United States

Background
Kagami-Ogata syndrome (KOS, OMIM 608149) is a rare genetic imprinting disorder involving microdeletions and epimutations affecting a maternally inherited locus (14q32.2) in chromosome 14. Neonates commonly present abnormal phenotypic features such as facial dysmorphia, abdominal wall defects, and skeletal abnormalities.  Around 80 cases of KOS were reported in literature, and the incidence rate is estimated at less than 1 in 1,000,000 newborns.

Case Presentation
We describe the clinical case of a preterm newborn found with polyhydramnios who was delivered by C-section at 32 weeks by a 30-year-old African American female (G4 P3 Ab1 LC2) with a history of severe pre-eclampsia and sickle cell trait. Fetal ultrasound revealed an omphalocele, lung mass, and left-axis deviation of the heart. Chest X-ray indicated features associated with respiratory distress syndrome (RDS) and a bell-shaped chest indicating pulmonary hypoplasia. A chromosome microarray was performed to determine the underlying cause of this newborn presentation.

Discussion
Chromosome microarray analysis confirmed homozygosity of chromosome 14, indicating paternal uniparental isodisomy, which supports the diagnosis of KOS. This case demonstrates the classical symptoms including coat hanger deformity, presence of omphalocele, and bell-shaped thorax revealed by imaging. This patient exhibits facial dysmorphism characterized by hirsute forehead, depressed nasal bridge, micrognathia, webbed neck, and small ears. KOS can be mistaken for other diseases like Beckwith-Wiedemann syndrome, trisomy 18, androgenic mosaicism due to phenotypic overlap. That is why when there are symptoms suggestive of BWS like macrosomia, polyhydramnios, and omphalocele are present, with genetic testing not confirming it, KOS should be tested. The management entails supportive measures like mechanical ventilation, tube feeding, and therapy for developmental delay, necessitating a multidisciplinary approach.

AMA Research Challenge 2024 

Exploring Kagami-Ogata Syndrome: Insights from a Case Report​

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Background: Hepatosplenic T-cell lymphoma (HSTL) is a rare and aggressive form of peripheral T-cell lymphoma that affects the liver and spleen without involving the lymph nodes. It typically occurs in young adults with cytotoxic T-cell proliferation of the TCR γδ type and is associated with immunosuppression. In this case, we present an elderly patient who developed HSTL of the TCR αβ type after being treated for indolent b-cell lymphoma.

Case Presentation: A 76-year-old man with a history of chronic lymphocytic leukemia (CLL) presented with altered mental status. He completed treatment for CLL with obinutuzumab and venetoclax 3 years prior and was in remission. On examination, patient appeared confused. Laboratory data showed hepatocellular liver injury (ALT 342 U/L, AST 800 U/L, ALP 821 U/L, T. Bilirubin 7.1 mg/dL). A CT scan of abdomen and pelvis demonstrated hepatomegaly and mild splenomegaly without lymphadenopathy. Histological analysis of liver biopsy revealed benign hepatocytes with prominent atypical lymphoid infiltrate involving hepatic sinusoids and portal tracts. The lymphoid population appeared atypical with enlarged irregular nucleus and increased apoptosis. Immunohistochemistry revealed atypical lymphoid cells which were positive for CD3, CD2, TCR-β, TIA-1and Granzyme B. The Ki-67 index was up to 40%. Flow cytometry analysis of the peripheral blood demonstrated lack of B-cells and no immunophenotypic abnormal T-cells. The abnormal T-cells were also identified in the bone marrow. The diagnosis of hepatosplenic T-cell lymphoma, TCR- αβ type was rendered. The patient received cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone with 50% dose reduction due to renal failure. Initially his condition improved; however, on day 5, he developed acute hypoxic respiratory failure secondary to Influenza A and Rhinovirus pneumonia and died from shock and multiorgan failure.

Discussion: HSTL is a rare, aggressive disease with a variable clinical presentation. About 20% of cases occurs in chronic immunosuppression. Our patient had a history of CLL in remission and at HSTL diagnosis, showed hypogammaglobulinemia and no B-cells in the peripheral blood flow cytometry. This clinical setting has not been reported before. Historically, HSTL primarily affects adolescents and young adults, with a median age at diagnosis of approximately 35 years. Most HSTL cases express TCR γδ (~75%) or TCR αβ (~20%), the latter with worse prognosis. There is currently no standard of care treatment, and outcomes are poor without a stem cell transplant.


Hepatosplenic T-cell Lymphoma, αβ type, presenting in an elderly patient status post indolent B-cell lymphoma treatment


Background
Immune thrombocytopenia (ITP) remains a diagnostic challenge, with many primary and secondary causes that are often difficult to discern. COVID-19 infection and vaccination have been implicated in causing ITP; however, no case of ITP has been documented after receiving multiple uneventful COVID vaccine doses. Here we present a case of ITP presumably secondary to his 5th mRNA COVID-19 booster. 

Case Presentation
A 76-year-old male with Type 2 Diabetes Mellitus, Hypertension, and Hyperlipidemia, presented to the emergency department for a low platelet count of 8x10^3/uL found on outpatient blood work done at his primary care physician’s office. The patient had received the 5th dose of mRNA COVID-19 vaccine booster 4 days before presentation and developed a rash on bilateral lower extremities the day after receiving the vaccine. On the day of admission, the patient had minorbleeding from the gums. Otherwise, he denied fevers, lymphadenopathy, URI symptoms, epistaxis, hemoptysis, abdominal pain, nausea, vomiting, diarrhea, hematochezia, melena, new medications, or new illness. The patient denied personal or family history of bleeding, clotting or thrombocytopenia. The patient had received 4 doses of the Moderna vaccine in the past without any adverse reaction. 

Peripheral smear revealed 1-2 schistocytes, PLASMIC score of 3. Treatment included dexamethasone 40mg daily x 4 days and intravenous immunoglobulin (IVIG) 0.5g/kg x 3 days. The fourth dose of IVIG was held in the setting of acute kidney injury with Creatinine rise 1.1 to 1.4, which improved to 1.3 after IV fluids. The patient did not require transfusion and platelet count improved to 126x10^3/uL on discharge. Of note, the patient developed marginal zone B-cell lymphoma 6 months after his initial presentation. 

Discussion
This case illuminates the potential for confounding variables and the elusive nature in diagnosing ITP. Recognizing the distinction between primary ITP and secondary ITP is crucial in guiding management and improving patient outcomes. Primary ITP is a diagnosis of exclusion, and typically responds well to steroids and IVIG. Despite this patient’s subsequent diagnosis of marginal zone B-cell lymphoma, he responded well to combination of IVIG and steroid treatment. As secondary ITP induced by lymphoma treatment is usually successful only when underlying disease is controlled, patient’s thrombocytopenia may not be related to lymphoma. Identifying the root cause of thrombocytopenia informs appropriate treatment strategies and management of the patient's overall health. IVIG is an expensive therapy, and its use should be carefully considered to reduce medical expenditure and improve patient outcomes.

Immune Thrombocytopenia After 5th Dose of mRNA COVID Vaccine

Background: Cancers of Unknown Primary (CUPs) are undifferentiated neoplasms for which standardized diagnostic work-up fails to identify the primary tumor responsible for metastatic seeding. They can be categorized into favorable and unfavorable subsets. Unfavorable subsets include poorly differentiated neuroendocrine carcinomas and poorly differentiated peritoneal serous carcinomas. Favorable subsets include metastatic squamous cell carcinoma (SCC) and adenocarcinoma confined to isolated nodes or a single metastatic site. SCC originating in the retroperitoneal cavity is exceedingly rare. Some of the cases were reported as SCC of unknown primary. Little is known about its pathogenesis and clinical features; therefore, the optimal treatment is unclear. Here, we report a case diagnosed as SCC caused by human papillomavirus (HPV) infection and possibly arising in the retroperitoneal cavity. Next-generation sequencing (NGS) determined the treatment in this rare case.

Case presentation: A 61-year-old female presented to our clinic with incidental right retroperitoneal paraaortic lymphadenopathy found on a CT scan following hospitalization for urosepsis. She underwent a biopsy at the hospital, which revealed a SCC associated with HPV. SCC was positive for HPV, a known risk factor for gynecological and head and neck cancers. Extensive ENT workup with pan endoscopy and full gynecologic workup was done, followed by colonoscopy, GI endoscopy, and mammography. No primary source was detected. NGS was performed, and it revealed ER and PIK3CA mutations, which are primarily positive in primary breast cancer. It was also positive for PD-L1 mutation, commonly found in many solid tumors. The patient was started on a 12-week chemotherapy with Paclitaxel and Carboplatin. Post-chemotherapy PET scan showed a decrease in size and intensity of lymph nodes with no hypermetabolic activity, suggestive of radiological remission. Based on the sequencing results, the patient was started on Anastrozole as she was ER-positive. Serial CT scan surveillance showed lymph nodes decreasing in size, signifying the patient was still in remission.

Discussion:
The management of CUPs is highly challenging. However, with the advent of genomic sequencing, we could identify targetable mutations. In our case, three targetable mutations were detected: ER, PIK3CA, and PDL-1. These mutations give us specific targets against which very effective therapeutic options are available, highlighting the importance of genomics for the future treatment of CUP. NGS helps personalize cancer care and tailor the management of these poorly understood diseases. Further research and case studies are needed to understand better the etiology, optimal treatment strategies, and prognostic factors of this uncommon condition.

New treatment options in CUP: a case report

Opsoclonus-myoclonus-ataxia syndrome (OMAS) due to Pembrolizumab: a case report
Background
Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare yet debilitating neurological condition in adults; few reports have documented this condition in relation to immune checkpoint inhibitors (ICIs). Pembrolizumab, an ICI, used in the treatment of many forms of cancers can cause a wide range of side effects referred to as immune-related adverse events (IRAEs).
Case
We report a case of a patient with breast cancer who developed OMAS while receiving neoadjuvant chemotherapy that included pembrolizumab. Extensive work-up was unrevealing. She received steroids for treatment of OMAS that were discontinued due to side effects.
Discussion
ICI toxicity needs to be considered on the differential for patients with new-onset OMAS. Paraneoplastic panels play an important role in determining the etiology of OMAS. Establishing an etiology for OMAS is important, especially in patients with underlying malignancy, due to the impact on the treatment of OMAS and the malignancy.

Opsoclonus-myoclonus-ataxia syndrome (OMAS) due to Pembrolizumab: a case report

Introduction 
Serum free light chain assay (FLC) is a valuable tool in diagnosing multiple myeloma. The prozone phenomenon, or hook effect, occurs with exceptionally high antigen levels, leading to underestimated FLC levels and false negatives. (2). FLC levels are routinely used for confirming multiple myeloma suspicions. This is a case of newly diagnosed multiple myeloma (MM) that exhibited the prozone effect on the FLC assay, delaying diagnosis.  

Case 
A 62-year-old woman presented to the emergency department after her outpatient lab work showed evidence of renal failure. Her symptoms included fatigue, shortness of breath, pallor and back pain. Labs revealed BUN 118 mg/dL, creatinine 11.9 mg/dL, hemoglobin 7 g/dl, calcium 10 mg/dL, and profound hypogammaglobulinemia. Computed tomography of the chest abdomen and pelvis showed small lytic lesions in the posterior aspect of T10-11. The patient was admitted for acute renal failure secondary to suspected multiple myeloma. Serum protein electrophoresis revealed M spike in the gamma globulin region. Initial FLC showed low levels of kappa light chain free serum <0.6 mg/L with high kappa/lambda ratio. Bone marrow biopsy demonstrated a hypercellular marrow (80% plasma cells), with FISH studies showing 4:14 translocation. Repeat FLC with dilution showed kappa light chain of 18403.8 mg/L and a kappa/lamda ratio of > 1000.00. Beta 2 microglobulin was found to be elevated at 36.89 mg/L, significant proteinuria with Bence-Jones protein was noted, and lytic foci were found in the calvarium, bilateral humeral shafts, and bilateral radial shafts on osseous survey. Initial therapeutic regimen consisted of cyclophosphamide, bortezomib, dexamethasone and daratumumab. Cyclophosphamide and dexamethasone were stopped due to intolerable side effects. Repeat kappa free light chains measured at 40 mg/L and ratio at 2.0. The patient remains dialysis dependent and ultimate plan is for autologous bone marrow transplant.  

Discussion 
The prozone effect, a rare lab phenomenon, occurs when high FLC levels interrupt complex formation, leading to underestimated antigen levels. (2). In FLC assays, multivalent proteins act as linkers, but very high FLC levels saturate binding sites, paradoxically decreasing fully formed complexes. (4). This effect can be overcome by dilution of the sample.  In the above case, the initial findings of FLC were variable, notable for an elevated kappa/lambda ratio and decreased kappa light chains. After dilution high levels of FLC resulted. This confirms that the low levels initially noted were a result of the Prozone effect. Timely recognition of the prozone effect ensures accurate diagnosis, prevents delays in therapy thus reducing disease morbidity.

Prozone Puzzles: Navigating the Quirky Realm of Diagnostic Testing

Background
Hemolytic transfusion reactions due to red blood cell (RBC) alloantibodies are one of the leading causes of transfusion-associated death. RBC alloantibodies also cause significant morbidity in the form of delayed hemolytic transfusion reactions. Herein, we present the case of one allo-immunized patient with severe anemia, who had to wait 3 months to receive a blood transfusion due to the unavailability of compatible blood in the United States.
Case Presentation
A 59-year-old female with a history of chronic anemia requiring frequent transfusions, and end-stage kidney disease (ESRD) on hemodialysis (HD) presented to the hospital with complaints of fatigue and worsening anemia (hemoglobin [Hb] < 6mg/dl). She denied chest pain, shortness of breath, syncope, and active bleeding. She had consulted 3 different hospitals in New York requesting a blood transfusion, which hadn’t been done due to the unavailability of compatible blood. Laboratory results showed severe normocytic, normochromic anemia (Hb 5.0
g/dl) and a low reticulocyte count of 2.55%. Haptoglobin, lactate dehydrogenase, and bilirubin were within normal limits, ruling out hemolysis. Endoscopy and colonoscopy were negative for gastrointestinal bleeding. Iron, B12, and folate levels were found to be normal; all of which were suggestive of chronic disease anemia. The patient’s blood group was A, RhD negative.
She was found to have antibodies against I, JKa, U, E, S and s antigens. The NY Blood Center was contacted, confirming the unavailability of RhD-negative, compatible packed red blood cell units (PRBC). The patient’s sister was tested and found to have compatible blood for donation. 1 PRBC was administered 2 weeks after hospital admission, after which the patient was stable to continue HD.
Discussion
The prevalence of alloimmunization in chronic transfusion patients is around 2-
8%. Alloimmunization risk is determined by the differences between donor and recipient RBC antigens, recipient genetic characteristics, and recipient inflammatory state at the time of initial antigen exposure. In our case, the patient had an increased risk for alloimmunization due to a history of multiple transfusions, female sex, and being RhD negative.
Conclusion
Alloimmunization can lead to significant morbidity in chronic transfusion patients due to a lack of compatible blood units. It is imperative to establish strategies to decrease primary RBC alloimmunization and mitigate the dangers of existing RBC alloantibodies in this population. Both antigen-matched transfusion and using leukocyte filters during transfusion might represent effective strategies to prevent alloimmunization due to white blood cells.

Significant Delays in Transfusion Due to Unavailability of Compatible Blood for a Highly Allo-immunized Patient: A Case Report

Background
Pembrolizumab is a humanized recombinant monoclonal antibody to the programmed cell death receptor-1 (PD-1) which has immunomodulatory activity and is approved for treatment of many cancers. Aside from side effects associated with infusion therapy patients can develop immune related adverse events (irAEs). IrAEs occur in approximately 15-25% of patients on pembrolizumab as a result of immune enhancement leading to inflammatory toxicity. In clinical trials of pembrolizumab, less than 1% of immune mediated hepatitis (IMH) was observed, making liver toxicity an extremely rare side effect of PD1 inhibition.


Case Presentation

An 68 year-old male with urothelial cell carcinoma (UCC) who underwent radical nephroureterectomy with negative margins was found to have a suspicious mass along the surgical bed during surveillance imaging. Follow-up PET/CT confirmed a 2.4 cm mass with subsequent biopsy confirming relapse. The patient was started on Enfortumab vedotin and Pembrolizumab. Two weeks after the first cycle of therapy the patient developed colitis, tumor lysis syndrome and Steven Johnson syndrome (SJS). His liver enzymes were also elevated. Liver ultrasound was obtained shortly after due to development of ascites which showed coarsened echotexture suggestive of diffuse hepatocellular process without focal hepatic lesions. Ascitic fluid studies were negative for malignancy. CT abdomen/pelvis revealed cirrhosis not seen on imaging two weeks prior.


Discussion and Conclusion

Pembrolizumab associated hepatic injury presents after 1-3 months after initiation of treatment. Studies have shown earlier onset of liver dysfunction resulted in shortened overall survival. The pattern of injury is usually hepatocellular however there have been cases of mixed or cholestatic. Even though histology usually reflects IMH with prominent lymphocytic infiltrates of activated T cells, immunoglobulin levels are usually normal and autoantibodies are not present. Historically, fatal cases associated with immune checkpoint inhibitors (ICI) have occurred in patients with cholestatic patterns of liver injury or severe irAEs such as SJS.

Due to potentially fatal outcomes associated with liver injury, monitoring with routine liver tests should be protocol for patients receiving ICI therapy. Rapid improvement of alkaline phosphatase and bilirubin has been seen with corticosteroid treatment. In instances of inadequate response to corticosteroids alone, addition of a second immunosuppressive agent may be beneficial. However, complete recovery is rare with long-term cholestasis or hepatic failure being the eventual outcome. As ICI use becomes more prevalent, prompt recognition and proper management of irAEs will aid clinical decision making and improve outcomes.


Single dose of pembrolizumab leading to rapid, irreversible hepatic injury

Background
Rhabdomyosarcoma (RMS) is the most common soft-tissue tumor in children and adolescents but is rare in adults. RMS has three main subtypes: alveolar, embryonal, and pleomorphic. The embryonal subtype includes sarcoma botryoides, anaplastic type, and spindle cell type. Spindle cell rhabdomyosarcoma(SCR), comprising 5%-10% of RMS cases, is considered a distinct entity related to embryonal RMS. These tumors resemble leiomyomas histologically. With a 5-year survival rate of only 27% in adults, further research is needed. We report a case of a 21-year-old female with spindle cell rhabdomyosarcoma in the left frontal region.

Case Presentation
A 21-year-old female presented with a left frontal extracranial mass and intermittent headaches for the past year. Initial CT imaging revealed a 3.2 x 2.3 x 2.9 cm mass extending from the subcutaneous tissue through the bone intracranially. Initially suspected as a meningioma, MRI and angiogram later confirmed its growth and hypervascularity. Surgical resection was performed, and the pathology identified spindle cell rhabdomyosarcoma with FUS:TFCP2 fusion and positive IMHC markers (MYOD1, CKAE/AE, desmin, CD9, SSX-C, myogenin). Postoperatively, she developed a pulmonary embolism and was treated with apixaban. Subsequent visits for nausea, vomiting, and headaches led to observations of intracranial bleeding. Apixaban reversal was administered, and a six-week chemotherapy regimen (vincristine, adriamycin, cyclophosphamide) was initiated. A chest X-ray suggested possible pulmonary metastasis. Remaining treatment was continued at another facility.

Discussion
Sarcomas represent 1% of adult solid malignancies, with SCR being exceptionally rare (0.041 per 100,000). Predominantly found in the paratesticular region and head/neck of children, it is rarer in adults, especially in females. Diagnosis relies on histology, with MYOD1 as a primary marker, indicating poor prognosis when mutated. PIK3CA, involved in the mTOR pathway and also associated with SCR, was negative in this case. Spindle cell rhabdomyosarcoma in adults presents unpredictably, often forming in the lower extremities, abdomen, or inguinal region. Therefore, the frontal lobe tumor in this case demonstrates a distinct, uncommon location. Treatment follows general rhabdomyosarcoma guidelines, including cyclophosphamide and vincristine, with additional monitoring needed for metastasis and recurrence.

Spindle cell rhabdomyosarcoma in adults is a rare and complex malignancy. This case highlights the importance of recognizing its distinct pathological and immunohistochemical characteristics and demonstrates the effectiveness of surgical intervention followed by targeted chemotherapy. Understanding these nuances is crucial for enhancing diagnostic accuracy, optimizing treatment plans, and improving patient outcomes.


Spindle Cell Rhabdomyosarcoma in a Young Adult: A Rare Case with Unique Clinical Features

Objectives:
1. Outline the clinical background and pathophysiological mechanisms of spur cell hemolytic anemia
2. Discuss and highlight the presentation and interventions for a case of severe cirrhosis with associated end-stage hemolytic anemia
3. Evaluate and explore factors contributing to the unexpected clinical improvement of hemolytic anemia without liver transplantation

Background:
- Spur cell hemolytic anemia was first discussed in 1964 when a peripheral blood smear from a cirrhotic patient revealed erythrocytes with irregularly shaped projections
- Commonly associated with end-stage liver disease, this condition arises from disruptions in membrane lipid metabolism which leads to formation of acanthocytes— derived from the Greek word “acantho” meaning thorn
- Spur cell hemolytic anemia is a poor prognostic indicator, often requiring a liver transplant for clinical amelioration

Case Presentation: 
A 41-year-old female patient with decompensated cirrhosis secondary to chronic alcohol use (MELD 38) presented with jaundice and laboratory evidence of new onset acute anemia

Discussion:
- Cirrhosis disrupts lipid and cholesterol metabolism in the liver, leading to the accumulation of abnormal proteins, which alters the erythrocyte membrane and increases susceptibility to hemolysis
- The exact pathophysiology remains unclear, but it is believed that these membrane alterations result in the formation of abnormal red blood cells, such as target cells and acanthocytes, which are prone to hemolysis
- Liver transplantation is the only definitive treatment for spur cell hemolytic anemia, as it directly addresses the underlying cause of the condition
- The median survival for patients diagnosed with spur cell hemolytic anemia is approximately 1.9 years, with significantly higher mortality rates in those who are unable to undergo a liver transplant
- For patients ineligible for transplant, supportive care is the mainstay of management, aimed at minimizing symptoms and improving quality of life

Conclusion: 
- Spur cell hemolytic anemia, though associated with poor prognosis, can be managed with supportive care, including blood transfusions, liver disease management (albumin, diuretics), alcohol abstinence, and nutritional support
- The effectiveness of these treatments depends on the patient’s clinical status, MELD score, and the presence of comorbidities

Supportive Treatment of Spur Cell Hemolytic Anemia in the Setting of Decompensated Liver Failure

While Gastric cancer is the second leading cause of cancer-related mortality worldwide, its metastatic spread to the breast is extremely rare. This article illustrates a patient with primary diffuse-type gastric cancer which metastasized to the breast. 


A 52-year-old post-menopausal woman presented to the hospital with severe abdominal pain and constipation. Imaging showed lymphadenopathy gastric wall thickening, and a pulmonary nodule. Biopsy revealed diffuse type, poorly differentiated adenocarcinoma. A CT-PET showed hypermetabolic nodularity suspicious for primary breast malignancy versus metastatic disease. This was subsequently proven to be metastatic via immunochemistry staining. This case represents one of very few documented cases of gastric adenocarcinoma metastasizing to the breast and emphasizes the key role of immunohistochemistry in the diagnostic process.

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Exploring Kagami-Ogata Syndrome: Insights from a Case Report

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Hepatosplenic T-cell Lymphoma, αβ type, presenting in an elderly patient status post indolent B-cell lymphoma treatment

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Exploring Kagami-Ogata Syndrome: Insights from a Case Report​

Next from AMA Research Challenge 2024

Hepatosplenic T-cell Lymphoma, αβ type, presenting in an elderly patient status post indolent B-cell lymphoma treatment

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Exploring Kagami-Ogata Syndrome: Insights from a Case Report