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Human Mutation 2023Germline pathogenic variants in predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification is essential...
Germline pathogenic variants in predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification is essential for reliable diagnosis of -related tumor predisposition and identification of individuals who may benefit from surveillance. Since 2015, most labs have followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) sequence variant classification guidelines for germline variant curation. However, these general guidelines lack gene-specific nuances and leave room for subjectivity. Consequently, a group of experts joined ClinGen to form the and miRNA-Processing Genes Variant Curation Expert Panel (VCEP), to create - specific ACMG/AMP guidelines for germline variant curation. The VCEP followed the FDA-approved ClinGen protocol for adapting and piloting these guidelines. A diverse set of 40 variants were selected for piloting, including 14 known Pathogenic/Likely Pathogenic (P/LP) variants, 12 known Benign/Likely Benign (B/LB) variants, and 14 variants classified as variants of uncertain significance (VUS) or with conflicting interpretations in ClinVar. Clinically meaningful classifications (i.e., P, LP, LB, or B) were achieved for 82.5% (33/40) of the pilot variants, with 100% concordance among the known P/LP and known B/LB variants. Half of the VUS or conflicting variants were resolved with four variants classified as LB and three as LP. These results demonstrate that the -specific guidelines for germline variant curation effectively classify known pathogenic and benign variants while reducing the frequency of uncertain classifications. Individuals and labs curating variants should consider adopting this classification framework to encourage consistency and improve objectivity.
Topics: Humans; Genetic Testing; Genetic Variation; Genome, Human; Genomics; Neoplasms; Germ Cells; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 38084291
DOI: 10.1155/2023/9537832 -
JPMA. the Journal of the Pakistan... Dec 2023Intraocular medulloepithelioma is a rare, congenital tumour of the non-pigmented ciliary epithelium. It most frequently arises from the ciliary body but can also have...
Intraocular medulloepithelioma is a rare, congenital tumour of the non-pigmented ciliary epithelium. It most frequently arises from the ciliary body but can also have its origin from the retina, iris and optic nerve. The age when lesion first appears is typically around 2-10 years. Nearly 50-60% of patients having this lesion may also have secondary features such as cataract and neovascular glaucoma. Those with extrascleral medulloepithelioma are at risk for metastasis. Systemic correlation of the tumour with pleuropulmonary blastoma/DICER1 gene is reported in the literature. Here, we report a case of a 15 years old boy with one year history of right eye proptosis and painful red right eye along with decreased vision for one week. He was assessed and operated for cataract elsewhere three years back. The ophthalmology team managed him for endophthalmitis with intravenous antibiotics, followed by 2 sessions of cryotherapy and finally an enucleation of right eye was performed due to severe pain and no vision in the involved eye. His left eye, general physical examination and systemic evaluation were normal. Histopathology revealed the diagnosis of 'malignant teratoid medulloepithelioma'. Therefore, evaluation of systemic associations for DICER1 gene mutations was performed by the oncology team. For high risk feature of scleral invasion on histopathology, he was treated with chemotherapy. Since the tumour is of rare occurrence; an international expert team with vast research experience in PPB/DICER1 associated tumours was also contacted. He was registered in International PPB/DICER1 registry where a detailed central radiology and pathology review was performed. Genetic counseling and surveillance plan was also suggested by the international registry.
Topics: Humans; Male; Child; Child, Preschool; Adolescent; Ciliary Body; Neuroectodermal Tumors, Primitive; Pulmonary Blastoma; Neoplasms, Germ Cell and Embryonal; Cataract; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 38083935
DOI: 10.47391/JPMA.8253 -
Journal of Pediatric Surgery Mar 2024Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have...
BACKGROUND
Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have been misdiagnosed and we may have missed DICER1-associated PPBs, a diagnosis with important clinical implications for patients and their families. To gain insight in potential misdiagnoses, we systematically assessed somatic DICER1 gene mutation status in an unselected, retrospective cohort of patients with a CPAM diagnosis.
METHODS
In the Amsterdam University Medical Center (the Netherlands), it has been standard policy to resect CPAM lesions. We included all consecutive cases of children (age 0-18 years) with a diagnosis of CPAM between 2007 and 2017 at this center. Clinical and radiographic features were reviewed, and DICER1 gene sequencing was performed on DNA retrieved from CPAM tissue samples.
RESULTS
Twenty-eight patients with a surgically removed CPAM were included. CPAM type 1 and type 2 were the most common subtypes (n = 12 and n = 13). For 21 patients a chest CT scan was available for reassessment by two pediatric radiologists. In 9 patients (9/21, 43%) the CPAM subtype scored by the radiologists did not correspond with the subtype given at pathology assessment. No pathogenic mutations and no copy number variations of the DICER1 gene were found in the DNA extracted from CPAM tissue (0/28).
CONCLUSIONS
Our findings suggest that the initial CPAM diagnoses were correct. These findings should be validated through larger studies to draw conclusions regarding whether systematic DICER1 genetic testing is required in children with a pathological confirmed diagnosis of CPAM or not.
LEVEL OF EVIDENCE
Level IV.
Topics: Child; Humans; Infant, Newborn; Infant; Child, Preschool; Adolescent; Cohort Studies; Retrospective Studies; Pulmonary Blastoma; Cystic Adenomatoid Malformation of Lung, Congenital; DNA; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 37989646
DOI: 10.1016/j.jpedsurg.2023.10.031 -
MedRxiv : the Preprint Server For... Nov 2023Current clinical variant analysis pipelines focus on coding variants and intronic variants within 10-20 bases of an exon-intron boundary that may affect splicing. The...
BACKGROUND
Current clinical variant analysis pipelines focus on coding variants and intronic variants within 10-20 bases of an exon-intron boundary that may affect splicing. The impact of newer splicing prediction algorithms combined with splicing assays on rare variants currently considered Benign/Likely Benign (B/LB) is unknown.
METHODS
Exome sequencing data from 576 pediatric cancer patients enrolled in the Texas KidsCanSeq study were filtered for intronic or synonymous variants absent from population databases, predicted to alter splicing via SpliceAI (>0.20), and scored as potentially deleterious by CADD (>10.0). Total cellular RNA was extracted from monocytes and RT-PCR products analyzed. Subsequently, rare synonymous or intronic B/LB variants in a subset of genes submitted to ClinVar were similarly evaluated. Variants predicted to lead to a frameshifted splicing product were functionally assessed using an splicing reporter assay in HEK-293T cells.
RESULTS
KidsCanSeq exome data analysis revealed a rare, heterozygous, intronic variant (NM_177438.3():c.574-26A>G) predicted by SpliceAI to result in gain of a secondary splice acceptor site. The proband had a personal and family history of pleuropulmonary blastoma consistent with syndrome but negative clinical sequencing reports. Proband RNA analysis revealed alternative transcripts including the SpliceAI-predicted transcript.Similar bioinformatic analysis of synonymous or intronic B/LB variants (n=31,715) in ClinVar from 61 Mendelian disease genes yielded 18 variants, none of which could be scored by MaxEntScan. Eight of these variants were assessed ( n=4, n=2, n=2) using splice reporter assay and demonstrated abnormal splice products (mean 66%; range 6% to 100%). Available phenotypic information from submitting laboratories demonstrated phenotypes in 2 families (1 variant) and breast cancer phenotypes for in 3 families (2 variants).
CONCLUSIONS
Our results demonstrate the power of newer predictive splicing algorithms to highlight rare variants previously considered B/LB in patients with features of hereditary conditions. Incorporation of SpliceAI annotation of existing variant data combined with either direct RNA analysis or assays has the potential to identify disease-associated variants in patients without a molecular diagnosis.
PubMed: 37961416
DOI: 10.1101/2023.10.30.23297632 -
Surgical Case Reports Nov 2023Pleuropulmonary blastoma (PPB) is an extremely rare and malignant pediatric lung tumor. Purely cystic PPB has a more favorable prognosis than solid PPB, but may be...
BACKGROUND
Pleuropulmonary blastoma (PPB) is an extremely rare and malignant pediatric lung tumor. Purely cystic PPB has a more favorable prognosis than solid PPB, but may be difficult to distinguish from a certain type of "benign" congenital pulmonary airway malformation before and during surgery. The influence of tumor rupture on long life prognosis has not been clarified in detail.
CASE PRESENTATION
A 5-month-old boy underwent emergency transfer from another hospital due to a left thoracic cystic lesion and left pneumothorax detected on chest radiography performed for persistent wheeze and cough. Contrast-enhanced computed tomography of the chest revealed marked deviation of the mediastinum to the right due to a giant cystic lesion and pneumothorax. Thoracotomy was performed on hospital day 2. A cystic lesion had developed from the distal alveolar region of lower lobe of the left lung and the tumor showed a tiny adhesion to the left diaphragm and a tiny rupture near the adhesion. Partial lung excision including the cyst and scraping of the adhesion were performed. Histopathological investigations revealed immature blast cell-like mesenchymal cells and differentiated striated muscle cells in a dense cambium layer were found under the epithelium of the cystic lesion. Type I PPB was diagnosed.
CONCLUSIONS
Surgery should be performed with the possibility of type I PPB in mind when an extrapulmonary cystic lung lesion is found. Since issues such as the pathogenesis and long-term prognosis of ruptured cases remain unclear, continued careful follow-up of this case will be required.
PubMed: 37930461
DOI: 10.1186/s40792-023-01777-7 -
JCO Precision Oncology Sep 2023Germline pathogenic loss-of-function (pLOF) variants in are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and...
Germline pathogenic loss-of-function (pLOF) variants in are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). The most common pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently. Identifying these variants can trigger surveillance algorithms with potential for early detection of -related cancers and cascade testing of family members. However, some patients with -associated tumors have no pLOF variants detected by germline or tumor testing. Here, we present two patients with SLCT whose tumor sequencing showed only a somatic missense RNase IIIb variant. Conventional exon-directed germline sequencing revealed no pLOF variants. Using a custom capture panel, we discovered novel intronic variants, ENST00000343455.7: c.1752+213A>G and c.1509+16A>G, that appear to interfere with normal splicing. We suggest that when no pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed.
Topics: Male; Female; Humans; Sertoli-Leydig Cell Tumor; Ovarian Neoplasms; Introns; Germ-Line Mutation; Mutation; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 37883719
DOI: 10.1200/PO.23.00189 -
EJC Paediatric Oncology Dec 2023While all childhood cancers are rare, tumors that are particularly infrequent or underrepresented within pediatrics are studied under the umbrella of the Children's...
While all childhood cancers are rare, tumors that are particularly infrequent or underrepresented within pediatrics are studied under the umbrella of the Children's Oncology Group Rare Tumor committee, divided into the Retinoblastoma and Infrequent Tumor subcommittees. The Infrequent Tumor subcommittee has traditionally included an emphasis on globally rare tumors such as adrenocortical carcinoma, nasopharyngeal carcinoma, or those tumors that are rare in young children, despite being common in adolescents and young adults, such as colorectal carcinoma, thyroid carcinoma, and melanoma. Pleuropulmonary blastoma, gonadal stromal tumors, pancreatic tumors including pancreatoblastoma, gastrointestinal stromal tumor, nonmelanoma skin cancers, neuroendocrine tumors, and desmoplastic small round cell tumors, as well as other carcinomas are also included under the heading of the Children's Oncology Group Rare Tumor committee. While substantial challenges exist in rare cancers, inclusion and global collaboration remain key priorities to ensure high quality research to advance care.
PubMed: 37829670
DOI: 10.1016/j.ejcped.2023.100024 -
Genes Aug 2023The identification of cancer predisposition syndromes (CPSs) plays a crucial role in understanding the etiology of pediatric cancers. CPSs are genetic mutations that...
The identification of cancer predisposition syndromes (CPSs) plays a crucial role in understanding the etiology of pediatric cancers. CPSs are genetic mutations that increase the risk of developing cancer at an earlier age compared to the risk for the general population. This article aims to provide a comprehensive analysis of three unique cases involving pediatric patients with CPS who were diagnosed with multiple simultaneous or metachronous cancers. The first case involves a child with embryonal rhabdomyosarcoma, nephroblastoma, glioma, and subsequent medulloblastoma. Genetic analysis identified two pathogenic variants in the gene. The second case involves a child with alveolar rhabdomyosarcoma, juvenile xanthogranuloma, gliomas, and subsequent JMML/MDS/MPS. A pathogenic variant in the gene was identified. The third case involves a child with pleuropulmonary blastoma and pediatric cystic nephroma/nephroblastoma, in whom a pathogenic variant in the gene was identified. Multiple simultaneous and metachronous cancers in pediatric patients with CPSs are a rare but significant phenomenon. Comprehensive analysis and genetic testing play significant roles in understanding the underlying mechanisms and guiding treatment strategies for these unique cases. Early detection and targeted interventions are important for improving outcomes in these individuals.
PubMed: 37761810
DOI: 10.3390/genes14091670 -
Pediatric Blood & Cancer Nov 2023Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Given the rarity of PPB, the role of positron emission tomography...
Assessing the role of positron emission tomography and bone scintigraphy in imaging of pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry.
BACKGROUND
Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Given the rarity of PPB, the role of positron emission tomography (PET) and bone scintigraphy (bone scans) in diagnostic evaluation and surveillance has not been documented to date. Available PET and bone scan data are presented in this study.
PROCEDURES
Patients with PPB enrolled in the International PPB/DICER1 Registry and available PET imaging and/or bone scan reports were retrospectively abstracted.
RESULTS
On retrospective analysis, 133 patients with type II and III (advanced) PPB were identified with available report(s) (PET scan only = 34, bone scan only = 83, and both bone scan and PET = 16). All advanced primary PPB (n = 11) and recurrent (n = 8) tumors prior to treatment presented with F-fluorodeoxyglucose (FDG)-avid lesions, with median maximum standardized uptake values of 7.4 and 6.7, respectively. False positive FDG uptake in the thorax was noted during surveillance (specificity: 59%). Bone metastases were FDG-avid prior to treatment. Central nervous system metastases were not discernable on PET imaging. Sensitivity and specificity of bone scans for metastatic bone disease were 89% and 92%, respectively. Bone scans had a negative predictive value of 99%, although positive predictive value was 53%. Four patients with distant bone metastases had concordant true positive bone scan and PET.
CONCLUSION
Primary, recurrent, and/or extracranial metastatic PPB presents with an FDG-avid lesion on PET imaging. Additional prospective studies are needed to fully assess the utility of nuclear medicine imaging in surveillance for patients with advanced PPB.
Topics: Humans; Child, Preschool; Retrospective Studies; Fluorodeoxyglucose F18; Positron-Emission Tomography; Radionuclide Imaging; Sensitivity and Specificity; Bone Neoplasms; Registries; Radiopharmaceuticals; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 37592371
DOI: 10.1002/pbc.30628 -
Radiology Case Reports Oct 2023Congenital pulmonary airway malformation (CPAM) is a rare congenital dysplastic malformation characterized by failure of bronchial development and localized glandular...
Congenital pulmonary airway malformation (CPAM) is a rare congenital dysplastic malformation characterized by failure of bronchial development and localized glandular overgrowth. Previously known as Congenital Cystic Adenoid Malformation (CCAM), CPAM is classified into 5 types, from type 0 to type IV, depending upon the origin of pulmonary areas of the lung, cyst size, and cyst appearance. CPAM is a rare congenital anomaly typically diagnosed prenatally in ultrasound. However, few cases are diagnosed in childhood and even fewer in adulthood. CPAM can be differentiated from pulmonary sequestration based on the origin of the arterial supply; the former has its arterial supply from the pulmonary artery, whereas pulmonary sequestration has its arterial supply from the systemic circulation. Another differential diagnosis of CPAM includes congenital bronchogenic cyst, congenital lobar emphysema, pleuropulmonary blastoma, congenital cystic bronchiectasis, and congenital diaphragmatic hernia. The most common presentation is recurrent chest infection and chest pain, whereas other presentation includes pneumothorax and hemoptysis. Here, we present a case of a 6-year-old child with recurrent episodes of fever and cough diagnosed as a type II CPAM based on computed tomography findings.
PubMed: 37539443
DOI: 10.1016/j.radcr.2023.07.018