Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition.

Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2­dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

Clinical, pathologic, and molecular analyses of superficial low-grade fibromyxoid sarcoma in two young patients: A rare and deceptive mimic of benignancy.

Low-grade fibromyxoid sarcoma (LGFMS) is a histopathologically deceptive soft tissue neoplasm with bland cytology, which is typically encountered in deep soft tissue of adults. We report two cases of superficial LGFMS in young patients (16 and 21 years old, respectively), which were difficult to diagnose on histopathologic and clinical findings alone. LGFMS commonly mimics benign neoplasms such as cellular neurothekeoma, fibromatosis, neurofibroma, and perineurioma. Malignancies included in the differential diagnosis are soft tissue neoplasms such as dermatofibrosarcoma protuberans and myxofibrosarcoma. A high degree of reported variation in pattern and cellularity among LGFMS further complicates the diagnosis. Careful examination and appropriate immunohistochemistry panels including MUC4 are essential for narrowing the differential diagnosis. Molecular studies for possible FUS translocation can confirm the diagnosis of LGFMS. Sufficient sampling and workup of these lesions are critical, especially in younger patients. Young age and superficial presentation can easily sway dermatopathologists/dermatologists toward an incorrect diagnosis of benignancy.

Craniorachischisis with Exencephaly.

BACKGROUND: Neural tube defects can be as mild as spina bifida, to as severe as anencephaly, with only a fraction of these cases presenting as both craniorachischisis and exencephaly. Case report: The G3, P1011 mother was 25-years old, who at an estimated fetal gestational age of 17 weeks had a fetal diagnosis of anencephaly based on a sonogram, resulting in elective pregnancy termination. The female fetus had an open neural tube defect, consisting of craniorachischisis and exencephaly. No abnormalities were noted in any other organs. Conclusion: Although mostly associated with anencephaly, craniorachischisis can also be associated with exencephaly in early pregnancy.

A Case of Reversible Infantile Respiratory Chain Deficiency Presenting With Hypotonia, Hyperammonemia, and Failure to Thrive.

Reversible infantile respiratory chain deficiency, previously termed reversible infantile cytochrome c oxidase (COX) deficiency myopathy, is a rare mitochondrial disorder that is characterized by severe hypotonia and generalized muscle weakness in infancy that is associated with lactic acidosis. Affected infants will spontaneously recover, if they survive the first months of life. Here, we present the case of a 4-week-old girl who initially presented with hyperammonemia, hypotonia, and failure to thrive, for which she was referred for genetic evaluation. After several tests, a distinct genetic syndrome could not be identified and she continued to deteriorate. A muscle biopsy was performed and demonstrated severe mitochondrial myopathy with abundant COX-negative fibers. Ultrastructural abnormalities of the mitochondria, diagnostic of mitochondrial myopathy, were identified on electron microscopy. Molecular studies revealed the classic homoplasmic disease causing mutation, m.14674 T>C in the MT-TE gene, associated with reversible COX deficiency. Although hyperammonemia is an unusual presentation for mitochondrial myopathies, specifically reversible infantile respiratory chain deficiency, it should be included in the list of possible presenting symptoms for this condition.

Virilization and Enlarged Ovaries in a Postmenopausal Woman.

A patient with postmenopausal bleeding and virilization was found to have bilaterally enlarged ovaries with a yellow cut surface. Histology revealed cortical stromal hyperplasia with stromal hyperthecosis. This hyperplastic condition should not be mistaken for an ovarian neoplasm.

Identifying MRONJ-affected bone with digital fusion of functional imaging (FI) and cone-beam computed tomography (CBCT): case reports and hypothesis.

Surgical debridement of medication-related osteonecrosis of the jaw (MRONJ) lesions is far less predictable than lesion resection. Margins for surgical debridement are guided by surrogate markers of bone viability, such as bleeding and bone fluorescence, which limit debridement to visibly necrotic bone. In contrast, surgical resection is extensive, including a substantial portion of surrounding bone. The concept that the MRONJ lesion is a composite of affected but viable ("compromised") and necrotic bone is supported by histopathological data. Hence, removing only the necrotic bone during lesion debridement could inadvertently leave behind residual compromised bone in the lesion, subsequently contributing to persistence or reestablishment of the lesion. Using 2 case reports, this manuscript illustrates a novel assessment of the MRONJ lesion to enable demarcation of both the compromised and necrotic portions of the lesion. This assessment uses tumor-surveillance functional bone imaging data that may already be available for cancer patients with MRONJ and fuses these data digitally with computed tomography/cone-beam computed tomography imaging of the jaw obtained during MRONJ assessment. If validated, preoperative functional imaging-based assessment of the MRONJ lesion could enable surgeons to eliminate both the compromised and nonviable portions of the lesion precisely with conservative debridement, matching surgical resection in outcome.