Metachronous Type I pleuropulmonary blastoma and atypical choroid plexus papilloma in a young child

Pleuropulmonary blastoma (PPB) is a rare childhood tumor, often associated with germline DICER1 mutations and a risk for development of other benign and malignant tumors, a constellation termed DICER1 syndrome. A 1‐year‐old male was diagnosed with Type I PPB and screened regularly thereafter for detection of intrathoracic and intraabdominal disease. Ten months after diagnosis of PPB, he presented with headaches and vomiting. He was diagnosed with atypical choroid plexus papilloma, a lesion not previously reported with PPB. The presence of central nervous system symptoms in patients with PPB or a phenotype suggestive of DICER1 syndrome should prompt early intracranial imaging.     

Familial pleuropulmonary blastoma in Australia

We present three cases of pleuropulmonary blastoma (PPB) in Australian children. Each had a family history of childhood tumors which collectively included PPB, infant lung cyst, cystic nephroma, medullo-epithelioma and a Sertoli-Leydig ovarian tumor. Two of the patients also had additional malignancies: a concurrent bladder rhabdomyosarcoma and a post therapy non-PPB malignant lung tumor. In two cases, the family histories were elicited years after the PPB diagnosis. Archived pathology material allowed revision of pathologic diagnoses from decades earlier. These cases illustrate the importance of detailed inquiry into family medical history and the pleiotropy of the PPB-related familial cancer predisposition syndrome, which appears to result from heterozygous DICER1 mutations.     

A pair of DICER1‐positive monozygotic twins: One with pleuropulmonary blastoma,another with acute transient hepatitis

Pleuropulmonary blastoma (PPB) is the most common primary malignant neoplasm of the lung in children that is associated with a germline mutation in DICER1. In this report, we share an interesting case of a pair of monozygotic twins: one of them developed PPB when she was 4‐year old, while the other developed acute transient hepatitis when she was 5‐year old. Next‐Gen sequencing for DICER1 mutations of their family revealed that both twins and their mother had c.C3675A mutation. The mother also had a history of multinodular goiter. Identification of DICER1 mutation carriers and close surveillance of individuals at risk for DICER1 syndrome may allow early detection and hence better outcome.     

Type III pleuropulmonary blastoma in a dicer1 germline mutation carrier: The management of residual lung cystic lesions

Pleuropulmonary blastoma (PPB) is a rare malignancy of childhood. It often represents a manifestation of a hereditary tumor predisposition syndrome (DICER1 syndrome). Because of its malignant potential, surgical resection of cystic lung lesions is recommended in germline DICER1 mutation carriers. We present a case of a 3‐year‐old male child with type III PPB successfully managed with ifosfamide, vincristine, actinomycin‐D, and doxorubicin (IVADo) chemotherapy and surgery. A heterozygous germline pR688X mutation of DICER1 gene was demonstrated. Six years after primary diagnosis, several small lung cysts remained stable without further therapy. The management of residual asymptomatic lung cysts represents a clinical challenge in these patients.     

DICER1 syndrome: Approach to testing and management at a large pediatric tertiary care center

1 Background

To expand the current knowledge of DICER1 syndrome and to propose criteria for genetic testing based on experience at a pediatric tertiary care center.

2 Procedure

This study involved a retrospective chart review of the 78 patients (47 probands and 31 family members) seen in the Cancer Genetics Program at The Hospital for Sick Children (SickKids) who were offered genetic testing for DICER1.

3 Results

Of 47 probands offered genetic testing for DICER1, 46 pursued testing: 11 (23.9%) carried a pathogenic variant and one proband (2.1%) carried a missense variant of uncertain significance with evidence for pathogenicity. Thirty‐one family members of variant‐positive probands were offered testing: eight of the 25 who agreed to testing carried their familial variant (32.0%). Overall, 20 patients were identified to have a variant in DICER1 (eight males, 12 females). Of these, 13 (65.0%) presented with clinical manifestations associated with the syndrome. The most common lesions were pleuropulmonary blastoma (PPB) (five of 20 patients, 25.0%) and pineoblastoma (three of 20 patients, 15.0%). The average age at which individuals were diagnosed with a primary neoplasm was 5.2 years (range 0.8–20 years, median 3.0). Surveillance at our institution, with a median follow‐up time of 23 months, has identified PPB in two asymptomatic individuals. These lesions were identified at early stages, thus potentially reducing treatment‐related morbidity and mortality.

4 Conclusion

This study further delineates the DICER1 syndrome phenotype and demonstrates the feasibility of a DICER1 syndrome surveillance protocol for the early detection of tumors.     

Evolution of Renal Cysts to Anaplastic Sarcoma of Kidney in a Child With DICER1 Syndrome

Anaplastic sarcoma of kidney (ASK) is a rare neoplasm recently associated with DICER1 mutations. We report a child with germline DICER1 mutation who developed ASK in preexisting septated renal cysts, which were likely cystic nephroma. From age 2.5 to 6 years, sonographic imaging illustrated changes in the size and number of renal cysts, followed at age 8.8 years by a mass, pathologically an ASK. Lung cysts resected in infancy were diagnosed retrospectively as pleuropulmonary blastoma. Both tumors had acquired somatic DICER1 mutations. Ultrasonographic evolution of renal cysts to ASK has not previously been documented. Children with both pulmonary and renal cysts are candidates for DICER1 mutation testing.     

A case of neuroblastoma in DICER1 syndrome: Chance finding or noncanonical causation?

DICER1 syndrome is an inherited disorder associated with at least a dozen rare, mainly pediatric‐onset tumors. Its characterization remains incomplete. Some studies suggested that neuroblastoma (NB) may be involved in this syndrome. Here, we describe the case of a 14‐year‐old female presenting with a multinodular goiter (MNG) and a collision tumor composed of NB and cystic nephroma (CN). She is a carrier of a deleterious germline mutation in exon 23 of DICER1 and harbored different somatic mutations in the CN and MNG. However, no second hit was found in the NB, questioning its status as a DICER1‐related tumor.     

Mutiple DICER1‐related lesions associated with a germline deep intronic mutation

Germline DICER1 pathogenic variants predispose to numerous benign and malignant tumors. In this report, we describe DICER1 gene analysis in an adolescent diagnosed with multinodular goiter, ovarian Sertoli–Leydig cell tumor, and lung cyst. DICER1 mutational screening at the DNA level failed to detect any pathogenic variant. Subsequent messenger RNA (mRNA) analysis revealed a 132 nucleotide intronic sequence exonization. This truncating event was caused by a deep intronic mutation generating a de novo acceptor splice site. This study demonstrates that some undetected DICER1 mutations should be investigated at the mRNA level.     

儿童胸膜肺母细胞瘤38例诊治分析

目的探讨儿童胸膜肺母细胞瘤的发病年龄、临床表现、病理分型及特点、治疗原则及预后情况。方法回顾性研究自2002年3月至2018年3月期间首都医科大学附属北京儿童医院收治的38例胸膜肺母细胞瘤患儿临床资料,并进行统计描述。结果38例中男18例,女20例;首诊诊断为非肿瘤性病变者占比47.4%(18/38),从出现症状到手术或化疗干预的时间范围为5~210 d;Ⅰ型4例(10.5%),中位诊断年龄22个月;Ⅱ型12例(31.6%),中位诊断年龄37个月;Ⅲ型22例(57.9%),中位诊断年龄39.5个月。治疗方式包括手术及化疗。术中见肿瘤最大直径为2~18 cm,手术时间25~210 min,术中出血量2~500 mL(1例出血500 mL病例于术中行胸膜剥脱术);化疗方案多采用IVADo(异环磷酰胺+阿霉素+长春新碱+放线菌素D)和IVA(异环磷酰胺+长春新碱+放线菌素)方案,5年无瘤生存率为69.2%。结论胸膜肺母细胞瘤是一种较为罕见的儿童恶性肿瘤,临床表现缺乏特异性,误诊率高,预后较差,需要手术与化疗联合进行治疗。儿科医生应该充分认识到PPB的严重性,对于出现气胸、多发部位肺囊性病变、肺囊肿家族史、PPB家族史、DICER1家族性综合征的胸腔占位性病变患儿应警惕本病的可能,并做到严密监测及随访。     

Germline APC mutations are not commonly seen in children with sporadic hepatoblastoma

Hepatoblastoma is the most common primary liver tumor in childhood and occurs more commonly in families with familial adenomatous polyposis. Germline mutations of the gene responsible for familial adenomatous polyposis--adenomatous polyposis coli (APC)--are described in patients with hepatoblastoma even without a family history. We investigated children presenting with apparently sporadic hepatoblastoma between 1991 and 2004. Blood samples were available from 29 children (18 boys) whose conditions were diagnosed at a median age of 22 months (range 6-119 months). No germline APC mutations were found, which does not support the need for routine screening in sporadic hepatoblastoma in the absence of a suggestive family history of colorectal cancer or suspicion of familial adenomatous polyposis.     

TSC1 and TSC2 mutations in tuberous sclerosis,the associated phenotypes and a model to explain observed TSC1/ TSC2 frequency ratios

Tuberous sclerosis (TSC) is a multisystem disease with manifestations in the central nervous system, skin, kidneys, heart, and other visceral organs. The development of TSC is associated with alterations within a gene on chromosome 9q34 ( TSC1) and a gene on chromosome 16p13 ( TSC2). Most de-novo patients show a mutation in TSC2, whereas only 50% of all familial cases can be related to TSC2 mutations. In the present study, 68 unrelated patients with confirmed clinical manifestations of TSC were tested for mutations in the TSC1 and TSC2 genes. In total, we studied 59 sporadic cases and 9 familial cases, including one large family with TSC2 linkage. Two pathogenic mutations were found in TSC1. The TSC2 gene analysis revealed 29 mutations, including 3 large deletions and 26 small mutations, 15 of them truncating. CONCLUSION: the TSC1-TSC2 mutation ratio in our group of patients differs significantly from the 1:1 ratio previously predicted on the basis of linkage studies. There is an obvious paradox between the observed frequency of TSC1 mutations in familial cases and sporadic cases. An interestingly mild phenotype, observed in one of our TSC1 mutation carriers, led to the elaboration of a model that provides a plausible explanation for this paradox. We propose the presence of a very mildly affected patient group with TSC1-related disease who are not regularly detected by clinical diagnosis.     

Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9

Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. Approximately 10-25% of familial and sporadic cases are caused by mutations in NPHS2 (podocin). Mutations in exons 8 and 9 of the WT1 gene have been found in patients with isolated SRNS and in SRNS associated with Wilms' tumor (WT) or urogenital malformations. However, no large studies have been performed to date to examine whether WT1 mutations in isolated SRNS are restricted to exons 8 and 9. To address this question, we screened a worldwide cohort of 164 cases of sporadic SRNS for mutations in all 10 exons of the WT1 gene by multiplex capillary heteroduplex analysis and direct sequencing. NPHS2 mutations had been excluded by direct sequencing. Fifteen patients exhibited seven different mutations exclusively in exons 8 and 9 of WT1. Although it is possible that pathogenic mutations of WT1 may also reside in the introns, regions of the gene that were not able to be screened in this study, these data together with our previous results (Ruf et al.: Kidney Int 66: 564-570, 2004) indicate that screening of WT1 exons 8 and 9 in patients with sporadic SRNS is sufficient to detect pathogenic WT1 mutations and may open inroads into differential therapy of SRNS.     

TSHR is the main causative locus in autosomal recessively inherited thyroid dysgenesis

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and results in mental retardation if untreated. Eighty-five percent of CH cases are due to disruptions in thyroid organogenesis and are mostly sporadic, but about 2% of thyroid dysgenesis is familial, indicating the involvement of genetic factors in the aetiology of the disease. In this study, we aimed to investigate the Mendelian (single-gene) causes of non-syndromic and non-goitrous congenital hypothyroidism (CHNG) in consanguineous or multi-case families. Here we report the results of the second part (n=105) of our large cohort (n=244), representing the largest such cohort in the literature, and interpret the overall results of the whole cohort. Additionally, 50 sporadic cases with thyroid dysgenesis and 400 unaffected control subjects were included in the study. In familial cases, first, we performed potential linkage analysis of four known genes causing CHNG (TSHR, PAX8, TSHB, and NKX2-5) using microsatellite markers and then examined the presence of mutations in these genes by direct sequencing. In addition, in silico analyses of the predicted structural effects of TSHR mutations were performed and related to the mutation specific disease phenotype. We detected eight new TSHR mutations and a PAX8 mutation but no mutations in TSHB and NKX2-5. None of the biallelic TSHR mutations detected in familial cases were present in the cohort of 50 sporadic cases. Genotype/phenotype relationships were established between TSHR mutations and resulting clinical presentations. Here we conclude that TSHR mutations are the main detectable cause of autosomal recessively inherited thyroid dysgenesis. We also outline a new genetic testing strategy for the investigation of suspected autosomal recessive non-goitrous CH.     

Cytogenetic abnormalities in 42 rhabdomyosarcoma: a United Kingdom Cancer Cytogenetics Group Study.

BACKGROUND: Rhabdomyosarcomas are the most common type of pediatric soft tissue sarcoma. The cytogenetic literature on RMS is biased towards the less common alveolar subtype (ARMS), which is frequently associated with specific translocations and the PAX3/7-FKHR fusion genes. Relatively few karyotypes are reported for the embryonal subtype (ERMS). The aim of this study was to further cytogenetic knowledge of RMS subtypes. PROCEDURE: Representative examples of all karyotypes from UKCCG; member laboratories were reexamined and their histopathologies reviewed through the United Kingdom Children's Cancer Study (Group) (UKCCSG). Molecular evidence for the PAX3/7-FKHR fusion genes was available for five ERMS and seven ARMS cases and compiled with the karyotypes. RESULTS: Clonal chro mosome aberrations were characterized for 25 ERMS and 17 ARMS cases. Thirty-six percent of the ERMS cases involved translocation breakpoints in the 1p11-q11 region. Ten of the seventeen cases of ARMS showed cytogenetic evidence for the t(2;13)(q35;q14), consistent with molecular data available from four of these. Two further ARMS cases revealed a PAX3-FKHR and a variant PAX7-FKHR fusion gene product that were not detected cytogenetically. CONCLUSIONS: Many of the karyotypes from both subtypes were complex. The frequent involvement of the 1p11-1q11 region and gain of chromosomes 2, 8, 12, and 13 in ERMS may be functionally significant. There was no evidence for involvement of the PAX3/7-FKHR genes in ERMS, and cryptic involvement was found in some ARMS. There were no consistent chromosomal rearrangements associated with apparently translocation negative ARMS cases.     

Cytogenetic and p53 profiles in congenital cystic adenomatoid malformation: insights into its relationship with pleuropulmonary blastoma.

Congenital cystic adenomatoid malformation (CCAM), a developmental anomaly of lung, shares many features with the pediatric tumor pleuropulmonary blastoma (PPB). Both may show benign epithelium-lined cysts and mesenchymal proliferation, often with skeletal muscle differentiation. Before its recognition as a distinct entity, PPB was described in several reports as "rhabdomyosarcoma arising in CCAM." Abnormal karyotypes in PPB often show excess material from chromosome 8. It has also been suggested that PPB may harbor p53 mutations. We examined the karyotype and searched for p53 mutations (via immunostaining and single-strand conformation polymorphism analysis) in 11 CCAM and in 2 PPB. Karyotypes were normal in all CCAM and showed clonal abnormalities in both PPB. There was marked and diffuse immunopositivity for nuclear p53 in the epithelial cells of CCAM and PPB. Strong staining was also observed in approximately 50% of the stromal cells in all PPB, but was seen in the stroma of only 2 of 10 CCAM, where it was faint and focal. TP53 mutations were not identified in CCAM or PPB. We conclude that CCAM does not contain the clonal chromosomal aberrations reported in PPB and shows less stromal p53 immunostaining than PPB. Since p53 mutations were not identified in either entity, the observed p53 immunoreactivity may be caused by another mechanism; its role in PPB and CCAM pathogenesis remains to be determined. Overall, these findings provide evidence that CCAM is nonneoplastic. Although some may view CCAM as a PPB precursor, it remains biologically distinct in terms of karyotype and p53 status.     

Pediatric paraganglioma: an early manifestation of an adult disease secondary to germline mutations

BACKGROUND: Paraganglioma (PGL) and phaeochromocytoma (PCC) are chemotherapy and radiation-resistant neuroendocrine tumors that arise from sympathetic tissue, and rarely occur in children. PCC may be associated with predisposing (germline) conditions like the multiple endocrine neoplasia type 2 (MEN2; OMIM 164761), von Hippel-Lindau syndrome (VHL; OMIM 193300), and rarely neurofibromatosis type 1 syndrome (NF1; OMIM 162200) and multiple endocrine neoplasia type 1 (MEN1; OMIM 131100). PGL, on the other hand, may be related to predisposing germline conditions like the familial PGL syndrome and the NF1 syndrome. In adult studies, one of the highest predisposing factors for germline mutation among patients presenting apparently sporadic PCC/PGL was their age at presentation. The aim of this study was to determine the rate of germline mutations among the rare patients presenting with sporadic PGL during childhood. PROCEDURE: In this study, we report the genetic analysis for predisposing conditions for the only three PGL cases retrospectively identified at our pediatric institution in the last 20 years. RESULTS: None had NF1 clinical associated lesions. Mutation screening of genes associated to VHL (VHL), MEN (RET), and familial PGL (SDH-B, -C, and -D) showed that all cases had germline deletions in the SDHB gene. We report a novel mutation, c.778 del C. Importantly, several non-symptomatic relatives were found to be carriers, thus ensuring them a clinical follow-up. CONCLUSION: According to our findings, PGL presenting during childhood represents an early manifestation of an adult disease caused by predisposing germline mutations. These results underline the importance of genetic studies in pediatric PGLs.     

Broad and unexpected phenotypic expression in Greek children with steroid-resistant nephrotic syndrome due to mutations in the Wilms’ tumor 1 (<Emphasis Type="Italic">WT1</Emphasis>) gene

Mutations in the Wilms’ tumor suppressor gene 1 (WT1), most commonly within exons 8 or 9 or intron 9, are found in cases with the overlapping conditions of Denys–Drash and Frasier syndromes, as well as in patients with steroid-resistant nephrotic syndrome (SRNS). This study investigated the presence of WT1 gene mutations in cases with childhood SRNS, along with an evaluation of their clinical outcome. Twenty-seven Greek children with sporadic (19 cases) and familial (8 cases) SRNS were tested. Four phenotypically female patients with sporadic SRNS were found to carry de novo WT1 mutations, including two cases with p.R394W, and one case each with p.R366H, or n.1228+5G>A. Karyotype analysis found 46XX in three cases, but 46XY in one. No phenotype–genotype correlations were apparent in the WT1 gene positive cases since their clinical presentation varied broadly. Interestingly, one patient with a pathological WT1 nucleotide variation responded fully to combined therapy with cyclosporine A and corticosteroids. This study further illustrates that investigation of WT1 gene mutations is clinically useful to support definitive diagnosis in children presenting with SRNS in order to direct the most appropriate clinical management.     

P53 gene mutations in pleuropulmonary blastomas

Pleuropulmonary blastoma (PPB) is rarechildhoodtumororiginating fromeitherlung orpleura. Although several cytogenetic changes, such as trisomy 2, trisomy 8, and loss of 17p material, have been reported, evidence of gene mutations is still lacking. Pathologically, PPB shares similarities with rhabdomyosarcoma in which p53 mutations are frequently detected. Possible implication of p53 mutations in PPB was investigated. PPBs of 3 patients were analyzed for occurrence of p53 mutations by using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method, and the nature of mutations was confirmed by direct sequencing. Two PPBs were confirmed to harbor p53 mutations. One was a Val to Leu substitution at codon 173, and another was a ArgArg to TrpCys substitution at codons 282 and 283. In each tumor, only the mutated allele was detected, suggesting inactivation of p53. Both patients with mutations had fatal outcome, while the remaining patient in whom no mutation was detected is disease free for 3 years after completion of treatment. The results raise the possibility that p53 inactivation can occur as a nonrandom genetic change involving the pathogenesis and outcome of PPB. Further studies in a larger series are necessary to clarify these matters.     

儿童肾病综合征致病基因筛查策略的探讨

目的 通过儿童散发性肾病综合征（NS）致病基因及其突变特点,探讨儿童NS致病基因的筛查策略。方法 收集复旦大学附属儿科医院肾脏风湿科2011年1月1日至2013年12月31日的所有住院NS患儿的临床资料,依据发病年龄分为先天性NS（3月龄内）、婴儿型NS（～12月龄）、儿童早发型NS（～5岁）和儿童迟发型NS（～14岁）;对儿童早发型和迟发型NS再依据对糖皮质激素（GC）治疗反应分为GC敏感（SSNS）和GC耐药（SRNS）,SRNS又分为初发型和迟发型SRNS。先天性NS行NPHS1、NPHS2、PLCE1、LAMB2、LMX1B、COQ2基因所有外显子和WT1基因8、9外显子直接测序;婴儿型NS行NPHS1、NPHS2、PLCE1基因所有外显子和WT1基因8、9外显子直接测序;儿童早发型和迟发型NS行NPHS2基因所有外显子和WT1基因8、9外显子直接测序,以及NPHS1等8个基因42个常见突变位点的SnapShot分析。结果 238例NS患儿进入本文分析,男139例。①8/10例（80％）先天性NS患儿检出NPHS1基因致病性突变;②12例婴儿型NS患儿检出3例WT1（25.0%）、2例NPHS2（16.7%）和1例NPHS1（8.3%）基因突变;③8/132例（6.1％）早发型NS患儿检出基因突变,均属于初发型SRNS（8/32,25.0%）,其中WT1 3例（9.4％）、NPHS2 2例（6.3%）、NPHS1 2例（6.3%)和INF2 1例（3.1%),19例迟发型SRNS和81例SSNS患儿均未检出相关基因突变;④84例儿童迟发型NS中未检出基因致病性突变。结论 先天性NS、婴儿型NS和儿童早发型NS中的初发型SRNS患儿应是临床基因筛查的对象。NPHS1是本文先天性NS患儿的主要致病基因,推荐在先天性NS患儿行NPHS1基因检测。NPHS1、NPHS2和WT1基因突变频率在婴儿型NS和儿童早发型NS中的初发型SRNS患儿中较高,推荐这些人群中优先选择这3个基因作为目标基因进行筛查。不推荐常规在SSNS和迟发型SRNS患儿中行基因检测。