Oral cancer in a 5-year-old boy: a rare case report and review of literature.

Oral cancer in children is rare. Diagnosis may be delayed as a result of confusion with reactive lesions. Furthermore, cancer staging, with or without bony invasion, can be complicated during tooth eruption. Literature on pediatric oral cancers is lacking, making determination of the possible etiopathology difficult. We describe an exceptional case of a 5-year-old male child who presented with anterior maxillary gingival pseudoepitheliomatous hyperplasia that progressed to carcinoma cuniculatum with invasive oral squamous cell carcinoma (OSCC). Because of the interesting timing of events, we hypothesize that human papillomavirus (HPV) inoculation through cutaneous squamous papilloma played a contributory role. A review of similar case reports in the literature is included. Biopsy of suspicious oral lesions should not be delayed because of the young age of the patient. Atypical hyperplasia should include squamous cell carcinoma (SCC) in the differential diagnoses. For surgical management of aggressive lesions during the mixed dentition, permanent successors should be included in the surgical margins to prevent recurrence.

The importance of considering monogenic causes of autoimmunity: A somatic mutation in KRAS causing pediatric Rosai-Dorfman syndrome and systemic lupus erythematosus.

OBJECTIVES: Clinicians need to be aware of the growing list of defined monogenic etiologies of autoimmune diseases. This is particularly relevant when evaluating children, as these rare monogenic forms of autoimmunity tend to present very early in life. METHODS AND RESULTS: By harnessing the transformative power of next generation sequencing, we made the unifying diagnosis of RAS-associated autoimmune leukoproliferative disease (RALD), caused by the somatic gain-of-function p.G13C KRAS mutation, in a boy with the seemingly unrelated immune dysregulatory conditions of Rosai-Dorfman and systemic lupus erythematosus (SLE). CONCLUSIONS: This case expands our understanding of the clinical phenotypes associated with the extremely rare condition of RALD, and emphasizes the importance of always considering the possibility of a monogenic cause for autoimmunity, particularly when the disease manifestations begin early in life and do not follow a typical clinical course.

Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction.

INTRODUCTION: Discriminating between placentally-mediated fetal growth restriction and constitutionally-small fetuses is a challenge in obstetric practice. Placental growth factor (PlGF), measurable in the maternal circulation, may have this discriminatory capacity. METHODS: Plasma PlGF was measured in women presenting with suspected fetal growth restriction (FGR; ultrasound fetal abdominal circumference <10th percentile for gestational age) at sites in Canada, New Zealand and the United Kingdom. When available, placenta tissue underwent histopathological examination for lesions indicating placental dysfunction, blinded to PlGF and clinical outcome. Lesions were evaluated according to pre-specified severity criteria and an overall severity grade was assigned (0-3, absent to severe). Low PlGF (concentration <5th percentile for gestational age) to identify placental FGR (severity grade≥2) was assessed and compared with routine parameters for fetal assessment. For all cases, the relationship between PlGF and the sampling-to-delivery interval was determined. RESULTS: Low PlGF identified placental FGR with an area under the receiver-operator characteristic curve of 0.96 [95% CI 0.93-0.98], 98.2% [95% CI 90.5-99.9] sensitivity and 75.1% [95% CI 67.6-81.7] specificity. Negative and positive predictive values were 99.2% [95% CI 95.4-99.9] and 58.5% [95% CI 47.9-68.6], respectively. Low PlGF outperformed gestational age, abdominal circumference and umbilical artery resistance index in predicting placental FGR. Very low PlGF (<12 pg/mL) was associated with shorter sampling-to-delivery intervals than normal PlGF (13 vs. 29.5 days, P < 0.0001). DISCUSSION: Low PlGF identifies small fetuses with significant underlying placental pathology and is a promising tool for antenatal discrimination of FGR from fetuses who are constitutionally-small.

Successful clinical treatment and functional immunological normalization of human MALT1 deficiency following hematopoietic stem cell transplantation.

MALT1 mutations impair normal NF-κB activation and paracaspase activity to cause a novel combined immunodeficiency. The clinical and immunological phenotype of MALT1 deficiency can be successfully treated with hematopoietic stem cell transplantation following reduced intensity conditioning.

Melanotic neuroectodermal tumour of infancy: a case report.

Melanotic neuroectodermal tumour of infancy is a rare benign pigmented tumour that typically appears in the first year of life. We report an atypical presentation of this tumour, associated with an erupted primary tooth in a 7-month-old boy. We discuss the clinical, radiographic and histologic features of this rare tumour, as well as its surgical management and the follow-up treatment plan.

Impaired NLRP3 inflammasome activity during fetal development regulates IL-1ß production in human monocytes.

Interleukin-1ß (IL-1ß) production is impaired in cord blood monocytes. However, the mechanism underlying this developmental attenuation remains unclear. Here, we analyzed the extent of variability within the Toll-like receptor (TLR)/NLRP3 inflammasome pathways in human neonates. We show that immature low CD14 expressing/CD16(pos) monocytes predominate before 33 weeks of gestation, and that these cells lack production of the pro-IL-1ß precursor protein upon LPS stimulation. In contrast, high levels of pro-IL-1ß are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL-1ß. The lack of secreted IL-1ß in these monocytes parallels a reduction of NLRP3 induction following TLR stimulation resulting in a lack of caspase-1 activity before 29 weeks of gestation, whereas expression of the apoptosis-associated speck-like protein containing a CARD and function of the P2×7 receptor are preserved. Our analyses also reveal a strong inhibitory effect of placental infection on LPS/ATP-induced caspase-1 activity in cord blood monocytes. Lastly, secretion of IL-1ß in preterm neonates is restored to adult levels during the neonatal period, indicating rapid maturation of these responses after birth. Collectively, our data highlight important developmental mechanisms regulating IL-1ß responses early in gestation, in part due to a downregulation of TLR-mediated NLRP3 expression. Such mechanisms may serve to limit potentially damaging inflammatory responses in a developing fetus.

Diffuse angiopathy in Adams-Oliver syndrome associated with truncating DOCK6 mutations.

Adams-Oliver syndrome (AOS) is a rare malformation syndrome characterized by the presence of two anomalies: aplasia cutis congenita of the scalp and transverse terminal limb defects. Many affected individuals also have additional malformations, including a variety of intracranial anomalies such as periventricular calcification in keeping with cerebrovascular microbleeds, impaired neuronal migration, epilepsy, and microcephaly. Cardiac malformations can be present, as can vascular dysfunction in the forms of cutis marmorata telangiectasia congenita, pulmonary vein stenoses, and abnormal hepatic microvasculature. Elucidated genetic causes include four genes in different pathways, leading to a model of AOS as a multi-pathway disorder. We identified an infant with mild aplasia cutis congenita and terminal transverse limb defects, developmental delay and a severe, diffuse angiopathy with incomplete microvascularization. Whole-genome sequencing documented two rare truncating variants in DOCK6, a gene associated with a type of autosomal recessive AOS that recurrently features periventricular calcification and impaired neurodevelopment. We highlight an unexpectedly high frequency of likely deleterious mutations in this gene in the general population, relative to the rarity of the disease, and discuss possible explanations for this discrepancy.

Somatic mosaicism for the p.His1047Arg mutation in PIK3CA in a girl with mesenteric lipomatosis.

We describe a patient who presented with a localized growth of mature fat tissue, which was surgically removed. MRI imaging identified diffuse increase in visceral adipose tissue. Targeted deep sequencing of the resected tissue uncovered a p.H1047R variant in PIK3CA, which was absent in blood. This report expands the phenotypic spectrum of mosaic PIK3CA mutations.

Hierarchical maturation of innate immune defences in very preterm neonates.

BACKGROUND: Preterm neonates are highly vulnerable to infection. OBJECTIVES: To investigate the developmental contribution of prematurity, chorioamnionitis and antenatal corticosteroids (ANS) on the maturation of neonatal microbial pathogen recognition responses. METHODS: Using standardized protocols, we assayed multiple inflammatory cytokine responses (IL-1ß, IL-6, TNF-α and IL-12/23p40) to three prototypic Toll-like receptor (TLR) agonists, i.e. TLR4 (lipopolysaccharide), TLR5 (flagellin) and TLR7/8 (R848), and to the non-TLR retinoic acid-inducible gene I (RIG-I)-like receptor agonist, in cord blood mononuclear cells from neonates born before 33 weeks of gestation and at term. RESULTS: TLR responses develop asynchronously in preterm neonates, whereby responses to TLR7/8 were more mature and were followed by the development of TLR4 responses, which were also heterogeneous. Responses to TLR5 were weakest and most immature. Maturity in TLR responses was not influenced by sex. Overall, we detected no significant contribution of ANS and chorioamnionitis to the developmental attenuation of either TLR or RIG-I responses. CONCLUSIONS: The maturation of anti-microbial responses in neonates born early in gestation follows an asynchronous developmental hierarchy independently of an exposure to chorioamnionitis and ANS. Our data provide an immunological basis for the predominance of specific microbial infections in this age group.

Successful approach to treatment of Helicobacter bilis infection in X-linked agammaglobulinemia.

Helicobacter bilis, an unusual cause of chronic infections in patients with X-linked agammaglobulinemia (XLA), is notoriously difficult to diagnose and eradicate. Based on the limited number of cases reported worldwide, we highlight the typical features of H. bilis infection in XLA and provide a rational and successful approach to diagnosis and treatment of this challenging infection.

The role of angiogenesis in the transformation of plexiform neurofibroma into malignant peripheral nerve sheath tumors in children with neurofibromatosis type 1.

PURPOSE: The role of angiogenesis in the transformation of peripheral neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) remains elusive and forms the objective of this study. EXPERIMENTAL DESIGN: Archival tissue from 5 children with NF1 and PNF, who developed MPNST between the ages of 8 and 15 years were analyzed for differences in microvasculature. The role of proangiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF), and its receptors Flk-1 and Flt-1, and vessel maturity, defined as von Willebrand factor (vWf), α-smooth muscle actin+ (SMA+), were evaluated by immuno-histochemistry. RESULTS: A qualitative evaluation of the vasculature showed predominantly α-SMA+/vWf+ more stable vessels in PNF, and an irregular meshwork of α-SMA-/vWf+ endothelial cells structures in MPNST. In NF and PNF tumor cells were VEGF-, in contrast to VEGF+ tumor cells in MPNST. If present, the VEGF stain was confined mainly to the perivascular spaces in PNF, unlike the mainly stromal VEGF stain in MPNST. VEGF receptors also manifested a tumor stage-specific pattern. Flk-1 and Flt-1 were restricted to the mature, well-formed vasculature in PNF, but exhibited a diffuse pattern in MPNST. CONCLUSION: Our study provides a rare opportunity to document consistent and histologically detectable differences in the vascular organization of PNF and MPNST. It permits a pair-wise evaluation of the malignant conversion of benign PNF into its malignant counterpart, in the same patients. The phenotypic variations and characteristics of the vessels in these tumors are consistent with the idea that a strong proangiogenic drive contributes to the progressive growth in MPNST.

Abnormal liver transaminases and conjugated hyperbilirubinemia at presentation of acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. While hepatitis is a well-known complication during the treatment phase of ALL, the association of abnormal liver biochemistries at initial presentation of leukemia is poorly described. The aim of this study is to examine the prevalence and assess the clinical impact of hepatitis at diagnosis in children with ALL. PROCEDURE: All children diagnosed with ALL at BC Children's Hospital between 2001 and 2006 were included. Charts were reviewed and data recorded to a computerized spreadsheet. Descriptive statistical analyses were performed. RESULTS: One hundred forty-seven ALL patients were identified. Over one third of patients had abnormal liver transaminase values (AST and/or ALT). Of the patients with abnormal transaminases, (52%) had ALT elevations twice the upper limit of normal. Risk factors for elevated transaminases included a high WBC count at diagnosis, older age, bulky disease, and T-cell leukemia. Conjugated hyperbilirubinemia was observed in 3.4% of subjects. Of these cases, 60% received steroids prior to induction chemotherapy and all had rapid resolution of their hyperbilirubinemia to normal levels. CONCLUSIONS: Elevated transaminases are common at initial presentation of ALL and are likely due to hepatic injury from leukemic infiltrates. Conjugated hyperbilirubinemia at presentation may require treatment modification and dose reduction. A short course of steroids prior to initiation of induction chemotherapy appears to result in rapid resolution of the hyperbilirubinemia with subsequent ability to provide full dosing of induction chemotherapy.

Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature.

We describe the clinicopathologic features of 15 patients who had histiocytic lesions that followed acute lymphoblastic leukemia (ALL). Twenty-one separate histiocytic lesions were evaluated that covered a wide spectrum, some conforming to the usual categories of juvenile xanthogranulomas (5), Langerhans' cell histiocytosis (1), Langerhans' cell sarcoma (4), Rosai-Dorfman disease (1), and histiocytic sarcoma (4). Most were atypical for the category by histology, phenotype, or abnormally high turnover rate. Seven low-grade lesions defied easy categorization and were characterized only as "atypical histiocytic lesion" following ALL. For those evaluated, the molecular signature of the prior leukemia was present in the histiocytic lesion. In 3 of 15 patients, the leukemia and histiocytic lesion shared immunoglobulin H or monoclonal TCR gene rearrangements and, in 4 of 15 patients, clonal identity was documented by fluorescence in situ hybridization. Four patients died of progressive disease, 3 of whom had histiocytic sarcoma and 1 who had an atypical lesion. One patient died of recurrent ALL. The other 10 patients are alive, 7 after recurrences and treatment with surgery and/or chemotherapy. The post-ALL lesions are more aggressive than their native counterparts, but despite the demonstration of the presence of the leukemia signature in 7 of 15 patients, the prognosis is generally favorable, except for patients with histiocytic sarcoma. It remains unclear whether the histiocytic lesions arise as a line from the original ALL or whether transdifferentiation is involved.

Pre- and postnatal findings in a boy with duplication of the bladder and intestine: report and review.

We describe a boy with a septated bladder and dilated bowel loop found on prenatal ultrasonography. Subsequent prenatal MRI diagnosed a probable caudal duplication anomaly. Postnatal investigations and surgical findings confirmed duplication of bladder, urethra, and bowel from distal ileum to rectum. This is the first reported case of combined bladder and colon duplication suspected antenatally with thorough imaging investigations including fetal MRI. While diagnosis of bladder duplication has been described, prenatal diagnosis of intestinal duplication has not been documented previously. This report of prenatal imaging with surgical and pathological correlation contributes to our detailed understanding of the spectrum of anatomy seen in caudal duplication anomaly.

Therapy resistant neonatal seizures, linear vesicular rash, and unusually early neuroradiological changes: incontinentia pigmenti: a case report, literature review and insight into pathogenesis.

CASE PRESENTATION: A substance abusing G2P1 mother spontaneously delivered at term an appropriate for gestational age girl. Neonatal seizures appeared at 21 hours and empiric anticonvulsive and antimicrobial treatment was started. At 25 hours, first vesicles appeared. While routine evaluations remained normal, a head CT revealed multifocal ischemic injuries, and a later MRI showed multifocal petechiae and diffusion abnormalities in the corticospinal tracts. The clinical diagnosis of incontinentia pigmenti (stage 1) was secured by histopathology. Follow-up at 13 months showed global developmental delay. DISCUSSION: We discuss the unusually early bilateral, fronto-occipital corticomedullar ischemias (CT day 3). On the MR imaging (day 7) extensive symmetric cerebral corticomedullar destruction and diffusion sequences with corticospinal tracts abnormalities are seen, which then evolve (day 26) to extensive symmetric cerebral destruction. We review the literature, genetics, suspected pathophysiology and possible neonatal manifestation. CONCLUSION: Incontinentia pigmenti is rare and, therefore, diagnosis is frequently delayed. Nevertheless, in the setting of therapy refractory seizures, excluded infections, and linear vesicular rash, a high index of suspicion is needed. This is the first report of simultaneous corticomedullar involvement as early as the third day of life.

Renal cystic diseases: a review.

This review aims to assist in the categorization of inherited, developmental, and acquired cystic disease of the kidney as well as to provide a pertinent, up-to-date bibliography. The conditions included are autosomal-dominant polycystic kidney disease, autosomal-recessive polycystic kidney disease, unilateral renal cystic disease (localized cystic disease), renal simple cysts, multicystic dysplastic kidney, pluricystic kidney of the multiple malformation syndromes, juvenile nephronophthisis and medullary cystic disease, medullary sponge kidney, primary glomerulocystic kidney disease, and glomerulocystic kidney associated with several systemic disorders mainly of genetic or chromosomal etiology, cystic kidney in tuberous sclerosis, and in von Hippel-Lindau syndrome, cystic nephroma, cystic variant of congenital mesoblastic nephroma, mixed epithelial stromal tumor of the kidney, renal lymphangioma, pyelocalyceal cyst, peripylic cyst and perinephric pseudocyst, acquired renal cystic disease of long-term dialysis, and cystic renal cell carcinoma and sarcoma. Whereas the gross and histologic appearance of some of these conditions may be diagnostic, clinical and sometimes molecular studies may be necessary to define other types.