

Cerebro-costo-mandibular syndrome in a father and a female fetus: early prenatal ultrasonographic diagnosis and autosomal dominant transmission.

Ultrasonography in a female fetus revealed cystic cervical hygroma, severe micrognathia, and vertebral and upper limb anomalies suggestive of cerebro-costo-mandibular syndrome (CCMS) which was diagnosed ultrasonographically at 16 weeks' gestation. The father is affected and presents with a Pierre Robin sequence, short stature and typical costovertebral anomalies. CCMS is a rare and severe disorder. The high frequency of sporadic cases, vertical transmission, and the excess of sibs affected via horizontal transmission suggest dominant autosomal mutation with possible germinal mosaicism. The vertical familial case detailed in the present report is a reminder of the high risk when one parent or one sibling is affected and the extreme variability of phenotype and costal ossification. Early prenatal ultrasound diagnosis is possible in a severely affected fetus.     

Prenatal diagnosis of inherited epidermolysis bullosa in a patient with no family history: a case report and literature review

OBJECTIVE: The junctional form of epidermolysis bullosa (EB) is a recessively inherited mechanobullous disease in which minimal trauma results in blister formation at the dermal-epidermal junction. A rare form associated with pyloric atresia (JEB-PA) is a severe clinical subtype leading to rapid demise after birth, thus justifying prenatal diagnosis. The case characterized by abnormal ultrasound findings at 35 weeks of gestation (gastric dilatation associated with polyhydramnios) of a patient with no family history is reported. METHOD: Postabortion skin biopsies were analyzed by immunofluorescence that revealed marked reduction of integrin alpha6beta4 in accordance with the diagnosis of JEB-PA. RESULTS: Amniotic fluid contained excess total protein (4 MoM), abnormally high AFP (20.4 MoM) related to skin lesions and abnormally elevated digestive enzyme suggestive of fetal vomiting of bile. The electrophoretic pattern of cholinesterases was unusual (additional slow band). Maternal serum AFP was 3.14 MoM and free beta-hCG 13.1 MoM. Because of these concomitant findings, JEB-PA was suspected. CONCLUSION: The case under study was atypical because of late clinical manifestations of the disease: polyhydramnios, gastric enlargement. As maternal serum AFP at 15 weeks may be normal, it was suggested that discovery of polyhydramnios during the second or the third trimester should prompt biochemical analysis of amniotic fluid, such as AFP and GGTP assay in all cases.     

Prenatal diagnosis of a fetus with an extra idic(X)(q27)

A fetus with an extra idic(X)(q27) was ascertained during prenatal diagnosis. The derived X and one normal X chromosome were late replicating. Due to lack of previous experience, genetic counselling presented obvious difficulties and the fetal phenotype could be only tentatively predicted.     

Acid-base relationship between mother and fetus in gestosis (pre-eclampsia) and in pregnant women with a labile blood pressure.

Simultaneous blood microsamples were taken from the maternal ear and uterine cervix and the fetus of healthy pregnant women, those with labile hypertension, and those with severe gestosis (pre-eclampsia). The po2, pH, BE and pco2 were studied. The fetuses showed no signs of asphyxia. The differences in BE values between the women withe gestosis and their fetuses were significantly greater than in the cases of healthy pregnancy. No differences were seen between healthy and gestotic gravida groups in po2, pH and pco2 values. This favours the opinion that in gestosis of the mother the fetus has a tendency to metabolic acidosis, which apparently places it in a poorer position than the fetuses of healthy mothers, should acute asphyxia occur. At the time of study the po2 of the fetuses of gravidas with a labile blood pressure was lower than that of fetuses of healthy gravidas.     

Alpha-fetoprotein and acetylcholinesterase are not predictive of fetal junctional epidermolysis bullosa, Herlitz variant.

Junctional epidermolysis bullosa, Herlitz variant (junctional EB-Herlitz) is a lethal autosomal recessive skin disorder currently amenable to prenatal diagnosis only by direct analysis of fetal skin. However, elevated levels of alpha-fetoprotein, as well as the presence of acetylcholinesterase in amniotic fluid, have been associated with other severe fetal genodermatoses. Fetal skin samplings were performed in ten pregnancies at risk for fetal junctional EB-Herlitz, with three fetuses affected on the basis of electron microscopic detection of blisters within the lamina lucida and abnormal hemidesmosomes. In neither affected nor unaffected pregnancies were maternal serum or amniotic fluid alpha-fetoprotein levels elevated. Moreover, alpha-fetoprotein levels in both maternal serum and amniotic fluid were not statistically different comparing affected and unaffected fetuses. Acetylcholinesterase was not present in the amniotic fluid samples of the three affected pregnancies. Unlike other severe fetal genodermatoses, neither alpha-fetoprotein nor acetylcholinesterase was predictive of junctional EB-Herlitz.     

Structural cardiac abnormalities in the fetus: reliability of prenatal diagnosis and outcome

The outcomes of 129 pregnancies in which the fetus was found to have a structural cardiac abnormality are reviewed. Over a 30-month period from January 1985 to June 1987, 1924 patients were referred to the British Heart Foundation Research Centre for Perinatal Cardiology at Guy's Hospital for fetal cardiac scanning. A total of 129 structural cardiac abnormalities was diagnosed; 53% of these patients were referred because of an abnormal 'four-chamber view' on ultrasound at the referring hospital; 47 of the pregnancies (69% of the 68 patients referred before 28 weeks) were terminated, and in the remaining 82 pregnancies outcome was poor with only 20 infants (16%) surviving longer than 11 months. The prenatal diagnosis was fully or partly correct in 96% of the 111 cases where it was possible to verify the diagnosis by post-mortem or postnatal diagnosis. In the 82 pregnancies not terminated, 13 of the 22 cases given a moderate or good prognosis survived more than 11 months (59% survival), but only seven of the 60 (12% survival) given a fatal, poor or uncertain prognosis. The benefits of a multidisciplinary approach are discussed.     

Structural cardiac abnormalities in the fetus: reliability of prenatal diagnosis and outcome

Summary. The outcomes of 129 pregnancies in which the fetus was found to have a structural cardiac abnormality are reviewed. Over a 30 month period from January 1985 to June 1987, 1924 patients were referred to the British Heart Foundation Research Centre for Perinatal Cardiology at Guy's Hospital for fetal cardiac seanning. A total of 129 structural cardiac abnormalities was diagnosed; 53% of these patients were referred because of an abnormal 'four-chamber view' on ultrasound at the referring hospital; 47 of the pregnancies (69% of the 68 patients referred before 28 weeks) were terminated, and in the remaining 82 pregnancies outcome was poor with only 20 infants (16%) surviving longer than 11 months. The prenatal diagnosis was fully or partly correct in 96% of the 111 cases where it was possible to verify the diagnosis by post-mortem or postnatal diagnosis. In the 82 pregnancies not terminated, 13 of the 22 cases given a moderate or good prognosis survived more than 11 months (59% survival), but only seven of the 60 (12% survival) given a fatal, poor or uncertain prognosis. The benefits of a multidisciplinary approach are discussed.     

Chromosome 15q overgrowth syndrome: prenatal diagnosis, molecular cytogenetic characterization, and perinatal findings in a fetus with dup(15)(q26.2q26.3)

ObjectiveTo present molecular cytogenetic characterization of a prenatally detected duplication of 15q26.2 → q26.3 in a fetus with overgrowth.Case ReportA 34-year-old para 0 woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a derivative chromosome 15, or der(15), with additional material at the end of the long arm of one chromosome 15. Parental karyotypes were normal. Fetal overgrowth was first noted at 21 weeks of gestation. Repeated amniocentesis was performed at 22 weeks of gestation. Array comparative genomic hybridization revealed a 4.71-Mb duplication from 15q26.2 to 15q26.3 encompassing the IGF1R gene. Fluorescence in situ hybridization analysis using the bacterial artificial chromosome clone probes specific for 15q26.2-q26.3 and the subtelomeric region of 15q showed a direct duplication and no terminal deletion in the der(15). Polymorphic DNA marker analysis determined a paternal origin of the duplication of 15q. Level II ultrasound at 23 weeks of gestation revealed a fetal biometry equivalent to 26 weeks. The pregnancy was subsequently terminated, and a 1062-g (>99^th centile) malformed fetus was delivered at 24 weeks of gestation with craniofacial dysmorphism, craniosynostosis, and overgrowth.ConclusionThe present case provides evidence for prenatal overgrowth, craniosynostosis, and characteristic facial dysmorphism in association with a duplication of 15q26.2 → q26.3 and a duplication of the IGF1R gene. Prenatal diagnosis of fetal overgrowth should include a differential diagnosis of the chromosome 15q overgrowth syndrome.     

Plasma ACTH, beta-lipotropin and beta-endorphin in the human fetus and their mother during delivery (author's trans)

Adrenocorticotropic hormone (ACTH), beta-lipotropin (beta-LPH) immunoreactivity (IR) and beta-endorphin (beta-EP) immunoreactivity (IR) were measured by high-sensitive radioimmunoassay in maternal and umbilical cord plasma samples which were obtained simultaneously in 12 cases. Mean IR-beta-LPH in maternal (690.1 +/- 138.6 pg/ml, +/- S.E.) and cord venous plasma (1114.8 +/- 94.2 pg/ml) were significantly higher than that of normal adults (93.0 +/- 8.2 pg/ml). Mean IR-beta -EP in maternal (125.8 +/- 24.0 pg/ml) and cord venous plasma (130.6 +/- 20.6 pg/ml) were significantly higher than that of normal adults (6.0 +/- 0.9 pg/ml). There were significant positive correlations between IR-beta-LPH and IR-beta-EP in maternal and cord venous plasma. Mean beta-EP to beta-LPH molar ratio of 0.19 +/- 0.03 in maternal plasma was significantly (p less than 0.05) higher than that of cord venous plasma (0.13 +/- 0.01). There was no significant correlation between the levels of these three hormones in maternal plasma and the levels in cord venous plasma. These data suggest that ACTH, IR-beta-LPH and IR-beta-EP were elevate during labor, delivery responding the stress. Beta-LPH and beta-EP in cord venous plasma were fetal and/or placental origin.     

Mutation analysis in the family of a Taiwanese boy with with epidermolysis bullosa simplex dowling-meara.

Epidermolysis bullosa simplex (EBS) is a group of hereditary bullous diseases characterized by intraepidermal blistering due to mechanical stress-induced degeneration of basal keratinocytes. The major subtypes of EBS, including EBS Dowling-Meara (EBS-DM), are caused by mutations of the basal keratin genes, keratin 5 (KRT5) or keratin 14 (KRT14). Here, we describe the first reported pedigree of EBS-DM in Taiwan. The proband was a 5-day-old newborn, who presented with numerous blisters of various sizes, some of which were hemorrhagic, as well as erosions on the extremities and hard palate since birth. Biopsy of a new vesicle showed subepidermal and basal cleavage with infiltration of eosinophils and neutrophils. Electron microscopy revealed cytolysis of basal cells and clumping of tonofilaments forming thick bundles and peculiar electron-dense round or oval basket-weave bodies. These features are characteristic of EBS-DM. The proband's mother had also suffered from a similar blistering disorder since birth, with gradual appearance of mottled pigmentation on the trunk, diffuse irregular or linear palmoplantar hyperkeratosis, and nail dystrophy. Mutation analysis revealed a heterozygous point mutation (R125C) in helix 1A of keratin 14 in the proband and his mother. The detection of this pathogenic point mutation enables future prenatal diagnosis in this family.