Phenotype-genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation.

BACKGROUND: The recessive X-linked disorder hemophilia A (HA) is rarely expressed in female carriers, most of whom express about half of normal factor VIII activity ( FVIII: C). OBJECTIVE: To propose an integrative assessment model for the binary role of the phase between the mutated F8 and the active X-chromosome (Xa) in FVIII: C in HA carriers. METHODS: We studied 67 females at risk of severe HA, comprising five symptomatic females ( FVIII: C < 1.5 IU dL(-1) ) and 14 controls. A correlation study between FVIII: C (observed vs. expected) and X-chromosome inactivation (XCI) patterns (XIPs; androgen receptor gene [AR] system) in blood leukocyte DNA was performed in carriers, by comparison of a model correlating FVIII: C and XIP with arbitrary models devoid of biological significance, and with FVIII: C levels in non-carriers (mean model) as a proxy from background data dispersion not influenced by XIP. RESULTS: We provide proof-of-concept example from a family presenting with extremely skewed XIPs in which the severe HA phenotype appeared in a heterozygous carrier of a crossover between AR and F8 loci that phased the mutated F8 with the maternally inherited Xa. Furthermore, four cases of severe HA affected women who had a combination of a heterozygous F8 mutation and extremely skewed XIPs in leukocytes or oral mucosa are presented. Correlation analyses between FVIII: C levels and XIPs in carriers (n = 38) but not in non-carriers (n = 20) showed highly significant differences between the proposed correlation model and models without biological significance. The data support a binary influence of XCI, either increasing or decreasing the FVIII: C, subject to the underlying phase set between the F8 mutation and XCI. CONCLUSIONS: Our evidence suggests that the phase between XCI and mutated F8 acts as a molecular switch conditioning FVIII: C levels and HA expression in carriers.

Acenocoumarol therapy in pediatric patients.

To determine guidelines for administering and monitoring acenocoumarol therapy in children, 93 patients (median 5.1 years, range: 0.2-18 years) were prospectively evaluated over a 33-month period. The loading doses used were: <1 year, 0.20 mg x kg-1; >1-5 years, 0.09 mg x kg-1; 6-10 years, 0.07 mg x kg-1; 11-18 years, 0.06 mg x kg-1. In this study, the loading dose and the dose to achieve and maintain target therapeutic range (TTR) for acenocoumarol are age-dependent, with infants having the highest and teenagers having the lowest requirements. The use of a different loading dose according to age has allowed most of the children (80%) in all the age groups to achieve TTR in less than 1 week. No patients had serious bleeding or thrombotic complications. We conclude that there is an age-dependent response to acenocoumarol in pediatric patients. The implementation of an age-adjusted loading dose regimen reduces the length of hospitalization required to achieve effective anticoagulant therapy.

Prothrombotic disorders in children with moyamoya syndrome.

BACKGROUND AND PURPOSE: Moyamoya syndrome is an uncommon chronic occlusive cerebrovascular disease in children. The origin of moyamoya syndrome remains undetermined. The role of the prothrombotic disorders contributing to its pathogenesis has not been completely elucidated. The purpose of this study was to determine the frequency of prothrombotic disorders in a pediatric population with moyamoya syndrome. METHODS: From May 1992 to April 2000, a prospective study of 10 consecutive children with moyamoya syndrome was carried out at a single center. Evaluation included the following assays: protein C, protein S, antithrombin, plasminogen, activated protein C resistance, factor V Leiden, and prothrombin gene mutations. Lupus anticoagulant, anticardiolipin antibodies, and anti-beta(2)-glycoprotein I antibodies assays were also performed. The clinical characteristics, underlying diseases, family history of thrombosis, radiological findings, treatment, and outcome were also recorded. RESULTS: In our series, prothrombotic disorders were detected in 4 patients (40%). Inherited protein S deficiency was found in 1 patient; lupus anticoagulant and anticardiolipin antibodies were detected in the remaining 3 patients. One presented persistent lupus anticoagulant for 2.7 years until his death. In the case of the other 2 patients, 1 has maintained lupus anticoagulant for 9 months, whereas the other has kept anticardiolipin/anti-beta(2)-glycoprotein I antibodies for 10 months. CONCLUSIONS: We report the hemostatic data of the largest prospective pediatric study carried out at a single center in the western hemisphere. In 4 patients (40%), a prothrombotic disorder was detected. It is tempting to speculate that these hemostatic abnormalities may contribute to the pathogenesis of moyamoya syndrome in some of our patients.

Prothrombotic abnormalities in children with venous thromboembolism.

PURPOSE: The aim of this study was to determine the frequency of acquired or inherited prothrombotic disorders in a pediatric population with venous thromboembolism (VTE). PATIENTS AND METHODS: From May 1992 to April 1998, 56 consecutive children with VTE were prospectively studied at a single center. RESULTS: The median age was 8.4 years (range, 0.1-18 years). There was a male predominance. Fifty (89%) children had thrombosis in the lower venous system. Risk factors were detected in 54 (96%) children. Twenty-one (38%) thrombotic episodes were related to central venous lines. Family history of thrombosis was positive in 13 (23%) patients. In 26 (46%) patients, a prothrombotic disorder was detected. Nine of them had inherited disorders (protein C deficiency, 5 patients; protein S deficiency, 3 patients; Factor V Leiden mutation, 1 patient), and 13 children had acquired disorders (antiphospholipid antibodies, 5 patients; antithrombin deficiency, 8 patients). The remaining four showed combined abnormalities (Factor V Leiden mutation associated with inherited protein S deficiency, 1 patient; acquired antithrombin deficiency, 2 patients and inherited antithrombin deficiency, 1 patient). CONCLUSIONS: In the series, a high percentage of prothrombotic disorders was detected; thus, a complete hemostatic evaluation should be performed in all of the children with VTE whether the patients have one or more risk factors.

Prethrombotic disorders in children with arterial ischemic stroke and sinovenous thrombosis.

BACKGROUND: Arterial ischemic stroke (AIS) and sinovenous thrombosis (SVT) are relatively rare events in children. The contribution of prethrombotic disorders to the etiology of these entities has not been completely elucidated. OBJECTIVES: To determine the frequency of inherited and acquired prethrombotic disorders in a pediatric population with AIS and SVT and to report clinical and radiological features. METHODS: From May 1992 to April 1997, 30 consecutive children with AIS and 10 children with SVT were assisted at a single institution. Hemostatic evaluation was performed for all the children. Evaluation included the following assays: protein C, protein S, antithrombin, plasminogen, activated protein C resistance, factor V Leiden mutation, and the detection of antiphospholipid antibodies. Data concerning baseline demographics, risk factors, presenting features, family history of thrombosis, and radiological findings were also recorded. RESULTS: One or more prethrombotic disorders were present in 9 children (30%) with AIS (inherited protein S deficiency, 2 patients; inherited protein C deficiency, 1 patient; acquired antithrombin deficiency, 2 patients; antiphospholipid antibodies, 3 patients; and antiphospholipid antibodies and plaminogen deficiency, 1 patient) and in 5 children (50%) with SVT (inherited protein S deficiency, 1 patient; acquired antithrombin deficiency, 3 patients; and antiphospholipid antibodies, 1 patient). CONCLUSIONS: Most children studied presented both a variety of risk factors for thrombosis and concomitant prethrombotic disorders. Therefore, a complete hemostatic evaluation for all children with AIS and SVT should be performed, despite the presence of obvious clinical risk factors or lack of family history of thrombosis.

Familial idiopathic myelofibrosis and multiple hemangiomas.

Idiopathic myelofibrosis (MF) is a rare disease in childhood. The clinical spectrum is very variable. Familial idiopathic MF has been recorded exceptionally. In previous reports idiopathic MF in childhood has been described in association with congenital anomalies and with chromosome abnormalities, although neither of these features have been reported in a familial context. We report two sisters with idiopathic MF and multiple eruptive hemangiomas. Details of their clinical signs, laboratory findings, and histologic features are described.

Molecular characterization of beta-thalassemia genes in an Argentine population.

This study was designed to identify the beta-thalassemia mutations in an Argentine population. Seventy-one pediatric patients and 101 available relatives were studied (85 chromosomes). Diagnosis of beta-thalassemia was made by conventional hematological procedures. Molecular studies were carried out by dot-blot and restriction endonuclease analysis on amplified DNA to detect the eight most frequent mutations in the Mediterranean area. We were able to identify 95.3% of the beta-thalassemia mutations in the subjects under study. The four common defects (C-39, 47%; IVS-I nt 110, 22.4%; IVS-I nt 1, 9.4%; and IVS-I nt 6, 5.9%) account for 84.7% of the beta-thalassemia alleles. The alleles and their distributions showed a close similarity to the spectrum of alleles in Italy. The differences might represent the influence of other immigrations, especially from Spain. We conclude that beta-thalassemia in Argentina originated mainly from Italian immigrants. This study will enable us to design an adequate approach to genetic counseling and/or prenatal diagnosis for couples at risk.