Clinical presentation, genotype-phenotype correlations, and outcome of pancreatic neuroendocrine tumors in Von Hippel-Lindau syndrome.

PURPOSE: Data regarding the clinical management and follow-up of pancreatic neuroendocrine tumors (PanNETs) associated with Von Hippel-Lindau (VHL) syndrome are limited. This study aimed to assess clinical presentation, genotype-phenotype correlations, treatment and prognosis of PanNETs in a series of VHL syndrome patients. METHODS: Retrospective analysis of data of patients observed between 2005 and 2020. RESULTS: Seventeen patients, including 12 probands and 5 relatives (mean age 30.8 ± 18.4; 7 males), were recruited. PanNETs were found in 13/17 patients (77.5%) at a median age of 37 years: 4/13 (30.7%) at the time of VHL diagnosis and 9 (69.3%) during follow up. Six (46.1%) PanNET patients underwent surgery, whereas seven were conservatively treated (mean tumor diameter: 40 ± 10.9 vs. 15 ± 5.3 mm respectively). Four patients (30.7%) had lymph node metastases and a mean tumor diameter significantly larger than the nonmetastatic PanNETs (44.2 ± 9.3 vs. 17.4 ± 7 mm, p = 0.00049, respectively). Five (83.3%) operated patients had stable disease after a median follow up of 3 years whereas one patient showed liver metastases. Six (85.7%) non-resected PanNETs were stable after a median follow-up of 2 years, whereas one patient developed a new small PanNET and a slight increase in diameter of a pre-existing PanNET. No correlation was found between the type of germline mutation and malignant behavior of PanNETs. CONCLUSIONS: PanNETs are a common disease of the VHL syndrome and can be the presenting feature. Tumor size rather than genetic mutation is a prognostic factor of malignancy.

Fatal respiratory infection due to ST308 VIM-1-producing Pseudomonas aeruginosa in a lung transplant recipient: case report and review of the literature.

BACKGROUND: Data regarding the prevalence of metallo-ß-lactamases (MBLs) among Pseudomonas aeruginosa isolates in cystic fibrosis patients are scarce. Furthermore, there is limited knowledge on the effect of MBL production on patient outcomes. Here we describe a fatal respiratory infection due to P. aeruginosa producing VIM-type MBLs in a lung transplant recipient and the results of the subsequent epidemiological investigation. CASE PRESENTATION: P. aeruginosa isolates collected in the index patient and among patients temporally or spatially linked with the index patient were analyzed in terms of antibiotic susceptibility profile and MBL production. Whole-genome sequencing and phylogenetic reconstruction were also performed for all P. aeruginosa isolates producing VIM-type MBLs. A VIM-producing P. aeruginosa strain was identified in a lung biopsy of a lung transplant recipient with cystic fibrosis. The strain was VIM-1-producer and belonged to the ST308. Despite aggressive treatment, the transplant patient succumbed to the pulmonary infection due to the ST308 strain. A VIM-producing P. aeruginosa strain was also collected from the respiratory samples of a different cystic fibrosis patient attending the same cystic fibrosis center. This isolate harbored the blaVIM-2 gene and belonged to the clone ST175. This patient did not experience an adverse outcome. CONCLUSIONS: This is the first description of a fatal infection due to P. aeruginosa producing VIM-type MBLs in a lung transplant recipient. The circulation of P. aeruginosa isolates harboring MBLs pose a substantial risk to the cystic fibrosis population due to the limited therapeutic options available and their spreading potential.

Oxidative stress biomarkers in Fabry disease: is there a room for them?

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder, caused by deficient activity of the alpha-galactosidase A enzyme leading to progressive and multisystemic accumulation of globotriaosylceramide. Recent data point toward oxidative stress signalling which could play an important role in both pathophysiology and disease progression. METHODS: We have examined oxidative stress biomarkers [Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), thiolic groups] in blood samples from 60 patients and 77 healthy controls. RESULTS: AOPP levels were higher in patients than in controls (p < 0.00001) and patients presented decreased levels of antioxidant defences (FRAP and thiols) with respect to controls (p < 0.00001). In a small group of eight treatment-naïve subjects with FD-related mutations, we found altered levels of oxidative stress parameters and incipient signs of organ damage despite normal lyso-Gb3 levels. CONCLUSIONS: Oxidative stress occurs in FD in both treated and naïve patients, highlighting the need of further research in oxidative stress-targeted therapies. Furthermore, we found that oxidative stress biomarkers may represent early markers of disease in treatment-naïve patients with a potential role in helping interpretation of FD-related mutations and time to treatment decision.

Apolipoprotein C-III predicts cardiovascular mortality in severe coronary artery disease and is associated with an enhanced plasma thrombin generation.

BACKGROUND: Apolipopoprotein C-III (apo C-III) plays a pivotal role in controlling plasma triglyceride (TG) and contributes to the atherogenic properties of TG-rich lipoproteins. OBJECTIVES: (i) To examine the predictive value of serum apo C-III for cardiovascular mortality in the setting of secondary prevention of coronary artery disease (CAD); and (ii) to evaluate possible associations between apolipoprotein levels and the thrombin generation assay, a global test to estimate plasma thrombogenic potential. METHODS AND RESULTS: A cohort of 633 patients with angiographically proven CAD was prospectively followed for a median follow-up of 57 months. The large majority of them (92%) underwent coronary (endovascular or surgical) revascularization. During the follow-up, 91 (14.3%) out of 633 patients died, with 64 events (10.1%) attributed to cardiovascular causes. After adjustment for all the other predictors of mortality during univariate analysis (i.e. age, statin therapy, myocardial infarction history, diabetes, hs-CRP and creatinine), elevated apo C-III levels (> or = 10.5 mg dL(-1)- the median value) significantly predicted both total and cardiovascular mortality (HR for total mortality 2.22 with 95% CI 1.16-4.24; HR for cardiovascular mortality 2.35 with 95% CI 1.19-4.62). In a subgroup of 225 subjects, apo C-III levels were significantly associated with endogenous thrombin potential in regression models (standardized beta coefficient = 0.207, P = 0.002). CONCLUSIONS: Basal concentrations of apo C-III levels > or = 10.5 mg dL(-1) in CAD patients independently predicted cardiovascular mortality during the subsequent 5-year period. Such concentrations were associated with an enhanced plasma endogenous thrombin generation, suggesting a complex interplay between TG-rich particles and the coagulation cascade as well as a new 'thrombogenetic' role for apo C-III.

Homocysteine, traditional risk factors and impaired renal function in coronary artery disease.

BACKGROUND: To establish whether the frequent finding of a moderate-intermediate increase in plasma total homocysteine (tHcy) causes coronary artery disease (CAD), the authors evaluated the number of coexisting major traditional risk factors, as well as the major tHcy determinants, in patients with the same degree of CAD but different tHcy levels. MATERIALS AND METHODS: The authors studied 180 patients with CAD, who were divided into three groups according to tHcy levels: 60 patients with normal tHcy, 60 patients with moderate (15-30 micromol L(-1)) and 60 patients with intermediate hyperhomocysteinaemia (30-100 micromol L(-1)). The patient groups were matched for gender, age and number of affected coronary vessels. All patients were checked for the presence of traditional risk factors for CAD (i.e. hypertension, diabetes, hyperlipidaemia, smoking habit, familial history, obesity), as well as determinants of tHcy levels. The population was subdivided into those having, or not, a substantial burden of traditional risk factors (i.e. < 4 and > or = 4, respectively). RESULTS: There was a significant trend towards a reduced number of subjects within the group with > or = 4 risk factors across increasing tHcy levels (51.7%, 37.8%, 26%, for normal, moderate, intermediate tHcy, respectively, chi2 for linear-trend = 0.006). Folate and vitamin B12 concentrations, estimated glomerular filtration rate (GFR), MTHFR 677C > T polymorphism were the major determinants of tHcy in this population. CONCLUSIONS: In patients with the same degree of CAD, those with hyperhomocysteinaemia had a reduced burden of traditional risk factors as compared with those with normal tHcy levels. Hyperhomocysteinaemia was significantly associated with an emerging non-traditional risk factor such as lower GFR.

Interaction between smoking and PON2 Ser311Cys polymorphism as a determinant of the risk of myocardial infarction.

BACKGROUND: Increased oxidative stress is thought to play a role in the pathogenesis of the atherothrombotic process. Paraoxonases (PONs) are closely related antioxidant enzymes encoded by clustered genes on chromosome 7q. We evaluated three PON polymorphisms (PON1 Leu55Met and Gln192Arg; PON2 Ser311Cys) as possible risk factors for coronary atherosclerotic disease (CAD) and/or its main thrombotic complication, myocardial infarction (MI). MATERIALS AND METHODS: We studied 890 subjects with angiographic documentation of coronary vessels (272=CAD-free; 618=CAD). In the CAD group, 341 subjects had a previous MI. RESULTS: Frequencies of various genotypes were not significantly different between CAD-free subjects and the entire CAD population. In the latter group, there were more carriers of the PON2 311Cys variation among those who had suffered a MI than among those who had not (P<0.01 by chi2). The adjusted OR for MI among PON2 311Cys carriers was 1.5 (95%CI, 1.03-2.19). A gene-environmental interaction was found between PON2 Ser311Cys and smoking. Smoking by itself was associated with an increased MI risk. Among smokers, however, the MI risk was related to PON2 genotype: Cys/Cys homozygotes (OR=5.3; 95%CI, 1.7-16.4) and Ser/Cys heterozygotes (OR=2.1; 95%CI, 1.3-3.6) were at greater risk than Ser/Ser subjects (OR=1.2; 95%CI, 0.8-1.8). The PON2 polymorphism did not influence the MI risk among nonsmokers. CONCLUSIONS: In CAD subjects, a proportion of the risk of MI may be influenced by the interaction between smoking and a polymorphism in the antioxidant enzyme PON2.

Clinical, biochemical and molecular findings in a series of families with hereditary hyperferritinaemia-cataract syndrome.

Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal dominant disease caused by mutations in the iron responsive element (IRE) of the l-ferritin gene. Despite the elucidation of the genetic basis, the overall clinical spectrum of HHCS has been less well studied as, to date, only individual case reports have been described. Therefore, we studied a total of 62 patients in 14 unrelated families, with nine different mutations. No relevant symptoms other than visual impairment were found to be associated with the syndrome. A marked phenotypic variability was observed, particularly with regard to ocular involvement (i.e. age range at which cataract was diagnosed in 16 subjects with the C39T: 6-40 years). Similarly, serum ferritin levels varied substantially also within subjects sharing the same mutation (i.e. range for the A40G: 700-2412 microg/l). We followed an HHCS newborn in whom well-defined lens opacities were not detectable either at birth or at 1 year. The lens ferritin content was analysed in two subjects who underwent cataract surgery at different ages, with different cataract morphology. Values were similar and about 1500-fold higher than in controls. These observations suggest that: (i) in HHCS the cataract is not necessarily congenital; (ii) in addition to the IRE genotype, other genetic or environmental factors may modulate the phenotype, especially the severity of the cataract.

Homozygosity for angiotensinogen 235T variant increases the risk of myocardial infarction in patients with multi-vessel coronary artery disease.

OBJECTIVE: Molecular variants of the angiotensinogen (AGT) and the angiotensin II type 1 receptor (ATR) genes have been associated with the risk of coronary artery disease (CAD) and myocardial infarction (MI), but data so far available are conflicting. The primary object of the paper is to verify this possible association by a rigorous, angiographically controlled study in a large sample of patients with or without multi-vessel CAD. DESIGN: We designed a large case-control study in Italian patients candidates for coronary artery bypass grafting, with angiographically documented multi-vessel CAD, compared to subjects with angiographically documented normal coronary arteries. METHODS AND RESULTS: AGT M235T and ATR A1166C gene polymorphisms were analysed in 699 subjects; 454 patients were candidates for coronary artery bypass grafting, having angiographically documented (mainly multi-vessel) CAD. An appropriate documentation of previous MI was obtained from 404/454 (89%, 247 with and 157 without MI). Subjects (n = 245) with angiographically documented normal coronary arteries, were included as control group (CAD-free group). CAD patients had a substantial burden of conventional risk factors as compared with controls free of coronary atherosclerosis. Age, gender, smoking habit and number of stenosed vessels were the only differences between patients with or without previous myocardial infarction, who were similarly exposed to the other conventional risk factors (including hypertension). AGT M235T and ATR A1166C allele and genotype frequencies were similar between CAD and CAD-free patients. In the CAD group, AGT 235T allele was found more frequently in subjects with a previous myocardial infarction (0.494 versus 0.414; P < or = 0.05). By logistic regression, homozygosity for AGT 235T variant appeared to confer 1.9-fold increased risk for MI in both the univariate and the multivariate (adjusted for age, gender, smoking habit and number of stenosed vessels) model. CONCLUSIONS: AGT 235 T homozygous patients with multivessel CAD have an increased risk of myocardial infarction as compared with subjects with clinically similar phenotype but different genotype.

Homocysteine and atheromatous renal artery stenosis.

Hyperhomocysteinemia is an independent risk factor for vascular disease, frequently observed in patients with severe renal impairment. Hyperhomocysteinemia has never been considered as a possible risk factor in renal artery stenosis. We investigated plasma folate and vitamin B12, methylenetetrahydrofolate reductase (MTHFR) C677T and cystathionine beta-synthase (CBS) 844ins68 polymorphisms, and homocysteine levels before and after methionine (100 mg/kg) loading in 58 patients with angiographically documented renal artery stenosis and mildly impaired renal function. One hundred and two normotensive subjects with angiographically normal coronary arteries and no history or clinical or angiographic evidence of atherosclerosis in other vascular districts, were considered as a control group. Mean total homocysteine levels were significantly higher in patients than in controls (P<0.01), as was the prevalence of hyperhomocysteinemia (51.7% vs. 32.3%, P<0.05). However, MTHFR alleles and genotypes as well as CBS 844ins68 mutation frequencies were similar in the two groups, whereas a lower folate level was observed in the patients. Moreover, patients with MTHFR A/A genotype showed a poorer folate status than control subjects, suggesting that a subclinical folate deficiency may be very frequent in renal artery stenosis, regardless of C677T mutation. In conclusions, hyperhomocysteinemia is common in patients with atheromatous renal artery stenosis; a subclinical folate deficiency seems to be involved, regardless of MTHFR thermolabile or CBS insertion genotypes. Folate supplementation might be useful in the management of overall vascular risk of these patients.

Severe multisystemic hypersensitivity reaction to carbamazepine including dyserythropoietic anemia.

OBJECTIVE: To report a case of multisystemic hypersensitivity reaction to carbamazepine. CASE SUMMARY: An 81-year-old white man was admitted to our hospital because of fever, morbilliform pruritic rash, and jaundice. Fifty days before admission he had taken carbamazepine 200 mg p.o. tid because of seizures. During the first few days following admission, a maculopapular rash progressed to generalized erythroderma with subsequent extensive skin exfoliation. After discontinuing carbamazepine the fever disappeared within 72 hours and hepatic function tests returned to normal within four days. Moreover, after admission the hemoglobin values gradually fell to 6.7 g/100 mL. A bone marrow aspirate showed hypercellularity with marked dyserythropoietic abnormalities, and the bone marrow biopsy showed large and diffused infiltration due to the presence of a low-grade small lymphocytic lymphoma. No specific therapy for the lymphoma was undertaken. The biochemical follow-up showed a total improvement of hemoglobin values. Eight months after drug discontinuation, the patient was asymptomatic; peripheral blood cell count and hemoglobin concentrations were persistently normal. DISCUSSION: To the best of our knowledge, this is the first published case report implicating carbamazepine as the cause of anemia associated with bone marrow hypercellularity and dyserythropoietic changes, instead of hypocellularity and reduction of erythroid precursors. An interesting point raised by our observation is the possible relation between carbamazepine intake and actual lymphoproliferative disease. The development of non-Hodgkin's lymphoma following carbamazepine treatment has been reported, with regression after the drug was discontinued. However, in our case, a bone marrow biopsy repeated eight months after drug discontinuation confirmed the diagnosis of low-grade lymphoma. CONCLUSIONS: This case report describes a severe multisystemic reaction, characterized by generalized erythroderma; and renal, hepatic, and bone marrow failure in a patient who started carbamazepine therapy 50 days beforehand.

Analysis of ferritins in lymphoblastoid cell lines and in the lens of subjects with hereditary hyperferritinemia-cataract syndrome.

Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal and dominant disease caused by heterogeneous mutations in the iron responsive element (IRE) of the 5' untranslated flanking region of ferritin L-chain mRNA, which reduce the binding to the trans iron regulatory proteins and make L-chain synthesis constitutively upregulated. In the several families identified so far, the serum and tissue L-ferritin levels are fivefold to 20-fold higher than in nonaffected control subjects, iron metabolism is apparently normal, and the only relevant clinical symptom is early onset, bilateral cataract. Some pathogenetic aspects of HHCS remain obscure, with particular reference to the isoferritins produced by HHCS cells, as well as the mechanism of cataract formation. We analyzed lymphoblastoid cell lines obtained from two nonaffected control subjects and from HHCS patients carrying the substitution A40G (Paris-1), G41C (Verona-1), and the deletion of the residues 10-38 (Verona-2) in the IRE structure. Enzyme-linked immunosorbent assays specific for the H- and L-type ferritins showed that L-ferritin levels were up to 20-fold higher in HHCS than in control cells and were not affected by iron supplementation or chelation. Sequential immunoprecipitation experiments of metabolically-labeled cells with specific antibodies indicated that in HHCS cells about half of the L-chain was assembled in L-chain homopolymers, which did not incorporate iron, and the other half was assembled in isoferritins with a high proportion of L-chain. In control cells, all ferritin was assembled in functional heteropolymers with equivalent proportion of H- and L-chains. Cellular and ferritin iron uptake was slightly higher in HHCS than control cells. In addition, we analyzed the lens recovered from cataract surgery of a HHCS patient. We found it to contain about 10-fold more L-ferritin than control lens. The ferritin was fully soluble with a low iron content. It was purified and partially characterized. Our data indicate that: (1) in HHCS cells a large proportion of L-ferritin accumulates as nonfunctional L-chain 24 homopolymers; (2) the concomitant fivefold to 10-fold expansion of ferritin heteropolymers, with a shift to L-chain-rich isoferritins, does not have major effects on cellular iron metabolism; (3) L-chain accumulation occurs also in the lens, where it may induce cataract formation by altering the delicate equilibrium between other water-soluble proteins (ie, crystallins) and/or the antioxidant properties.

Hereditary hyperferritinemia-cataract syndrome caused by a 29-base pair deletion in the iron responsive element of ferritin L-subunit gene.

Iron availability regulates ferritin synthesis posttranscriptionally by the interaction between iron-regulatory proteins (IRPs) and an iron responsive element (IRE), a stem-loop sequence located on the 5' untranslated region of ferritin mRNA. IRPs recognize IREs as a sequence/structure motif, blocking ferritin translation. Recently, we and others independently described families with a combination of hyperferritinemia (serum L-ferritin > or = 1,000 microg/L, without iron overload) and congenital bilateral cataract, transmitted as an autosomal-dominant trait. The molecular basis were two distinct point mutations in the highly conserved CAGUG(X) hexaloop of L-ferritin IRE on chromosome 19. A new three-generation family with a similar phenotype and a unique genotype is here reported. DNA amplification by polymerase chain reaction and sequence analysis showed a 29-base pair deletion in the L-ferritin IRE, involving the whole 5' sequence essential to the base pairing of the IRE stem. This deletion is predicted to cause the disruption of IRE stem-loop secondary structure and the nearly complete abolition of the negative control of ferritin synthesis by IRE/IRP binding. Hereditary Hyperferritinemia-Cataract Syndrome (HHCS) appears as a new genetic disorder with a unique phenotype associated with at least four different mutations in the L-ferritin IRE. Hematologists should take into account HHCS in the differential diagnosis of unexplained hyperferritinemia.

Mutation analysis of the HLA-H gene in Italian hemochromatosis patients.

Hemochromatosis (HH) is an inborn error of iron metabolism, frequent among Caucasians, characterized by progressive iron loading that, if untreated, causes high morbidity and death. HLA-H, a putative HH gene, has recently been isolated. The large majority of patients so far studied are homozygous for a single mutation, which results in a cysteine-to-tyrosine substitution at amino acid 282 of the protein. A second, less frequent, variant, His63Asp, has an undefined role in the pathogenesis of the disease. Here we report that the Cys282Tyr change accounts for 69% of HH chromosomes in a series of 75 unrelated Italian patients who fulfilled well-defined criteria for HH diagnosis. Sixty-four percent of patients were Cys282Tyr homozygous, 10% were heterozygous, and 21% carried the normal allele. The same mutation was rare in normal controls. The His63Asp variant was less frequent but had a similar frequency among affected and normal chromosomes. Subjects without two copies of the Cys282Tyr change were both isolated patients and individuals from families with a 6p-linked disease. Mutation analysis of the HLA-H gene, carried out by RNA-SSCP in the latter patients, did not reveal any significant nucleotide abnormality in coding sequences and intron-exon boundaries. The absence of mutations in HLA-H gene was confirmed in three cases by direct sequencing. Major deletions or rearrangements of the gene were excluded by Southern blotting. The existence of patients with clinical and histological features of HH, but without mutations in HLA-H gene, suggests that in Italy the disease is more heterogeneous than reported in northern Europe.

Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the "Verona mutation")

Recently, we described a new genetic disorder (the "hereditary hyperferritinemia-cataract syndrome") clinically characterized by the combination of elevated serum ferritin and congenital bilateral nuclear cataract, both cotransmitted as an autosomal dominant trait. In affected subjects, hyperferritinemia (ranging from 950 to 2,259 micrograms/L) is typically not related to iron overload. Differently from subjects with hereditary hemochromatosis, they have normal to low levels of serum iron and percent of transferrin saturation and absence of iron overload in parenchymal organs. When unnecessary phlebotomies are performed, they rapidly develop iron-deficient anemia, with persistently elevated levels of serum ferritin. By RNA-single-strand conformation polymorphism screening of the L-subunit ferritin gene on chromosome 19, we were able to identify in affected subjects a mutation in the 5' untranslated region. This mutation involves the five nucleotides sequence [CAGUG] of the iron-responsive element (IRE), which is critical for the posttranscriptional regulation of ferritin synthesis by means of IRE-binding protein (IRE-BP). Thus, it is very likely to provide the molecular basis for the iron-insensitive upregulation of ferritin synthesis in affected subjects.

Resistance to activated protein C in healthy women taking oral contraceptives.

Resistance to activated protein C (APC) is at present considered the most frequent laboratory abnormality in patients with deep-vein thrombosis. An increased risk for venous thrombosis is associated to the use of oral contraceptives (OC). We studied APC sensitivity in 50 healthy women taking OC and in 50 healthy controls, matched for age, smoking habit, educational and social levels, and the main biochemical routinary parameters. Subjects with a personal or familial history of thrombosis and also with chronic or acute diseases were excluded. Protein C, protein S, antithrombin III and lupus anticoagulant activity (LAC) were also evaluated. Increased fibrinogen and protein C levels, decreased protein S. and shortened PT and APTT were also observed in women taking OC. APC sensitivity ratio (APC-SR) was significantly lower in the OC group than in a control group (2.6 +/- 0.38 v 2.81 +/- 0.35, P < 0.01). Seven of eight women with APC ratio < or = 2 (APC resistant) were OC users: the difference of prevalence was statistically significant (chi-squared test, P < 0.05). Only two out of eight women were found heterozygous for the Leiden factor V mutation. Two APC-resistant women without the Leiden mutation subsequently discontinued OC and both then normalized their APC-SR. We conclude that acquired factors, i.e. oral contraceptives, may play an important role in determining plasma APC resistance.

PIP: During April-June 1994, at Borgo Roma Polyclinic in Verona, Italy, clinical researchers compared data on 50 healthy women 18-41 who used low-dose combined oral contraceptives (OCs) with data on 50 healthy women matched for age, smoking, education, social class, and biochemical routinary parameters. Almost all the subjects were medical students or medical staff working in the hospital where the study occurred. The researchers aimed to examine the prevalence of resistance to activated protein C (APC) in both groups. They also evaluated protein C, protein S, antithrombin III, and lupus anticoagulant activity. The APC-sensitivity ratio (APC-SR) was much lower in OC users than nonusers (2.6 vs. 2.81; p 0.01). Seven of the eight women with an APC-SR of no greater than 2 (i.e., demonstration of APC resistance) used OCs (p 0.05). Prevalence of APC resistance was higher among OC users than nonusers (14% vs. 2%; p 0.05). Among the eight women with APC resistance, two were heterozygous for the Leiden factor V mutation. One of these women used OCs and the other did not. Two APC resistant women who did not have the Leiden factor V stopped using OCs and their APC-SR subsequently normalized. OC users had higher fibrinogen and protein C levels, a lower protein S level, and shorter prothrombin and activated partial thromboplastin times than nonusers. These findings suggest that OCs may contribute to plasma APC resistance, which in turn increases the risk of venous thrombosis.

A linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract.

The only genetic disorder with elevated serum ferritin levels so far described is hereditary HLA-related haemochromatosis. On the other hand, hereditary cataract is both genotypically as well as phenotypically heterogenous, and no specific locus or any useful marker has been yet identified. We studied two Italian families in whom a combination of elevated serum ferritin not related to iron overload and congenital nuclear cataract is transmitted as an autosomal dominant trait. Affected individuals have normal serum iron and transferrin saturation, but high serum ferritin. Red cell counts are normal and venesection therapy rapidly produces iron-deficiency anaemia. This genetic disorder, which is characterized by hyperferritinaemia, differs from hereditary HLA-related haemochromatosis mostly for the absence of iron overload. A gene responsible for the congenital nuclear cataract likely maps on chromosome 19q close to the ferritin L-subunit gene. Within families with autosomal dominant congenital cataract, serum ferritin might be an early marker of disease.