The simple virilizing (SV) form of 21-hydroxylase deficiency (21-OHD) is primarily characterized by androgen excess. Gonadal dysfunction is widely acknowledged; however, systemic complications, including renal injury, are often overlooked. This report presents a rare case involving a 25-year-old female diagnosed with SV 21-OHD, who subsequently experienced unanticipated renal insufficiency and secondary polycythemia. Genetic analysis confirmed compound heterozygous mutations in the CYP21A2 gene. The patient demonstrated significant hyperandrogenemia and polycythemia driven by erythropoietin. Following erythrocytapheresis and glucocorticoid replacement therapy, androgen levels normalized, resulting in marked renal function recovery and resolution of polycythemia. This case and a mechanistic review illustrate the potential interplay between chronic hyperandrogenism, erythropoiesis dysregulation, and kidney injury, underscoring the importance of timely hormonal management for the preservation of long-term renal function in CAH (Congenital adrenal hyperplasia).

Monochorionic (MC) twins are at risk of acute exsanguination after single fetal demise (sFD) due to their shared placental circulation, which may result in sequelae for survivors. To evaluate the prevalence of ante- and postnatal brain injury and long-term neurodevelopmental impairment (NDI) in co-twins after sFD. Secondary outcomes were the prevalence of termination of pregnancy (TOP), neonatal death (NND) and potential risk factors for brain injury. PubMed, Embase, Scopus and Web of Science were searched to identify relevant studies in October 2024. Studies reporting MC twin pregnancies with spontaneous sFD. Studies with selective feticide, twin reversed arterial perfusion sequence, twin anaemia-polycythaemia sequence, congenital anomalies, higher-order multiple pregnancies, fetoscopic laser surgery and double fetal demise were excluded. Systematic review and meta-analysis were performed following the PRISMA and MOOSE guidelines. Thirteen studies involving 311 survivors after sFD were included. The prevalence of TOP, NND, brain injury and NDI was 3% (95% CI: 0%-7%), 6% (95% CI: 0%-16%), 27% (95% CI: 18%-37%), 6% (95% CI: 3%-11%), respectively. The median GA at birth in survivors with brain injury was 29 weeks (IQR 27.7-34.1) compared to 36 weeks (IQR: 32.3-37.0) in the overall group of survivors. Brain injury occurs in one in four survivors and is associated with lower GA at birth, suggesting a double-hit injury due to a combination of exsanguination and (severe) prematurity. NDI occurs in one in 20 survivors, compared to two-thirds of those with brain injury. PROSPERO number: CRD42024608912.

Polycythemia is a physiologic adaptive response to hypoxia seen in children with cyanotic congenital heart disease (Cyanotic CHD). Globally, due to timely cyanotic CHD interventions, polycythemia is underreported or understudied. Timely identification and treatment of polycythemia among unoperated cyanotic CHDs avoids serious hematologic and related complications. This study aimed to determine the burden and factors associated with polycythemia among patients with cyanotic CHD enrolled in chronic care. This observational cross-sectional study used a semi-structured questionnaire to collect relevant sociodemographic and clinical data. Children with cyanotic CHD aged 1 month to 18 years were included. Polycythemia was considered when the hemoglobin was ≥ 17 g/dl on the complete blood count report of an automated hematology analyzer. Bivariate and multivariable binary logistic regression models were used to identify associated variables. In this study, 384 patients with cyanotic CHD were included, 55.2% males. The median age of study participants was 42 months (Interquartile range/IQR: 20.3-91.5). The median altitude of residence and age at cyanotic CHD diagnosis were 2355 m (IQR: 1826-2470) and 4 months (IQR: 1-12), respectively. Polycythemia was documented in 38% (146) [95% CI: 33.1-43.1] of participants. Males had almost doubled odds of polycythemia, aOR = 1.66 (95% CI: 1.01-2.70). Children with oxygen saturation < 70 and 70-90 had almost tripled odds of polycythemia, aOR 2.71 (95% CI: 1.25-5.88) and aOR 2.79 (1.46-5.33), respectively. Moreover, children with tricuspid atresia had tripled odds of polycythemia, aOR 3.20 (95% CI: 1.19-8.55). Additionally, children who had no phlebotomies in the last six months had reduced odds of polycythemia, aOR 0.07(0.02-0.22). The burden of polycythemia among patients with cyanotic CHD is huge. Male sex, saturation level, diagnosis of tricuspid atresia and phlebotomy frequency were associated with polycythemia among patients with cyanotic CHD. Males with cyanotic heart disease, children with tricuspid atresia, and cyanotic CHDs with saturation of oxygen below ninety should receive targeted screening for polycythemia during chronic follow-up.

Sex and gender diversity includes people who are intersex, transgender, and nonbinary. Americans are identifying as sex and gender diverse (SGD) in increasing numbers. Although data are limited on the diagnosis and management of stroke in SGD communities, the current literature suggests that there may be unique health needs among these marginalized populations. Health disparities and community-specific stressors may influence the frequency of stroke and traditional cerebrovascular disease risk factors among SGD people. In addition, transgender and gender-diverse people have higher rates of atypical stroke risk factors, such as sexually transmitted infections and an increased mental health burden. The adverse effects of some gender-affirming therapies can increase the rates of stroke, particularly in transfeminine people who use long-term estrogen as part of their medical gender transition. Decisions to discontinue hormonal therapy after stroke should be weighed against the psychological risks of doing so. In addition, some commonly prescribed medications for stroke prevention could interact with gender-affirming hormone therapies. Neurologists should collaborate with primary care providers and endocrinologists to screen for and manage cerebrovascular disease risk factors for the primary and secondary prevention of stroke. Limited evidence suggests intersex people may be at higher risk of cerebrovascular disease, particularly those with congenital adrenal hyperplasia (CAH). People diagnosed with CAH have unique risk factors of stroke including treatment with stress-dose corticosteroids or polycythemia due to hyperandrogenism. Creating affirming environments and increasing knowledge of health care for SGD communities may lead to improved equitable treatment of SGD patients with stroke by increasing community trust in health providers and incorporating use of best practices in clinical care and research settings. Limited data exist on stroke clinical presentations and how stroke is experienced and treated among SGD people, particularly among those with multiple marginalized identities, those presenting with acute stroke, and those requiring secondary stroke prevention. Primary familial and congenital erythrocytosis (PFCE), originally described as primary familial and congenital polycythemia, is characterized by isolated erythrocytosis in an individual with a normal to slightly enlarged spleen and absence of disorders causing secondary erythrocytosis. Clinical manifestations relate to the erythrocytosis and include rubor, and may or may not include hyperviscosity syndrome (headache, dizziness, altered mentation, visual disturbances, tinnitus, paresthesia, fatigue, lassitude, and weakness) and arterial and/or venous thromboembolic events. Although the majority of individuals with PFCE have absence of or only mild manifestations of hyperviscosity syndrome such as headache or dizziness, some affected individuals have severe and even fatal complications including arterial hypertension, coronary artery disease, myocardial infarction, intracerebral hemorrhage, and deep vein thrombosis (DVT). Phlebotomy-induced iron deficiency results in lassitude, impaired intellect, and impaired athletic performance, especially in children. Iron deficiency may also increase the risk of thromboses. Leukocyte count and differential are normal and platelet count tends to be low normal or slightly low due to hemodilution from increased red blood cells and increased whole blood volume. The clinical diagnosis of PFCE can be established in a proband with isolated absolute erythrocytosis, normal serum P50, below normal erythropoietin concentration, erythroid progenitors grown in vitro that are hypersensitive to extrinsic erythropoietin, and a family history consistent with autosomal dominant inheritance. The molecular diagnosis is established by identification of a heterozygous pathogenic variant in EPOR by molecular genetic testing in an individual with erythrocytosis. Treatment of manifestations: Maintain good hydration; DVT precautions in higher-risk situations (e.g., long-distance airline flights). While the majority of individuals with PFCE are asymptomatic and require no additional treatment, some undergo phlebotomy to decrease symptoms. Hyperviscosity treatment is based on severity of symptoms and includes consideration of aspirin; if phlebotomy is performed, isovolemic replacement by isotonic fluids and correction of iron deficiency. Treatment of hypertension and cardiovascular disease per internist or cardiologist. Treatment of diabetes and hyperlipidemia per internist or diabetes specialist. Thromboemolic events are treated with standard acute therapy, evaluation for additional thombophilic risk factors, and consideration of aspirin therapy and/or life-long anticoagulation. Surveillance: Full blood count as needed; assess and document symptoms and severity of hyperviscosity syndrome at each visit or as needed; cardiology assessment including blood pressure measurement, echocardiography, plasma lipid panel, hemoglobin A1c every few years or as recommended by cardiologist; 24-hour blood pressure in those with increased blood pressure; assess for any clinical manifestations suspicious for a thromboembolic event at each visit or as needed. Agents/circumstances to avoid: Dehydration; activities that could increase blood viscosity (e.g., living or prolonged stay at high altitudes, scuba diving, and smoking); additional cardiovascular risks (e.g., hypertension, hyperlipidemia, diabetes, and obesity); erythropoiesis-stimulating agents. Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives in order to identify as early as possible those with PFCE who would benefit from education regarding treatment for clinical manifestations and agents/circumstances to avoid, namely, exposure to hypoxia and erythropoiesis-stimulating agents. PFCE is inherited in an autosomal dominant manner. Many individuals diagnosed with PFCE have an affected parent; a significant proportion of individuals (likely exceeding 10%) have the disorder as the result of a de novo pathogenic variant. Each child of an individual with EPOR-related PFCE has a 50% chance of inheriting the EPOR pathogenic variant. Once the EPOR pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for PFCE are possible.

JAK2 unmutated erythrocytosis encompasses a heterogeneous spectrum of hereditary and acquired entities. The foremost step is excluding polycythemia vera (PV) with JAK2 mutation screening (exons 12-15). Apparent polycythemia such as physiological outliers or relative polycythemia secondary to volume contraction should be considered. A historical overview of hematocrit (Hct) and hemoglobin (Hgb) levels helps distinguish longstanding from acquired erythrocytosis. Serum erythropoietin (Epo) levels are variably informative. Hereditary erythrocytosis should be considered in longstanding erythrocytosis with a positive family history; causes include EPOR mutations (subnormal Epo), high oxygen affinity hemoglobin variants, PIEZO1 mutations, 2,3-bisphosphoglycerate deficiency, methemoglobinemia, and germline oxygen sensing pathway mutations (HIF2A-PHD2-VHL). Acquired erythrocytosis results from central (cardiopulmonary disease) or peripheral (renal artery stenosis) hypoxia, Epo-producing tumors (renal cell carcinoma) or drugs (testosterone, sodium glucose co-transporter-2 inhibitors (SGLT2-i), erythropoiesis stimulating agents). Idiopathic erythrocytosis is an ill-defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology. Cytoreductive therapy should be avoided. Phlebotomy should be considered for symptom control. Cardiovascular risk optimization and low-dose aspirin are advised, while the role of HIF2A inhibitors remains unclear. EPO mutations which produce hyperactive, hepatic-like Epo were identified. In cases with negative workup but high clinical suspicion, an expanded next generation sequencing panel for hereditary erythrocytosis is recommended. Among drugs, SGLT2-i-associated erythrocytosis is increasingly recognized. Advances in molecular hematology are expected to improve the characterization of "idiopathic erythrocytosis". Results from prospective studies are needed to elucidate the underlying pathology and guide management.