Rodzinna częściowa lipodystrofia w diagnostyce różnicowej zespołu policystycznych jajników

  According to current diagnostic criteria, polycystic ovary syndrome (PCOS) is effective as a diagnosis of exclusion. Here, we present a case of a 31-year-old woman with a history of oligomenorrhoea and hirsutism, who, despite a “muscular” appearance and a normal body mass index (22.27 kg/m2), was found to have an extreme insulin resistance and diabetes accompanied by hyperandrogenism and polycystic ovaries. An autoimmune screen for possible latent autoimmune diabetes in adults was negative. She was subsequently found to have familial partial lipodystrophy (FPLD2, OMIM #151660) caused by an R482Q mutation in the LMNA gene encoding lamin A/C. This mutation results in arginine to glutamine substitution at the protein level, while phenotypically this condition presents with a loss of body fat, insulin resistance, dyslipidaemia, and other features mimicking PCOS. Interestingly her mother, with a history of myocardial infarction and diabetes at the age of 46 but no oligomenorrhoea, was also found to harbour the same mutation (LMNA R482Q). Conclusions: Our case highlights the importance of assessment of adipose tissue distribution, as well as a significance of assessment of glucose tolerance and insulin resistance in the differential diagnosis of PCOS. Furthermore, patients with atypical adipose tissue distribution should be referred for formal genetic testing. (Endokrynol Pol 2015; 66 (6): 550–554)    Według aktualnych kryteriów diagnostycznych, zespół policystycznych jajników (PCOS) jest rozpoznaniem z wykluczenia. W pracy przedstawiono przypadek 31-letniej kobiety z wywiadem zaburzeń miesiączkowania o typie rzadkich miesiączek oraz hirsutyzmu, u której mimo „muskularnego” wyglądu i prawidłowego wskaźnika masy ciała (22,27 kg/m2) stwierdzono bardzo wysoką insulinooporność, cukrzycę i hiperandrogenizm ze współistniejącą morfologią policystycystyczną jajników. Badania autoimmunologiczne w kierunku możliwej autoimmunologicznej cukrzycy u dorosłych (tzw. LADA) były ujemne. Przeprowadzono diagnostykę genetyczną, rozpoznając rodzinną lipodystrofię częściową spowodowaną przez mutację laminy A/C genu R842Q (FPLD2, OMIM # 151660). Powyższa mutacja prowadzi do podstawienia argininy glutaminą (R482Q) na poziomie białka, natomiast fenotypowo objawia się utratą tkanki tłuszczowej, insulinoopornością, dyslipidemią, jak również cechami naśladującymi PCOS. Co ciekawe u matki pacjentki również rozpoznano tę samą mutację (lamina A/C genu R842Q). U matki wystąpił również zawał serca i cukrzyca w wieku 46 lat, jednak nie było u niej zaburzeń miesiączkowania o typie oligomenorrhoea. Wnioski: Opisany przypadek podkreśla znaczenie oceny dystrybucji tkanki tłuszczowej, jak również znaczenie oceny tolerancji glukozy i insulinooporności w diagnostyce różnicowej PCOS. Autorzy pracy zalecają również, aby pacjentki z nietypowym rozkładem tkanki tłuszczowej były kierowane do dalszej diagnostyki genetycznej. (Endokrynol Pol 2015; 66 (6): 550–554)

Association of Maternal and Fetal Single-Nucleotide Polymorphisms in Metalloproteinase (MMP1, MMP2, MMP3, and MMP9) Genes with Preeclampsia

Background. Metalloproteinases (MMPs) play a pivotal role during the process of trophoblast invasion and placentation. The appearance of five functional single-nucleotide polymorphisms (SNP) in the genes of the metalloproteinases most commonly implicated in the implantation process may influence the development of preeclampsia. Methods. Blood samples were collected from 86 mothers and 86 children after preeclampsia and 85 mothers and 85 children with uncomplicated pregnancies. The distribution of genotypes for −1607 1G/2G MMP1, −735 C/T MMP2, −1306 C/T MMP2, −1171 5A/6A MMP3, and −1562C/T MMP9 polymorphisms was determined by RFLP-PCR. Results. The occurrence of 1G/1G MMP1 or 5A/5A MMP3 genotype in the mother or 1G/1G MMP1 or 5A/6A MMP3 genotype in the child is associated with preeclampsia development. Moreover, simultaneous maternal and fetal 1G/1G homozygosity increases the risk of preeclampsia development 2.39-fold and the set of maternal 5A/5A and fetal 5A/6A MMP3 genotypes by over 4.5 times. No association between the carriage of studied MMP2 or MMP9 polymorphisms and the predisposition to preeclampsia was found. Conclusion. The maternal 1G/1G MMP1 and 5A/5A MMP3 and fetal 1G/1G MMP1 and 5A/6A MMP3 gene polymorphisms may be strong genetic markers of preeclampsia, occurring either individually or together

Association between idiopathic recurrent pregnancy loss and genetic polymorphisms in cytokine and matrix metalloproteinase genes

Objectives: Recurrent reproductive loss (RPL) is a global health issue affecting a significant number of women. Approximately half of miscarriages have an unexplained etiology. Familial aggregation and twins studies prove that some cases of the RPL could have a genetic background. Recent evidences suggest that cytokines (e.g. IL-6, TNF alpha or TGF beta) and matrix metalloproteinases (MMP) are important for maintenance of pregnancy. Single gene polymorphisms (SNP), affecting these proteins production or their function may predispose to the loss of the pregnancy. The aim of this study was to evaluate the association between the following polymorphisms of IL6 (rs1800795), TNF (rs1800629), TGFB1 (rs1800471), MMP1 (rs1799750), MMP2 (rs2285053 and rs243865), MMP3 (rs35068180), MMP9 (rs3918242) and the recurrent pregnancy loss in polish population.Material and methods: Study subjects comprised of 67 patients with a history of recurrent pregnancy loss (≥ 2 miscarriages in history) and 75 controls. The distribution of genotypes for selected polymorphisms were determined by RFLP-PCR.Results: Maternal genotypes GG TNF, or 5A/5A MMP3 may be associated with the recurrent pregnancy loss. No association between the IL6, TGFB1, MMP1, MMP2, or MMP9 studied polymorphisms and the predisposition to miscarriage was found.Conclusions: This study demonstrated a possible association between rs1800629 TNF, rs35068180 MMP3 polymorphisms and recurrent pregnancy loss

Resistance to thyroid hormone due to a novel mutation in the thyroid beta receptor (THRβ) gene coexisting with autoimmune thyroid disease—A case report

Resistance to thyroid hormone (RTH) is a syndrome characterized by impaired responsiveness of target tissues to thyroid hormones. The relationship between RTHβ and thyroid autoimmunity has been under research. In this study, we demonstrate a case report of a woman with a novel mutation in THRβ gene coexisting with autoimmune thyroid disease (AITD). The 36-year-old woman has been treated since childhood for a thyroid disease. Based on high levels of thyroid hormones (THs) and elevated concentrations of thyroperoxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively), she received unnecessary long-term treatment with methimazole and finally underwent subtotal thyroidectomy. After the surgery, her TSH level remained significantly elevated, despite the treatment with 150 + 15 µg of thyroxine and triiodothyronine. A sequence analysis of the THRβ gene revealed a novel dinucleotide substitution affecting codon 453, resulting in the replacement of the normal proline with an asparagine (c.1357_1358delinsAA, p.(Pro453Asn)). The mutation has not been described in the literature yet; however, THRβ codon 453 represents a mutational hot spot, frequently altered in the TH receptor ß gene. After establishing the diagnosis of RTH, the patient was treated with 300 µg of thyroxine, which showed clinical improvement and normalization of TSH. The coexistence of RTHβ and AITD may additionally impede establishment of a proper diagnosis, leading to unnecessary therapy and delayed correct treatment. The presented case encourages a closer cooperation between clinical endocrinologists and geneticists

NGS analysis of collagen type I genes in Polish patients with Osteogenesis imperfecta: a nationwide multicenter study

Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue. It presents with a wide spectrum of skeletal and extraskeletal features, and ranges in severity from mild to perinatal lethal. The disease is characterized by a heterogeneous genetic background, where approximately 85%–90% of cases have dominantly inherited heterozygous pathogenic variants located in the COL1A1 and COL1A2 genes. This paper presents the results of the first nationwide study, performed on a large cohort of 197 Polish OI patients. Variants were identified using a next-generation sequencing (NGS) custom gene panel and multiplex ligation probe amplification (MLPA) assay. The following OI types were observed: 1 (42%), 2 (3%), 3 (35%), and 4 (20%). Collagen type I pathogenic variants were reported in 108 families. Alterations were observed in α1 and α2 in 70% and 30% of cases, respectively. The presented paper reports 97 distinct causative variants and expands the OI database with 38 novel pathogenic changes. It also enabled the identification of the first glycine-to-tryptophan substitution in the COL1A1 gene and brought new insights into the clinical severity associated with variants localized in “lethal regions”. Our results contribute to a better understanding of the clinical and genetic aspects of OI

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life