Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive lysosomal storage disorder caused by mutations in the SMPD1 gene, resulting in sphingomyelin accumulation. With a birth prevalence of 0.25-0.6 per 100,000, it is more prevalent in Ashkenazi Jewish and Middle Eastern populations. The disease features a clinical spectrum ranging from severe, early-onset neurodegeneration (infantile neurovisceral ASMD) to chronic, non-neurological visceral involvement (chronic visceral ASMD) and intermediate forms (chronic neurovisceral ASMD). The chronic visceral form is characterized by liver dysfunction, respiratory symptoms, and hepatosplenomegaly, which can lead to secondary thrombocytopenia. The majority of patients exhibit thrombocytopenia and/or mild bleeding manifestations, most commonly easy bruising and epistaxis, whereas clinically significant bleeding events, including gastrointestinal or variceal hemorrhage, occur less frequently. Systematic platelet-function studies in patients with ASMD are currently lacking. Evidence retrieved from biological models indicates that ASMD contributes to platelet dysfunction, including impaired secretion and thrombin generation, mediated by complex pathological mechanisms. These findings underscore the importance of hematological monitoring and further research in patients with this condition and could potentially offer new therapeutic possibilities.

Lipedema is a chronic disorder characterized by a disproportionate accumulation of subcutaneous adipose tissue in the extremities, typically sparing the hands and feet. It is commonly associated with pain, hypersensitivity, easy bruising, edema, and fibrotic nodules. Despite growing awareness, there is still no consensus on evidence-based therapeutic approaches. This integrative review aimed to identify physical therapy strategies described in the scientific literature for the assessment and conservative management of lipedema. Searches were conducted in the PubMed/MEDLINE, BVS, PEDro, Embase, and Cochrane databases, followed by critical appraisal and evidence synthesis, with applicable PRISMA-ScR checklist items used as a reporting guide for the study selection process. The findings indicate that physical therapy plays a key role in conservative treatment, particularly through complete decongestive therapy, compression therapy, exercise, manual therapy, and electrophysical agents. These interventions show potential benefits in reducing pain, improving functional capacity, controlling edema, and preventing disease progression. However, the available evidence remains limited, underscoring the need for more robust clinical trials to support evidence-based physical therapy practice in the treatment of lipedema.

Geroderma osteodysplasticum (GO) is an ultra-rare inherited connective tissue disorder. We report a retrospective case series of two Moroccan patients with geroderma osteodysplasticum carrying the same recurrent Golgi Ras-associated binding (RAB) GTPase-binding protein (GORAB) variant. Patient 1 was an 11-year-old boy who presented in January 2026, and Patient 2 was a five-year-old girl who presented in September 2024; both were born to consanguineous parents. They harbored the identical homozygous pathogenic truncating GORAB variant (NM_152281.3:c.79C>T; p.Arg27*), confirmed by targeted Sanger sequencing and clinical exome sequencing, respectively, and classified as pathogenic in ClinVar (rs770355472). One of these patients (Patient 2) had previously been reported as an isolated case. Both patients presented with the classical triad of cutaneous laxity with pseudo-aged skin, generalized joint hyperlaxity, and growth retardation. Patient 1 additionally exhibited cryptorchidism and delayed bone age. Patient 2 presented with severe factor V deficiency (<1% activity), thoracolumbar kyphoscoliosis with vertebral wedging, and a bleeding diathesis characterized by recurrent epistaxis and easy bruising. Management was primarily supportive and multidisciplinary, including clinical monitoring and treatment tailored to individual manifestations. Follow-up demonstrated persistence of the underlying connective tissue disorder with variable clinical severity but no major disease-specific complications. The identification of the identical GORAB p.Arg27* variant in two unrelated Moroccan consanguineous families raises the possibility of a founder effect warranting further population-based investigation. By comparing two phenotypically distinct patients carrying the same pathogenic variant, this report highlights the clinical variability associated with GORAB-related disease and suggests that hemostatic evaluation should be considered in patients with GO who present with a personal or family history suggestive of a bleeding disorder.

Germline pathogenic variants in the RUNX1 gene lead to the condition RUNX1-familial platelet disorder (RUNX1-FPD). This condition is associated with a 30%-50% lifetime risk of hematologic malignancies, including acute myeloid leukemia. In addition to physical manifestations including prolonged bleeding and easy bruising, individuals with RUNX1-FPD face profound psychosocial challenges. Individuals 18-39 years old may particularly struggle in their experiences with RUNX-FPD as they navigate developmental milestones. This descriptive, cross-sectional study includes participants aged 18-39, enrolled in the NIH RUNX1 Natural History Study (19-HG-0059). Each participant completed a structured psychosocial self-report assessment that included demographic factors, patient-reported outcomes on mental health symptomatology, psychiatric treatment history, and traumatic stress symptomatology. Open-ended questions asked participants to identify the most difficult part of living with RUNX1-FPD and how RUNX1-FPD has impacted their lives. Twenty-two participants completed the measures and were included in the analyses. Participants' mean age was 31 years (SD = 5.1). Fifty percent of participants reported higher than average anxiety scores, 59% reported they had been treated by a mental health professional, and 64% reported traumatic stress symptomatology. Living with the chronic uncertainty of cancer development and overall distress from recommended lifelong monitoring processes emerged as themes from the illustrative exemplar quotes. With this study, we describe the significant psychosocial and mental health challenges that emerging adults with RUNX1-FPD face. Access to psychological counseling, peer support groups, and genetic counseling can help individuals process their risk, manage anxiety, and make informed decisions. More research is needed to explore effective coping strategies, resilience-building techniques, and patient-centered resources to improve quality of life for those living with a hereditary predisposition to hematologic malignancies.

Ehlers Danlos syndrome (EDS) is a group of hereditary connective tissue disorders that manifests clinically with skin hyperelasticity, hypermobility of joints, atrophic scarring, and fragility of blood vessels. It is largely diagnosed clinically, although identifying the gene encoding the collagen or proteins interacting with it is necessary to identify the type of EDS. Identifying the type of EDS to guide management and counseling is important. In 2017, a new international classification of EDS was proposed with 13 different variants. This syndrome is heterogeneous and has been classified into six types (classical, vascular, hypermobile, arthrochalasis, kyphoscoliotic, and dermatosparaxis), with the causative collagen pathology being different for each type. Asymptomatic, nonsyndromic joint hypermobility, Ehlers-Danlos syndrome, and hypermobility spectrum disorders (particularly the hypermobile type) are the commonest phenotypes associated with joint hypermobility. Compilations of these syndromes can be chronic pain, dysautonomia, gastrointestinal dysmotility, mast cell activation, and anxiety and phobic states. Many new variants have been identified with the advancements, which tend to be more complex and clinically overlapping. Clinical recognition of EDS variants is important. For instance, it is important to know that the patient has the vascular type, which is associated with arterial rupture and organ perforation, with potentially life-threatening consequences.

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.