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Familial porencephaly is a rare condition usually transmitted as an autosomal dominant trait with incomplete penetrance. We describe a new family in which six members across four generations had congenital hemiplegia. Cerebral imaging was performed in three patients and showed porencephaly in all cases. In order to provide effective genetic counseling, three asymptomatic carriers were investigated by cerebral computerized tomography (three patients) and cerebral magnetic resonance imaging (one patient). These investigations failed to show any congenital abnormalities. We conclude that cerebral imaging is unreliable to detect obligate carriers of familial porencephaly.

Deletions of the short arm of chromosome 6 are relatively rare, the main features being developmental delay, craniofacial malformations, hypotonia, and defects of the heart and kidney, with hydrocephalus and eye abnormalities occurring in some instances. We present the molecular cytogenetic investigation of six cases with 6p deletions and two cases with unbalanced translocations resulting in monosomy of the distal part of 6p. The breakpoints of the deletions have been determined accurately by using 55 well-mapped probes and fluorescence in situ hybridization (FISH). The cases can be grouped into two distinct categories: interstitial deletions within the 6p22-p24 segment and terminal deletions within the 6p24-pter segment. Characteristics correlating with specific regions are: short neck, clinodactyly or syndactyly, brain, heart and kidney defects with deletions within 6p23-p24; and corneal opacities/iris coloboma/Rieger anomaly, hypertelorism and deafness with deletions of 6p25. The two cases with unbalanced translocations presented with a Larsen-like syndrome including some characteristics of the 6p deletion syndrome, which can be explained by the deletion of 6p25. Such investigation of cytogenetic abnormalities of 6p using FISH techniques and a defined set of probes will allow a direct comparison of reported cases and enable more accurate diagnosis as well as prognosis in patients with 6p deletions.

We have studied a girl with multiple congenital anomalies, growth and mental deficiency, characteristic facial anomalies, cataracts, cerebellar atrophy, and severe hypocholesterolemia. Death occurred at age 7 years. After excluding several syndromes, i.e., peroxisomal disorders, mevalonic acidaemia, and Marinesco-Sjögren syndrome, it is concluded that this girl had severe Smith-Lemli-Opitz Syndrome (SLOS) with exceptionally long survival. This diagnosis was confirmed through assay of 7-dehydrocholesterol in cultured fibroblasts.

Between October 1985 and December 1993, 421 patients underwent fetal blood sampling for rapid karyotyping (426 samplings, 5 twin pregnancies). The aim of the study was to evaluate cordocentesis in terms of results, complications and additional information in this specific indication especially in case of abnormal pregnancy sonogram. The fetal loss rate possibly related to fetal blood sampling was 1.9%. Abnormal sonograms represented 91% of rapid karyotype indications. Chromosomal abnormalities were found in 9.5% of abnormal sonograms and in 16.9% of fetal structural anomalies (37 cases). The commonest chromosomal abnormality was trisomy 21 (11 cases). In conclusion, cordocentesis is a safe and reliable method for rapid karyotyping although it is associated with more risks than in other indications (congenital infections). The high rate of chromosomal abnormalities pleaded for ultrasonographic screening in a population usually not investigated by cytogenetic studies.

Homozygous alpha-thalassaemia or Bart's hydrops fetalis is a genetic disease with autosomal recessive transmission. The condition is lethal for the fetus because of hypoxia and anemia. For the mother there is an increased risk of the severe forms of preeclampsia and its complications. The diagnosis can be suspected in presence of suggestive ultrasonographic anomalies, where both parents come from South-East Asia or China. Confirmation is based on the identification of the typical deletions or mutation of the alpha globin gene by molecular genetics. We report a rare clinical case of Bart's hydrops fetalis diagnosed because of fetal growth retardation, fetal cardiomegaly and increased size of placenta on the 26 weeks fetal echography. This case underscores the need to include the alpha thalassemias in medical and midwifery education in countries where they were almost inexistent a generation ago.

Objective To compare the diagnostic accuracy of two-dimensional (2D) ultrasound and three-dimensional (3D) computed tomography (CT) for the diagnosis of fetal skeletal anomalies. Methods Eleven pregnant women underwent 2D ultrasound and 3D-CT. Ten fetuses presented skeletal anomalies on 2D ultrasound and one fetus had a normal ultrasound exam but a familial history of osteopetrosis. We compared retrospectively the diagnoses established on 2D ultrasound and 3D-CT with the neonatal and/or postmortem work-up, which were used as the gold standard. Results 2D ultrasound provided the correct diagnosis in only two of the 11 cases. CT yielded the correct diagnosis in eight; in six of these, 2D ultrasound had been inconclusive. 3D-CT was more accurate than was 2D ultrasound in visualizing vertebral anomalies (abnormal shape of the vertebral bodies, abnormal interpedicular distance), pelvic bone malformations (delayed ossification of the pubic bones, abnormal acetabular shape) and enlarged metaphysis or synostoses in long bones. In three cases, neither 2D ultrasound nor CT provided the correct diagnosis. Conclusion In this series, which included a variety of skeletal dysplasias, 3D-CT had a better diagnostic yield than did 2D ultrasound. Both imaging techniques are useful in the management of fetal dysplasia; 2D ultrasound is a useful screening test and 3D-CT is a valuable complementary diagnostic tool. Copyright © 2007 ISUOG. Published by John Wiley & Sons, Ltd.

Objective The aim of this study was to determine whether karyotyping should be performed for every fetal malformation detected in low risk populations. Methods A karyotype was obtained from 428 fetuses examined over a 10-year period after fetal malformation was diagnosed using obstetrical ultrasound. These fetuses were separated into two groups, one with isolated malformations and the other with multiple malformations. The association between each type of malformation and the result of karyotype was evaluated. Results Forty-eight chromosomal abnormalities were encountered in 428 fetuses (11.2%). The karyotype was abnormal in 32/343 (9.3%) fetuses with isolated malformations and 16/85 (18.8%) fetuses with multiple malformations (p = 0.022). The probability of an abnormal karyotype among the group of isolated malformation depended on the anatomical system involved (p < 0.001). Our study demonstrated several isolated malformations without chromosomal abnormality (hydronephrosis with high obstruction, unilateral multicystic dysplastic kidney, gastroschisis, intestinal dilatation, meconium peritonitis, cystic adenomatoid malformation, pulmonary sequestration, tumor, vertebral anomaly). Conclusion Each fetus with multiple malformations needs a chromosomal analysis. Within the group of isolated malformations, our study emphasizes that medical maternal history and the type of malformation need to be taken into account before performing a fetal karyotype. Copyright © 2005 John Wiley & Sons, Ltd.

The 3 affected children from 2 different wedlocks of the mother have been previously described (11). Search by FISH analysis in the mother revealed she is a carrier of balanced translocation of clear terminal G bands of equal sizes of the long arms of chromosomes 10 and 14. Chromosomal slides of the last child (Patient 3) could be analysed by fish and revealed that he did inherit the derivative chromosome 10. He had a partial trisomy 14 and a partial deletion of the long arm of chromosome 10. The clinical pictures correspondence to the possibly abnormal karyotypes will be discussed.

We have characterised a point mutation causing the substitution of serine for glycine at position 661 of the alpha1(I) chain of type I collagen in a child with a severe form of osteogenesis imperfecta. An identical glycine substitution in the alpha2(I) chain was previously detected in a woman with post-menopausal osteoporosis. Two of her sons were heterozygous for the mutation and the third son was homozygous as a result of uniparental isodisomy. Biochemical profiles of the type I collagen heterotrimers were studied in each of the patients and compared with a control. Medium and cell-layer collagens were overmodified in all patients. Overmodification was obvious in the patient with the alpha 1(I) mutation but mild in the patients with the alpha 2(I) mutation, being slightly less evident in the heterozygote than in the homozygote. Investigation of the melting curves of the mutant collagen trimers in all three patients showed the same slight decrease in thermal stability and, hence, a lack of correlation with phenotypic severity. In contrast, the degree of overmodification of the collagen alpha chains was correlated with the phenotypic severity. The clinical observations in these patients illustrate the possibly predominant role of mutations in the collagen alpha1(I) chains over the same mutations in the alpha2(I) chains in determining the clinical outcome.

Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy (ADCA type II) is a rare neurodegenerative disorder with marked anticipation. We have mapped the ADCA type II locus to chromosome 3 by linkage analysis in a genome-wide search and found no evidence for genetic heterogeneity among four families of different geographic origins. Haplotype reconstruction initially restricted the locus to the 33 cM interval flanked by D3S1300 and D3S1276 located at 3p12–p21.1. Combined multipoint analysis, using the Zmax-1 method, further reduced the candidate interval to an 8 cM region around D3S1285. Our results show that ADCA type II is a genetically homogenous disorder, independent of the heterogeneous group of type I cerebellar ataxias.

Foetal blood sampling was performed at 35 weeks of gestation due to abnormal foetal ultrasound findings. There was apparent monosomy 21 (45,XX,-21) in all mitoses analyzed. The infant died at 37 weeks during delivery. Examination disclosed facial anomalies, clubfeet, hypoplasia of the left urogenital tract, agenesis of corpus callosum, ventricular dilatation, and heterotopias. Reevaluation of the karyotype showed an unbalanced translocation t(1;21) (q44;q22.11) which resulted from a maternal balanced translocation. These findings were confirmed by fluorescence in situ hybridization and molecular studies with chromosome 21 specific markers. The latter showed a proximal deletion of the maternally derived chromosome 21 including all loci from centromere down to the D21S210 locus. This case illustrates the need for complementary cytogenetic and molecular investigations in cases of apparent monosomy 21.

We describe a family with an autosomal dominant form of retinal-cerebellar atrophy. There is an extreme variability in age of onset and severity of the clinical symptoms: some patients remain nearly asymptomatic throughout their entire life; others develop severe retinal and cerebellar symptoms after the age of 35 years; others suffer from a severe disorder with onset in adolescence and death during the third decade of life; in others the onset is in early childhood with prevalence of cerebellar symptoms. There is neither dementia nor epilepsy in any of the patients. Four out of five autopsies showed, a severe retinal atrophy, and all five autopsies were also characterized by (1) a cerebellar atrophy affecting the spinocerebellar and olivocerebellar tracts, the cerebellar cortex and the efferent cerebellar pathways, (2) an involvement of the pyramidal pathways and of the motor neurons of brain stem and spinal cord, and (3) an atrophy of the subthalamic nucleus and to a much lesser extent of the pallidum, with also some damage to the substantia nigra. The posterior columns are much less affected except in one patient. In this family, we have excluded linkage with the two loci for spinocerebellar ataxia, i.e., SCA1 on chromosome 6p and SCA2 on chromosome 12q as well as with the locus for Machado-Joseph disease (MJD) on chromosome 14q. A genome-wide search is currently being performed to detect the disease locus responsible.

In this report, we describe three sibs presenting an identical malformation syndrome i.e.: acrocephaly, brachydactyly, prominent metopic ridge, broad depressed nasal bridge, narrow maxillae, obesity and normal intelligence. We discuss the relationship between this combination of clinical signs and symptoms most compatible with the diagnosis of Summitt syndrome and the Carpenter syndrome.

Cordocentesis was performed in 234 pregnancies (241 fetuses) for rapid karyotyping. The indication was in 86% of cases: abnormal ultrasound. The abnormality encountered were IUGR (85 fetuses) or morphologic abnormality of the pregnancy (130 fetuses). The other indications were maternal mosaicism, mosaicism in cultured amniotic cells, maternal age (late booking), fragile X syndrome, confirmation of abnormal karyotype obtained by amniocentesis. The fetal karyotype was established in 97.5% (6 failures), 18 karyotypes were abnormal in the group "abnormal ultrasound" (208 pregnancies, 8.6%; 215 fetuses, 8.3%). No maternal complication were observed, there were 6 fetal losses (2.5%).

The authors describe a girl with retarded growth, renal malformations, retinal coloboma and hypoplasia of the thumbs like reported in the acro-renal-ocular syndrome. In addition, they found defects of the ribs and spine and cleft palate, not previously described in this syndrome. The was noted to have minor anomalies of the hands, which might represent a mild manifestation of this autosomal dominant syndrome.

Two unrelated children presented with similar clinical features (facial dysmorphism and multiple joint dislocations) suggesting the diagnosis of Larsen syndrome. Both carried an inherited unbalanced translocation resulting in partial trisomy 1q and partial monosomy 6p. Analysis of skin collagen from one of the probands disclosed a decreased alpha 1/alpha 2 chain ratio of collagen type I, increased thermal stability and increased hydroxylation of proline and lysine. The present findings suggest that, as a result of the chromosome rearrangements, both patients have a mutation on a gene involved in collagen production, located either on chromosome 1q or, more probably, on 6p. It is furthermore suggested that other cases of Larsen syndrome are the result of a similar mutation.

Partial androgen insensitivity syndrome (PAIS) is an X-linked disorder resulting from defects in the intracellular androgen receptor (AR). The cloning of the AR cDNA has provided the molecular tools to identify gene abnormalities. Gene deletions being the exception in PAIS, prenatal diagnosis of PAIS resulting from a single base mutation in high risk families is not practical unless the mutation is already known. Brown et al. (1989) reported that 10% of normal X chromosomes present a Hind III 6.7/3.5 kb polymorphism. In this study, we report the association of the Hind II polymorphism in a woman whose son has a PAIS associated with a very low androgen receptor concentration: we differentiated the two maternal X chromosomes and characterized the affected allele. These data demonstrate that the presence of Hind III polymorphic fragments could be used in prenatal diagnosis of androgen insensitivity syndrome in high risk families.

1000 cases of genetic counseling have been reviewed. Most patients are sent to the genetic center by gynecologists (68.4%), mostly because of a personal or previous familial history (64%). This previous history concerns mainly congenital malformations (44%, 283/640) and mental retardation (24%, 154/640). Generally, the patients consult outside a pregnancy, nevertheless one fourth comes after conception and this occurs more often when the proband is a family member (38% versus 19% when the proband is a spouse and 20% when the proband is a child). Ten percent of the patients knowing they could be at risk because spouse or child is affected consult after having already had a child or having had another child. The mode of inheritance of the diseases for which patients with previous family history consult is as follows: mendelian inheritance (36%), multifactorial inheritance (19%), chromosomal defect (18%), non genetic (5%), variable inheritance (2%), unknown (15%) and insufficient information (5%). The majority of patients coming for previous familial history could be tranquilized, the recurrence risk was either small or minimal. In 2.6% of the cases, a high recurrence risk has been given and the risk could not be evaluated in 7% of the cases. The importance of genetic counseling is stressed by the fact that antenatal diagnosis could be proposed to half of the patients with a recurrence risk equal or higher than 1%.

The authors report the results of chromosomal analyses performed on 6235 amniocenteses and 559 choriocenteses. Whereas the frequencies of chromosomal anomalies observed respectively on amniocenteses and choriocenteses did not differ significantly, the comparison of the types of aberrations found revealed, in chorion villi, a relatively high proportion of lethal anomalies, never encountered in amniocyte cultures. Furthermore, chromosomal mosaicism was observed 10 times more frequently on chorion villi than on amniotic cells. These results are globally comparable to those reported in other surveys. In view of literature reports of discordances between fetal chorionic karyotypes, never found in amniocenteses, rapid karyotyping from chorion villi is not as reliable as from amniotic cells. Taking into account the risk of cytogenetic discordance specific to choriocentesis, it is recommended that this method be strictly limited to pregnancies with high genetic risk.

Renal length, width, and thickness were measured in 261 normal fetuses, and the volume of the kidney was calculated. Normal values of these parameters are given for gestational age. Applications to the detection of congenital malformations are discussed, and a case report of renal polycystic disease is presented.

Alphafetoprotein (AFP) and concanavalin A non-reactive alphafetoprotein determination and the acetylcholinesterase (AchE) qualitative test have been performed on amniotic fluid samples from 33 normal pregnancies, 44 pregnancies with fetal malformations and 8 normal pregnancies with elevated amniotic fluid alphafetoprotein (3 false positive AFP results, 5 contaminations with fetal blood). The validities of these three tests in detecting abnormal pregnancies are compared. The usefulness of the existing complementary tests in the detection of neural tube defects in a low neural tube defect incidence area is discussed. Risk figures for open spina bifida according to the prior risk situation and the results of maternal serum AFP, amniotic fluid AFP, AchE qualitative test and ultrasound examination have been calculated.

The reproductive history of a woman diagnosed as having a thalidomide syndrome clearly shows that she is affected by the Holt Oram syndrome (autosomal dominant inheritance). The problem of considering a phenocopy in genetic counselling is discussed. A study of the family illustrates the wide range of clinical manifestations of the Holt Oram syndrome. Embryological considerations are given.

Neurological, ophthalmological and genetic investigations were performed on a family, a member of which presented with a rare association of tapeto-retinal degeneration, protanopia and Charcot-Marie-Tooth disease (CMT), and asked for genetic counseling. The neurological enquiry was completed by measurement of motor nerve conduction velocity in several completed by measurement of motor nerve conduction velocity in several members of the family. The propositus was submitted to a muscle biopsy. The ophthalmological examination included ophthalmoscopy, fluorescein angiography, electroretinogram and electrooculogram. The propositus, a woman aged 40, had typical CMT disease and her father also had a mild form of it. She had protanopia as had her father, her son and her nephew. In addition she had large macular pigmented changes, described as retinal dystrophy, "flavus flavimaculatus." Her mother had only senile pigmented modification of the fundus and her three daughters had mild macular pigmented changes, like "salt and pepper." Two genes are probably involved: one for protanopia with X linked recessive inheritance, the other responsible of CMT and tapeto-retinal degeneration, with an autosomal dominant inheritance, giving a 50% risk of recurrence., Case Reports, Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

Prenatal echographical findings of a partial sirenomelic fetus are described. An attempt was made to terminate pregnancy by administration of prostaglandin F2 alpha, but uterine rupture occurred. The teratogenic role of vitamin A ingested by the mother in the periconceptional period is discussed.

Amniocentesis was performed in view of a paternal balanced chromosomal rearrangement t(4;20)(p16;p12), inv(18)(p11q11). The pregnancy was complicated by severe oligohydramnios. The fetal karyotype was unbalanced: 46XX, der(4), t(4;20)(p16;p12), inv(18) (p11q11)pat., thus resulting in partial trisomy 20p and monosomy 4p. In addition, the amniotic fluid alpha-fetoprotein (AFP) became increasingly elevated with gestational age. The pregnancy was terminated at 25 weeks. The fetus presented with typical facial dysmorphic features, unilateral cleft lip and palate, severe renal hypoplasia, consistent with the 4p-(Wolf-Hirschhorn) syndrome.

We report on two fetuses with a lethal form of multiple-pterygium syndrome born to first cousins. The two pregnancies aborted spontaneously in the 2nd trimester, the fetuses, 10-11 weeks of embryonic age, showing multiple pterygia and multiple cartilaginous fusions. One had cleft lip and palate. In both cases the microscopic anatomy of the placenta showed villi with scalloped border and intravillous trophoblastic invaginations.

S-100 protein, which is found essentially in the astrocytes of the nervous system, was assayed in amniotic fluids by Particle Counting ImmunoAssay. It was present in 19 cases of anencephaly out of 26, in 1 case of open spina bifida out of 5 and in each of the 4 cases of fetal death, whereas it was not detected in the 48 control amniotic fluids collected between the 16th and the 35th week of gestation. Thirty-one amniotic fluids from fetuses with other congenital malformations were devoid of detectable S-100. The presence of S-100 in amniotic fluid of anencephalic fetuses can presumably be considered as a biological sign of necrosis of the exencephalic brain and seems specific to damage of the central nervous system accompanied by neural tube defect.

We report on two sibs with Dandy-Walker malformation and tetramelic postaxial polydactyly. We conclude that this is a new autosomal recessive syndrome.

We have measured the levels of alpha-feto protein in 127 samples of amniotic fluid, obtained in the course of antenata diagnosis, using the immunoelectrophoretic method of Laurell. The mean, the upper limit of normal and the extreme levels of alpha-feto protein in liquor have been calculated for each gestational age. The difficulties which have been met with in interpreting the results (false positives and false negatives) have been discussed.

S-100 protein, essentially of astrocytic origin, is present in the amniotic fluid of anencephalic fetuses. Its detection reflects tissue necrosis and could be complementary for prenatal diagnosis.

Ten thousand children born consecutively in a university hospital were surveyed for the presence of major congenital malformations. About 2% (174) had a major congenital defect. Seventy-eight percent (135 of 174) of these malformations are associated with increased recurrence risk (greater than 1%), and 9% carry a high recurrence risk (greater than or equal to 10%). On the basis of the recurrence risk of 1% or higher and the feasibility of prenatal diagnosis, such a procedure should be considered in future pregnancies in 45% (79 of 174) of the mothers, especially inasmuch as 40% were primiparae younger than 36 years.

Three related new cases with almost complete trisomy 11p due to paternal balanced translocation 46, XY, t(7; 11) (q36.1; p11.1) are reported. The proband (Case 1) was a malformed stillborn with exomphalos, case 2 was diagnosed in the first trimester by direct chromosome preparations from chorionic villi, and confirmed on fetal products after termination of pregnancy. Case 3, a cousin to cases 1 and 2, was a 29-weeks-old fetus with omphalocele discovered at ultrasound. Literature reports of trisomy 11p are reviewed with regard to those new cases, and the possible relationship of this chromosome imbalance with the Beckwith-Wiedemann Syndrome is discussed.