Pulmonary Fibrosis in Children.

: Pulmonary fibrosis (PF) is a very rare condition in children, which may be observed in specific forms of interstitial lung disease. None of the clinical, radiological, or histological descriptions used for PF diagnosis in adult patients, especially in situations of idiopathic PF, can apply to pediatric situations. This observation supports the view that PF expression may differ with age and, most likely, may cover distinct entities. The present review aims at summarizing the current understanding of PF pathophysiology in children and identifying suitable diagnostic criteria.

Molecular and cellular characterizations of human cherubism: disease aggressiveness depends on osteoclast differentiation.

BACKGROUND: Cherubism is a rare autosomal dominant disorder of the jaws caused by mutation of the SH3BP2 gene. The bone is replaced by a fibrous granuloma containing multinucleated giant cells. Cells of the cherubism granuloma have never been systematically analyzed. Hence, the aim of this study was to characterize the cells in human cherubism granulomas, to determine the osteoclastic characteristics of the multinucleated giant cells and to investigate the potential role of TNF-α in human cherubism. RESULTS: Seven granulomas were analyzed in pathology, molecular biology and immunohistochemistry. Granulomas were composed mainly of macrophages or osteoclasts within a fibroblastic tissue, with few lymphoid cells. Myeloid differentiation and nuclear NFATc1 localization were both associated with disease aggressiveness. OPG and RANKL immunohistochemical expression was unexpected in our specimens. Five granuloma cells were cultured in standard and osteoclastogenic media. In culture, cherubism cells were able to differentiate into active osteoclasts, in both osteoclastogenic and standard media. IL-6 was the major cytokine present in the culture supernatants. CONCLUSION: Multinucleated giant cells from cherubism granulomas are CD68 positive cells, which differentiate into macrophages in non-aggressive cherubism and into osteoclasts in aggressive cherubism, stimulated by the NFATc1 pathway. This latter differentiation appears to involve a disturbed RANK-L/RANK/OPG pathway and be less TNF-α dependent than the cherubism mouse model.

The calcineurin inhibitor tacrolimus as a new therapy in severe cherubism.

Cherubism is a rare genetic disorder characterized by extensive growth of a bilateral granuloma of the jaws, resulting in facial disfigurement. Cherubism is caused by gain-of-function mutations in the SH3BP2 gene, leading to overactivation of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-dependent osteoclastogenesis. Recent findings in human and mouse cherubism have suggested that calcineurin inhibitors might be drug candidates in cherubism medical treatment. A 4-year-old boy with aggressive cherubism was treated with the calcineurin inhibitor tacrolimus for 1 year, and clinical, radiological, and molecular data were obtained. Immunohistologic analysis was performed to compare preoperative and postoperative NFATc1 staining and tartrate resistant acid phosphatase (TRAP) activity. Real-time PCR was performed to analyze the relative expression levels of OPG and RANKL. After tacrolimus therapy, the patient showed significant clinical improvement, including stabilization of jaw size and intraosseous osteogenesis. Immunohistologic analyses on granuloma showed that tacrolimus caused a significant reduction in the number of TRAP-positive osteoclasts and NFATc1 nuclear staining in multinucleated giant cells. Molecular analysis showed that tacrolimus treatment also resulted in increased OPG expression. We present the first case of effective medical therapy in cherubism. Tacrolimus enhanced bone formation by stimulating osteogenesis and inhibiting osteoclastogenesis.

Head and neck teratoma: from diagnosis to treatment.

INTRODUCTION: Head and neck teratoma is a rare entity. Its prognosis mostly depends on the risk of neonatal respiratory distress, its extension and potential malignancy. Surgical management must be as complete as possible to avoid recurrences and malignant transformation. The authors present a retrospective analysis of 6 cervicofacial teratomas and a review of the literature. The aim of the study was to analyse prenatal, neonatal and postnatal management of teratoma. MATERIALS AND METHODS: Charts of children presenting with a head and neck teratoma, managed by our maxillofacial and plastic surgery unit, were analysed and antenatal, clinical, biological, radiological and pathological characteristics were collected. Surgical treatment, recurrences and surgical outcomes were analysed. RESULTS: Six patients were included: 2 with a cervical teratoma, 2 with a facial teratoma and 2 with intraoral teratomas. In 2 cases, the lesions were diagnosed antenatally and both patients required neonatal resuscitation. All the patients underwent early surgery, and 3 with complete excisions. All patients with an initial incomplete excision eventually presented a recurrence and therefore second look surgery. No malignant transformation was noted. CONCLUSION: Early prenatal diagnosis is crucial to neonatal care. Early surgery and meticulous follow-up are critical in the long-term favourable outcome.

Infant Odontogenic Myxoma: a specific entity.

INTRODUCTION: In children, and specifically in infants, odontogenic myxomas are extremely rare. In infants, myxoma seems to display mostly the same clinical, radiological and pathological characteristics. This paper presents a series of odontogenic myxomas in infant patients. MATERIALS AND METHODS: Four infant patients were included in this retrospective study. The clinical, radiological and pathological presentation was characterized and the treatment analysed. RESULTS: All patients presented with a rapidly evolving paranasal swelling. CT-scan showed a maxillary homogeneous unilocular and intraosseous tumour. In all cases, pathological examination revealed a loose myxoid stroma within stellate and spindle shaped cells. All patients underwent conservative surgery through a vestibular approach. CONCLUSION: This patient series and a review of the literature demonstrates that odontogenic myxoma is specific in infant. We propose the name of Infant Odontogenic Myxoma for this entity.

Pulmonary sarcoid-like granulomatous disease in an 11-month-old girl.

Sarcoidosis is a chronic granulomatous disease of unknown aetiology. It is extremely rare in children, especially the early onset form, presenting with eye, skin and joint symptoms but no lung involvement. We report an 11-month-old girl with granulomatous disease restricted to the lungs consistent with sarcoidosis. This unusual presentation has never been described in the paediatric literature so far.

PTCH1 mutation and local aggressiveness of odontogenic keratocystic tumors in children: is there a relationship?

Keratocystic odontogenic tumors (KCOTs) are locally aggressive jaw lesions that may be related to PTCH1 mutations in isolation or in association with nevoid basal cell carcinoma syndrome. We sought to clarify the role of PTCH1 mutation in KCOT aggressiveness. We assessed cyst pathological characteristics, Ki-67 immunostaining, and somatic and germinal PTCH1 mutation in 16 KCOTs from 10 unrelated patients. Ten PTCH1 mutations were identified in 16 tumors. All tumors with PTCH1 mutations presented the criteria of pathological aggressiveness. We also noted the presence of a chorionic epithelial structure apparently acting as a secondary germinal center in these same tumors. Ki-67 immunostaining was not associated with PTCH1 mutation. KCOTs harboring the mutation display a chorionic epithelial structure that acts as a secondary germinal center. Genetic and microenvironmental factors might interact to propel tumor development.

Tetrasomy 13q31.1qter due to an inverted duplicated neocentric marker chromosome in a fetus with multiple malformations.

Small supernumerary marker chromosome (sSMC) lacking alpha satellite DNA or endogenous centromere regions are rare and contain fully functional centromeres, called neocentromeres. We report on a woman with a 14-week gestation pregnancy with a cystic hygroma and cerebellar hypoplasia at ultrasound examination. Cytogenetic studies showed a karyotype 47,XY,+mar dn. This sSMC was observed in chorionic villi, lung, and muscle tissue. Array Comparative Genomic Hybridization showed a gain from 13q31.1 to 13qter region. Fluorescent in situ hybridization with pan alpha satellite probe and probes specific for chromosome 13 showed a marker corresponding to an inversion duplication of the 13q distal chromosomal region without alpha satellite DNA sequence, suggesting the presence of a neocentromere. Examination of the fetus showed dysmorphic features, cystic cervical hygroma, postaxial polydactyly of the right hand and left foot with short fingers, malrotation of the gut, and a micropenis with hypospadias. Genotype-phenotype correlation in tetrasomy 13q is discussed according to the four 13q chromosomal breakpoints reported (13q32, 13q31, 13q21, 13q14) for chromosome 13 supernumerary markers.

De novo monosomy 9p24.3-pter and trisomy 17q24.3-qter characterised by microarray comparative genomic hybridisation in a fetus with an increased nuchal translucency.

OBJECTIVES: Increased nuchal translucency (NT) during the first trimester of pregnancy is a useful marker to detect chromosomal abnormalities. Here, we report a prenatal case with molecular cytogenetic characterisation of an abnormal derivative chromosome 9 identified through NT. METHODS: Amniocentesis was performed because of an increased NT (4.4 mm) and showed an abnormal de novo 46,XX,add(9)(p24.3) karyotype. To characterise the origin of the small additional material on 9p, we performed a microarray comparative genomic hybridisation (microarray CGH) using a genomic DNA array providing an average of 1 Mb resolution. RESULTS: Microarray CGH showed a deletion of distal 9p and a trisomy of distal 17q. These results were confirmed by FISH analyses. Microarray CGH provided accurate information on the breakpoint regions and the size of both distal 9p deletion and distal 17q trisomy. The fetus was therefore a carrier of a de novo derivative chromosome 9 arising from a t(9;17)(p24.3;q24.3) translocation and generating a monosomy 9p24.3-pter and a trisomy 17q24.3-qter. CONCLUSION: This case illustrates that microarray CGH is a rapid, powerful and sensitive technology to identify small de novo unbalanced chromosomal abnormalities and can be applied in prenatal diagnosis.

Discordant prenatal diagnosis of trisomy 21 due to mosaic structural rearrangements of chromosome 21.

OBJECTIVES: Trisomy 21 mosaicism associated with a structural rearrangement of chromosome 21 is uncommon. We report on two prenatal diagnoses in which karyotypes showed mosaicism with an aberrant cell line, including a structural rearrangement of chromosome 21. METHODS: Both these cases were associated with increased nuchal translucency. Conventional and molecular cytogenetic analyses were performed on uncultured and cultured trophoblast and amniotic fluid cells. RESULTS: In Case 1, analysis of trophoblast cells revealed an abnormal karyotype of 47,XX,+mar.ish der(13/21)(D13Z1/D21Z1+)/46,XX. The amniocentesis showed a free non-mosaic trisomy 21. In Case 2, the trophoblast direct analysis showed a normal male karyotype whereas the long-term culture revealed a mosaicism for a dicentric long-arm isochromosome 21: 46,XY,idic(21)(p11)/45,XY,-21/46,XY. Amniocentesis showed an unbalanced non-mosaic karyotype 46,XY,idic(21)(p11) resulting therefore in trisomy for the long arm of chromosome 21. CONCLUSION: Our cases underline the importance of combining the direct analysis and long-term culture of trophoblast and emphasise the need for confirmatory studies in other tissues when mosaicism of structural rearrangement is encountered in chorionic villi. The meiotic and mitotic mechanisms of formation of these structural rearrangements of chromosome 21 are discussed.