42 research outputs found
Phosphomannomutase 2 (PMM2) variants leading to hyperinsulinism-polycystic kidney disease are associated with early-onset inflammatory bowel disease and gastric antral foveolar hyperplasia
Phosphomannomutase 2 (PMM2) deficiency causes Congenital Disorder of Glycosylation (PMM2-CDG), but does not have a recognised association with Inflammatory Bowel Disease (IBD). A distinct clinical syndrome of hyperinsulinism and autosomal recessive polycystic kidney disease (HIPKD) arises in the context of a specific variant in the PMM2 promotor, either in homozygosity, or compound heterozygous with a deleterious PMM2 variant. Here, we describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6, and 10 years of age. In each case, intestinal inflammation coincided with the unusual finding of gastric antral foveolar hyperplasia. IBD disease was of variable severity at onset but well controlled with conventional and first-line biologic treatment approaches. The organ-level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A). Analysis of published transcriptomic data suggests that IBD most likely arises due to an impact on epithelial cellular function. We identify a specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology
Syndromic Forms of Hyperinsulinaemic Hypoglycaemia A 15-year follow-up Study
OBJECTIVE: Hyperinsulinaemic hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in children. The molecular basis includes defects in pathways that regulate insulin release. Syndromic conditions like Beckwith-Wiedemann (BWS), Kabuki (KS) and Turner (TS) are known to be associated with a higher risk for HH. This systematic review of children with HH referred to a tertiary centre aims at estimating the frequency of a syndromic/multisystem condition to help address stratification of genetic analysis in infants with HH. METHODS: We performed a retrospective study of 69 patients with syndromic features and hypoglycaemia in a specialist centre from 2004 to 2018. RESULTS: Biochemical investigations confirmed HH in all the cases and several genetic diagnoses were established. Responsiveness to medications and the final outcome following medical treatment or surgery were studied. CONCLUSIONS: This study highlights the association of HH with a wide spectrum of syndromic diagnoses and that children with features suggestive of HH-associated syndromes should be monitored for hypoglycaemia. If hypoglycaemia is documented, they should also be screened for possible HH. Our data indicate that most syndromic forms of HH are diazoxide-responsive and that HH resolves over time; however a significant percentage continues to require medications years after the onset of the disease. Early diagnosis of hyperinsulinism and initiation of treatment is important for preventing hypoglycaemic brain injury and intellectual disability
Advancements in the Treatment of Cerebrovascular Complications of Cancer
Purpose of review: To present the new guidelines and therapeutic options regarding cerebrovascular complications of cancer, mainly ischemic stroke, cerebral venous thrombosis (CVT), and leptomeningeal carcinomatosis (LMC).
Recent findings: A temporal trend study (2019) revealed that clinicians are still reluctant to apply thrombolysis to cancer patients, although two new studies (2018) reported no increased mortality. Several clinical trials on direct oral anticoagulants (DOACs) showed their superiority or, at least, non-inferiority compared with low molecular weight heparins in the treatment of venous thromboembolism (VTE) (2018–2019). These trials helped in formulating the new guidelines that are being published and the decisions made for cancer-associated thrombosis (CAT) as a whole. A new DOAC antidote was also officially released (US 2018, Europe 2019). Summary: Thrombolysis is safe in a malignancy setting, thus cancer per se should not be considered a contraindication for thrombolysis. Clinical trials assessing the newest DOACs for cancer-associated arterial thrombosis are scarce; however, based on data from VTE studies, the newest DOACs seem to be safe for CAT in patients that are not in high risk of bleeding or suffering from certain malignancies. The treatment should not be ceased after 6 months, but rather continued as long as the cancer remains active. Decompressive craniectomy should maintain its place in patients with CVST in risk of herniation. Last, the future also holds much promise on the role of novel compounds to be used in LMC
Partial diazoxide responsiveness in a neonate with hyperinsulinism due to homozygous ABCC8 mutation
We report a case of partial diazoxide responsiveness in a child with severe congenital hyperinsulinaemic hypoglycaemia (CHI) due to a homozygous ABCC8 mutation. A term baby, with birth weight 3.8 kg, born to consanguineous parents presented on day 1 of life with hypoglycaemia. Hypoglycaemia screen confirmed CHI. Diazoxide was commenced on day 7 due to ongoing elevated glucose requirements (15 mg/kg/min), but despite escalation to a maximum dose (15 mg/kg/day), intravenous (i.v.) glucose requirement remained high (13 mg/kg/min). Genetic testing demonstrated a homozygous ABCC8 splicing mutation (c.2041-1G>C), consistent with a diffuse form of CHI. Diazoxide treatment was therefore stopped and subcutaneous (s.c.) octreotide infusion commenced. Despite this, s.c. glucagon and i.v. glucose were required to prevent hypoglycaemia. A trial of sirolimus and near-total pancreatectomy were considered, however due to the significant morbidity potentially associated with these, a further trial of diazoxide was commenced at 1.5 months of age. At a dose of 10 mg/kg/day of diazoxide and 40 µg/kg/day of octreotide, both i.v. glucose and s.c. glucagon were stopped as normoglycaemia was achieved. CHI due to homozygous ABCC8 mutation poses management difficulties if the somatostatin analogue octreotide is insufficient to prevent hypoglycaemia. Diazoxide unresponsiveness is often thought to be a hallmark of recessively inherited ABCC8 mutations. This patient was initially thought to be non-responsive, but this case highlights that a further trial of diazoxide is warranted, where other available treatments are associated with significant risk of morbidity. Learning points: Homozygous ABCC8 mutations are commonly thought to cause diazoxide non-responsive hyperinsulinaemic hypoglycaemia. This case highlights that partial diazoxide responsiveness in homozygous ABCC8 mutations may be present. Trial of diazoxide treatment in combination with octreotide is warranted prior to considering alternative treatments, such as sirolimus or near-total pancreatectomy, which are associated with more significant side effects
Variation in Glycemic Outcomes in Focal Forms of Congenital Hyperinsulinism - The UK Perspective
Context: In focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic β-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery. Objective: We describe surgical and nonsurgical outcomes of focal CHI in a national cohort. Methods: Patients with focal CHI were retrospectively reviewed at 2 specialist centers, 2003-2018. Results: Of 59 patients with focal CHI, 57 had heterozygous mutations in ABCC8/KCNJ11 (51 paternally inherited, 6 de novo). Fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography computed tomography scan identified focal lesions in 51 patients. In 5 patients, imaging was inconclusive; the diagnosis was established by frozen section histopathology in 3 patients, a lesion was not identified in 1 patient, and 1 declined surgery. Most patients (n = 56) were unresponsive to diazoxide, of whom 33 were unresponsive or partially responsive to somatostatin receptor analog (SSRA) therapy. Fifty-five patients underwent surgery: 40 had immediate resolution of CHI, 10 had persistent hypoglycemia and a focus was not identified on biopsy in 5. In the 10 patients with persistent hypoglycemia, 7 underwent further surgery with resolution in 4 and ongoing hypoglycemia requiring SSRA in 3. Nine (15% of cohort) patients (1 complex surgical access; 4 biopsy negative; 4 declined surgery) were managed conservatively; medication was discontinued in 8 children at a median (range) age 2.4 (1.5-7.7) years and 1 remains on SSRA at 16 years with improved fasting tolerance and reduction in SSRA dose. Conclusion: Despite a unifying genetic basis of disease, we report inherent heterogeneity in focal CHI patients impacting outcomes of both surgical and medical management
Using referral rates for genetic testing to determine the incidence of a rare disease: The minimal incidence of congenital hyperinsulinism in the UK is 1 in 28,389
This is the final version. Available from PLOS via the DOI in this record. Congenital hyperinsulinism (CHI) is a significant cause of hypoglycaemia in neonates and infants with the potential for permanent neurologic injury. Accurate calculations of the incidence of rare diseases such as CHI are important as they inform health care planning and can aid interpretation of genetic testing results when assessing the frequency of variants in large-scale, unselected sequencing databases. Whilst minimal incidence rates have been calculated for four European countries, the incidence of CHI in the UK is not known. In this study we have used referral rates to a central laboratory for genetic testing and annual birth rates from census data to calculate the minimal incidence of CHI within the UK from 2007 to 2016. CHI was diagnosed in 278 individuals based on inappropriately detectable insulin and/or C-peptide measurements at the time of hypoglycaemia which persisted beyond 6 months of age. From these data, we have calculated a minimum incidence of 1 in 28,389 live births for CHI in the UK. This is comparable to estimates from other outbred populations and provides an accurate estimate that will aid both health care provision and interpretation of genetic results, which will help advance our understanding of CHI.Wellcome Trus
Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism.
This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordData availability statement:
All non‐clinical data analysed during this study are included in this published article (and its
supplementary information files). Clinical and genotype data is available only through
collaboration as this can be used to identify individuals and so cannot be made openly
available. Requests for collaboration will be considered following an application to the
Genetic Beta Cell Research Bank (https://www.diabetesgenes.org/current‐research/genetic‐
beta‐cell‐research‐bank/). Contact by email should be directed to the Corresponding author.Code availability statement:
All code and software versions used specified in Methods.Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function1. This silencing is largely controlled by non-coding elements, and their disruption might cause human disease2. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1). HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a 'disallowed gene' in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene.Wellcome Trus
Epithelial ovarian tumors in adolescents: A retrospective pathologic study and a critical review of the literature
Objectives: The aim of this study was to further evaluate the pathologic features of epithelial ovarian neoplasms and their relative frequency among all ovarian tumors in the adolescent population. Design: We conducted a retrospective pathologic study of all cases of epithelial ovarian neoplasms in adolescents (aged 11-19 years) diagnosed in the pathology laboratory of our hospital over the past 25 years. Results: A total of 86 ovarian tumors were identified, including 23 epithelium-derived ovarian neoplasms (26.7%), 53 germ cell tumors (61.6%), 9 sex-cord stromal tumors (10.5%) and 1 benign Brenner tumor (1.2%). Most cases of epithelial tumors were found in patients 17 years of age or older (14/23 cases, 60.9%). All tumors were unilateral, and their size ranged from 2.5-21 cm (mean 11.7 cm). Epithelial tumors were further histologically subtyped into 21 benign cystadenomas (14 serous and 7 mucinous) and 2 mucinous borderline tumors. Conclusions: A relatively high frequency of epithelial ovarian neoplasms among all ovarian tumors in a purely adolescent population was found in our study. Age-related selection bias may account at least in part for the discrepancy between our data and most previous reports. The most common subtype of epithelial ovarian tumor in our series was the benign serous cystadenoma. © 2011 North American Society for Pediatric and Adolescent Gynecology
Myofibroblastoma of the Breast: Diagnostic Challenges of a Rare Benign Tumor
Breast myofibroblastomas (MFBs) are rare benign tumors that have recently been recognized as a distinct entity. They are more common in men and often coexist with gynecomastia. Fine needle aspiration cytology or core biopsy should always be performed for triple assessment; however, due to the multiple variants of the tumor, final diagnosis can be safely accomplished only postoperatively with the aid of immunohistochemistry. The main histological characteristic that differentiates MFBs from the majority of malignant mesenchymal breast lesions is the presence of spindle cells in a collagenous background. Low mitotic activity and vimentin and CD34 positivity have been reported as well. Surgical excision retains a pivotal diagnostic and curative role. Local resection is sufficient, but mastectomy can also be advocated either in cases of male patients with coexisting gynecomastia or in females with large tumors. Into this retrospective survey, three cases of breast MFB were consecutively enrolled. Two patients were postmenopausal females and one was male. Relevant literature is briefly reviewed. Clinical features, histogenesis, morphological, and immunochemical findings are discussed, while the role of the current diagnostic and therapeutic management of this uncommon neoplasm is emphasized. © 2013, Association of Surgeons of India
Recurrent episodes of syncope requiring pacemaker implantation as an initial presentation of neuromyelitis optica spectrum disorder
Neuromyelitis Optica Spectrum Disorders (NMOSD) can manifest with a variety of heterogeneous symptoms, mainly encompassing optic neuritis, acute myelitis and area postrema syndrome (hiccups, nausea, and vomiting). Syncopal episodes have rarely been described as an initial manifestation of NMOSD. Here, we report a case of a 42-year-old male who was diagnosed with NMOSD after initially presenting with intractable hiccups and recurrent episodes of syncope. This report is of particular interest, as it suggests that NMOSD should be included in the differential diagnosis of patients with intractable hiccups and heart rhythm disorders. © 202