Henry's Clinical Diagnosis And Management By La...

Background: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition.

Henry's Clinical Diagnosis and Management by La...

Results: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded.

The international BWS consensus group comprised 41 participants from 36 institutions across 11 countries, predominantly based in Europe, including clinicians, clinical and research scientists and patient group representatives with expertise in different aspects of BWS (clinical and molecular geneticists, paediatric endocrinologists, oncologists, orthopaedists, oro-facial surgeons and nephrologists). A modified Delphi consensus process was adopted4. Discussions occurred via conference calls, email communications and file exchanges. Two face-to-face meetings were held: a preliminary meeting of 11 participants (including one patient group representative) in February 2016 to identify the key issues to be addressed by the consensus group and a plenary 3-day meeting involving 35 participants (including 2 patient group representatives) in March 2017. During this plenary meeting, experts participated in one of the three subgroups (clinical, molecular or management) on the basis of their field of expertise, discussed the draft consensus documents and formulated and voted on the consensus recommendations (Box 1). This Consensus Statement summarizes the outcome of these discussions and is divided into three subject areas: clinical aspects; molecular aspects; and care and management.

BWS has classically been characterized by macroglossia, macrosomia, abdominal wall defects and an increased risk of embryonal tumours11,12,13,14,15,16,17. There is growing recognition that not all patients with BWS display all of these phenotypic features and that patients have remained undiagnosed because they did not present with one of these features, such as macrosomia, which was initially considered as a cardinal feature but is present in only one-half of the patients with an 11p15.5 molecular defect18,19. The clinical features outlined as part of the consensus BWSp scoring system include features that, when present, are more likely to lead to a positive diagnosis (termed 'cardinal features'), including macroglossia, exomphalos, lateralized overgrowth, multifocal Wilms tumour or nephroblastomatosis, hyperinsulinism and specific pathology findings (such as adrenal cytomegaly or placental mesenchymal dysplasia) (Box 2). Macrosomia has been defined according to different criteria in different clinical cohorts11,12,13,15,16,17, making it challenging to assess the role it has as a cardinal feature. Lateralized overgrowth is the novel term for hemihypertrophy (or hemihyperplasia), which is defined as asymmetric overgrowth of part of the body10. Embryonal tumours such as Wilms tumours and hepatoblastoma can occur outside of the diagnostic scope of BWSp; however, multifocal Wilms tumours are more likely to occur in BWSp. As a cardinal feature, hyperinsulinism is defined as prolonged hypoglycaemia in the context of elevated insulin levels that last >1 week and/or require escalated treatment20, while transient hypoglycaemia resolves without the need for further intervention. Although pathology findings cannot always be evaluated (especially when BWSp is not suspected prenatally or at birth and when placental samples are not collected), the diagnosis of BWSp should be considered in cases of adrenal cortex cytomegaly, placental mesenchymal dysplasia and pancreatic adenomatosis5. Additionally, if samples are available (especially from the placenta after birth) and the diagnosis is being considered, pathological investigation can be beneficial in making the clinical diagnosis.

The many previously proposed systems to define BWS have suggested various combinations of clinical features (with macroglossia, exomphalos and/or (asymmetric) overgrowth as major features)11,12,13,18,21,22 with the aim of optimizing the likelihood of a classical and molecularly confirmed diagnosis. Frequently cited and recent phenotype articles from the past 25 years were reviewed for the prevalence of individual clinical features (Supplementary information S1 (table)), which were then classified as cardinal or suggestive features (Box 2). As several of these articles referenced the same patient cohorts12,13,14,15,16,18,21,22,23,24,25,26, data were analysed from the nine articles describing apparently distinct cohorts11,12,14,15,18,21,23,25,26. The goal of this BWSp scoring system (Table 1; Box 2) was to recognize that BWS falls into a clinical spectrum and that some features that have long been considered to be classical parts of the syndrome are not present in every patient, and therefore, the diagnosis should not be dismissed owing to the absence of such features. Additionally, this Consensus Statement sought to include elements that could be pathognomonic for BWS. In addition to informing the presence of a diagnosis of classical BWS, the consensus group also determined that the same system could be used to provide guidance regarding when to pursue genetic testing. We compared this new scoring system with previously published systems (Supplementary information S2 (figure)) while keeping in mind that previous systems focused on the diagnosis of classical BWS and molecularly confirmed BWS and not the diagnosis of the BWSp.

Cardinal features are considered key to the clinical diagnosis, whereas suggestive features add to the likelihood of a clinical diagnosis and the indications for molecular testing but are less specific (Box 2). Cardinal and suggestive feature designations were analysed in the BWSp cohort reported by Ibrahim et al.11 and were shown to be largely superior to previous diagnostic systems (Supplementary information S2 (figure)). Limitations of the study were that transient hypoglycaemia versus prolonged hyperinsulinism were not typically distinguished in the prior cohorts, so this feature could therefore not be assessed, and that macrosomia was variably defined in previous cohorts11,12,13,14,17,18,21,22.

Clinical diagnosis within the BWSp beyond the clear diagnosis of classical BWS or a clear molecular diagnosis is challenging and requires a combination of molecular testing and physician opinion. There is currently not enough published data to provide clear clinical recommendations for patients with a score of

First-line molecular testing procedures should assay IC1 and IC2 methylation (Table 2, R9). Methylation is abnormal in cases of IC2 LOM, IC1 GOM, copy number variations (CNVs) and segmental upd(11)pat (both IC2 LOM and IC1 GOM)51. Abnormal methylation status confirms a diagnosis of BWSp, but its underlying mechanism must be established to define management, genetic counselling and recurrence risks48,51. Thus, if methylation is assayed using a technique that does not estimate DMR copy number, this should then be determined in all patients with IC1 and/or IC2 methylation abnormalities (Fig. 2). Currently, methylation-specific (MS) multiplex ligation-dependent probe amplification (MS-MLPA) is the most common diagnostic test, as it simultaneously detects DMR methylation status and copy number; however, other techniques (such as MS-PCR and MS quantitative PCR) are more sensitive in patients with low-level mosaicism (for a detailed list, see Refs 51,52,53,54 and the references within).

When a prenatal diagnosis of BWSp is suspected or confirmed, the management of individual congenital anomalies (for example, exomphalos or cardiac defect) generally follows standard protocols based on usual local practices. However, macrosomia might cause problems (for example, shoulder dystocia) at delivery, and therefore, growth should be carefully monitored in the latter stages of pregnancy and appropriate arrangements for delivery should be made (Table 4, R23,24). BWSp is also associated with polyhydramnios and premature birth. Potential post-delivery complications such as neonatal hypoglycaemia, respiratory obstruction from macroglossia, surgical repair of exomphalos and so on should be anticipated, and appropriate monitoring and facilities should be put in place.

The recommendations of the first international BWS consensus group described in this Consensus Statement provide a framework for improving the diagnosis and management of BWSp. As BWSp is characterized by complex genetics and variable multisystem phenotypes, it is important that a lead clinician is identified for each patient (Table 4, R22) to ensure coordination of the numerous aspects of care throughout childhood (Supplementary information S5 (table)). The proposed diagnostic and care pathways are intended to be practical and cost-effective (for example, targeting tumour surveillance to high-risk groups should reduce costs compared with universal surveillance strategies). Nevertheless, in some health-care systems and medicolegal environments, further evidence might be required to shift clinical practice (for example, tumour surveillance in North America). Thus, it is important that implementation of these consensus recommendations be accompanied by prospective audits in order to expand the evidence base for future consensus initiatives. 041b061a72