The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations

Fanconi anemia (FA) is characterized by progressive marrow failure, congenital anomalies, and predisposition to malignancy. Biallelic FANCD1/BRCA2 mutations are the genetic basis of disease in a small proportion of children with FA with earlier onset and increased incidence of leukemia and solid tumors. Patients with FA have increased sensitivity to chemotherapy and radiation, and upon development of a solid tumor, require modification of these therapies. We report clinical and molecular features of three patients with FA associated with FANCD1/BRCA2 mutations, including two novel mutations, and discuss treatment of malignancy and associated side effects in this particularly vulnerable group.     

Fanconi anemia gene mutations are not involved in sporadic Wilms tumor

Bi‐allelic germline mutations of the Fanconi anemia (FA) genes, PALB2/FANCN and BRCA2/FANCD1, have been reported in a few Wilms tumor (WT) patients with an atypical FA phenotype. Therefore, we screened a random cohort of 47 Dutch WT cases for germline mutations in these two FA‐genes by DNA sequencing and Multiplex Ligation‐dependent Probe Amplification (MLPA). Although several cases appeared to carry missense variants, no bi‐allelic pathogenic mutations were identified, indicating that bi‐allelic mutations in these FA‐genes do not contribute significantly to the occurrence of WT. Pediatr Blood Cancer. 2010;55:742–744. © 2010 Wiley‐Liss, Inc.     

Fanconi anemia and biallelic BRCA2 mutation diagnosed in a young child with an embryonal CNS tumor

Medulloblastoma, the most common pediatric malignant brain tumor often arises sporadically; however, in a subgroup of patients, there exist familial conditions such as Fanconi anemia with biallelic BRCA2 mutation that predispose patients to developing medulloblastoma. Biallelic inactivation of BRCA2 in Fanconi anemia has been previously described in only 11 patients with medulloblastoma in the literature to date. Here we report two siblings diagnosed with central nervous system embryonal tumors at an early age in association with biallelic BRCA2 inactivation, including the first reported case of a spinal cord primitive neuroectodermal tumor (PNET) in a BRCA2/FANCD1 kindred. Pediatr Blood Cancer 2009;53:1140–1142. © 2009 Wiley‐Liss, Inc.     

Synchronous occurrence of acute lymphoblastic leukemia and wilms tumor in two patients: underlying etiology and combined treatment plan

Synchronous cancers are extraordinarily rare in pediatric patients and present a therapeutic challenge. Patient A presented with synchronous unilateral Wilms tumor (WT) and standard‐risk (SR) B‐precursor acute lymphoblastic leukemia (ALL). Genetic testing revealed bialleleic BRCA2/FANCD1 mutations. Patient B, after SR B‐precursor ALL induction therapy, was noted on fever workup to have a renal mass; pathology demonstrated lesion indeterminate between WT and nephrogenic rest. Therapy was customized for each patient to treat both cancers. Both patients have ongoing remission from their cancers, without excessive toxicity. We report two regimens for treating synchronous WT and ALL and recommend screening such patients for cancer predisposition.     

CURRENT DIAGNOSIS OF INHERITED BONE MARROW FAILURE SYNDROMES

Prompt and accurate diagnosis is required for optimal treatment and genetic counseling of patients with inherited bone marrow failure syndromes (IBMFS). However, the diverse clinical picture of these syndromes and their rareness is often associated with diagnostic difficulties. Recently, an improved diagnostic approach is possible by the cloning of many of the causative genes. Fanconi anemia (FA) patients belong to at least 12 complementation groups, of which 11 genes have been cloned. An approach combining an induced chromosomal breakage test, detection of FANCD2-L by Western blot analysis, complementation group analysis, and detailed mutation analysis enables unraveling the causative mutation in the majority of patients. With the use of such strategies, genotype/phenotype correlations in FA are evolving. In dyskeratosis congenita mutations in DCK1, TERC, and TERT genes have been identified, but mutations have been found in less than half of these patients. In patients with Shwachman-Diamond syndrome, mutations in the SBDS gene were found in approximately 90% of patients. In Diamond-Blackfan anemia the RSP19 gene is mutated in 20–25% of patients. Heterozygote ELA2 mutations are found in 60–80% of severe congenital neutropenia patients. All patients with congenital amegakaryocytic thrombocytopenia have mutations in the thrombopoietin receptor gene c-Mpl.     

Current diagnosis of inherited bone marrow failure syndromes

Prompt and accurate diagnosis is required for optimal treatment and genetic counseling of patients with inherited bone marrow failure syndromes (IBMFS). However, the diverse clinical picture of these syndromes and their rareness is often associated with diagnostic difficulties. Recently, an improved diagnostic approach is possible by the cloning of many of the causative genes. Fanconi anemia (FA) patients belong to at least 12 complementation groups, of which 11 genes have been cloned. An approach combining an induced chromosomal breakage test, detection of FANCD2-L by Western blot analysis, complementation group analysis, and detailed mutation analysis enables unraveling the causative mutation in the majority of patients. With the use of such strategies, genotype/phenotype correlations in FA are evolving. In dyskeratosis congenita mutations in DCK1, TERC, and TERT genes have been identified, but mutations have been found in less than half of these patients. In patients with Shwachman-Diamond syndrome, mutations in the SBDS gene were found in approximately 90% of patients. In Diamond-Blackfan anemia the RSP19 gene is mutated in 20-25% of patients. Heterozygote ELA2 mutations are found in 60-80% of severe congenital neutropenia patients. All patients with congenital amegakaryocytic thrombocytopenia have mutations in the thrombopoietin receptor gene c-Mpl.     

Association between hereditary predisposition to common cancers and congenital multimalformations

In a previous article we reported that mutations favoring cancer at adulthood seemed to improve fertility and limit miscarriages. Because spontaneous abortion may result from anomalies in embryo, we questioned if an increased frequency of congenital malformation could be evidenced among cancer-prone families. Oncogenetics database (≈193 000 members) of the comprehensive cancer center Jean Perrin was crossed with regional registry of congenital malformations (≈10 000). Among children born between 1986 and 2011, 176 children with malformation matched in both databases. In breast/ovaries cancer-prone families, the risk for malformations was multiplied by 2.4 [1.2-4.5] in case of a BRCA1 mutation. Frequencies of malformation in BRCA2 and MMR mutated families were similar to families without a cancer syndrome. In comparison to malformations concerning a unique anatomical system, multimalformations were significantly more frequent in case of BRCA or MMR mutations: compared to families without cancer syndrome, the risk of multimalformations was multiplied by 4.1 [0.8-21.7] for cancer-prone families but with no known deleterious mutation, by 6.9 [1.2-38.6] in families with a known mutation but an unknown parental mutational status and by 10.4 [2.3-46.0] when one parent carried the familial mutation. No association with the type of anatomical system was found, nor with multiple births. These results suggest that BRCA and MMR genes play an important role in human embryogenesis and that if their function is lowered because of heterozygote mutations, congenital malformations are either more likely (BRCA1 mutations) and/or more susceptible to concern several anatomical systems.     

Loss of heterozygosity does not occur in BRCA1/2 mutant pediatric solid and central nervous system tumors

Utilization of tumor-only sequencing has expanded in pediatric cancer patients, which can lead to identification of pathogenic variants in genes that may be germline and/or have uncertain relevance to the tumor in question, such as the homologous recombination (HR) pathway genes BRCA1/2. We identified patients with pathogenic BRCA1/2 mutations from somatic tumor sequencing, and performed additional germline sequencing to assess for the presence of loss of heterozygosity (LOH). Of seven patients identified, four (57.1%) mutations were found in the germline and none had associated LOH. Our data suggest that BRCA1/2 mutations identified in this context are likely incidental findings.     

Variation in the BRCA2 gene in a child with medulloblastoma and a family history of breast cancer

The fact that BRCA genes operate as tumor suppressors is evident from the genetics of the different human disorders caused by inherited mutations. Germline mutations affecting 1 allele of either BRCA1 or BRCA2 confer susceptibility to different types of cancers such as breast cancer and medulloblastoma. A family with a history of cancer was identified in Eastern Turkey in which one of the family members (a 13-year-old boy) had medulloblastoma. Venous blood was collected from available family members. The BRCA1 and BRCA2 genes were sequenced in the patient with medulloblastoma and the healthy father. An Asn372His homozygous variation was noted in the BRCA2 gene in the patient with medulloblastoma whereas the variation was heterozygous in the healthy father. A biallelic homozygous variation was demonstrated in the BRCA2 gene, which is important in medulloblastoma suppression, and may have caused medulloblastoma formation in the 13-year-old boy. Further investigations in large human populations with medulloblastoma are necessary for further delineation of BRCA gene malfunctions and their relationship to medulloblastoma formation, and to clarify the therapeutic implications of these malfunctions.     

Chemotherapy for myeloid malignancy in children with Fanconi anemia

BACKGROUND: Children with Fanconi anemia (FA) have a markedly increased risk of developing myeloid malignancies. Historically, patients with FA and myeloid malignancy have extremely poor outcomes. There are currently no clinical trials or case series addressing the use of chemotherapy for children with FA, except in the context of preparative regimens for stem cell transplantation (SCT). In this report we describe the toxicity of a chemotherapy approach for patients with FA and myeloid malignancy to achieve cytoreduction prior to SCT. PATIENTS AND METHODS: Four patients with FA and myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) were treated with chemotherapy (fludarabine 30 mg/m(2) and cytosine arabinoside 300 mg/m(2) each on days 2-4 and granulocyte-colony stimulating factor (G-CSF) 5 microg/kg on days 1-5), termed reduced intensity FLAG prior to SCT. RESULTS: The chemotherapy was well tolerated with expected hematologic toxicity and no measurable toxicity in other organs. Two of the three patients with AML cleared blasts from their bone marrow. Reduction in marrow cellularity was also achieved in one patient with hypercellular MDS. CONCLUSION: These data indicate that children with FA and myeloid malignancy can tolerate chemotherapy and achieve clearance of disease. It remains unclear whether pre-SCT chemotherapy improves currently poor survival rates for SCT in FA patients with myeloid malignancies and further studies are needed to determine if there is a clinical role for this strategy.     

Hepatic tumours during androgen therapy in Fanconi anaemia

The occurrence of liver tumours in the course of Fanconi anaemia (FA) has been well documented. We present a case, review the literature and conclude that androgen therapy would increase the risk of developing tumours, most of which appear to be benign (adenomas or peliosis) and androgen-dependent, generally decreasing in size after cessation of treatment. Survival of patients is poor, mostly because of the rapid evolution of untreated FA, rather than rupture or degencration of the tumour. In the absence of an allogenic bone marrow transplantation, administration of haematopoietic growth factors might be effective. As a preventive measure, other types of unsubstituted androgens may be used.     

Stroke in a child with neurofibromatosis type 2

Neurofibromatosis types 1 (NF1) and 2 (NF2) are genetically distinct conditions caused by mutations in tumour suppressor genes that share a number of phenotypic features. Childhood stroke and vasculopathy have been associated with NF1, but not with NF2. We describe a case of brainstem stroke in a child with NF2.     

异基因造血干细胞移植治疗儿童范可尼贫血5例并文献复习

目的初步探讨异基因造血干细胞移植(HSCT)治疗范可尼贫血(FA)的疗效,为探索更加优化移植方案提供依据。方法回顾性分析2012年6月-2016年12月我院收治5例FA患儿进行HSCT的临床资料并复习相关文献。5例患儿中2例行非血缘相合HSCT治疗,3例行单倍体HSCT治疗。预处理方案以氟达拉滨(Flu)、低剂量环磷酰胺(CTX)、抗人胸腺/T淋巴细胞免疫球蛋白(ATG-G/F)为主干,根据移植前输血总量、是否合并白血病,在主干基础上±白消安(Bu)或±全身照射(TBI)。5例患儿回输CD34~+细胞中位计数为8.46(5.46~15.29)×10~6/kg,单个核细胞(MNC)中位计数为13.07(8.33~14.26)×10~8/kg。采用他克莫司和吗替麦考酚酯联合预防移植物抗宿主病(GVHD)。随访中位时间40.7(15~42)个月。结果 5例患儿HSCT预处理过程中,除1例合并严重消化道黏膜反应,其余耐受性尚可;中性粒细胞恢复中位时间10(8~13)d,血小板恢复中位时间16(12~61)d,无原发性植入失败发生;移植后3例发生移植物排斥,分别通过停用全部免疫抑制剂、回输供者干细胞后恢复为完全供者型;4例发生不同程度急性GVHD,3例需升级为二线免疫抑制治疗控制病情,2例发展为慢性GVHD;随访至2016年12月,2例无事件存活,2例存在慢性GVHD,目前病情控制理想,1例死亡。4例存活患儿移植后血细胞未再检测出FA相关基因突变,生长发育同正常同龄儿童,目前尚未发现合并实体肿瘤。结论对于缺乏同胞相合供者的FA患者,其他类型HSCT治疗采用"Flu+低剂量CTX+ATG±Bu或±TBI"预处理方案耐受性尚可,无原发性植入失败发生,但加用Bu或TBI对预处理相关毒性及远期预后的影响还需要深入研究;移植物排斥和GVHD仍是影响患儿生存主要因素,探索个体化、优化HSCT方案治疗FA的临床研究已成为必然。     

Management of choroid plexus tumours in children: 20 years experience at a single neurosurgical centre

OBJECTIVE: Tumours of the choroid plexus are rare tumours of neuro-ectodermal origin, accounting for less than 1% of all intracranial tumours. Most cases present in children less than 2 years of age. While choroid plexus carcinomas (CPC) are reported to have an extremely poor prognosis, choroid plexus papillomas (CPP) are generally regarded as benign tumours with a very favourable long-term outcome. Management dilemmas are associated with the choice of surgical procedure, tumour vascularity, the treatment of hydrocephalus and the value of adjuvant therapy. The objective of this study was to review our experience with this rare tumour over a 20-year period. METHODS: Patients were identified from the Great Ormond Street Neurosurgical Brain Tumour Database. Over a 20-year period (1979-1999), 34 children were identified with a choroid plexus tumour. There were 25 cases of CPP and 9 cases of CPC. A retrospective review of case notes, radiological imaging, operation reports and pathology was performed. RESULTS: The median age at presentation was 17 months (1-138) for CPP and 13 months (2-102) for CPC. There was no sex difference for CPP. However, 8 of the 9 CPCs were male (89%). A complete surgical resection was achieved in all 25 cases of CPP and in 3 cases of CPC (33%). The median survival for CPPs was 75.5 months (2-228), with a median follow-up of 73.5 months (2-228). The median survival for CPCs was 6 months (1-90), with a median follow-up of 6 months (1-90). CONCLUSION: With modern neurosurgical practise, a cure should be the aim for all children with CPP. There is no evidence that adjuvant therapy has any role in the primary management of these children. However, CPC still has an extremely poor prognosis, and the efficacy of adjuvant therapy remains to be established.     

Familial small cell carcinoma of the ovary

Ovarian tumors have a low incidence in childhood, accounting for 1% of malignancies within the ages of 0–17 years. Small cell carcinoma of the ovary is a rare histology and historically has a poor prognosis. We report a case of an 11‐year‐old female diagnosed with small cell carcinoma of the ovary and hypercalcemia (SCCOHT). There was a strong family history of the disease, a reduction in the age of onset in the proband, and the absence of BRCA mutations. This case suggests the phenomenon of genetic anticipation in an ovarian cancer. Pediatr Blood Cancer 2009; 53:1334–1336. © 2009 Wiley‐Liss, Inc.     

Tumour-like inflammatory abdominal conditions in children.

The presence of a tumour, poor general condition, features of anaemia, increased erythrocyte sedimentation rates and imaging suggesting malignancy were the common features in 4 different tumour-like abdominal conditions that are extremely rare in childhood. These conditions included: extensive retroperitoneal tumour with rib involvement that turned out to be an inflammatory lesion caused by Actinomyces in a 12-year-old girl; multi-loculated tumour of the mesentery/ovary caused by mesenteric lymphadenopathy in the course of a Salmonella enteritidis infection in a 2.5-year-old girl; tumour of the VII - VIII hepatic segments that turned out to be the focus of granuloma in the course of lambliasis in a 5.5-year-old boy with a history of purulent neck lymphadenopathy and a final suspicion of immunocompromise; and a multi-loculated tumour of the small pelvis and inguinal area that turned out to be an abscess of the iliopsoas muscle in a 16-year-old boy. Apart from the imaging, the lesions required cytological examination of the material harvested by fine-needle biopsies (liver tumour) or histopathological investigations (retroperitoneal tumour, mesenteric/ovarian tumour, liver tumour and--on second surgery--the pelvic tumour) and/or bacteriological examination (all cases), serological examination (liver tumour and mesenteric/ovarian tumour), protozoal investigation (liver tumour), and measurement of AFP levels (mesenteric/ovarian tumour). Surgical treatment (retroperitoneal tumour, mesenteric/ovarian tumour and tumour of the small pelvis) and guided antibiotic therapy (all cases including 15 weeks of antibiotics in the first case) allowed complete recovery in 3 patients (actinomycosis, mesenteric lymphadenopathy, abscess of the iliopsoas muscle). Antibiotic and antiprotozoal therapy cured the granulomatous hepatitis; however this patient tended to develop severe right-sided pleural/pulmonary changes (the child was referred for further diagnosis with suspicion of immunocompromise).     

Two Cases of Cystic Fibrosis in Japanese Children: Studies on the Essential Fatty Acid and Prostaglandin Metabolism

We describe the fatty acid (FA) and prostaglandin (PG) metabolism in two Japanese cases of cystic fibrosis (CF) with or without pancreatic insufficiency (PI). The diagnosis of CF was based on the elevated sweat chloride concentration by pilocarpine iontophoresis. A 1-month-old boy (case 1) showed poor weight gain, steatorrhea and scaly dermatitis, but no respiratory symptoms were noted. He had decreased levels of serum linoleate and arachido-nate, and increased palmitoleate and oleate levels, indicating essential fatty acid (EFA) deficiency. Supplementation of fat-emulsion improved his skin lesions and the altered FA pattern within a few months, associated with the definite reduction of the urinary PC F_za levels. Until two years of age, he has been free from respiratory symptoms. A 12-year-old girl (case 2) had had recurrent respiratory tract infections due to Pseudomonas ueruginoso and Staphylococcus aureus for several years, and her pancreatic functions were preserved. The FA patterns of her serum lipid were almost within the normal range. These results indicate that 1) the altered FA composition appeared to be a secondary consequence of PI commonly complicating CF and 2) the correction of the altered FA and PC metabolism might have a beneficial effect on the respiratory function of CF patients with EFA deficiency.     

Exploration of CTNNB1 ctDNA as a putative biomarker for hepatoblastoma

Driver mutations in the CTNNB1 gene (encoding β‐catenin) are a hallmark of sporadic hepatoblastoma (HBL). Our results show that CTNNB1 circulating tumour DNA (ctDNA) is readily detected in patients diagnosed with localised HBL, with serial sampling along the course of therapy and follow up providing a sensitive mechanism to monitor tumour dynamics and response to treatment. This exciting potential for CTNNB1 ctDNA to serve as a biomarker for treatment response in HBL holds clinical value, and requires assessment in a larger cohort of mixed tumour stages and recurrent disease.