OEIS complex: prenatal ultrasound and autopsy findings.

OBJECTIVE: To describe prenatal ultrasound and autopsy findings in fetuses with OEIS (omphalocele, bladder exstrophy, imperforate anus, spina bifida) complex. METHODS: This was a retrospective study of the nine cases with OEIS complex diagnosed at our center using detailed fetal ultrasound during the last 10 years. We summarized the fetal ultrasound findings that led to the diagnosis and compared them with the autopsy results. RESULTS: All affected fetuses were diagnosed using detailed fetal ultrasound after 16 weeks' gestation. The main prenatal findings were omphalocele, skin-covered lumbosacral neural tube defect, non-visualized bladder and limb defects. Prenatal sonography failed to detect the abnormal genitalia, bladder exstrophy and anal atresia. All cases had abnormalities in a 'diaper distribution', which helped in making the prenatal diagnosis. Eight of the nine couples chose to terminate the pregnancies following multidisciplinary counseling. The pregnancy that was continued was a case with dizygotic twins discordant for OEIS, and the affected fetus died in utero. CONCLUSIONS: The combination of the following ultrasound findings: ventral wall defect, spinal defect and a non-visualized bladder with or without limb defects, are characteristic of OEIS complex. Diagnosis can be made with confidence as early as 16 weeks' gestation, although earlier diagnosis may be possible.

A deletion mutation in GJB6 cooperating with a GJB2 mutation in trans in non-syndromic deafness: A novel founder mutation in Ashkenazi Jews.

A deletion of at least 140 kb starting approximately 35kb upstream (telomeric) to the GJB2 (CX26) gene was identified in 7 patients from 4 unrelated Jewish Ashkenazi families with non-syndromic hearing loss. These patients were heterozygous for one of the common mutations 167delT or 35delG in the GJB2 gene in trans to the deletion. The deletion started at 5' side of the GJB6 (CX30) gene including the first exon and it did not affect the integrity of the GJB2 gene. The deletion mutation segregated together with the hearing loss, and was not found in a control group of 100 Ashkenazi individuals. We suggest that the deletion is a recessive mutation causing hearing loss in individuals that are double heterozygous for the deletion and for a mutation in the GJB2 gene. The effect of the deletion mutation could be due to a digenic mode of inheritance of GJB2 and GJB6 genes that encode two different connexins; connexin 26 and connexin 30, or it may abolish control elements that are important in the expression of the GJB2 gene in the cochlea. Regardless which of the options is valid, it is apparent that the deletion mutation provides a new insight into connexin function in the auditory system. The deletion mutation was on the same haplotypic background in all the families, and therefore is a founder mutation that increases the impact of GJB2 in the etiology of prelingual recessive non-syndromic hearing loss in the Ashkenazi population.

Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C.

PURPOSE: Niemann-Pick disease type C (NP-C) is an autosomal recessive lipid storage disease manifested by an impairment in cellular cholesterol homeostasis. The clinical phenotype of NP-C is extremely variable, ranging from an acute neonatal form to an adult late-onset presentation. To facilitate phenotype-genotype studies, we have analyzed multiple Israeli NP-C families. METHODS: The severity of the disease was assessed by the age at onset, hepatic involvement, neurological deterioration, and cholesterol esterification studies. Screening of the entire NPC1 coding sequence allowed for molecular characterization and identification of disease causing mutations. RESULTS: A total of nine NP-C index cases with mainly neurovisceral involvement were characterized. We demonstrated a possible link between the severity of the clinical phenotype and the cholesterol esterification levels in fibroblast cultures following 24 hours of in vitro cholesterol loading. In addition, we identified eight novel mutations in the NPC1 gene. CONCLUSIONS: Our results further support the clinical and allelic heterogeneity of NP-C and point to possible association between the clinical and the biochemical phenotype in distinct affected Israeli families.

Variables influencing parental perception of inherited metabolic diseases before and after genetic counselling.

The present study was undertaken to characterize the variables that influence parental perception of metabolic disorders and their genetic origin before and after genetic counselling, the effect of counselling on parental attitudes towards prenatal diagnosis and pregnancy termination, and the factors affecting parental coping with burden. Parents of children with metabolic diseases from 32 Arab-Muslim families were interviewed, answering a pre-structured questionnaire. These interviews indicate the following. (1) Traditional belief and religious commitment are more important determinants than education in parental perception of inherited metabolic diseases. (2) The number of affected children has a greater impact on parental evaluation of the burden than the number of healthy children. The social component, i.e. the way families are viewed by society, is the most significant factor of the burden. (3) Parents use different techniques to divide responsibility regarding reproduction. Having a healthy child and the availability of prenatal diagnosis and pregnancy termination were the two most important factors in parental reproductive decision making. In the absence of a healthy child and when the burden was perceived as too heavy, parents tended 'not to decide'. (4) Parental attitude to pregnancy termination was dependent on two factors: religious commitment (leading to objection) and severity of disease (leading to flexibility and approval). (5) In almost all families, genetic counselling altered parental perception of the disease and its hereditary origin. We conclude that genetic counselling and population education may be helpful in the prevention of consanguineous marriages and in family planning, even in a society that values traditional beliefs very highly.

The role of midtrimester targeted fetal organ screening combined with the "triple test" and maternal age in the diagnosis of trisomy 21: a retrospective study.

OBJECTIVE: Our purpose was to evaluate the role of fetal ultrasonography in prenatal detection of trisomy 21. STUDY DESIGN: A retrospective study was performed on all cases of trisomy 21 diagnosed prenatally or postnatally between January 1990 and December 1993 in the Jerusalem metropolitan area. Our program of prenatal detection of trisomy 21 is a three-tiered, chronologically progressive screening that includes maternal age, biochemical serum markers, and targeted fetal organ survey. Sixty-seven thousand ninety-two babies were born during the study period; 17,084 maternal biochemistry analyses (triple test) were performed; and 6315 fetuses were karyotyped. RESULTS: One hundred eight cases of trisomy 21 were diagnosed prenatally and postnatally. The overall rate of detection of trisomy 21 was 92.2% when our recommendations were followed. Among those cases diagnosed prenatally, 66.6% of trisomy 21 cases had been referred for fetal karyotyping because of maternal age > or = 35 years, 18.5% because of abnormal triple test results, and 11.1% because of fetal ultrasonographic findings associated with trisomy 21. Among women < 35 years old, 80% of trisomy 21 cases were detected prenatally. Of these, 50% had been referred for karyotyping because of triple test results and 30% because of abnormal ultrasonographic findings. CONCLUSION: Midtrimester ultrasonographic targeted fetal organ screening plays a critical role in prenatal diagnosis of trisomy 21 among women under the age of 35 years.

A syndrome including thumb malformations, microcephaly, short stature, and hypogonadism.

We report on eight patients from seven different families affected with a syndrome which includes thumb defects, short stature, microcephaly, and mental retardation. Most of the patients had additional malformations, in particular amenorrhoea and azoospermia in the adults. There were no haematological manifestations and the chromosomes were normal without evidence of breakage even after stimulation. In five of the cases the probands' mother received hormonal treatment before or at the beginning of her pregnancy or both. The syndrome may be inherited as an autosomal recessive trait since the patients included both males and females and their parents were related in most cases. In addition, supporting this possibility, they all originated from a small village which may be considered as an isolate. However, in all cases but one, only one person was affected in each family and there was a significant apparent excess of healthy sibs of the probands. These observations may be the result of the variability of the syndrome or a more complex type of inheritance.

Trisomy 2: confined placental mosaicism in a fetus with intrauterine growth retardation.

In a pregnancy that was monitored due to increased risk for Down syndrome in the triple test, a normal karyotype was found in amniocentesis. Follow-up by serial ultrasound examinations revealed intrauterine growth retardation (IUGR) at 20 weeks of gestation. The parents decided to terminate the pregnancy and the karyotype of the placental fibroblasts was 47,XX,+2. Analysis of polymorphic markers of chromosome 2 demonstrated (a) that trisomy 2 was confined to the placenta (CPM), (b) that the trisomy 2 cell line was a result of a meiotic I error of paternal origin, and (c) that the fetal tissues with a normal karyotype were biparental disomy 2.

Aspartylglucosaminuria among Palestinian Arabs.

Aspartylglucosaminuria (AGU) is a rare disorder of glycoprotein metabolism caused by the deficiency of the lysosomal enzyme aspartylglucosaminidase (AGA). AGU is inherited as an autosomal recessive trait and occurs with a high frequency in Finland because of a founder effect. While very few patients with AGU have been reported from non-Finnish origin, we diagnosed the disorder in 8 patients originating from 3 unrelated families, all Palestinian Arabs from the region of Jerusalem. The clinical diagnosis of AGU is often difficult, in particular early in the course of the disease, and most of the patients are diagnosed after the age of 5 years. However, since these patients excrete early large amounts of aspartylglucosamine in urine, biochemical screening is easy by urine chromatography.

Renal anomalies in Marden-Walker syndrome: a clue for prenatal diagnosis.

Marden-Walker syndrome is an autosomal-recessive disorder characterized by psychomotor retardation, blepharophimosis, joint contractures, arachnodactyly, failure to thrive, and, infrequently, renal anomalies. We report on the prenatal diagnosis of Marden-Walker syndrome in a fetus which had had a previously affected sib with this syndrome. The ultrasonic findings indicative of the diagnosis in this fetus were intrauterine growth retardation and renal cystic disease. We emphasize the importance of renal anomalies which, when present in combination with other ultrasound evidence of this syndrome, should be used as a clue for the diagnosis of Marden-Walker syndrome.

Antley-Bixler syndrome and esophageal atresia in a patient with trisomy 21.

The Antley-Bixler syndrome (ABS) is characterized by craniofacial, skeletal and urogenital anomalies. While most patients with ABS die of severe respiratory complications in their first months, long-term survivors have been reported. We report an infant girl, born to a consanguineous couple, with craniofacial and skeletal anomalies, consistent with ABS, in addition to atresia of the esophagus and trisomy 21.

The regulatory role of tri-iodothyronine on the production of alpha-fetoprotein and albumin by mouse fetal liver cells.

The purpose of this study was to assess possible effects of tri-iodothyronine (T3) on the production of alpha fetoprotein (AFP) and albumin by mouse fetal liver cells. AFP from serum-free conditioned media of TIB73 mouse fetal liver cells was measured by immunoradiometric assay and albumin was measured by chromogenic assay. The expression of mRNAs was quantified by Northern blotting analysis. A marked inhibition of AFP secretion was found as well as an increase in albumin produced by T3 in a dose-dependent manner. The effects of T3 AFP and albumin secretion paralleled the effects of T3 on the steady-state expression of mRNAs encoding albumin and AFP. These data may point to a possible role of T3 in the transcriptional switch from AFP to albumin during fetal development and may explain the observation of high levels of AFP in cases of congenital hypothyroidism.

Survival in an infant with a prenatally diagnosed Meckel syndrome variant.

An infant with occipital encephalocele and unilateral multicystic kidney, diagnosed prenatally, was considered to have a variant of the Meckel syndrome (MS). This case is exceptional in that the infant was alive and healthy following surgical repair of the encephalocele, with normal function of the unaffected kidney, at age 5 months. Based on this experience, in fetuses or infants with MS, thorough evaluation of both kidneys is imperative prior to suggesting either termination of pregnancy, or withholding of life-sustaining medical treatment in infants already delivered.

Direct measurements of the dextran-dependent calcium uptake by rat peritoneal mast cells.

The metallochromic indicator murexide has been used to monitor calcium concentration changes during the dextran-induced, phosphatidylserine-dependent degranulation of rat peritoneal mast cells. The dextran-induced Ca2+-uptake showed an absolute dependence on the presence of phosphatidylserine. The extent of Ca2+-uptake increased with phosphatidylserine in a concentration-dependent manner. At 25 degrees C the half-life of the uptake process equalled 35 +/- 5 s. Exposure of the mast cells to dextran in the presence of Ca2+, but in the absence of phosphatidylserine, desensitized the cells. The subsequent addition of phosphatidylserine failed to restore the Ca2+-uptake activity. However, the Ca2+-ionophore A23187 did promote Ca2+ uptake by the cells without PS.