Hereditary haemochromatosis: Prevalence and characterization of the disease in a tertiary hospital in Aragon.

BACKGROUND: The main genetic cause of iron overload is haemochromatosis (HC). In recent years, the study of non-HFE genes (HFE2, HJV, HAMP, TRF2, SLC40A1, and BMP6) has become relevant thanks to next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) techniques. Our objectives were to estimate the prevalence of both HFE (C282Y/HY63D variants) and non-HFE variants attending a tertiary hospital in Aragón, to predict the effect of the variants on the protein, and to establish a genotype-phenotype correlation evaluating with the clinical context. METHODS: Retrospective descriptive study from 2006 to 2020 of patients attended at genetic consultation in a reference hospital for HC in Aragon. We calculated prevalence of HFE and non-HFE variants. We analysed non-HFE genes (HFE2, HJV, HAMP, TRF2, SLC40A1, and BMP6), used bioinformatics tools, consulted different databases and measured clinical parameters (laboratory and imaging). RESULTS: The prevalence of C282Y homozygous was 5.95% respect the total of cases and 0.025% respect our population. The prevalence of non-HFE HC variants was 1.94% respect the total of cases and 0.008% respect our population. We found 27 variants in non-HFE genes and 4 in HFE gene, of which 6 were classified as variant of uncertain clinical significance (VUS), or likely pathogenic or pathogenic according to the ACMG classification criteria. CONCLUSION: Our prevalence results are as expected, and similar to those obtained by other studies. Although some of the genetic findings explain the clinical symptoms of some of our patients, we remain have a high number of patients without a clear molecular diagnosis.

Effects of antidiabetic drugs on bone metabolism.

Objectives: The prevalence of diabetes mellitus type 2 (DMT2) is increasing exponentially worldwide. DMT2 patients have been found to be at a higher risk for bone fractures than the healthy population. Hence, improving our understanding of the impact of antidiabetic drugs on bone metabolism is crucial. Methods: A descriptive, retrospective study involving 106 patients receiving six groups of antidiabetic drugs: insulin; dipeptidylpeptidase four inhibitors (DPP4i); glucagon-like peptide type 1 receptor agonists (GLP1ra); sulfonylureas; sodium-glucose cotransporter two inhibitors (SGLT2i); and pioglitazone, in which osteocalcin (OC), bone alkaline phosphatase (BAP) and C-terminal telopeptide of collagen type 1 or beta-crosslaps (ß-CTx) were determined. Results: ß-CTx concentrations were higher in the patients treated with pioglitazone, as compared to patients treated with DPP4i (p=0.035), SGLT2i (p=0.020) or GLP1ra (p<0.001). The lowest ß-CTx concentrations were observed in the patients treated with GLP1ra. Conclusions: Bone remodeling is influenced by the type of antidiabetic drug administered to DMT2 patients. In our study, the patients who received pioglitazone showed higher ß-CTx concentrations, as compared to patients treated with other types of antidiabetic drugs. This finding highlights the convenience of avoiding these drugs, especially in postmenopausal women with DMT2. GLP1ra drugs were associated with the lowest ß-CTx concentrations, which suggests that these agents could exert beneficial effects on bone metabolism.

Analysis of the reasons for requesting HIV serology in the emergency department other than those defined in the targeted screening strategy of the "Urgències VIHgila" program and its potential inclusion in a future consensus document.

OBJECTIVE: To describe other reasons for requesting HIV serology in emergency departments (ED) other than the 6 defined in the SEMES-GESIDA consensus document (DC-SEMES-GESIDA) and to analyze whether it would be efficient to include any of them in the future. METHODS: Review of all HIV serologies performed during 2 years in 20 Catalan EDs. Serologies requested for reasons not defined by the DC-SEMES-GESIDA were grouped by common conditions, the prevalence (IC95%) of seropositivity for each condition was calculated, and those whose 95% confidence lower limit was >0.1% were considered efficient. Sensitivity analysis considered that serology would have been performed on 20% of cases attended and the remaining 80% would have been seronegative. RESULTS: There were 8044 serologies performed for 248 conditions not recommended by DC-SEMES-GESIDA, in 17 there were seropositive, and in 12 the performance of HIV serology would be efficient. The highest prevalence of detection corresponded to patients from endemic countries (7.41%, 0.91-24.3), lymphopenia (4.76%, 0.12-23.8), plateletopenia (4.37%, 1.20-10.9), adenopathy (3.45%, 0.42-11.9), meningoencephalitis (3.12%, 0.38-10.8) and drug use (2.50%, 0.68-6.28). Sensitivity analysis confirmed efficiency in 6 of them: endemic country origin, plateletopenia, drug abuse, toxic syndrome, behavioral-confusional disorder-agitation and fever of unknown origin. CONCLUSION: The DC-SEMES-GESIDA targeted HIV screening strategy in the ED could efficiently include other circumstances not previously considered; the most cost-effective would be origin from an endemic country, plateletopenia, drug abuse, toxic syndrome, behavioral-confusional-agitation disorder and fever of unknown origin.

No increase in the CTG repeat size during transmission from parent with expanded allele: false suspicion of contraction phenomenon.

Objectives: Myotonic dystrophy type 1 (DM1), also known as Steinert's disease, is a chronic, progressive and disabling multisystemic disorder with a broad spectrum of severity that arises from an autosomal-dominant expansion of the Cytosine-Thymine-Guanine (CTG) triplet repeat in the 3' untranslated region of the DMPK gene (19q13.3). Case presentation: In this study, we report the case of a family with several intergenerational expansions of the CTG repeat, with an additional case of a false suspicion of contraction phenomenon due to TP-PCR limitations. Conclusions: The meiotic instability of the (CTG)n repeats leads to genetic anticipation where increased size of DM1 mutation and a more severe phenotype have been reported in affected individuals across generations. Even if extremely rare, a decrease in the CTG repeat size during transmission from parents to child can also occur, most frequently during paternal transmissions.

Association Between VDR and CYP24A1 Polymorphisms, Atopic Dermatitis, and Biochemical Lipid and Vitamin D Profiles in Spanish Population: Case-Control Study.

BACKGROUND: Atopic dermatitis (AD) is the most prevalent inflammatory skin disorder, characterized by impaired epidermal barrier function and an altered immune response, both of which are influenced by vitamin D deficiency. Single-nucleotide polymorphisms (SNPs) in VDR and CYP24A1 have been previously associated with AD. OBJECTIVE: We sought to characterize the associations between the VDR and CYP24A1 polymorphisms and the vitamin D and lipid biochemical profile in children diagnosed with AD. METHODS: A total of 246 participants (143 patients with AD and 103 healthy controls) were enrolled in this study. Genotyping for polymorphisms in VDR (rs2239185, rs1544410, rs7975232, rs2238136, rs3782905, rs2239179, rs1540339, rs2107301, rs2239182, and rs731236) and CYP24A1 (rs2248359 and rs2296241) was performed by allele-specific polymerase chain reaction using integrated fluidic circuit technology. Serum levels of calcium, phosphorus, and vitamin D were measured, and the biochemical lipid profile was determined. RESULTS: Among VDR SNPs, rs2239182 exerted a protective effect against the development of AD, whereas rs2238136 was identified as a risk factor for AD. The GCC haplotype (rs2239185-G, rs1540339-C, and rs2238136-C) appeared to protect against the development of AD. rs2239182-CC was associated with higher 25(OH)D concentrations, whereas rs2238136-TT, rs2239185-GA, and rs2248359-TT were present in a large proportion of patients with serum vitamin D deficiency. rs2239185-AA, rs2239182-CC, and rs1540339-CC were associated with higher serum total cholesterol; rs2239182-TT was associated with lower low-density lipoprotein cholesterol; and rs2239182-TC with lower high-density lipoprotein cholesterol. Both CYP24A1 SNPs (rs2296241-AA and rs2248359-TT) were associated with higher high-density lipoprotein cholesterol levels. CONCLUSIONS: The VDR SNP rs2238136 is a risk factor for AD and other SNPs in VDR and CYP24A1, which may lead to alterations in biochemical parameters that influence the risk of AD. Our findings highlight the complex genetic basis to AD and indicate that interrelationships between different genetic factors can lead to alterations in vitamin D metabolism or lipid profiles, which in turn may influence the development of AD.

First case of very late-onset FHL2 in Spain with two variants in the PRF1 gene.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal disorder characterized by the proliferation and infiltration of macrophages and hyperactivated T lymphocytes that escape from the physiological control pathways and favour the existence of an environment of excessive inflammation and tissue destruction. HLH has been classified into two types: a primary or familial autosomal recessive form, caused by mutations in genes encoding proteins involved in the granule-dependent cytotoxic pathway (familial hemophagocytic lymphohistiocytosis [FHL] types 1-5); and other secondary or acquired form, generally associated with infections, malignancy, autoimmune diseases, metabolic disorders or primary immunodeficiencies. Since the first familial hemophagocytic lymphohistiocytosis-2 (FHL2) causative mutation in the PRF1 gene was described in 1999, more than 200 mutations have been identified to date. Here, we report the first case of very late-onset FHL2 in a Spanish 72-year-old female with splenomegaly, hypertriglyceridemia, hypofibrinogenemia, pancytopenia and marrow hemophagocytosis harbouring in heterozygosity two PRF1 variants proposed as causative in this study. The heterozygous mutation c.445G>A (p.Gly149Ser) identified in the exon 2 results in a missense mutation previously described as a probable pathogenic variant associated with the development of FHL2. Affecting the same exon, c.272C>T (p.Ala91Val) is the most prevalent variant of this gene. Although it was initially classified as benign, recent studies support its potential pathogenic role, considering it a variant of uncertain significance associated with a risk of developing FHL2. The genetic confirmation of FHL made possible an adequate counselling to the patient and direct relatives and provided important information for her control and follow-up.

Hereditary hemochromatosis: An update vision of the laboratory diagnosis.

Haemochromatosis (HC) is an inherited disorder of iron metabolism. The 85-90% of Hereditary hemochromatosis cases are caused by mutations in HFE gene (HC type 1). The remaining 10-15% of HC cases are caused by mutations in other non-HFE genes (HJV, HAMP, TRF2, SLC40A1, BMP6). The study of patients for the diagnosis of HC has an important laboratory approached: analysis of biochemical parameters and genetic studies. To confirm a case, it is necessary to carry out a genetic study of the C282Y and H63D mutations. The presence of C282Y mutation in homozygosis is compatible with the diagnosis of HC type 1. Due to the incomplete penetrance of this mutation and the variable phenotypic expression, the severe forms of the disease are relatively rare. The study of variants in non-HFE genes allows more detailed study of both non-classic HC cases and those with more severe clinical expression. The genotype characterization of a patient not always justified the phenotype expression of the symptoms in this disease. All laboratory clinicians must consider recommendation provide by the experts in the Materia.

A novel pathogenic variant in LCAT causing FLD. A case report.

BACKGROUND: Fish-eye disease (FED) is due to a partial deficiency in LCAT activity. Nevertheless, Familial lecithin-cholesterol acyltransferase deficiency (FLD), also called Norum disease, appears when the deficiency is complete. They are both rare genetic disorders inherited in an autosomal recessive manner. Clinical signs include decreased circulating HDL cholesterol and dense corneal opacity. Kidney injuries also affect patients suffering from FLD. The diagnosis of FLD is based on the presence of characteristic signs and symptoms and confirmed by genetic testing. CASE PRESENTATION: We present a case of a 63-year-old man showing an altered lipid profile with low HDL cholesterol, chronic kidney disease (CKD) and corneal disorders. He was referred to genetic counseling in order to discard genetic LCAT deficiency due to decreased visual acuity caused by corneal opacity. A massive DNA sequencing was conducted using a multigene panel associated with lipid metabolism disturbances. RESULTS AND GENETIC FINDINGS: Two likely pathogenic variants in LCAT were identified and later confirmed by Sanger sequencing. Both (c.491 G > A and c.496 G > A) were missense variants that originated an amino acid substitution (164Arginine for Histidine and 166Alanine for Threonine, respectively) modifying the protein sequence and its 3D structure. CONCLUSIONS: FLD and FED sharing common biochemical features, and the existence of other diseases with similar clinical profiles underline the need for a timely differential diagnosis aiming to address patients to preventive programs and future available therapies. This case, added to the reduced number of publications previously reported regarding FLD and FED, contributes to better understanding the genetic characteristics, clinical features, and diagnosis of these syndromes.

Acute cholestatic hepatitis probably associated with risperidone.

OBJECTIVE: Risperidone is an atypical neuroleptic drug widely used due to the lower incidence and severity of hepatic adverse effects in comparison to phenothiazines. Although idiosyncratic reversible hepatotoxicity may occur in association with risperidone, the interaction with fluoxetine might increase the risk of toxic liver injury in a vulnerable patient. METHODS AND RESULTS: We present a case of acute cholestatic hepatitis probably associated with the use of risperidone after only a few days of therapy in a patient also treated with fluoxetine. The patient, a 64-year-old male, developed a rapid increase in liver enzymes after starting treatment with only four doses of risperidone 2 mg/day. CONCLUSIONS: We recommend obtaining baseline liver function tests before starting risperidone and regular monitoring to screen patients for liver damage during therapy whenever a patient is also receiving fluoxetine.

Factores asociados con displasia de alto grado y cáncer en adenomas colorrectales / Associated factors with high grade dysplasia and cancer in colorectal adenomas

Con el objetivo de determinar los factores de riesgo asociados a displasia de alto grado(DAG) y cáncer (CA), se estudiaron en forma prospectiva todos los pólipos colorrectados durante un período de dos años y medio (6/91 a 12/93). Las variables analizadas fueron: edad, sexo y síntomas de presentación de los pacientes y números, localización, tamaño e histología de los pólipos. Los adenomas fueron clasificados de acuerdo con el porcentaje de componente velloso en: tubulares y vellosos A (1 por ciento-25 por ciento de componente velloso), vellosos B (26 por ciento-75 por ciento), vellosos C (76 por ciento-99 por ciento) y vellosos D (100 por ciento). Se resecaron 100 pólipos en 67 pacientes (1.49 pólipos/paciente). La edad promedio fue 63.9 +/- 10.3 años y 47 eran hombres (70 por ciento). El motivo de consulta más frecuente fue la hematoquezia (46 por ciento) y todos estos pacientes presentaron pólipos en recto y colon sigmoides. Noventa y tres (93 por ciento) pólipos fueron adenomas: tubulares 40 (43 por ciento), vellosos A 17 (18 por ciento). velloso B 16 (17 por ciento), vellosos C 12 (13 por ciento) y vellosos D 8 (9 por ciento); 5 (5 por ciento) hiperplásicos, 1 (1 por ciento) hamartoma y 1 (1 por ciento) inflamatorio. Del total de los adenomas, tenían focos de adenocarinoma 10 (11 por ciento), displasia leve 28 (30 por ciento), moderada 42 (45 por ciento) y DAG 20 (14 por ciento). El 20 por ciento de los adenomas vellosos C Y D tenían CA contra el 3.6 por ciento de los vellosos A (p:adenomas vellosos C y D tenían DAG contra el 10.7 por ciento de los vellosos A (p:pólipos con DAG fue 1.78 +/- 0.6 cm y el los sin DAG, 1.28 +/- 0.7 cm (NS). No se observaron complicaciones de la polipectomía. Concluimos que los pólipos predominaron en el sexo masculino con una relación 2 a 1 y que los pólipos se localizaban en rectosigma en los pacientes que consultaron por hematoquezia. La displasia de alto grado y el cáncer se asociaron significativamente al porcentaje de componente velloso del pólipo, pero no a su tamaño ni a la edad y sexo de los pacientes. (AU)

Factores asociados con displasia de alto grado y cáncer en adenomas colorrectales / Associated factors with high grade dysplasia and cancer in colorectal adenomas

Con el objetivo de determinar los factores de riesgo asociados a displasia de alto grado(DAG) y cáncer (CA), se estudiaron en forma prospectiva todos los pólipos colorrectados durante un período de dos años y medio (6/91 a 12/93). Las variables analizadas fueron: edad, sexo y síntomas de presentación de los pacientes y números, localización, tamaño e histología de los pólipos. Los adenomas fueron clasificados de acuerdo con el porcentaje de componente velloso en: tubulares y vellosos A (1 por ciento-25 por ciento de componente velloso), vellosos B (26 por ciento-75 por ciento), vellosos C (76 por ciento-99 por ciento) y vellosos D (100 por ciento). Se resecaron 100 pólipos en 67 pacientes (1.49 pólipos/paciente). La edad promedio fue 63.9 +/- 10.3 años y 47 eran hombres (70 por ciento). El motivo de consulta más frecuente fue la hematoquezia (46 por ciento) y todos estos pacientes presentaron pólipos en recto y colon sigmoides. Noventa y tres (93 por ciento) pólipos fueron adenomas: tubulares 40 (43 por ciento), vellosos A 17 (18 por ciento). velloso B 16 (17 por ciento), vellosos C 12 (13 por ciento) y vellosos D 8 (9 por ciento); 5 (5 por ciento) hiperplásicos, 1 (1 por ciento) hamartoma y 1 (1 por ciento) inflamatorio. Del total de los adenomas, tenían focos de adenocarinoma 10 (11 por ciento), displasia leve 28 (30 por ciento), moderada 42 (45 por ciento) y DAG 20 (14 por ciento). El 20 por ciento de los adenomas vellosos C Y D tenían CA contra el 3.6 por ciento de los vellosos A (p:adenomas vellosos C y D tenían DAG contra el 10.7 por ciento de los vellosos A (p:pólipos con DAG fue 1.78 +/- 0.6 cm y el los sin DAG, 1.28 +/- 0.7 cm (NS). No se observaron complicaciones de la polipectomía. Concluimos que los pólipos predominaron en el sexo masculino con una relación 2 a 1 y que los pólipos se localizaban en rectosigma en los pacientes que consultaron por hematoquezia. La displasia de alto grado y el cáncer se asociaron significativamente al porcentaje de componente velloso del pólipo, pero no a su tamaño ni a la edad y sexo de los pacientes.