Camelia Stefanovici

A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype

Background Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. Methods Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype–phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. Results This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. Conclusions Our genotype–phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention.

Myxoinflammatory Fibroblastic Sarcoma in Children and Adolescents: Clinicopathologic Aspects of a Rare Neoplasm

Myxoinflammatory fibroblastic sarcoma (MIFS), originally described as a low-grade malignant soft-tissue tumor in adults, has recently been reported in children and in non-acral sites. This report describes the clinicopathologic features of a series of 5 MIFS in children and adolescents (3 males, 2 females), ranging in age from 5 to 17 years (mean, 13 years). These tumors presented as small, superficial, slowly growing soft-tissues masses of the scalp, neck, middle finger, forearm, and thigh. Histologically, the tumors were composed of spindled and plump polygonal cells with prominent nuclear pleomorphism, nuclear pseudoinclusions; large eosinophilic nucleoli; myxoid foci intermingled with spindled foci; and an accompanying inflammatory infiltrate of lymphocytes, plasma cells, and variable neutrophils. Immunohistochemical analysis revealed variable reactivity for CD34 and smooth muscle actin in the tumor cells. Genetic analysis in 3 cases showed no rearrangements of TGFBR3 or MGEA5. Follow up in 4 cases revealed no recurrence or metastasis. These 5 cases of childhood and adolescent MIFS demonstrate an expanded age range and topographic distribution and a favorable outcome. The differential diagnosis and importance of recognizing this rare neoplasm in young patients are discussed.

Prevalence of Peripheral Eosinophilia at Diagnosis in Children With Inflammatory Bowel Disease.

Background and Objective: Inflammatory bowel disease (IBD) encompasses 2 disorders of unknown etiology: Crohn disease (CD) and ulcerative colitis (UC). There has been a continuous search for markers for disease activity. Eosinophils are granulocytic leukocytes that are implicated in the pathogenesis of IBD. The aim of this study was to examine the prevalence and significance of peripheral eosinophilia (PE) at diagnosis in children with IBD. Methods: A comprehensive chart review of all children with diagnosed as having IBD between January 2006 and August 2014 was performed. Patients with PE at diagnosis were compared with those without in relation to disease clinical activity and disease course. Results: A total of 109 children (mean age 14.6 ± 2.77, range 4.5–17.9 years, 55 boys) with IBD (68 with CD and 41 with UC) who were studied for a mean duration of 2.82 ± 1.89 (range 0.1–9.2 years) were identified. At diagnosis, 44 (40.4%) children had PE, which was more prevalent in patients with UC compared with those with CD (61.3% vs 36.3%, P < 0.05). At diagnosis, PE was more common in patients with high eosinophilic count in colonic biopsy samples (P < 0.01) and was significantly associated with disease activity as indicated by Pediatric CD Activity Index for children with CD (P < 0.05), Pediatric UC Activity Index for children with UC (P < 0.01). Conclusions: PE is a common finding at diagnosis in children with IBD especially in those with UC. Patients with PE at diagnosis are more likely to present with higher clinical activity indices. PE is associated with more eosinophils in colonic biopsy samples.

Aggressive Metastatic Inflammatory Myofibroblastic Tumor After Allogeneic Stem Cell Transplant With Fatal Pulmonary Toxicity From Crizotinib.

Inflammatory myofibroblastic tumors (IMTs) are rare tumors with an intermediate spectrum of biological behavior. IMTs are uncommon secondary malignancies after hematopoietic stem cell transplant. The presence of anaplastic lymphoma kinase rearrangements in 50% of IMTs has led to therapeutic trials with crizotinib, although limited experience remains with crizotinib use in children. We describe the first reported case of a highly aggressive and metastatic IMT (secondary malignancy) in an 8-year-old girl following umbilical cord blood transplant. Although tumor response was demonstrated with anaplastic lymphoma kinase inhibition, she later developed fatal pulmonary toxicity from diffuse alveolar damage, a feature felt most likely to be due to crizotinib.

Intracranial atypical teratoid/rhabdoid tumor presenting as an axillary mass: a case report and review of literature.

Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon, high-grade pediatric malignancy of the central nervous system (CNS) that rarely metastasizes outside the CNS (Chang stage M4). We describe a child with the sole metastasis of an AT/RT to an axillary lymph node and no other site of extra-CNS disease at presentation. The tumor included areas of rhabdoid cells and failed to express the SMARCB1 gene product (INI1). The metastatic site in this patient is unusual for 3 reasons: (1) it is anatomically unexpected for a CNS tumor, (2) no other extra-CNS metastasis or primary tumor outside the CNS was found, and (3) no cardiac septal defect or vascular anomaly was identified. This site as the presenting lesion and sole metastasis of an intracranial AT/RT has not been previously reported. We attempt to explain this phenomenon.

Transplantation-associated thrombotic microangiopathy isolated to a congenital anomaly of the lung

TA‐TMA is a post‐hematopoietic stem cell transplant complication with clinical features of hemolytic anemia and thrombocytopenia. A 26‐month‐old child who had had an allogeneic transplant for treatment of DBA developed severe TA‐TMA with heavy red blood cell and platelet transfusion dependence. Incidentally, he was found to have a lung sequestration. TA‐TMA resolved and transfusion dependence resolved after resection of the sequestration. The finding suggests the malformation vasculature was selectively vulnerable to the trigger of TA‐TMA—raising perhaps a clue to basic pathophysiology of TA‐TMA and/or vascular malformations.