Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease.

The prognosis of autosomal recessive polycystic kidney disease is known to correlate with genotype. The presence of two truncating mutations in the PKHD1 gene encoding the fibrocystin protein is associated with neonatal death while patients who survive have at least one missense mutation. To determine relationships between genotype and renal and hepatic abnormalities we correlated the severity of renal and hepatic histological lesions to the type of PKHD1 mutations in 54 fetuses (medical pregnancy termination) and 20 neonates who died shortly after birth. Within this cohort, 55.5% of the mutations truncated fibrocystin. The severity of cortical collecting duct dilatations, cortical tubule and glomerular lesions, and renal cortical and hepatic portal fibrosis increased with gestational age. Severe genotypes, defined by two truncating mutations, were more frequent in patients of less than 30 weeks gestation compared to older fetuses and neonates. When adjusted to gestational age, the extension of collecting duct dilatation into the cortex and cortical tubule lesions, but not portal fibrosis, was more prevalent in patients with severe than in those with a non-severe genotype. Our results show the presence of two truncating mutations of the PKHD1 gene is associated with the most severe renal forms of prenatally detected autosomal recessive polycystic kidney disease. Their absence, however, does not guarantee survival to the neonatal period.

Prenatal transmission of dengue: two new cases.

Dengue is commonly observed in most tropical countries, but its transmission from mother to fetus has not been frequently described. We report two such cases. The first signs of dengue in the infants appeared on the 3rd and 9th days of life. In both, a bacterial infection was suspected initially. In areas where it is endemic, the diagnosis of dengue should be considered in the neonate with signs of bacterial infection. When dengue is suspected in a pregnant woman, laboratory investigation and extended observation of the newborn are advised.

Diverse genetic mechanisms operate to generate atypical betaS haplotypes in the population of Guadeloupe.

In a survey of the chromosomal background associated with the sickle cell gene in Guadeloupe, a French Caribbean island, we identified 37 unrelated patients with sickle cell disease (27 SS, nine SC, and one S-beta-thalassemia) of 477 unrelated sickle cell patients where the beta3 gene was linked to 20 different atypical haplotypes. These atypical chromosomes account for about 5% of the overall betaS chromosomes in this population. To investigate the origin of these atypical betaS haplotypes, we performed extensive typing of betaS and betaA chromosomes. Twenty-two different 5' subhaplotypes were identified among the betaS chromosomes. Fifteen of 20 different atypical haplotypes are likely to be the product of recombination by a single crossover around the <> 5' to the beta-globin gene, or between a major betaS haplotype and one of the betaS haplotypes present in the population. The remaining cases require genetic mechanisms (gene conversions, additional substitutions in a given haplotype) other than crossovers to generate these atypical haplotypes.

[Acute childhood gastroenteritis study at Central University Hospital of Pointe-à-Pitre/Abymes, Guadeloupe, from November 1997 to March 1998]. / Enquête sur les gastro-entérites aiguës infantiles au CHU de Pointe-à-Pitre/Abymes, Guadeloupe, de novembre 1997 à mars 1998.

To determine the role of enteric pathogens in acute childhood diarrhoea in Guadeloupe, 161 children (108 cases and 53 controls) from 0 to 2 years of age, admitted to Pointe-à-Pitre/Abymes University Hospital, were evaluated over a five-month period. A known enteric pathogen was identified in 40.8% of children. The most commonly identified aetiologic agents were Salmonella (16.7% of cases), especially Haddar serotype and Rotavirus (20.5%). This virus was isolated more often in the dry season. Adenovirus were detected in 3.6% of diarrhoeal stools and were not significatively associated with diarrhoeal disease. No Shigella, Campylobacter or parasites were found.

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.

[Sickle cell anemia and pregnancy: review of 68 cases in Guadeloupe]. / Drépanocytose et grossesse: revue de 68 observations en Guadeloupe.

Pregnancy in women with major sickle cell syndromes is a high risk maternofetal situation. This descriptive study presents the features and the clinical course of 68 pregnancies in sickle cell women who were delivered in Guadeloupe from January 1(st) 1993 to December 31(st) 1997. Specific complications were observed in all hemoglobin types, but with a severer course in SS women. Painful vaso-occlusive crises were the main causes of hospitalisation (88% of SS pregnancies and 27% of SC pregnancies) associated most often with worsening anemia and / or infection. Acute chest syndrome was observed in all genotypes at any time throughout pregnancy and during the post partum period. One death occurred (a 16 years old SBeta(+)thal woman). Fetal mortality and morbidity were also high, intrauterine growth retardation and fetal death being the most frequent fetal complications. The rates of prematurity (21%) and caesarean section (48%) were higher than in the whole population. Three (3) neonatal deaths occurred. A multidisciplinary and specific approach, vigilance of health care providers and patient compliance are required to manage efficiently pregnancy, delivery and post partum in sickle cell women.

[Analysis of hospitalization of adult sickle-cell patients in Guadeloupe]. / Analyse des hospitalisations chez les patients drépanocytaires adultes en Guadeloupe.

PURPOSE: To determine the characteristics of acute hospitalizations in adult patient with sickle-cell disease in Guadeloupe. METHODS: We retrospectively studied clinical features of adult patients followed up by the "Centre Caribeen de la Drépanocytose" (CCD) in 1996. Data were collected from the medical records of the hospitalized patients and the longitudinal records of the CCD. RESULTS: Sixty-three (25%) of the 251 patients who were followed up by the CCD required hospitalization in 87 cases (1.38 hospitalizations/patient). Mean age of the hospitalized patients was 27.5 years (range 17 to 71 years). Most hospitalizations involved men (29 [31%] vs 34 [22%] for women, P < 0.05), and most were for homozygous patients with sickle-cell anemia: 39 (31%) SS, 19 (18.55%) SC and five (21.75%) S beta thal. A painful vaso-occlusive crisis was noted in 67 episodes. There were nine acute chest syndromes (ACS), six of them occurred following a vaso-occlusive crisis. We noted 39 infectious episodes. The increase in C-reactive protein (> 100 mg/L) was associated with ACS or urinary infection. A patient with renal failure died during septicemia. CONCLUSION: This study confirms the need for prevention of painful crises and other severe complications in patients with sickle-cell disease.

Morphological features of the human umbilical vein in normal, sickle cell trait, and sickle cell disease pregnancies.

Pathological changes often occur in the placenta of women with sickle cell disease (SCD). These alterations are caused by sickling of erythrocytes and vasoocclusion in the placental circulation, leading to regional hypoxia. However, the morphological status of the umbilical cord, which is in close physical association with the placenta, is not documented under such conditions. To explore this, the umbilical vein structure in healthy, sickle cell trait (the heterozygous state), and SCD pregnancies was studied using scanning (SEM) and transmission electron microscopy (TEM). Interestingly, the sickle cell trait umbilical vein architecture was morphologically similar to that in control veins, whereas numerous alterations were seen in the SCD umbilical vein wall. In SEM, the SCD umbilical vein endothelial cells showed atypical morphologies. TEM analysis of the tunica media showed (1) smooth muscle cell proliferation and increase in the thickness of the basement membrane underlying the cells; (2) areas of necrosis; (3) reduplication of the inner elastic lamina. Such features were often seen in sickle patients vasculature at autopsy. Our findings could have importance because tissue hypoxemia is an integral part of vasoocclusion. We conclude that the SCD umbilical vein may be an additional tool for studying vasoocclusion in sickle cell disease.

Prevalence of fragile-X syndrome and FRAXE among children with intellectual disability in a Caribbean island, Guadeloupe, French West Indies.

Fragile-X syndrome (FXS) is the most common cause of inherited intellectual disability. Although FXS has been identified in all the main ethnic groups, little is known about its prevalence with respect to ethnicity. Since the identification of the FXS primary defect, diagnosis involving DNA analysis has been made possible, allowing efficient screening strategies to be considered. The present authors have carried out FXS screening among children belonging mainly to the Afro-Caribbean ethnic group (163 boys and 85 girls) affected with moderate to severe intellectual disability of previously unknown origin. We have found a 6.7% and 0% prevalence among boys and girls, respectively, yielding a minimum FXS incidence of 0.42 per 1000 male births per year. Family studies have resulted in genetic counselling for several individuals. FRAXE screening was also achieved and no FRAXE case was detected in this study.

Sickle cell disorder, beta-globin gene cluster haplotypes and alpha-thalassemia in neonates and adults from Guadeloupe.

We have studied haplotype of beta(S) chromosome and alpha-globin gene status in 534 patients (255 adults and 279 children of whom 159 neonates) from Guadeloupe with various sickle cell-related conditions, namely SS (n = 298), SC (n = 170), S-beta-thal (n = 56), and other rare forms (n = 10). Haplotype data on beta(S) chromosomes confirm our previous observation that Benin type is the most prevalent (75%) beta(S) chromosome in Guadeloupe, in disagreement with the historical records. Comparison of the frequency of distribution of various beta(S) haplotypes between neonates and adults on the one hand and between SS and SC cases on the other shows that the current beta(S) haplotype distribution in this island is not distorted by haplotype-related differential survival. We also show that the frequency of alpha-thalassemia (-3.7 kb) in Guadeloupe is one of the highest recorded in this region involved in Atlantic slave trade and also failed to reveal any age-dependent increase in frequency. We conclude that the African component of Guadeloupe is distinct from that of Brazil and Cuba but is close to that of Jamaica.

[Conditions of use and access to care of sickle cell anemia patients. Analysis of the literature]. / Conditions d'usage et d'accès aux soins des drépanocytaires. Analyse de la littérature.

In order to identify the care access and life conditions and non-compliance risk factors of sickle-cell patients, we performed a literature survey on these subjects, and on other chronic pathologies and care systems used as references. The data showed a positive influence of good quality of life, social support and family environment on diabetes mellitus patients compliance, and the negative effect of poor socioeconomic status on adequate prenatal care. Concerning sickle-cell disease, there were few data on the non-compliance risk factors. However, the authors identified factors which influence the patient health status and showed the negative result of the disease on the quality of life of the patient and his family. A new study has been induced by these conclusions on the sickle-cell disease cohort of Guadeloupe reference center.

Efficiency of prenatal counselling for sickle cell disease in Guadeloupe.

As in most caribbean countries, Sickle Cell Disease (SCD) is a major public health problem in Guadeloupe. A prenatal counselling program was developed, at an early stage of pregnancy, for at-risk couples. Over a 6 year period, 144 couples at-risk of having a child with homozygous sickle cell (SS: n = 103) or sickle cell C disease (SC: n = 41) were seen for prenatal counselling. Among those belonging to the SS risk group, 64 (62%) underwent prenatal diagnosis (PND), which allowed identification of 27 SS fetuses, with an induced abortion rate of 70%. Among those of the SC risk group, 14 (34%) accepted PND and the diagnosis of SC was made in 5 cases with an induced abortion rate of 60%. Factors, appeared to play a role in seeking PND and induced abortion, were the type of risk (SS or SC), multiparity, existence of affected child in the family and gestational age at the time of counselling. Our experience reveals that, an early prospective identification of at-risk couples combined with education to increase the awareness of the problem at the individual and population level need to be achieved to further improve the efficiency of our prevention program.

Molecular characterization of beta-thalassemia mutations in Guadeloupe.

In order to perform genetic counselling and prenatal diagnosis of Hb-S-beta-thalassemia disease and beta-thalassemia, we have delineated the spectrum of beta-thalassemia alleles in the Guadeloupean population. A sample of 63 unrelated families was analyzed including 70 beta-thalassemia carriers, 52 Hb-S-beta-thalassemia, and 8 patients with different beta-thalassemic hemoglobinopathies. Among the eleven mutations identified, four of them [-29 (A --> G), IVS-I-5 (G --> A), IVS-II-1 (G --> A), and IVS-I-5 (G --> C)] account for 77.6% of the beta-thalassemia chromosomes present in the studied families. The seven other variants, CD 24 (T --> A), IVS-I-2 (T --> C), Poly A (T --> C), -88 (C --> T), IVS- 11-849 (A --> G), Hb E, and Hb Lepore are less frequent. As a result, Hb S-beta+-thalassemia type 1 (low Hb A values: 5-15%) together with Hb S-beta(omicron)-thalassemia phenotypes are as frequent as Hb S-beta+-thalassemia type 2 (high Hb A values: 20-30%) in the Guadeloupean population. Patients with Hb S-beta+-thalassemia type 2 have milder hematological manifestations of the disease compared to patients with Hb S-beta(omicron)-thalassemia and Hb S-beta+-thalassemia type 1. This first report on the type and nature of beta-thalassemia mutations in Guadeloupe shows that prenatal diagnosis of Hb S-beta-thalassemia and beta-thalassemia should be feasible by direct detection of point mutation in most cases.

10-year educational programme aimed at rheumatic fever in two French Caribbean islands.

BACKGROUND: In less developed countries, rheumatic fever still occurs. We started a long-term educational programme in two French Caribbean islands that was directed at the public and at health-care workers to see whether we could reduce the incidence of rheumatic fever. METHODS: Our 10-year programme started in 1981 in Martinique and Guadeloupe, and was based in the community and in clinics and hospitals. The programme established a registry of all cases of primary and secondary rheumatic fever (diagnosed by Jones' modified criteria), with systematic hospital admission of children. We graded carditis as severe, mild, or subclinical, and acute glomerulonephritis was defined by oedema, proteinuria, and haematuria for less than 3 months. The educational part of the programme targeted the public and health-care workers, including doctors, with written information distributed in schools or via radio and television broadcasts or videotapes. For the public, the benign clinical presentation of the initial streptococcal infection was contrasted with the severity of later heart disease. FINDINGS: The first months of the programme led to a 10-20% increase in the number of rheumatic fever cases admitted to hospital, because of the renewed attention paid to the disease. Therefore we took 1982 as the baseline year. In 1982-83 the incidence of rheumatic fever was 19.6 per 100 000 inhabitants aged under 20 in Martinique, and 17.4 per 100 000 in Guadeloupe. In 100 Martinique children and 97 Guadeloupe children in 1982-83, 40 and 71% had carditis, respectively (severe in 10 and 32%). Rheumatic fever was preceded by symptomatic sore throat in 52 and 41% of cases, respectively. The disease was not seen in children with active streptococcal cutaneous infections. Disease frequency was highest in the poorest areas and families, a finding that persisted over time. The programme was associated with a progressive decline in the frequency of rheumatic fever: final reduction of 78% in Martinique and 74% in Guadeloupe. The frequency of carditis also fell. Apart from two outbreaks in one hospital, the frequency of acute glomerulonephritis also declined; 31% of cases had had sore throat, while 56% had skin infections. The cost of the programme during the 4 most intensive years was FFr 250 000 (US$ 44 500) in each island. The cost of childhood rheumatic fever, excluding late sequelae, was initially (in 1982) about FFr 7.8 million (US$ 1426 000). The cost fell to an average of Ffr 550 000 (US$ 100 000) per year in 1991-92. INTERPRETATION: A rapid decline in rheumatic fever incidence was achieved at modest cost. Such a programme needs to be continued because of the risk of disease resurgence.

beta S haplotypes, alpha-globin gene status, and hematological data of sickle cell disease patients in Guadeloupe (F.W.I.).

The beta gene cluster haplotypes, alpha gene status, Hb F level and hematological parameters have been characterized in 154 unrelated Guadeloupe patients with sickle cell disease: 112 with sickle cell anemia, 26 with SC disease, 15 with Hb S-beta-thalassemia, and one patient with Hb S in association with the hereditary persistence of fetal hemoglobin. Fourteen haplotypes in 16 combinations were found, the three major African haplotypes were present on 92% of all chromosomes: 73% Benin, 11% Bantu, 8% Senegal. Among SS patients, 57% were Benin homozygotes, one patient was a Senegal homozygote, one patient was a Bantu homozygote, and all the others were heterozygous. The A gamma T chain was observed on seven chromosomes and about 5% of the analyzed beta S chromosomes exhibited atypical haplotypes. The common haplotype beta C was found in all patients with SC disease. An interesting feature was the high frequency (44%) of deletional alpha-thalassemia among SS patients. Two patients have an alpha-gene globin triplication. The DNA haplotypes and alpha-gene status have been correlated with hematological parameters in these patients. The anthropological aspect of these data is interesting as the haplotypes of the beta-globin gene throw light on the slave trade from the various parts of Africa to the Caribbean Islands in particular, and North America in general.

[Natural history of sickle cell anemia]. / Histoire naturelle de la drépanocytose.

Sickle-cell anaemia is characterized by three categories of clinical signs: anaemia, vaso-occlusive phenomena and infective complications, which are described here according to age. The natural history of the disease can be divided into four periods: the neonatal period which is asymptomatic but important to organize an effective protection; the first 5 years of life are characterized by a high risk of mortality, a high level of morbidity due to severe infections, episodes of acute anaemia and painful crises typical of that age-group; the life of older children and adolescents is dotted with painful crises; it is in this period that degenerative tissue pathology begins; in adulthood, the acute episodes are less frequent, but multiple complications develop. Some of them (cerebral vascular accidents or lung diseases) may be fatal, while others are the source of chronic and disabling lesions, notably ocular, orthopaedic and renal lesions, which affect the functional prognosis. Pregnancy remains a high risk. There is, therefore, a striking contrast between the basic physiopathological mechanism (polymerization of haemoglobin S) and the various clinical manifestations which depend on the type of haemoglobin, on the social and sanitary conditions in each country and on other reasons which remain to be elucidated.