Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development.

Denys-Drash syndrome is a rare human developmental disorder affecting the urogenital system and leading to renal failure, intersex disorders and Wilms' tumour. In this report, four individuals with this syndrome are described carrying germline point mutations in the Wilms' tumour suppressor gene, WT1. Three of these mutations were in the zinc finger domains of WT1. The fourth occurred within intron 9, preventing splicing at one of the alternatively chosen splice donor sites of exon 9 when assayed in vitro. These results provide genetic evidence for distinct functional roles of the WT1 isoforms in urogenital development.

Differential diagnosis of hydrops fetalis.

Apart from isoimmunization, a number of conditions may present as hydrops fetalis and now account for a large proportion of hydropic infants. A large differential diagnosis must be considered when investigating the hydropic fetus and placenta while in utero, in the neonatal period, and at autopsy. An investigative protocol is proposed.

Some causes of genotypic and phenotypic discordance in monozygotic twin pairs.

The use of the adjective "identical" rather than monozygotic leads to misunderstandings about the biology of monozygotic twinning. Most monozygotic twin pairs are not identical; there may be major discordance for birth weight, genetic disease, and congenital anomalies. These indicate that postzygotic events may lead to the formation of two or more cell clones in the inner cell mass and early embryo that actually stimulate the monozygotic twinning event. There is also evidence that there may be unequal allocation of numbers of cells to the monozygotic twins; this may have widespread implications for the cascade of developmental events during embryogenesis, formation, and vascularization of the placenta. Large-scale zygosity testing at birth could be the template for analysis of twin outcomes and their biologic causes.

Hydrops revisited: literature review of 1,414 cases published in the 1980s.

This paper reviews 47 series of hydrops fetalis (804 cases) and 610 individual cases published since 1980. From this large number of cases, guidelines are derived for prenatal diagnosis and management.

Zygosity and placental anatomy in 15 consecutive sets of spontaneously conceived triplets.

Most triplets are trizygotic because they result from assisted reproduction. Prognosis is generally good. We analyzed 15 sets of triplets who were conceived spontaneously. Six sets were monozygotic, 7 were dizygotic, and only 2 sets were trizygotic. Considered as 45 twin pairs, 25 pairs (56%) were monozygotic. Twenty percent of these twins died as a result of twin-twin transfusion. Spontaneously conceived triplets have high risks compared with those resulting from assisted reproduction. These risks result from a high proportion of monozygotic embryos, many of whom have monochorionic placentas with vascular anastomoses, causing twin-to-twin transfusion.

Mirror-image dental fusion and discordance in monozygotic twins.

A pair of monozygotic twins had similar but not identical dental anomalies. One twin had fusion of deciduous mandibular lateral incisor and canine on the left, with normal dentition on the right; the co-twin had right mandibular incisor/canine fusion, with aplasia of the lateral incisor on the left. These findings are discussed in the context of the related phenomena of situs inversus, mirror-imaging in twins, and gradients of severity of anomalies in the four copies of the mandibular developmental dental field.

Microscopic study of holoprosencephalic facial anomalies in trisomy 13 fetuses.

The cerebral and facial anatomy of four trisomy 13 fetuses was studied in order to delineate the varying degrees of expression of severity of holoprosencephaly. Fetal heads were serially sectioned and analyzed microscopically in the horizontal plane. Examples of cyclopia, cebocephaly, and a proposed new category, premaxillary dysgenesis, were studied. The last category represents the least severe end of the facial spectrum of holoprosencephaly in this series. In this condition, there are deficiencies or clefts within the premaxilla, in contrast to the usual site of clefting between the maxilla and the premaxilla. There is asymmetry of the defects in the anterior midface of all four cases.

Investigation of acephalus.

We report twins, one of whom was diagnosed as grossly abnormal by ultrasound at 28 weeks' gestation. Postmortem angiographic investigation of this acardiac twin and of the inter-fetal placental anastomoses are reported. The acardiac fetus had a 45,X chromosome constitution, while the other twin had apparently normal chromosomes (46,XX). The association of chromosome anomaly with holoacardius acephalus is discussed.

Twin zygosity testing for medical purposes.

After being poisoned by eating the mushroom species Cortinarius speciosissimus, a twin developed interstitial nephritis with acute renal failure. He received a renal transplant from his living twin brother, who was presumed dizygotic on phenotypic grounds. Fifteen years later, the twins were zygosity tested by DNA "fingerprint analysis" and found to be monozygotic, despite important phenotypic discordances. The recipient has discontinued immunosuppression therapy and remains well after 9 months. We suggest that, for medical and other reasons, zygosity should be determined at birth on all like-sexed twins.

Congenital contractures, edema, hyperkeratosis, and intrauterine growth retardation: a fatal syndrome in Hutterite and Mennonite kindreds.

We present clinical findings in infants from three kindreds (two Hutterite and one Mennonite) with an apparently unique, fatal disorder. The major manifestations consist of severe intrauterine growth retardation, congenital contractures, and tense skin which is easily eroded. The skin is tightly drawn over the face, giving an abnormal appearance consisting of a narrow, pinched nose, small mouth, limited jaw mobility, and ectropion (in one). One infant had first-degree hypospadias. Apart from this, there were no organ malformations and the infants did not have hydrops. Histologically, the skin showed hyperkeratosis. It is postulated that this is a tissue dysplasia and that all of the clinical effects are secondary. The disorder appears to be an autosomal recessive trait. The two Hutterite families are from different endogamous subdivisions. They are related as fourth cousins once-removed and fifth cousins in multiple ways through the six nearest common ancestors of all four parents. There are 25 founders (11 couples and three individuals) who are common ancestors. We computed the probability of joint descent of the four alleles in each pair of parents and in a sample of Alberta Hutterite couples, assuming that each of the common founders in turn was the original carrier. For an allele from one particular founder couple, there is a relatively greater probability of identity by descent for each pair of parents than on the average for other couples of the same endogamous subdivision.

Two pairs of male monozygotic twins discordant for Wiedemann-Beckwith syndrome.

Wiedemann-Beckwith syndrome (WBS) is a congenital anomaly syndrome which classically consists of exomphalos, macroglossia, and gigantism. The syndrome is also associated with a variety of minor anomalies and affected individuals have an increased risk of developing rare embryonal cell tumors. To date, 15 monozygotic (MZ) twin pairs have been reported of which 13 are discordant for WBS. All except one pair of the discordant WBS twin pairs have been female. We report two pairs of male MZ twins, each discordant for WBS.

Morquio syndrome (MPS IVA) and hypophosphatasia in a Hutterite kindred.

A patient is described who has Morquio syndrome (MPS IVA). He is a member of the Hutterite Brethren and genealogic analysis discloses a high inbreeding coefficient for the proband. The proband's sibship is segregating two autosomal recessive disorders, ie, MPS IVA and infantile hypophosphatasia. Two other families each have one or the other of these diseases but not both. The three families are distantly related.

A perinatal mortality survey in south-east London, 1970-73: the pathological findings in 726 necropsies.

The primary necropsy finding are presented for 726 perinatal deaths; the classification of the 1958 British Perinatal Mortality Survey is used, and results of the two surveys are compared. Lethan malformation has replaced intrapartum hypoxia as the most common cause of perinatal death. There has been substantial reduction in intracranial trauma but an increase in intraventricular haemorrhage and, possible, extrapulmonary infection. Chromosome abnormalities occurred in 28 of 500 karyotyped infants (5-6 per cent). Indications for genetic counselling, and antenatal diagnosis in any subsequent pregnancy, were apparent in 10 per cent of cases.

Computer graphic three-dimensional reconstruction of normal human embryo morphogenesis.

Three-dimensional computer graphic reconstructions of four human embryos at Carnegie stages 11 to 23 portray the relationships and dimensions of individual organ systems. This paper illustrates the cranial, neural, pharyngeal, gut, vascular and nephric architecture in these developing embryos. This technology can be applied to in situ hybridization and immunohistochemistry to map zones and times of developmental gene activity.

Angiosarcoma of the heart.

A 17-year-old boy presented with severe chest pain which partially subsided on anti-inflammatory medication. Five week later he was admitted with fully developed cardiac tamponade. Within five days surgical exploration revealed an nonresectable right atrial tumour. Management of angiosarcoma of the heart is discussed.

Nephroblastomatosis and multiple bilateral nephroblastomata. Histologic, therapeutic, and theoretical aspects.

A hemihypertrophic girl had multiple sequential bilateral Wilms' tumors over a period of five years. Diagnostic biopsy and resected specimens showed also the presence of nephroblastomatosis, presumably the substrate from which these multiple tumors arose. The patient died of complications of chemotherapy and dialysis after bilateral nephrectomy, but also had residual tumor. The relationships between nephroblastomatosis, Wilms' tumor, bilateral Wilms' tumor, and teratogenic disorders are discussed, and the therapeutic implications of the nephroblastomatosis/nephroblastoma complex are considered.

Etiology of neural tube defect in man--Do teratogens play any part? Evidence from sex ratios.

Neural tube defect (NTD) is more common among spontaneously aborted fetuses than in infants born in the third trimester, but there is no direct evidence that NTD-affected conceptuses, presenting at these two different gestational ages, are components of a single disease process. Evidence for homology is here presented in an analysis of the sex ratios of spontaneously and therapeutically aborted NTD-affected fetuses, and of sex ratios differing with variations in prevalence of NTD-affected infants. If it could be shown conclusively that NTD is a single disease process, with an inverse relationship between components expressed early and late in gestation, there would be implications for the ascertainment of families at risk for NTD, and for the search for environmental factors potentially involved in the causation of NTD.

Intraabdominal testis with yolk sac tumor in a 2-year-old child.

A case of a large yolk sac tumor in an undescended testicle in a 2-year-old child is presented. No such similar finding has been reported in a young child. Despite the large size of the primary tumor, the high level of serum alpha-fetoprotein and the relatively late clinical presentation, this was a stage I lesion, and the child responded to surgical resection of the tumor and chemotherapy.

Balloon tracheal occlusion for congenital diaphragmatic hernia: experimental studies.

PURPOSE: Temporary tracheal occlusion is an effective strategy to enlarge fetal lungs, but the optimal technique to accomplish occlusion is unknown. External clips are effective when applied fetoscopically (Fetendo clip), but require a difficult fetal neck dissection. This study was undertaken to assess the feasibility of intratracheal balloon occlusion, revisiting the internal occlusion strategy. METHODS: (1) The internal diameter (ID) of human fetal trachea (53 fetuses; 14 to 41 weeks' gestation) was compared using a computer-assisted image analyzer and sonography, ex vivo. (2) Volume to diameter relationship of the balloon (balloon configuration curve) was defined using an image analyzing computer. (3) Using the trachea of fetal sheep, pressures that break balloon tracheal seal (seal pressure) were investigated. RESULTS: (1) Between 16 and 41 weeks' gestation, tracheal ID (range, 0.7 to 5.4 mm) correlates significantly with gestational age. (2) Balloon volume required to achieve tracheal seal could be determined based on the tracheal growth curve and the balloon configuration curve. (3) Tracheal seal breaking points varied depending on the tracheal specimen tested. CONCLUSION: Internal tracheal occlusion using a balloon is feasible with minimal tracheal damage if the balloon volume is adjusted to fetal tracheal growth.

Velamentous cord insertion in monochorionic twin gestation. An added risk factor.

OBJECTIVE: To study the effects of umbilical cord insertion combinations on outcomes in monochorionic (MC) twin placentas. STUDY DESIGN: Sixty consecutive MC placentas were analyzed by cord insertion patterns with regard to growth discordance, placental parenchymal sharing, types and patterns of intertwin vascular anastomoses, perinatal mortality and frequency of fetofetal transfusion. Cord insertions were classified as central/eccentric (CEN) or velamentous/marginal (VEL). RESULTS: Forty-five percent of the twins had VEL insertions. The CEN/VEL combination was found in 53% of pairs. The CEN/VEL group had the highest rates of growth discordance > 20%, unequal placental parenchymal sharing, uncompensated anastomoses and perinatal demise. CONCLUSION: VEL cord insertion and the CEN/VEL combination are indicators of high-risk subgroups within MC twins. VEL cord insertions can be diagnosed by ultrasound, identifying these high-risk groups.