Search

Holoprosencephaly (HPE) is a severe brain malformation which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, SIX3, which is considered to be the functional orthologue of Drosophila genes sine oculis (so) and optix, has been found to be mutated in the homeodomain, in some patients with HPE (HPE2 on chromosome 2p21). We report a new HPE family, presenting a wide spectrum of clinical features, ranging from cyclopia to hypotelorism, in which a mutation was found for the first time in the SIX domain of SIX3: a GG insertion creates a frameshift leading to a nonsense mutation downstream in the homeodomain region. [ABSTRACT FROM AUTHOR]

Examines the association between Sonic hedgehog gene expression during early human development and holoprosencephaly. Clinical manifestations of the disease; Mode of inheritance; Factors involved in dysgenesis/agenesis of the pituitary gland.

We report a large kindred in which palmoplantar keratoderma occurred in association with breast or ovarian cancer or both. This kindred consisted of 61 members of four generations. Thirty-five individuals had palmoplantar keratoderma, including eight women who also had breast or ovarian cancer or both. Five of the six women with breast cancer and both the women with ovarian cancer have died. The proband presented with a yellowish, uniform hyperkeratosis surrounded by a red border covering the entire suface of the palms and soles. Light microscopic examination showed features of epidermolytic hyperkeratosis, and ultrastructural examination revealed the typical markers for this entity, cytolysis and clumps of keratin filaments. This kindred is the first, to our knowledge, to have an association of epidermolytic hyperkeratosis and internal malignancy. [ABSTRACT FROM AUTHOR]

Split hand-split foot malformation (SHFM) is characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits. SHFM is usually an autosomal dominant condition and at least five loci have been identified in humans. Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients. We screened the coding region of DACTYLIN by single-strand conformation polymorphism and sequencing, and found no point mutations. However, Southern, pulsed field gel electrophoresis and dosage analyses demonstrated a complex rearrangement associated with a approximately 0.5 Mb tandem duplication in all the patients. The distal and proximal breakpoints were within an 80 and 130 kb region, respectively. This duplicated region contained a disrupted extra copy of the DACTYLIN gene and the entire LBX1 and beta-TRCP genes, known to be involved in limb development. The possible role of these genes in the SHFM3 phenotype is discussed.

We herein report a male patient known as having a XYY karyotype. At the age of 26 years a Prader-Willi syndrome (PWS) was diagnosed. Before that time the whole symptomatology was ascribed to the XYY syndrome. This is the first reported association of PWS and polygonosomal abnormality in a male adult (whose height is above average).

We report on a female fetus of 24 weeks whose clinical and radiological findings were compatible with boomerang dysplasia (BD). However, histopathology was unusual with a lateral fan shaped diaphyseal ossification. This has never been described either in typical atelosteogenesis I (AT-I) or in BD. The purpose of this report is to find out if this condition is a separate lethal bone dysplasia or another histological feature of the nosological group of AT-I and BD.

We report the first case of the association of Sotos syndrome and gastric carcinoma (containing signet ring cells) in a twin patient. The other-probably monozygous-twin is also affected by the Sotos syndrome. The association of malign tumors in Sotos syndrome and other overgrowth syndromes is discussed.

Holoprosencephaly (HPE) is a developmental defect due to a failure of cleavage of the forebrain. The brain malformations are usually associated with facial anomalies. From a series of 258 HPE records involving at least one affected child, 97 cases in 79 families with nonsyndromic and nonchromosomal HPE were selected. The male:female ratio was 0.87. A high degree of familial aggregation was observed in 23/79 families (29%). A segregation analysis performed in the 79 nuclear families led to the conclusion that the transmission of nonsyndromic HPE is compatible with an autosomal dominant mode of inheritance. Under this hypothesis, the penetrance was estimated as 82% for major types (alobar, semilobar, lobar) and 88% when major and minor types (atypical) were included. The proportion of sporadic cases was estimated to be 68%. This genetic model allows a prediction of the recurrence risk after an isolated case of 13% for major types and 14% when minor types are included.

Congenital microcoria is an autosomal dominant disorder characterized by a pupil with a diameter <2 mm. It is thought to be due to a maldevelopment of the dilator pupillae muscle of the iris, and it is associated with juvenile-onset glaucoma. A total genome search for the location of the congenital microcoria gene was launched in a single large family. We found linkage between the disease and markers located on 13q31-q32 (Zmax = 9.79; theta = 0). Haplotype analysis narrowed the linked region to an interval <8 cM between markers D13S1239 proximally and D13S1280 distally.

Intracerebral cysts and porencephaly or arachnoid cysts are rarely but are repeatedly reported in orofaciodigital (OFD) syndrome type 1. We report on 2 families in which OFD syndrome type 1 was observed with central nervous system (CNS) malformations and 3 sporadic cases of OFD with CNS defects, most likely representing fresh mutations for OFD 1. In one case, vermis hypoplasia was present; in another, periventricular heterotopiae were noted. We review the literature on CNS anomalies in OFD syndromes and stress the difficulties in genetic counseling and functional prognosis for children of OFD 1 female carriers prenatally diagnosed with a malformation of the brain. As for CNS malformations, renal cystic disease is an often overlooked complication specific to OFD 1. In 1 family, cystic medullary disease was noted in OFD 1 carriers, leading 1 patient to dialysis by age 35 years and the other to severe renal insufficiency by age 28 years. Longitudinal follow-up of OFD 1 carriers should be performed, and renal function should be assessed in those with cysts because the functional prognosis of this developmental anomaly may be worse than usually reported in the literature.

BBB syndrome and G syndrome were originally reported as distinct X-linked disorders. Clinical studies indicated that BBB and G syndromes were likely to represent variant expression of the same disorder, now referred to as "Opitz" GBBB syndrome. Several occurrences of male-to-male transmission in both syndromes led to the hypothesis that GBBB syndrome was a single autosomal dominant, sex influenced disorder, now tentatively mapped to 5p12-13. We report on a large pedigree in which GBBB syndrome appears to cosegregate with a pericentric inversion of the X chromosome inv(X)(p22.3q26). It indicates the possible existence of a true X-linked form of GBBB syndrome, which does not appear phenotypically different from its autosomal counterpart. The gene could map in the vicinity of the breakpoints, in Xp or Xq. The existence of two genes affecting a common pathogenetic pathway could explain the gender-dependent expressivity of GBBB phenotype.

Two groups of infertile men with obstructive azoospermia were screened for cystic fibrosis (CF) gene mutations (delta F508, exons 3, 4, 7, 10, 11, 14a, 17b, 19, 20, 21). The first group was composed of 26 patients with congenital agenesis of vas deferens (CAVD). The second group was composed of 12 patients with obstructive azoospermia associated with chronic suppurating respiratory disease (Young's syndrome). Of the group with CAVD, 77% of patients showed at least one mutation in the CF transmembrane conductance regulator (CFTR) gene. The delta F508 mutation occurred most frequently (54%), and the second most frequent mutation to occur was R117H (27%). Six patients were double heterozygotes. In Young's syndrome, no CF mutations were detected. CAVD can be considered as an incomplete clinical form of CF. However, the differences observed in CF mutations between CF and CAVD suggest that they are different disorders resulting from mutations in the same gene. Young's syndrome is a very different clinical entity.

We report our experience of 15 cases of gastroschisis which occurred between 1981 and 1993. All but one were diagnosed antenatally by ultrasound between 16 and 32 weeks of pregnancy. We made a termination of the pregnancy in 3 cases, for multiple malformations in 2 cases and one case of very early premature rupture of the membranes (PROM). When checked (11 cases), the karyotype was normal. We made a cesarean section in 11 cases: the indication was a complication for 6 (fetal distress, PROM, polyhydramnios, large dilatation of the gut). We noted growth retardation in 7 newborns and prematurity in 5/12 (mean gestational age of 36.8 weeks). The preoperative study of the gut noted 5 cases with intestinal damage and one case of complete necrosis of the gut. The global prognosis is not as good as usual, with a perinatal mortality of 41.6% (5/12). We discuss this latter point and examine the literature.

Linkage data for familial incontinentia pigmenti (IP2) and 17 X chromosomal markers are reported. The linkage previously found between IP2 and the F8C locus is confirmed (Z max = 11.85 at theta = 0.028). Linkage is established with distal markers DXS1108 (Z max = 10.06 at theta = 0.00) and DXYS154 (Z = 9.07 at theta = 0.019). Multipoint analysis supports the distal localization of the IP2 gene with respect to the F8C locus.

The authors report Larsen Syndrome in a male newborn with severe cervical spine malformations: segmentation abnormalities of the cervical spine and atlanto-axial dislocation. The severity of the cervical malformations occurring more often in the autosomal recessive form is emphasized.

Previous linkage analysis of families with X-linked severe combined immunodeficiency (SCIDX1) mapped this locus to a large region encompassing about 10 to 20 cM at Xq12-21. We have analyzed in SCIDX1 families the segregation of 7 highly polymorphic microsatellites repeats localized to this region, including a new polymorphic microsatellite at the DXS135 locus described in this study, to refine the mapping of this disease locus. The observations of genetic recombinants within the previously defined SCIDX1-region allow us to establish new flanking markers at the DXS135 and DXS227 loci, which significantly reduce the region harboring the SCIDX1 locus to a distance estimated between 3 to 5 cM. The existence of multiple, highly polymorphic markers in the refined SCIDX1 region will greatly improve the accuracy of carrier detection and prenatal diagnosis for SCIDX1.

The cystic fibrosis (CF) gene has been cloned and a major mutation identified (delta F508). This 3-bp deletion has been found in approximately 70% of CF chromosomes. We have used the strategy of denaturing gradient gel electrophoresis followed by direct sequencing of the polymerase chain reaction products, in order to detect other mutations in exons 10, 11 and 20 of the CF transmembrane conductance regulator gene. A new mutation, F1286-S, was found in exon 20. It involves a nucleotide change of T-->C at nucleotide 3989 and changes a phenylalanine into serine at position 1286 of the protein.

We report the study of five independent X-linked hydrocephalus (HSAS1) families with polymorphic DNA markers of the Xq28 region. A total of 58 individuals, including 7 living affected males and 22 obligate carriers, have been studied. Maximum lod score was 7.21 at theta = 2.40% for DXS52 (St14-1). A single recombination event was observed between this marker and the HSAS1 locus. Other markers studied were DXS296 (Z = 2.02 at theta = 2.5%), DXS304 (Z = 4.37 at theta = 7.8%), DXS74 (Z = 3.50 at theta = 0%), DXS15 (Z = 1.96 at theta = 5.7%), DXS134 (Z = 3.31 at theta = 0%), and F8C (Z = 5.79 at theta = 0%). These data confirm the localization of the HSAS1 gene to Xq28 and provide evidence for genetic homogeneity of this syndrome. In addition, examination of two obligate recombinant meioses along with multipoint linkage analysis supports the distal localization of the HSAS1 locus with respect to the DXS52 cluster. These observations are of potential interest for future studies aimed at HSAS1 gene characterization.

We performed mutation analysis and RFLP haplotype analysis of chromosomes associated with classical phenylketonuria (PKU) in contemporary French families. We also did genealogical reconstructions for seven obligate carriers in five contemporary French-Canadian families living in eastern Quebec, who carry the M1V mutation causing PKU. The M1V mutation, heretofore considered to be associated exclusively with French-Canadians, was found on 4 of 152 independent French chromosomes. The French and Quebec M1V mutations all occurred on RFLP haplotype 2. The contemporary mutant French chromosomes clustered in southern Brittany (Finistère Sud). Genealogical reconstructions of the Quebec families identified 53 shared ancestors and a center of diffusion in the Perche region in 17th century France. The two clusters in France, one historical and the other contemporary, are not incompatible, if one assumes the possibilities that settlers returned from Nouvelle France or moved from Perche to southern Brittany. The M1V mutation is serving as a useful marker for historical demography.

The authors report a family with triphalangeal thumb with nail hypoplasia: one of them has also split feet. They believe that the existence of such families must make very circumspect with regard to genetic counseling for a minor problem such as triphalangeal thumb.

The name opsismodysplasia is proposed for a new chondrodysplasia, which was studied in three patients. Clinically, the condition is recognized at birth on the basis of shortness, short hands, and facial abnormalities with a short nose and a depressed bridge of nose. The most characteristic radiographic signs are: very retarded bone maturation; marked shortness of the bones of the hands and of the feet with concave metaphyses; and thin, lamellar vertebral bodies. The growth cartilage studied in one case showed a wide hypertrophic area containing thick connective tissue septa, irregular provisional calcification, and vascular invasion. Type I collagen was detected in the hypertrophic area by immunohistochemical and microchemical tests. The transmission of opsismodysplasia is probably autosomal recessive.

The aim of this work was to demonstrate the impact of ultrasonography in utero to gain a better understanding of the anatomy, growth, anatomical variations and function of the fetal kidney and urinary tract. Three main topics are discussed in this paper based on the authors' personal experience and data from the literature: 1) the technique of ultrasonography in utero, including the main difficulties encountered and limitations of this technique; 2) ultrasonographic study of the morphology, growth and anatomical variations of the fetal kidney. The length of the fetal kidney was found to be the most significant parameter for assessment of its growth. At term, the kidney measures slightly more than 4 cm in length, while the renal pelvis is usually no more than 10 mm thick; 3) current knowledge of the physiology of the fetal urinary apparatus especially the kidney. Excretory function of the kidney begins in the third month of gestation and its main role involves the regulation of the amniotic fluid.

We report on two sibs with a multiple congenital anomalies/mental retardation (MCA/MR) syndrome who have a first cousin with Möbius anomaly. This may represent a new MCA/MR syndrome.

More than 80% of the first degree relatives of 106 patients with iron overload - 97 with idiopathic haemochromatosis (I.H.) and nine with haemosiderosis secondary to alcohol induced liver disease (A.H. - were examined. Physical examination and measurement of plasma iron level and UIBC were done in all subjects; relatives who presented with some anomaly were submitted to a desferrioxamine test and, if the latter showed a high urinary iron output, to a liver biopsy. While absent in relatives of A.H. patients, iron overload was present in 78 out of 499 relatives of I.H. patients: 29 major and 49 minor forms. The major forms involved the sibships almost exclusively. The genetic analysis showed much evidence in favour of a recessive or rather intermediate form of inheritance, with heterozygous developing minor forms. However, other modes of transmission, especially polygenic (probably oligogenic), cannot be totally excluded. Data from recent studies showing a strong correlation between I.H. and certain HLA antigens do not conflict with the above conclusions.

Esterase D (ESD) gene dosage studies were performed on amniotic cells from a fetus at risk for del 13q14. The mother was a balanced carrier of an insertion in chromosome #20: 46,XXins(20;13)(p12;q1307q14.3). She had already given birth to a monosomic child with retinoblastoma (Rb) and to a phenotypically normal child trisomic for the same 13q14 segment. Both sibs displayed the expected proportionate gene dosage effects for ESD. A 153% value of ESD activity was found in the amniotic cells indicating unambiguously that the fetus was not monosomic for segment 13q14 and therefore not at increased risk for Rb. The mother delivered a phenotypically normal child who was confirmed to be trisomic for segment 13q14 by cytogenetic analysis and by gene dosage studies for ESD in cord blood cells and in lymphoblastoid cells.

Pachytene analysis was carried out in two infertile brothers, one heterozygous for two pericentric inversions of chromosomes 1 and 9, the second heterozygous for the pericentric inversion of chromosome 1. The synaptic behaviour of the bivalent 1 inversion was the most informative. Analysis of the chromomere pattern combined with centromeric heterochromatin staining and synaptonemal complexes visualization allowed precise description of synaptic initiation and extension leading to the homosynapsed loop. Heterosynapsis following alignment of the inverted segments was demonstrated. Non-homologous synapsed bivalents had the morphological aspects of straight bivalents with two distant blocks of centromeric heterochromatin. The possible sterilizing effect caused by the autosomal inversion is discussed.

From 7 cases of abnormalities involving chromosome 13, the structural gene(s) coding for coagulation factors VII and X were located in the region 13q34-13qter. Gene-dosage effects for these coagulation factors seem to act in both directions, causing a decrease when there is monosomy of segment 13q34, but also, as has not been demonstrated before, an increase when there is trisomy of this same segment.

TAR syndrome is usually an autosomal recessive disease; we report a family where the father of the propositus presented malformations of the feet, and review the known cases involving several generations. The authors of these cases concluded that the TAR syndrome is probably genetically heterogeneous.

Two additional pedigrees with familial recurrence of achondroplasia are described. Genetic risk for children of sibs of affected individuals or premutation carriers seems to be low, but it is advisable to monitor at risk pregnancies by midtrimester ultrasonography to diagnose fetal achondroplasia.

The results provided by the Fédération des Centres d'Etude et de Conservation du Sperme Humain (CECOS) are based on 15,283 requests for AID. They are analysed from the point of view of medical genetics. The genetic indications represent 0.77% of requests for AID and can be separated into four groups: dominant autosomal abnormalities in the man, previous children affected by autosomal recessive conditions, chromosomal abnormalities in the man, and a miscellaneous group. In 2,502 births, a total of 45 malformations was seen, including nine chromosomal abnormalities. The possibility of an early amniocentesis for prenatal diagnosis in every pregnancy after AID is discussed.

The name atelosteogenesis is proposed for a lethal chondrodysplasia characterized by deficient ossification of various bones, notably the humerus, femur, thoracic spine, and hand bones. Clinically, the patients have micromelic dwarfism with incurvated legs, club feet, often dislocation of the elbows, and, rarely, a cleft palate. The most characteristic radiographic signs are incomplete ossification of the vertebral bodies with coronal clefts of the lumbar and hypoplasia of the upper thoracic vertebral bodies, a distal hypoplasia and club shape of the humerus and the femur, and the lack of ossification of single phalanges and metacarpals in most patients. Histologically, there are clusters of chondrocytes surrounded by fibrous capsules and, more frequently, degeneration zones containing degenerated chondrocytes and copious amounts of metachromatic material in the epiphyses and the basal zone of the growth plate.

An association between trisomy 11p15 and Beckwith-Wiedemann syndrome is described in two brothers. The first presented at birth with gigantism and macroglossia, umbilical hernia and abdominal distention, hypoglycemia and atresia of the pulmonary artery, leading to the diagnosis of Beckwith-Wiedemann syndrome. Facial dysmorphism also included: a hypoplastic midface, hypertelorism, and a short nose with a flattened bridge. The karyotype showed a trisomy 11p15 with a monosomy 18p11, due to a t(11;18)(p154;p111)pat. His brother, born a year later, showed the same signs. The association between trisomy 11p15 and Beckwith-Wiedemann syndrome is in certain cases well established.

We report here the first case of a mosaic Down's syndrome in which both clones are trisomic for chromosome 21, one of them (90%) by a Robertsonian translocation (15;21) appearing de novo, and the other (10%) by an additional chromosome 21. Three hypotheses can explain the appearance of such a mosaic: that of a chimera formed by the fusion of two trisomy 21 zygotes, one of which had a Robertsonian translocation, the other an additional trisomy 21 zygote; that of a fusion between a chromosome 15 and a chromosome 21 in one of the early segmentation blastomeres of a trisomy 21 zygote; the more probable hypothesis of the occurrence of a fission at the break-attachment point of a Robertsonian translocation (15;21) in one of the cells arising from the early postzygotic divisions of a zygote which was a trisomy 21 by Robertsonian translocation (15;21).