Cushing's syndrome (CS) during pregnancy is an exceptionally rare but high-risk condition that poses major diagnostic and therapeutic challenges. Its low prevalence is mainly due to cortisol-induced infertility. Although its low prevalence stems primarily from cortisol-induced infertility, an increasing number of cases are being recognized due to enhanced clinical awareness and expanded use of assisted reproductive technologies. In contrast to the general population where pituitary adenomas predominate, pregnancy-associated CS demonstrates a distinct etiology pattern, with ACTH-independent causes accounting for the majority of cases, particularly benign adrenal adenomas. The physiological hypercortisolism of gestation complicates diagnostic testing, as urinary free cortisol and late-night salivary cortisol rise up to threefold, although circadian rhythmicity is usually preserved. Clinical features overlapping with normal pregnancy delay recognition, but specific signs such as wide violaceous striae, proximal myopathy, and easy bruising should raise suspicion. Untreated CS carries a markedly increased risk of maternal morbidity, including preeclampsia, diabetes, infections, and thromboembolic events, and adverse fetal outcomes such as prematurity, growth restriction, and fetal loss. Management requires a multidisciplinary team. Surgery in the second trimester, remains the treatment of choice. Medical therapy, mainly with metyrapone, may be considered in selected severe cases, whereas ketoconazole and cabergoline have more limited roles. Drugs such as mitotane and mifepristone are contraindicated during pregnancy, while osilodrostat lacks clinical evidence. In summary, early recognition and individualized management are essential to optimize maternal and fetal outcomes in this rare but high-risk condition.

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, and woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Affected individuals typically have some form of neurologic and/or cognitive delay (ranging from mild to severe). Most individuals have severe feeding issues, which can contribute to poor growth, and many require nasogastric or gastrostomy tube feeding. Many affected individuals have eye findings, including strabismus, nystagmus, refractive errors, and optic nerve hypoplasia. Seizures may be present and can be refractory to therapy.

Isolated neutropenia is often deemed benign in elderly patients, frequently attributed to age-related marrow changes, medications, or nutritional deficiencies. However, persistent and unexplained neutropenia may signal early clonal hematopoiesis or evolving myeloid malignancy. While acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) usually arises from multilineage cytopenia, presentation with isolated neutropenia and myeloproliferative neoplasia (MPN)-like features is exceedingly rare. This case underscores the importance of early, risk-adapted assessment in such scenarios. A 69-year-old woman presented with isolated mild neutropenia (absolute neutrophil count (ANC) 1,188/µL) and easy bruising. With no other cytopenias or symptoms, bone marrow biopsy was deferred. Six months later, she developed abdominal discomfort, anorexia, and massive splenomegaly. Laboratory tests revealed leukocytosis with left shift, anemia, thrombocytopenia, and nucleated red cells. Bone marrow biopsy showed > 40% myeloblasts, trilineage dysplasia, and mild fibrosis. JAK2 mutation and BCR-ABL were negative. Cytogenetics demonstrated i(17q) and del(20q); Fluorescence in situ hybridization (FISH) showed TP53 deletion in 81.91% of nuclei, establishing AML-MRC with high-risk features. She was started on azacitidine and venetoclax. Day 28 marrow showed minimal residual disease (blast 8%) but no metaphase growth prompting treatment continuation. She is currently on her fourth cycle with treatment-related transfusion-dependent cytopenias, prompting dose reduction. This case challenges the prevailing "watch-and-wait" paradigm in the evaluation of isolated neutropenia, particularly in older adults. It exposes the hidden risk of clinical inertia, where the absence of other overt cytopenias or symptoms may lead to missed opportunities for early diagnosis of high-risk clonal evolution. In resource-limited setting, this case underscores urgent need for heightened clinical vigilance. Likewise, it highlights the urgent need for a more risk-adapted approach to persistent isolated neutropenia and compels us to confront a critical question: how many patients are we failing to diagnose in time, and how many windows for potentially life-altering intervention are we silently allowing to close?

Vascular Ehlers-Danlos syndrome (vEDS) is a life-threatening connective tissue disorder that often remains undiagnosed before pregnancy and carries a markedly high risk of maternal mortality. We report the case of a 34-year-old pregnant woman who experienced sudden abdominal pain at 39 weeks of gestation and died shortly after delivery. Autopsy revealed an aortic rupture with histopathological findings suggestive of vEDS. Her family history included her father's sudden vascular death, and her personal history was notable for easy bruising and early-onset varicose veins. Next-generation sequencing-based postmortem genetic testing (PMGT) using formalin-fixed, paraffin-embedded liver tissue confirmed a pathogenic variant in COL3A1. This result facilitated genetic counseling for the family, allowing presymptomatic diagnosis and preventive management, including celiprolol therapy for at-risk relatives. This case underscores the value of PMGT in identifying the underlying cause of unexpected maternal death, particularly when conventional samples are unavailable.

Vitamin B12 deficiency is a common cause of normocytic or megaloblastic anemia. In 2.5% of cases, it can manifest as pseudo-thrombotic microangiopathy (pseudo-TMA), which mimics thrombotic thrombocytopenic purpura (TTP), an emergent hemolytic microangiopathy. This case report discusses a stable-appearing 45-year-old female with progressive fatigue, heavy menstrual bleeding, bleeding gums, and easy bruising. Laboratory testing demonstrated low vitamin B12 (121 pg/mL), pancytopenia, exaggeratedly elevated LDH, undetectable haptoglobin, low reticulocyte production index (RPI), and positive intrinsic factor antibody. She was diagnosed with pseudo-TMA. Unlike TTP, pseudo-TMA patients often appear clinically well and hemodynamically stable without renal or neurologic dysfunction. Other key differentiators of pseudo-TMA include progressive anemia, often with irregular red cell morphology; evidence of pancytopenia, neutropenia, and reticulocytopenia; and LDH levels exceeding 2500 units/L. While clinicians should maintain a low threshold for recognizing TTP as a hematologic emergency, they must also maintain awareness of pseudo-TMA to prevent misdiagnosis and unnecessary plasmapheresis and to optimize treatment.

This study aimed to identify the genetic cause of Ehlers-Danlos syndrome (EDS) in a Chinese family and to evaluate the functional impact of a deep intronic COL5A1 variant using a minigene assay. The genetic analysis was performed using medical whole-exome sequencing, covering 5,398 genes associated with human genetic diseases. A candidate variant was prioritized based on its segregation and potential effect on splicing. To confirm functional effects, wild-type and mutant minigene constructs were created and transfected into HEK293T cells. RT-PCR and sequencing were used to analyze splicing products. A heterozygous intronic COL5A1 variant (NM_000093.5: c.1774–95 C > T) was found in both the proband and her father, but not in the mother. Clinically, affected individuals showed features typical of classic Ehlers-Danlos syndrome (cEDS), including hyperextensible skin, atrophic scars, easy bruising, and joint hypermobility. Functional minigene assays demonstrated that the variant causes abnormal splicing, leading to pseudoexon inclusion, a frameshift (p.Gly592CysfsTer2), and the production of a truncated protein. Our findings provide functional evidence that the deep intronic COL5A1 variant c.1774–95 C > T disrupts normal splicing and is likely pathogenic in cEDS. This discovery broadens the mutational range of COL5A1, highlights the diagnostic value of deep intronic variants, and points to a possible therapeutic target for splice-modulating strategies.

Cushing's disease is a rare condition, and patients have a higher risk of thromboembolism, specifically venous events. We present a case of a middle-aged woman who underwent sleeve surgery many years ago and slowly regained weight. She had two episodes of unprovoked deep vein thrombosis (DVT), and no risk factors were identified at the time of these events. She presented 10 years later with easy bruising, myopathy, gradual weight gain, and insomnia, and was found to have ACTH-dependent pituitary Cushing's. She successfully underwent endoscopic resection of her pituitary macroadenoma. She had worsening myalgia and myopathy immediately after surgery and is now recovering from glucocorticoid withdrawal syndrome after having untreated Cushing's disease for many years. Her insomnia has resolved almost completely, she has lost 60 pounds, her hypertension has resolved completely, and now she is off medications and remains in remission after 22 months. We conclude that Cushing's disease should be viewed as a risk factor for unprovoked venous thromboembolism and screened for, especially in obese patients.

von Willebrand disease (vWD) is the most common inherited bleeding disorder. Various subtypes of vWD exist as either quantitative deficiencies or qualitative defects of the von Willebrand factor (vWF) protein and lead to an array of bleeding manifestations. Individuals with vWD typically have increased mucocutaneous bleeding including oral mucosal bleeding, epistaxis, and heavy menstrual bleeding. Other common bleeding manifestations including petechiae, easy bruising, surgical-related bleeding, postpartum hemorrhage, and trauma-induced bleeding. In more severe subtypes gastrointestinal bleeding, hemarthrosis, and intramuscular bleeding can occur. Given the spectrum of bleeding phenotypes, management can differ greatly from one individual to the next with the majority of individuals receiving on-demand treatment while more severely affected individuals may receive long-term prophylaxis. Common on-demand therapeutics include oral, intravenous, topical, and/or intranasal antifibrinolytics, intravenous, subcutaneous and/or intranasal desmopressin, and intravenous plasma-derived and recombinant-vWF replacement therapy. Long-term prophylactic regimens include hormonal therapies and regularly scheduled infusions of plasma-derived and recombinant-vWF concentrates. Over the past 100 years the therapeutic landscape for individuals with vWD has changed significantly and continues to evolve. There are numerous studies currently underway to evaluate new treatments including several drugs administered via subcutaneous injection, and vagal nerve stimulation. Historically individuals with vWD have poorer health-related quality of life and higher healthcare resource utilization compared to the general population, emphasizing the ongoing need for improved therapeutics.

• Philadelphia (Ph) chromosome–positive acute lymphoblastic leukemia (ALL), characterized by the t(9;22)(q34;q11.2) or BCR‑ABL1 rearrangement, occurs in about 3% of pediatric cases of ALL, 5% to 25% of adolescent and young adult cases, and 25% of adult cases, with prevalence increasing with age. Patients with ALL can present with fatigue, dyspnea, infections, and easy or spontaneous bruising or bleeding. In children, pain in the extremities or joints may be the only presenting symptom. • Data on the prevalence and incidence of Ph-positive ALL in Canada were not available at the time of the clinical review. However, according to estimates, 440 people in Canada were newly diagnosed with ALL (incidence rate of 1.5 per 100,000 people) in 2019.