Pediatric and Developmental Pathology

Inclusion cell disease (I-cell disease/Mucolipiodsis Type II) is an autosomal recessive lysosomal storage disorder that results in accumulation of substrates (cholesterol, phospholipids, and glycosaminoglycans) in various tissues. The clinical presentation of I-cell disease includes hepatomegaly, splenomegaly, cardiomegaly, upper respiratory infections, skeletal deformities, developmental delay, abnormal facies, and failure to thrive. We describe a case of I-cell disease in a neonate admitted to the Neonatal Intensive Care Unit for respiratory distress with initial suspicion of infection. Placental histopathological findings included syncytiotrophoblast vacuolization and positive lipid vacuoles highlighted with the special stain, Oil Red-O. Ultra-rapid whole genome sequencing from buccal swab identified compound heterozygous GNPTAB variants consistent with I-cell disease. Whole exome sequencing of placental tissue showed concordant pathogenic variants. To our knowledge, this is the first report of Oil Red-O staining of intracytoplasmic lipids within syncytiotrophoblast and successfully identifying variants by sequencing placental DNA in the setting of I-cell disease.

Hereditary thrombocytosis (HT) is a rare cause of elevated platelet counts in children, most commonly resulting from germline variants in THPO or MPL. We report the first description of bone marrow morphology in a pediatric patient with germline homozygous MPL Baltimore (K39N) variant, a functional polymorphism resulting in HT. The patient had persistent thrombocytosis from infancy without bleeding or thrombotic complications. Bone marrow biopsy demonstrated mild hypocellularity, increased megakaryocytes forming small clusters, and megakaryocytic atypia partially overlapping with the morphologic features of myeloproliferative neoplasms (MPN). However, a somatic cytogenetic or molecular abnormality was not identified and it was determined that the thrombocytosis and bone marrow morphology were driven by the homozygous germline MPL Baltimore variant. Literature review found reports of bone marrow morphology in HT showing varying degrees of megakaryocytic proliferation and atypia with differences seen between specific germline variants. Cases with germline MPL P106L variant have similar morphology as this homozygous MPL Baltimore case. While cases of germline MPL S550N are nearly identical to MPN with more severe megakaryocytic atypia and frequent development of marrow fibrosis. This case underscores the importance of considering HT in children with unexplained thrombocytosis and highlights the diagnostic pitfall of misclassifying HT as MPN.

Epithelioid fibrous histiocytoma (EFH) is a benign cutaneous neoplasm that is now recognized to be largely driven by ALK rearrangements. Rare cases of EFH and EFH-spectrum tumors with other receptor tyrosine kinase (RTK) fusions including RET and NTRK3 have been described, demonstrating the molecular heterogeneity of this entity. Herein, we report a 9-year-old female with a 1.5 cm right lateral chest wall lesion showing classic EFH morphology. Histology demonstrated a nodular dermal tumor extending to dermo-epidermal junction above and subcutaneous tissue below. The lesion was characterized by sheets of bland epithelioid/histiocytoid cells with a vaguely whorled architecture, prominent vessels, focal myxoid stroma, and no significant atypia, mitoses, or necrosis. On immunohistochemistry, the lesional cells were highlighted by CD68 and CD163, with patchy CD99 positivity. The lesional cells were negative for AE1/AE3, CD34, SMA, Desmin, S100, SOX10, CD10, ERG, CD1a, Langerin, CD30, and CD31. INI-1 was retained. Targeted solid tumor fusion analysis showed an ETV6::NTRK3 fusion. This case expands the molecular spectrum of EFH beyond ALK rearrangements and previously described RET and NTRK3 fusions.

Acute liver failure in the neonate generates a broad differential diagnosis of varying etiology including inborn errors of metabolism, infections, cholestatic disorders, gestational alloimmune liver disease (GALD), alpha-1 antitrypsin deficiency, total parenteral nutrition-related injury, malignancy, and others. We present a case of a neonate born at 39 weeks’ gestational age who presented on day 5 of life with coxsackievirus (part of the enterovirus family) encephalitis and COVID-19 infection and was subsequently found to be in acute liver failure (INR 1.7 up to 2.8 [not correctable with parenteral vitamin K], ammonia 87 umol/L up to 142 umol/L, AST 1864 IU/L, ALT 535 IU/L) with increasing alpha-fetoprotein. Evaluation for possible liver transplantation included an abdominal MRI, which showed a 2.4 × 1.7 × 2.1 cm round mass-like lesion in segment 2 of the liver, raising a differential diagnosis which included hepatoblastoma. This lesion and the background liver were biopsied. A nonspecific hepatitic pattern of injury was identified within the lesion and the background liver showed nodular post-necrotic changes with collapse of lobular architecture. While clinical case reports exist of acute hepatitis in neonates with COVID-19 alone and coxsackievirus alone, the role dual infection may play in causing severe liver injury is unique to our case and provides territory for continued investigation.

Pseudomyogenic hemangioendothelioma (PMH) is a rare, often multicentric neoplasm occurring primarily in soft tissue. Fewer than 50 cases of isolated bone lesions are described, with nearly all restricted to bone(s) of 1 region of the body. Two cases are described with diffuse bone involvement without soft tissue lesions, which has never been described in pediatric patients. We describe a unique case of PMH presenting as diffuse, polyostotic bone lesions in a 16-year-old. Neoplastic cells showed very weak, patchy staining for essential diagnostic stains, highlighting an important diagnostic pitfall. Additionally, the tumor showed uncharacteristic prominent histiocytic infiltrate without the usual associated neutrophils. Molecular sequencing detected ACTB::FOSB fusion transcript, confirming the diagnosis. This is the first described cases of diffuse, polyostotic PMH in a pediatric patient without soft tissue involvement. Furthermore, this is the first described case of histocyte-rich PMH. Overall, the case illustrates several unique features and diagnostic pitfalls important for pediatric pathologists to recognize in PMH. A high index of suspicion is necessary to perform the appropriate targeted molecular testing that might be needed to confirm the diagnosis.

Gaucher disease is a rare lysosomal storage disease caused by mutations in the GBA gene, resulting in the accumulation of glucosylceramides in macrophages. The perinatal/lethal form, also including fetal Gaucher disease, is a distinct and severe variant, usually presenting with non-immune hydrops fetalis, hepatosplenomegaly, ichthyosiform changes, and typical “Gaucher cells” seen on histology in various organs. Four cases of fetal/perinatal Gaucher disease are presented, 1 genetically confirmed and 3 histologically diagnosed, with a description of the prenatal findings and the pathological features at autopsy. In all 4 cases, hydrops was detected prenatally after the 24th week of gestation, leading to termination of pregnancy. Hepatosplenomegaly was confirmed at autopsy in 3 cases. Dysmorphic features included thick lips and eclabium, upturned nose, thick antitragus, and micropenis in the 2 male fetuses. Histologically, characteristic Gaucher cells were found in multiple organs, while in 2 cases brain involvement was reported. In conclusion, fetal Gaucher disease shows distinct pathological characteristics. Some facial features and micropenis are highlighted for the first time, whereas ichthyosiform body skin changes described in neonates and infants are not typically seen in the fetus. Brain involvement is variable. Further reporting of genotype-phenotype correlations is necessary in cases of fetal/perinatal Gaucher disease.

Glycogen storage disease type IV (Andersen disease) is caused by a deficiency of the glycogen branching enzyme. We report a case in which liver biopsy played a key role in establishing the diagnosis. A 2-year-old girl presented to our hospital with hepatomegaly. Despite extensive testing, no definitive diagnosis was made, prompting a liver biopsy. The biopsy tissue revealed characteristic cytoplasmic inclusions. Genetic analysis identified a mutation in the GBE1 gene, confirming the diagnosis of glycogen storage disease type IV. Various special stains were helpful in characterizing the accumulated substances.

Pediatric acute myeloid leukemia (AML) is heterogeneous, and molecular genetics strongly influence prognosis. Although t(8;21) AML is considered favorable, additional mutations such as ASXL1 can worsen outcomes. We report a 13-year-old boy with 2 months of fever, pancytopenia, and disseminated MRSA abscesses. Bone marrow showed myelokathexis but no blasts. Immunological evaluation excluded WHIM syndrome and inborn errors of immunity. After infection control and transient hematologic recovery, the child relapsed with recurrent fever and cytopenia. Peripheral smear revealed 85% myeloblasts; bone marrow confirmed AML with t(8;21), monosomy Y, del(9q), and ASXL1 mutation. He achieved remission with cytarabine-based induction and consolidation, but hematopoietic stem cell transplantation (HSCT) was declined. This case illustrates the diagnostic challenge of prolonged cytopenia and infection preceding AML. Myelokathexis suggested immune dysfunction but ultimately represented an early clonal abnormality. Although t(8;21) is favorable, ASXL1 mutation confers high-risk biology, supporting HSCT in first remission. Children with unexplained cytopenia require vigilant monitoring and genomic profiling. Integration of molecular risk factors should guide individualized treatment strategies.

Congenital sacrococcygeal teratomas (SCTs) are rare tumors with highly variable prognosis, influenced by associated abnormalities and marked histological heterogeneity. SCTs may exhibit somatic renal differentiation, encompassing a wide spectrum of cytological and architectural features, for which accepted diagnostic criteria are lacking. This renders the distinction between immature nephrogenic tissue and true nephroblastoma particularly challenging. We report an illustrative neonatal case of SCT containing a minor nephroblastomatous component and conducted a systematic review to evaluate management and outcomes in newborns (≤28 days old) with renal tissue identified within SCTs. A comprehensive search of PubMed, Scopus, and Web of Science yielded 532 records, of which 16 studies met inclusion criteria. Including the present case, 19 newborns were analyzed. Renal tissue was described as immature or ectopic nephrogenic tissue in 15 cases (79%) and as overtly malignant, consistent with Wilms tumor, in 4 cases (21%). All patients underwent surgical resection, while chemotherapy (n = 5; 26.3%) and radiotherapy (n = 2; 10.5%) were less frequently administered. Median follow-up was 29.5 months (range: 4-154), with no cancer-related mortality. In the absence of standardized diagnostic criteria, renal differentiation within SCTs represents a diagnostic and therapeutic dilemma, supporting a cautious, multidisciplinary management approach.

Drug-induced liver injury (DILI) in children remains a diagnostic challenge due to its broad clinical and histologic spectrum. Based on pathogenesis, DILI is classified as idiosyncratic, intrinsic (direct), or indirect. In the United States, antimicrobials and antiepileptic medications are the most commonly implicated agents. Because histologic features are often nonspecific, diagnosis and assessment of causality rely on clinicopathologic correlation. Although not always required, liver biopsy can aid in characterizing injury patterns, assessing severity, and excluding mimickers. This review highlights the major morphologic patterns of pediatric DILI, associated agents, and practical considerations for biopsy interpretation in routine practice.

Most thyroid nodules encountered in clinical endocrinology are epithelial in origin. In contrast, primary thyroid mesenchymal tumors are exceedingly rare but increasingly recognized with advances in immunohistochemistry and molecular diagnostics. Thyroid myofibroma is an exceptionally uncommon benign fibroblastic–myofibroblastic neoplasm, with only a limited number of cases reported to date. We report a 9-year-old girl with Turner syndrome (TS) and a prior myofibroblastic proliferation of the parotid gland 5 years earlier, who presented with a solitary thyroid nodule. Fine-needle aspiration (FNA) demonstrated a spindle-cell proliferation suspicious for an extrafollicular process. Lobectomy revealed a well-circumscribed, unencapsulated spindle-cell tumor composed of bland myofibroblastic cells arranged in fascicles within a collagenous stroma. The immunophenotype supported myofibroma. Targeted molecular testing identified a pathogenic PDGFRB variant and a novel variant of uncertain significance, confirming the diagnosis. No prior reports have described thyroid myofibroma associated with TS or a preceding salivary gland myofibromatous lesion, making this case unique and diagnostically and pathogenetically significant. Awareness of this entity is critical to avoid misclassification as other spindle-cell thyroid lesions on FNA. Integrated cytomorphology, immunophenotyping, and PDGFRB-focused molecular analysis provide a robust diagnostic approach and may offer insight into shared pathogenetic mechanisms linking TS and myofibroblastic proliferations.