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ABSTRACT: Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder with a wide heterogeneous clinical pattern. Intracranial haemorrhage in infants has been previously reported in the severe form of the FVII deficiency and it has a high fatality rate. We report a family with high consanguineous relations, who experienced death of two baby girls, the first with prenatal manifestation of foetal hydrocephalus secondary to intracranial bleeding and the second with postnatal intracranial bleeding, both with less than 1% activity of FVII. Genetic analysis revealed that both parents are heterozygous and both daughters homozygous for a point mutation gG9639A in exon 7, predicting Gly180Arg substitution. This mutation was described previously in a compound heterozygous patient with mild bleeding manifestation. It seems that in this family, the mutation in its homozygous state is fatal and the lethal clinical expression can appear in utero at an early stage of gestation.
Haemophilia 06/2009; 15(3):774-8. · 2.60 Impact Factor
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ABSTRACT: In previous studies we have shown a significant involvement of the growth hormone (GH)-IGF axis in animal models of type 1 diabetes mellitus, but the role of this endocrine system in type 2 diabetes mellitus is less well characterised. We therefore examined the endocrine and renal GH-IGF axis changes in db/db mice, a model of type 2 diabetes mellitus and nephropathy.
Obese and lean animals were followed, beginning at hyperglycaemia onset, for 4 weeks. Albuminuria and creatinine clearance, as well as kidney and glomerular morphology were assessed. Tissue protein levels were determined by western blotting and mRNA levels by RT-PCR.
Serum GH and IGF1 levels immediately prior to killing were decreased and liver mRNA levels of insulin-like growth factor binding protein 1 (Igfbp1) were increased in obese animals. Kidney weight was increased in obese animals, associated with hyperfiltration, albuminuria and glomerular hypertrophy. Administration of a somatostatin analogue (PTR-313) did not improve any of these parameters of diabetic renal involvement. Renal Igf1 mRNA was decreased and renal Igfbp1 mRNA and protein were significantly increased in obese animals. Renal insulin-driven levels of phosphorylated forkhead box O1 (FOXO1) were decreased in obese animals.
Diabetic db/db mice show significant renal changes (and IGFBP1 renal accumulation), similar to the findings in models of type 1 diabetes mellitus. A decreased signalling through the insulin receptor and decreased FOXO1 phosphorylation may allow Igfbp1 gene transcription. These renal changes are associated with low circulating IGF1 and GH levels and unchanged hepatic growth hormone receptor expression, unlike the condition in type 1 diabetes mellitus. This suggests that further GH inhibition to modulate renal complications in type 2 diabetes mellitus is not indicated.
Diabetologia 07/2007; 50(6):1327-34. · 6.81 Impact Factor
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ABSTRACT: Hyper- and hypokalemia may carry severe clinical consequences. Different regulatory mechanisms, including the kidney, exert a tight regulation of plasma potassium levels. The renal pathway of potassium handling begins in the proximal tubule followed by the fine-tuning of its secretion or absorption at the distal tubule, including the thick ascending limb of Henle's loop, the distal convoluted tubule and the cortical collecting duct. Genetic studies in recent years have clarified the role of specific tubular channels and transporters in the pathogenesis of unique hyper- and hypokalemic tubulopathies, some of them non-hypertensive (pseudohypoaldosteronism, Bartter and Gitelman syndromes) and others hypertensive by definition (including Liddle and Gordon syndromes). This article reviews the genetic and clinical spectrum of hypokalemic and hyperkalemic tubulopathies.
Cellular and Molecular Life Sciences CMLS 10/2006; 63(17):1962-8. · 6.57 Impact Factor
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ABSTRACT: Although normal pregnancy is the precursor of 25% of cases of maternal choriocarcinoma, intraplacental choriocarcinoma in an otherwise normal placenta associated with viable pregnancy has rarely been reported.
Examination of the placenta after delivery of a pale and small-for-date infant at term revealed intraplacental choriocarcinoma. There was no evidence of metastatic disease in the mother or child, but the mother exhibited postpartum rising levels of beta-HCG. The mother refused chemotherapy and disappeared from follow-up. Nine months later, she presented with metastatic choriocarcinoma of the lung. Eleven courses of the multi-drug EMA CO regimen effected a decrease of beta-HCG to normal and disappearance of lung metastases. To date, 28 months after the end of chemotherapy, the patient is alive and without evidence of gestational trophoblastic disease. Moreover, since then she has given birth to an additional two children.
This case is an example of natural disease progression of intraplacental choriocarcinoma metastasizing to the mother. Furthermore, it supports common knowledge that the multi-drug EMA CO regimen is effective treatment in poor prognosis metastatic choriocarcinoma.
European journal of gynaecological oncology 02/2006; 27(1):29-32. · 0.47 Impact Factor
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ABSTRACT: Four members of an extended consanguineous Bedouin family presented with different phenotypic variants of an autosomal recessive lysosomal free sialic acid storage disease. One affected individual had congenital ascites followed by rapid clinical deterioration and death, a presentation concordant with the clinical course of infantile free sialic acid storage disorder. His three first cousins had a more slowly progressive neurodegenerative disease, in line with the clinical phenotype of the milder form (Salla type) of this lysosomal disorder. Diagnosis of free sialic acid storage disease was based on clinical findings, histology, and biochemical assays of sialic acid. Molecular studies showed that all four affected individuals were homozygous for the same novel 983G > A mutation in exon 8 of the SLC17A5 gene, replacing glycine with glutamic acid at position 328 of the sialin protein. This family demonstrates the significant phenotypic variability of the disease in affected members of a single inbred kindred with precisely the same mutation, suggesting a role for modifier genes or environmental factors. It also highlights the need to consider this rare disorder in the differential diagnosis of congenital ascites and of unexplained psychomotor retardation, ataxia, and hypomyelination in infancy.
Molecular Genetics and Metabolism 06/2004; 82(2):167-72. · 3.19 Impact Factor
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ABSTRACT: A case of brachial artery pseudoaneurysm in a premature infant is reported. The lesion was surgically resected, and arterial continuity restored by end to end anastomosis. The postoperative period and follow up were uneventful.
Archives of Disease in Childhood - Fetal and Neonatal Edition 04/2003; 88(2):F152-3. · 3.05 Impact Factor
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ABSTRACT: Uncontrolled diabetes is associated with growth retardation. We investigated the effect of insulin-dependent diabetes on animal growth and IGF-I gene expression in the epiphyseal growth plate region of the long bones. We also studied the effect of GH administration on somatic growth in the diabetic state. Streptozotocin (STZ)-injected diabetic rats had a decreased somatic growth rate in comparison to controls. GH administration (2.5 U/kg day) in the diabetic animals (DGH group) prevented this decrease. Serum IGF-I levels were decreased in both diabetic and DGH animals. Within 72 h from diabetes onset, IGF-I mRNA levels in epiphyseal growth plate homogenates decreased whereas IGF-I receptor mRNA levels increased in diabetic animals. The decrease in IGF-I mRNA transcript levels was localized to the metaphyseal region by in situ hybridization. We conclude that in the STZ-induced diabetic state, the reduction in linear growth is associated with a parallel decrease in IGF-I gene expression at the epiphyseal growth plate area. Diabetic growth retardation can be reversed with GH administration, which does not reconstitute serum IGF-I levels. Therefore, we speculate that GH in this model may act locally through the skeletal GH-IGF-I system.
Acta Diabetologica 07/2002; 39(2):61-7. · 2.78 Impact Factor
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ABSTRACT: Deletions ranging from 100 Kb to 1 Mb--too small to be detected under the microscope--may still involve dozens of genes, thus causing microdeletion syndromes. The vast majority of these syndromes are caused by haploinsufficiency of one or several genes and are transmitted as dominant traits. We identified seven patients originating from an extended family and presenting with a unique syndrome, inherited in a recessive mode, consisting of cystinuria, neonatal seizures, hypotonia, severe somatic and developmental delay, facial dysmorphism, and lactic acidemia. Reduced activity of all the respiratory chain enzymatic complexes that are encoded in the mitochondria was found in muscle biopsy specimens of the patients examined. The molecular basis of this disorder is a homozygous deletion of 179,311 bp on chromosome 2p16, which includes the type I cystinuria gene (SLC3A1), the protein phosphatase 2Cbeta gene (PP2Cbeta), an unidentified gene (KIAA0436), and several expressed sequence tags. The extent of the deletion suggests that this unique syndrome is related to the complete absence of these genes' products, one of which may be essential for the synthesis of mitochondrial encoded proteins.
The American Journal of Human Genetics 11/2001; 69(4):869-75. · 10.60 Impact Factor
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ABSTRACT: PTR-3173 (S) is a novel somatostatin analogue that has been found to exert a prolonged inhibitory action on the growth hormone (GH)-insulin-like growth factor (IGF)-I axis, but not on insulin secretion. We investigated the potential effect of this agent on the development of markers of diabetic nephropathy in the nonobese diabetic (NOD) mouse model of insulin-dependent diabetes.
Female diabetic NOD mice treated with PTR-3173 (DS group) or saline (D) and their control groups of nonhyperglycemic age-matched littermates (C) and C mice treated with PTR-3173 (CS) were sacrificed three weeks after onset of diabetes.
Serum GH was elevated in the D group, decreased in the DS group, and unchanged in the CS group. Serum IGF-I was significantly decreased in both the D and DS groups. Kidney weight, glomerular volume, albuminuria, and creatinine clearance were increased in the D animals and showed a trend toward normalization in the DS animals. Renal extractable IGF-I protein and IGFBP1 mRNA were increased in the D group and normalized in the DS group.
GH antagonism by PTR-3173 has a blunting effect on renal/glomerular hypertrophy, albuminuria, and glomerular filtration rate (GFR) in diabetic NOD mice. This phenomenon is apparently associated with the prevention of renal IGF-I accumulation. Thus, modulation of GH effects may have beneficial therapeutic implications in diabetic nephropathy.
Kidney International 09/2001; 60(2):505-12. · 6.61 Impact Factor
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ABSTRACT: Post-transplantation lymphoproliferative disorders (PTLDs) and Kaposi's sarcoma (KS) are immunosuppression-related tumours developing in solid organ transplant patients. Although the Epstein-Barr virus (EBV) is detected in the majority of the PTLDs during the first year after transplantation, the proportion of EBV-negative PTLDs has increased in recent years. We report a case of a 17-year-old man who developed severe immune haemolytic anaemia, KS and human herpesvirus 8 (HHV-8)-associated, polymorphic-type PTLD 9 months after allogeneic renal transplantation from his HHV-8-seropositive father. It is suggested that: (i) HHV-8 may be associated with EBV-negative, polymorphous-type PTLD occurring less than 1 year after transplantation, and (ii) PTLD may be listed among other tumours, including KS, Castleman's disease and primary effusion lymphoma (PEL), that are related to HHV-8 infection.
British Journal of Haematology 06/2001; 113(2):425-8. · 4.94 Impact Factor
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Archives of Pediatrics and Adolescent Medicine 06/2001; 155(5):613-4. · 4.14 Impact Factor
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ABSTRACT: Autosomal dominant familial nephropathies with adult onset, no macroscopic cysts, and progressive deterioration include medullary cystic disease (ADMCKD) as well as other less specific entities. We studied a kindred of Jewish ancestry in which 15 members (both male and female) have suffered from chronic renal failure. The first evidence of renal involvement was observed between 18 and 38 years. It included hypertension followed by progressive renal insufficiency. No polyuria, anemia, gout, hematuria, nor proteinuria were seen. An average of 4.5 years elapsed from diagnosis to end-stage renal disease. Renal pathology at early stages of the disease showed extensive tubulointerstitial fibrosis and global glomerulosclerosis. Linkage analysis was performed at the two known loci of ADMCKD, on Chromosomes 1 and 16. Linkage to the chromosome 16 locus was excluded. However, linkage to the chromosome 1q21 locus of ADMCKD was established with a maximum two-point LOD score of 3.82 to D1S394. The disease interval could be narrowed to about 9 cM/7.4 Mb between D1S1156 and D1S2635. Multiple-point linkage analysis revealed a maximum LOD of 4.21, with a broad peak from markers D1S2858 and D1S2624. This report establishes linkage between a familial nephropathy characterized by hypertension and progressive renal failure to the locus described for ADMCKD, a disease classically associated with macroscopic corticomedullary cysts, salt-losing tubulointerstitial nephropathy, and anemia. This finding broadens the clinical spectrum of ADMCKD positioned on chromosome 1q21 locus.
American Journal of Medical Genetics 04/2001; 99(3):204-9.
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ABSTRACT: Atypical hemolytic uremic syndrome (HUS) associated with factor H deficiency (FHD) carries a poor prognosis. A 3-year-old girl with FHD-HUS reached end-stage renal disease at age 6 months after experiencing numerous relapses; she underwent a cadaveric renal transplant at age 46 months. One month after transplantation, she experienced an extensive non-hemorrhagic cerebral infarction. Later, hematologic and renal manifestations of HUS developed, followed by another massive cerebral infarction and death in spite of multiple plasma transfusions. A 14-month-old boy with FHD-HUS experienced numerous HUS episodes starting at the age of 2 weeks. Daily plasma transfusions during relapses brought about only a temporary state of remission. However, prophylactic twice-weekly plasma therapy has been successful in preventing relapses and preserving renal function. With this regimen, serum factor H was increased from 6 mg/dL to subnormal values of 12 to 25 mg/dL (normal >60 mg/dL). We conclude that FHD-HUS recurs because FHD is not corrected by renal transplantation. A hypertransfusion protocol may prevent FHD-HUS.
Journal of Pediatrics 04/2001; 138(3):412-7. · 4.11 Impact Factor
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ABSTRACT: Narcotic abuse has steadily become more prevalent in Israel and may result in an increasing number of children exposed prenatally to narcotics, with a consequent increase in the number of infants born with neonatal abstinence syndrome.
To report our experience with infants born to narcotic-addicted women between the years 1995 and 1998 at the Soroka University Medical Center.
The medical records of 24 newborns and their drug-addicted mothers admitted to our Medical Center for parturition were analyzed retrospectively. A diagnosis of NAS was established on the basis of the clinical presentation and anamnesis. The Finnegan Neonatal Abstinence Scoring System was used to assess drug withdrawal. Urine toxicological analysis for narcotics was done only for the year 1998.
Of the 24 newborn infants exposed prenatally to narcotics 23 (96%) developed NAS, and 78% (18 of the 23) had a Finnegan score of 8 or more. These 18 infants were treated pharmacologically (tincture of opium and/or phenobarbital) until the score was reduced to less than 8, after which they received supportive treatment. In one child who became lethargic after the first dose of tincture of opium, the medication was stopped and supportive treatment alone was given. Four of the five neonates with scores of 7 and less were given supportive treatment. One of five infants who had a low Finnegan score at birth nevertheless received pharmacological therapy to prevent further deterioration of his physical state since he was born with severe dyspnea. Ten of the 24 children (42%) were followed for lengths of time ranging from 6 to 22 months after discharge, all of whom showed normal development.
About three-quarters of newborns exhibiting withdrawal syndrome required pharmacological therapy. Previous information on maternal drug abuse is a crucial criterion for early detection and treatment.
The Israel Medical Association journal: IMAJ 02/2001; 3(1):17-20. · 1.02 Impact Factor
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ABSTRACT: Congenital unilateral hydrocephalus is extremely uncommon with 18 cases previously reported in the English literature. Two additional newborns with unilateral hydrocephalus are presented. The second baby also presented a mega cisterna magna. This unusual association between Dandy-Walker variant and unilateral hydrocephalus has not been previously reported. Following ventriculo-peritoneal shunt, the babies had a normal cognitive neurodevelopment. The role of cranial computed tomography (CT) in diagnosis and follow-up is emphasized.
European Journal of Radiology 01/2001; 36(3):161-4. · 2.61 Impact Factor
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ABSTRACT: We describe three cases of severe obstructive uropathy in children under 2 years of age, due to radiolucent renal stones. Metabolic work-up revealed only normouricemic hyperuricosuria (HU) as the single identifiable risk factor for urolithiasis (UL) in these infants. We reviewed records of 66 cases of pediatric UL seen in our service over an 8-year period. UL prevalence was greater for Bedouin than for Jewish children (1.02 vs. 0.13 cases/1,000 inhabitants at risk respectively, P<0.01). HU (>0.6 mg uric acid/dl GFR) was the only biochemical risk factor that differed between Bedouin and Jewish children (mean uric acid excretion index 0.8+/-0.39 vs. 0.55+/-0.26 mg/dl GFR respectively, P<0.05). Bedouin children comprised 85% of patients in the HU group versus 59% in the non-hyperuricosuric group (P<0.05). The mean age of onset of UL was 38+/-44 months and 93+/-52 months in the HU and the non-HU group, respectively (P<0.05). The UA excretion index in the HU group was inversely correlated with age (r=0.41, P<0.01) and its slope and constant were different from an age-matched non-UL control population. In conclusion, pediatric UL in southern Israel is predominant in Bedouin toddlers. HU was the only identifiable biochemical risk factor that could explain this difference.
Pediatric Nephrology 11/2000; 14(12):1105-10. · 2.52 Impact Factor
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Pediatrics in Review 09/2000; 21(8):281, 282-3. · 0.55 Impact Factor
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ABSTRACT: Two newborns with glomerulocystic kidney disease manifesting as late onset oligohydramnion and neonatal anuria, yet without severe respiratory distress, are presented. They had a similar perinatal course and associated clinical manifestations. No associated congenital or inherited malformation syndrome could be defined. Both infants' parents were first degree cousins and belonged to the same small Bedouin tribe, and neither they nor the infants' siblings had polycystic kidneys or renal insufficiency, pointing to either a possible genetic etiology or a common external toxic exposure.
Pediatric Nephrology 05/2000; 14(4):319-21. · 2.52 Impact Factor
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ABSTRACT: We investigated the changes in GH-IGF-I axis in non-obese diabetic (NOD)-mice, a model of insulin-dependent diabetes mellitus. Diabetic female NOD mice and their age- and sex-matched controls were sacrificed at 4, 14, 21 and 30 days (30d DM) after the onset of glycosuria. Serum GH levels increased and serum IGF-I levels decreased in the 30d DM group (182 +/- 32% and 45 +/- 24% of age-matched controls respectively, p < 0.05). Another group (30d DM + I) was given SC insulin, and its serum IGF-I levels remained decreased. Liver GH receptor (GHR) and GH binding protein (GHBP) mRNA levels, as well as liver membrane GH binding assays were deeply decreased in the 30d DM group in comparison to controls. GHR message and binding capacity remained decreased in the 30d DM + I group. Renal GHR mRNA was decreased at 21d DM but not at 14d DM, whereas GHBP mRNA remained unchanged throughout the experiment. In conclusion, increased serum GH levels are documented in NOD diabetic mice, similarly to the changes described in humans. The decrease in GHR levels and decreased serum IGF-I in spite of increased circulating GH suggest a state of GH resistance.
International Journal of Experimental Diabetes Research 02/2000; 1(1):9-18.
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ABSTRACT: Atypical hemolytic uremic syndrome (HUS) presents with the clinical features of hypertension, microangiopathic hemolytic anemia, and acute renal failure. Both dominant and recessive modes of inheritance have been reported. This study describes the genetic and functional analysis of a large Bedouin kindred with autosomal recessive HUS. The kindred consists of several related nuclear families in which all parent unions of affected children are consanguineous. A previous report demonstrated that a dominant form of HUS maps to chromosome 1q and that complement factor H (CFH), a regulatory component of the complement system, lies within the region and is involved in the dominant disorder. Early-onset and persistent hypocomplementemia in this Bedouin kindred prompted us to evaluate the CFH gene. Linkage analysis was performed, demonstrating linkage between the disorder and the markers near the CFH gene. Mutation analysis of the CFH coding region revealed a single missense mutation. Functional analyses demonstrate that the mutant CFH is properly expressed and synthesized but that it is not transported normally from the cell. This is the first study reporting that a recessive, atypical, early-onset, and relapsing HUS is associated with the CFH protein and that a CFH mutation affects intracellular trafficking and secretion.
The American Journal of Human Genetics 01/2000; 65(6):1538-46. · 10.60 Impact Factor
