Mutations In Children Research Articles

AB0680 Prevelance of mefv gene mutations in children with celiac disease

BackgroundCeliac disease is an autoimmune enteropathy caused by permanent sensitivity to gluten in genetically susceptible individuals. Mutations of the MEFV gene, which encodes pyrin protein, a negative regulator of inflammation,...

FRI0339 Prevelance of MEFV gene mutations in chidren with juvenil idiopathic arthritis

BackgroundMutations of the MEFV gene, which encodes pyrin protein, a negative regulator of inflammation, leads to Familial Mediterranean Fever (FMF). Recent studies with adults suggest that MEFV gene mutations may...

Exome sequencing reveals new causal mutations in children with epileptic encephalopathies

The management of epilepsy in children is particularly challenging when seizures are resistant to antiepileptic medications, or undergo many changes in seizure type over time, or have comorbid cognitive, behavioral, or motor deficits. Despite efforts to classify such epilepsies based on clinical and electroencephalographic criteria, many children never receive a definitive etiologic diagnosis. Whole exome sequencing (WES) is proving to be a highly effective method for identifying de novo variants that cause neurologic disorders, especially those associated with abnormal brain development. Herein we explore the utility of WES for identifying candidate causal de novo variants in a cohort of children with heterogeneous sporadic epilepsies without etiologic diagnoses. We performed WES (mean coverage approximately 40×) on 10 trios comprised of unaffected parents and a child with sporadic epilepsy characterized by difficult-to-control seizures and some combination of developmental delay, epileptic encephalopathy, autistic features, cognitive impairment, or motor deficits. Sequence processing and variant calling were performed using standard bioinformatics tools. A custom filtering system was used to prioritize de novo variants of possible functional significance for validation by Sanger sequencing. In 9 of 10 probands, we identified one or more de novo variants predicted to alter protein function, for a total of 15. Four probands had de novo mutations in genes previously shown to harbor heterozygous mutations in patients with severe, early onset epilepsies (two in SCN1A, and one each in CDKL5 and EEF1A2). In three children, the de novo variants were in genes with functional roles that are plausibly relevant to epilepsy (KCNH5, CLCN4, and ARHGEF15). The variant in KCNH5 alters one of the highly conserved arginine residues of the voltage sensor of the encoded voltage-gated potassium channel. In vitro analyses using cell-based assays revealed that the CLCN4 mutation greatly impaired ion transport by the ClC-4 2Cl(-) /H(+) -exchanger and that the mutation in ARHGEF15 reduced GEF exchange activity of the gene product, Ephexin5, by about 50%. Of interest, these seven probands all presented with seizures within the first 6 months of life, and six of these have intractable seizures. The finding that 7 of 10 children carried de novo mutations in genes of known or plausible clinical significance to neuronal excitability suggests that WES will be of use for the molecular genetic diagnosis of sporadic epilepsies in children, especially when seizures are of early onset and difficult to control.

Multiple pilomatricomas with somatic CTNNB1 mutations in children with constitutive mismatch repair deficiency

Constitutional mismatch repair deficiency (CMMR-D) due to biallelic germline mutations in one of four mismatch repair genes causes a childhood cancer syndrome characterized by a broad tumor spectrum including hematological malignancies, and brain and Lynch syndrome-associated tumors. Herein, we report three children who had in addition to CMMR-D-associated malignancies multiple pilomatricomas. These are benign skin tumors of hair matrical differentiation frequently associated with somatic activating mutations in the ß-catenin gene CTNNB1. In two of the children, the diagnosis of CMMR-D was confirmed by the identification of biallelic germline PMS2 mutations. In the third individual, we only found a heterozygous germline PMS2 mutation. In all nine pilomatricomas with basophilic cells, we detected CTNNB1 mutations. Our findings indicate that CTNNB1 is a target for mutations when mismatch repair is impaired due to biallelic PMS2 mutations. An elevated number of activating CTNNB1 alterations in hair matrix cells may explain the development of multiple pilomatricomas in CMMR-D patients. Of note, two of the children presented with multiple pilomatricomas and other nonmalignant features of CMMR-D before they developed malignancies. To offer surveillance programs to CMMR-D patients, it may be justified to suspect CMMR-D syndrome in individuals fulfilling multiple nonmalignant features of CMMR-D (including multiple pilomatricomas) and offer molecular testing in combination with interdisciplinary counseling.

MEFV gene mutations in Turkish children with juvenile idiopathic arthritis

Mutations of the Mediterranean fever (MEFV) gene, which encodes pyrin protein, leads to familial Mediterranean fever (FMF) and a connection between MEFV mutations and rheumatic diseases has been suggested. The aim of this study was to explore the frequency and clinical significance of MEFV mutations in children with juvenile idiopathic arthritis (JIA). In this study, children with JIA, who had no typical symptoms of FMF, were screened for the mutations in exons 2 and 10 of the MEFV gene by direct sequencing. A total of 96 children, 56 girls (58.3%), with a median age of 11 years (2-18 years) were included. Patients were classified according to JIA subgroups as oligoarthritis in 43 (44.8%), rheumatoid factor-negative polyarthritis in 22 (22.9%), rheumatoid factor-positive polyarthritis in 2 (2.1%), systemic arthritis in 12 (12.5%) patients, enthesitis-related arthritis in 16 (16.7%), and psoriatic arthritis 1 (1.04%). A total of 31 children (32.3%) had MEFV mutations: 25 heterozygous, 2 homozygous, and 4 compound heterozygous. There were 22 (11.4%) exon 10 mutations (M694V, R761H, K695R, V726A, R653H) and 15 (7.8%) exon 2 mutations (E148Q, G304R, E148V, T267I). The allele frequencies of MEFV mutations were found to be 19.27%, which is higher than the general population [p = 0.03, (odds ratio (OR):1.93, 95% confidence interval (CI): 1.09-3.41)]. MEFV mutation carrier rates were significantly higher in antinuclear antibody (ANA) negative than in ANA positive patients [p = 0.01, (OR: 0.25, 95% CI: 0.085-0.74)] and in males than in females [p = 0.001, (OR: 0.197, 95% CI: 0.078-0.495)]. Also, there was a statistically significant difference between the MEFV mutation carrier rates and the subgroups of JIA (p = 0.005). These findings suggest that mutations of the MEFV gene may be responsible for rheumatic diseases other than FMF, and patients with JIA especially males, ANA negatives, and ERA subgroups should be screened for MEFV gene mutations in countries where FMF is frequent.

Magnetic Resonance Angiography-Defined Intracranial Vasculopathy Is Associated with Silent Cerebral Infarcts, and Glucose-6-Phosphate Dehydrogenase Mutation in Children with Sickle Cell Anemia (S29.001)

Magnetic Resonance Angiography-Defined Intracranial Vasculopathy Is Associated with Silent Cerebral Infarcts, and Glucose-6-Phosphate Dehydrogenase Mutation in Children with Sickle Cell Anemia (S29.001)

Sodium Channel Gene Mutations in Children with GEFS+ and Dravet Syndrome: A Cross Sectional Study

Dravet syndrome or severe myoclonic epilepsy of infancy (SMEI) is a baleful epileptic encephalopathy that begins in the first year of life. This syndrome specified by febrile seizures followed by intractable epilepsy, disturbed psychomotor development, and ataxia. Clinical similarities between Dravet syndrome and generalized epilepsy with febrile seizure plus (GEFS+) includes occurrence of febrile seizures and joint molecular genetic etiology. Shared features of these two diseases support the idea that these two disorders represent a severity spectrum of the same illness. Nowadays, more than 60 heterozygous pattern SCN1A mutations, which many are de novo mutations, have been detected in Dravet syndrome. From May 2008 to August 2012, 35 patients who referred to Pediatric Neurology Clinic of Mofid Children Hospital in Tehran were enrolled in this study. Entrance criterion of this study was having equal or more than four criteria for Dravet syndrome. We compared clinical features and genetic findings of the patients diagnosed as Dravet syndrome or GEFS+. 35 patients (15 girls and 20 boys) underwent genetic testing. Mean age of them was 7.7 years (a range of 13 months to 15 years). Three criteria that were best evident in SCN1A mutation positive patients are as follows: "Normal development before the onset of seizures, onset of seizure before age of one year, and psychomotor retardation after onset of seizures. Our genetic testing showed that 1 of 3 (33.3%) patients with clinical Dravet syndrome and 3 of 20 (15%) patients that diagnosed as GEFS+, had SCN1A mutation. In this study, normal development before seizure onset, seizures beginning before age of one year and psychomotor retardation after age of two years are the most significant criteria in SCN1A mutation positive patients.

Clinical and molecular genetic analysis of a new mutation in children with Wolfram syndrome: A case report

A 12‑year‑old Chinese girl presented with gradual vision loss and insulin‑dependent diabetes mellitus and was suspected to suffer from Wolfram syndrome (WFS). A series of clinical examinations were performed, as well as direct DNA sequencing to screen the entire coding region of the WFS1 gene in the patient's family, including her parents and a brother. Ophthalmological examination revealed counting fingers/10cm in the right eye and hand motions/10cm in the left eye. Ophthalmoscopical examination identified bilateral optic atrophy without any signs of diabetic retinopathy. A hearing test was performed and revealed that the hearing ability for high frequency sounds was decreased. Urinary output in 24h was >5,000ml. In addition, a base substitution at c.2411T>C (Leu804Pro) in exon8 was identified which was homozygous with the patient and heterozygous with the healthy parents and the brother. In the present case, a neuroophthalmology consult performed in the early stages of the disease was crucial for early diagnosis. In addition, this case study highlights the importance of performing a hearing test as well as collecting and analyzing 24‑h urine output in patients presenting with juvenile diabetes mellitus patients and optic atrophy without any signs of diabetic retinopathy.

Prevalence of Transmitted HIV-1 Drug Resistance Mutations in Children and Adolescents in São Paulo, Brazil

HIV drug resistance genotype testing, performed on 39 HIV-infected treatment-naive children from 2000 to 2011, identified 5 children (12.8%) with drug resistance mutations: 5.3% to nucleoside reverse transcriptase inhibitors, 5.3% to nonnucleoside reverse transcriptase inhibitors and 7.7% to protease inhibitors. There was a trend for increasing prevalence of drug resistance mutations during the 11-year study period.

Prevalence of Germline TP53 Mutations in a Prospective Series of Unselected Patients with Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a hallmark cancer in families with Li Fraumeni syndrome (LFS) caused by mutations in the TP53 gene. The prevalence of germline TP53 mutations in children diagnosed with ACC ranges from 50-97%. Although existing criteria advocate for TP53 testing in all patients with ACC regardless of age at diagnosis, the overall prevalence of germline mutations in patients diagnosed with ACC has not been well studied. A total of 114 patients with confirmed ACC evaluated in the University of Michigan Endocrine Oncology Clinic were prospectively offered genetic counseling and TP53 genetic testing, regardless of age at diagnosis or family history. Ninety-four of the 114 patients met with a genetic counselor (82.5%), with 53 of 94 (56.4%) completing TP53 testing; 9.6% (nine of 94) declined testing. The remainder (32 of 94; 34%) expressed interest in testing but did not pursue it for various reasons. Four of 53 patients in this prospective, unselected series were found to have a TP53 mutation (7.5%). The prevalence of mutations in those diagnosed over age 18 was 5.8% (three of 52). There were insufficient data to estimate the prevalence in those diagnosed under age 18. None of these patients met clinical diagnostic criteria for classic LFS. Three of the families met criteria for Li Fraumeni-like syndrome; one patient met no existing clinical criteria for LFS or Li Fraumeni-like syndrome. Three of the four patients with mutations were diagnosed with ACC after age 45. Genetic counseling and germline testing for TP53 should be offered to all patients with ACC. Restriction on age at diagnosis or strength of the family history would fail to identify mutation carriers.

Unexpected High Frequency of GATA2 Mutations in Children with Non-Familial MDS and Monosomy 7

AbstractAbstract 1699Haploinsufficiency of GATA2 results in three overlapping clinical entities unified by the predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML): i) familial MDS/AML, ii) Emberger syndrome, and iii) an immunodeficiency termed monocytopenia with mycobacterium avium infections (MonoMAC)/ dendritic cell, monocyte, B- and NK-lymphoid deficiency (DCML). All these conditions manifest with a wide heterogeneity of symptoms predominantly affecting the hematologic and immune systems.To investigate the frequency of GATA2 defects in children and adolescents with MDS registered in the retrospective and prospective studies of the European Working Group of MDS and JMML in Childhood (EWOG-MDS), we first identified children from families with MDS/AML affecting multiple individuals, or children with MDS and preexisting lymphedema or immunodeficiency. We measured telomere length in hematopoietic cells to rule out an underlying defect of the telomerase complex, performed SNP-Array analysis, and excluded cases with germline RUNX1 aberrations. We identified heterozygous GATA2 mutations in 11 offspring of 8 distinct pedigrees: 4 previously reported missense mutations affecting the 2nd zinc finger (ZF2) T357A, S447R and R396Q/W; a novel exon 5 skipping mutation c.1018-10_1037del; and one novel nonsense mutation S201X and two novel frameshift mutations S139CfsX45, and V70LfsX114, all resulting in a premature stop codon prior to ZF2. The median age at diagnosis of MDS was 13.6 (11.0–16.9) years. Karyotype abnormalities were detected in 10/11 (91%) children: in 9 at initial presentation and in one during disease progression. Most patients carried the aneuploidies monosomy 7 (−7; n=5), trisomy 8 (+8; n=4), or both (n=1). Additionally, the recurrent translocation +1,der(1;7)(q10;p10) was detected in three patients. Interestingly, in one patient, the initial karyotype 45,XY,-7 transformed at relapse after hematopoietic stem cell transplantation (HSCT) to 46,XY,-7,+8,+21. Two additional patients with hypocellular MDS since adolescence and GATA2 hotspot mutations referred to us carried the aneuploidies −7 or +8, respectively.We next extended our study to children registered to EWOG-MDS in Germany with non-familial MDS and monosomy 7. Unexpectedly 8/51 (16%) patients with −7 carried GATA2 aberrations: 7 missense mutations within ZF2 and a germline 3.6Mb deletion 3q21.2–21.3 encompassing GATA2. In depth review of patient’s history identified preexisting features of immunodeficiency as seen on laboratory tests and clinical exam (i.e. generalized verrucosis) in 5 of these 8 patients. The germline status was confirmed in cases where non-hematopoietic specimens were available.The combined analysis of all 21 patients identified additional comorbidities that, to our knowledge, were previously not reported in patients with GATA2-deficiency. These affected the urogenital system (nonselective glomerular proteinuria in one family, vesicoureteral reflux in a single case), neurodevelopmental delay and aggressive behavior in two cases, and ulcerative colitis in 2 families. At diagnosis of MDS, refractory cytopenia of childhood (RCC) was present in 43% of cases, while 33% presented with RAEB, and remaining 24% of patients with RAEBt and myelodysplasia related AML. Following HSCT as first line therapy, 10 of 12 children are alive, while all 4 children treated with AML-like therapy prior to HSCT succumbed. Five patients with RCC are followed closely with a watch and wait regimen.Finally, to study the genetic factors initiating clonal evolution, we subjected selected cases to targeted next generation sequencing of 103 cancer-associated genes. Based on preliminary data, some GATA2-deficient patients carry acquired mutations of genes previously reported in malignant processes (such as ASXL1, RUNX1, TET2, and 14 more genes).In summary, we identified a high frequency of GATA2 mutations among children and adolescents cases with sporadic MDS with monosomy 7 in children and adolescents. Some of these patients had a mild preexisting immunodeficiency. Outcome following HSCT without prior intensive chemotherapy was similar to what can be expected in children with MDS without GATA2 mutations. The genotype-phenotype correlation and mechanisms of clonal evolution are not understood and warrant further studies. Disclosures:No relevant conflicts of interest to declare.

Clinical manifestation of chronic pancreatitis associated with SPINK1 mutations in children

s / Pancreatology 12 (2012) 502–597 565 We present the case of a 54 year old female patient, who underwent surgery for a neuroendocrine tumor, with a large pancreatic tail mass, diagnosed by computer tomography. Laparoscopic distal resection of the pancreas was conducted. The perioperative period was complicated by an infection of the wound and suppuration. The patient was discharged on the 7th day after the operation. Postoperative histopathological examination revealed the intrapancreatic accessory spleen. Accessory spleen mimicking a pancreatic tumor is difficult to diagnose. Some papers compare examination methods, but usually they are complicated, expensive and unavailable to patients. Moreover, in most of cases, EUS-FNA is impossible due to splenic vessels. In such cases, minimal invasive procedures appear to offer a good alternative to classic operations.

5′UTR Repeat Polymorphisms of the BMPR2 gene in Children with Pulmonary Hypertension associated with Congenital Heart Disease

The mutations of bone morphogenetic protein receptor type 2 (BMPR2) in patients with idiopathic pulmonary hypertension has been well defined. We investigated the occurrence of BMPR2 mutation and genetic polymorphisms in children with pulmonary hypertension associated with congenital heart disease (aPH/CHD) and correlated with the pulmonary haemodynamic and vasoreactivity. BMPR2 mutation/polymorphisms were determined in 30 aPH/CHD children. All children underwent cardiac catheterisation to obtain baseline haemodynamic data. The 5'UTR containing promoter region and all the exons [1-13] of BMPR2 gene were genotyped for possible genetic variants that may be related to the aPH/CHD. None of our 30 patients (median-age 90 months) with aPH/CHD (mean PAP 48±17mmHg, PVR 6.7±4.2WUm(2)) has had any BMPR2 mutation. Fifteen of them had single nucleotide polymorphism, rs1061157 and/or 5'UTR-polymorphism, specifically GGC repeat variant in seven patients; AGC repeat variant in one patient; and nine base pairs duplication (CTTCTTCGG) in one patient. The GGC repeat ≥13 was found in three out of six of children with aPH/CHD with normal PVR vs. two out of 24 children with aPH/CHD with high PVR. The odd ratio between these two subgroups of aPH/CHD is 0.09 (95% CI 0.02-0.34). In our cohort, there was no BMPR2 mutation in children with aPH/CHD while nine out of 30 of them have 5'UTR repeat polymorphisms. Our data suggests the occurrence of GGC repeat ≥13 at the 5'UTR region may have some protective effect towards pulmonary vasculopathy in children who have been exposed to high pulmonary blood flow due to CHD.

Early‐onset absence epilepsy: SLC2A1 gene analysis and treatment evolution

To determine the prevalence of SLC2A1 mutations in children with early-onset absence epilepsy (EOAE) and to investigate whether there were differences in demographic and electroclinical data between patients who became seizure-free with anti-epileptic drug (AED) monotherapy (group I) and those who needed add-on treatment of a second AED (group II). We reviewed children with EOAE attending different Italian epilepsy centers. All participants had onset of absence seizures within the first 3 years of life but otherwise conformed to a strict definition of childhood absence epilepsy. Mutation analysis of SLC2A1 was performed in each patient. Eighty-four children (57 in group I, 27 in group II) fulfilled the inclusion criteria. No mutation in SLC2A1 was found. There were no statistical differences between the two groups with regard to F/M ratio, age at onset of EOAE, early history of febrile seizures, first-degree family history for genetic generalized epilepsy, duration of AED therapy at 3 years after enrollment, use of AEDs at 3 years, failed withdrawals at 3 years, terminal remission of EOAE at 3 years, and 6-month follow-up EEG data. Mean duration of seizures/active epilepsy was significantly shorter in group I than in group II (P = 0.008). We demonstrate that in a large series of children with rigorous diagnosis of EOAE, no mutations in SLC2A1 gene are detected. Except for duration of seizures/active epilepsy, no significant differences in demographic and electroclinical aspects are observed between children with EOAE who responded well to AED monotherapy and those who became seizure-free with add-on treatment of a second AED.

Magnetic resonance angiography‐defined intracranial vasculopathy is associated with silent cerebral infarcts and glucose‐6‐phosphate dehydrogenase mutation in children with sickle cell anaemia

Silent cerebral infarct (SCI) is the most commonly recognized cause of neurological injury in sickle cell anaemia (SCA). We tested the hypothesis that magnetic resonance angiography (MRA)-defined vasculopathy is associated with SCI. Furthermore, we examined genetic variations in glucose-6-phosphate dehydrogenase (G6PD) and HBA (α-globin) genes to determine their association with intracranial vasculopathy in children with SCA. Magnetic resonance imaging (MRI) of the brain and MRA of the cerebral vasculature were available in 516 paediatric patients with SCA, enrolled in the Silent Infarct Transfusion (SIT) Trial. All patients were screened for G6PD mutations and HBA deletions. SCI were present in 41·5% (214 of 516) of SIT Trial children. The frequency of intracranial vasculopathy with and without SCI was 15·9% and 6·3%, respectively (P<0·001). Using a multivariable logistic regression model, only the presence of a SCI was associated with increased odds of vasculopathy (P=0·0007, odds ratio (OR) 2·84; 95% Confidence Interval (CI)=1·55-5·21). Among male children with SCA, G6PD status was associated with vasculopathy (P=0·04, OR 2·78; 95% CI=1·04-7·42), while no significant association was noted for HBA deletions. Intracranial vasculopathy was observed in a minority of children with SCA, and when present, was associated with G6PD status in males and SCI.

Systemic mastocytosis associated with t(8;21) acute myeloid leukemia in a child: Detection of the D816A mutation of KIT

Systemic mastocytosis (SM) associated with t(8;21) acute myeloid leukemia (AML) is very rare, and the D816 mutation of the KIT gene has previously been detected only in adult patients. We herein report the case of a 5-year-old female presenting with AML harboring t(8;21)(q22;q22). Her AML was refractory to chemotherapy, and bone marrow mastocytosis developed simultaneously at the initial diagnosis and during chemotherapy. The D816A mutation of KIT was detected. SM associated with t(8;21) AML, accompanied by a KIT mutation in children may result in a poor prognosis, despite the fact that t(8;21) AML are generally considered to have a favorable risk.

Prevalence of SCN1A mutations in children with suspected Dravet syndrome and intractable childhood epilepsy

Mutations of the gene encoding the α1 subunit of neuronal sodium channel, SCN1A, are reported to cause Dravet syndrome (DS). The prevalence of mutations reported in such studies (mainly in clinically confirmed DS) seems high enough to make genetic diagnosis feasible. In fact, commercially operating genetic diagnostic laboratories offering genetic analyses of SCN1A are available. Still, the exact prevalence of mutations of SCN1A remains elusive. Fukuoka University has been serving as a genetic diagnostic laboratory for DS for the last 10 years. In this study, we determined the prevalence of SCN1A mutations (SCN1A, SCN2A, SCN1B and SCN2B) in 448 patients with suspected DS and intractable childhood epilepsy. A total of 192 SCN1A mutations were identified in 188 of 448 patients (42.0%). The frequencies of SCN1A mutations in suspected severe myoclonic epilepsy of infancy (SMEI), its borderline phenotype (SMEB) and intractable epilepsy were 56.2%, 41.9% and 28.9% respectively. In addition, four SCN2A mutations were identified in 4 of 325 patients. No mutations of SCN1B and SCN2B were identified. These results are potentially helpful for the diagnosis of DS at early stage.

Prevalence of Transmitted HIV-1 Drug Resistance Mutations in Children and Adolescents in São Paulo, Brazil

​​​​The Pediatric Infectious Disease Journal® (PIDJ) is a complete, up-to-the-minute resource on infectious diseases in children. Through a mix of original studies, informative review articles, and unique case reports, PIDJ delivers the latest insights on combating disease in children — from state-of-the-art diagnostic techniques to the most effective drug therapies and other treatment protocols. It is a resource that can improve patient care and stimulate your personal research. VISION:The Pediatric Infectious Disease Journal will improve the health of children globally by fostering a better understanding of infectious disease prevention and treatment in children. MISSION: The Pediatric Infectious Disease Journal will serve ESPID and its members as well as the global infectious disease community as the leading resource for publication of pediatric infectious disease research and acting as a forum to further the education of pediatricians and specialists in pediatric infectious disease globally. VALUES​: We value high quality research, teaching, and practice in the field of pediatric infectious diseases. We support the ESPID and the wider pediatric infectious disease community in disseminating important new work and ideas. We wish to provide a fair and rapid review process for submitted manuscripts. We wish to provide easy and convenient access for our readership Official Journal of the European Society for Paediatric Infectious Diseases (ESPID) ​

Prevalence of TP53 p.R337H mutation in children with cancer from a public hospital in southern Brazil.

10593 Background: Childhood cancers are a common feature in Li-Fraumeni/Li Fraumeni-Like Syndromes (LFS/LFL), associated with the inheritance of a germline TP53 mutation. Recently, a specific germline mutation in exon 10 of the TP53 gene, p.R337H, has been reported at a high prevalence in Southeastern Brazil. Initial studies on this mutation claimed that the main, if not exclusive, cancer risk in carriers is childhood adrenocortical carcinoma (ADR). However, others recent reports identified p.R377H carriers among LFL families and among a larger spectrum of tumors, such as choroid plexus carcinoma (CPC) and osteosarcoma. The aim of this study was to assess the frequency of the p.R337H mutation in children diagnosed with tumors of the LFS/LFL spectrum: ADR, sarcoma, central nervous system tumors, leukemia, germline cell tumors and Wilm’s tumor) at the Children’s Cancer Institute of Rio Grande do Sul (Brazil) between 1998 and 2011. Methods: Family history (FH) was recorded in pedigrees, and DNA was extracted from peripheral blood and FFPE samples by standard methods. Screening for the p.R337H mutation was performed by allelic discrimination (TaqMan assay) and by TP53 exon 10 sequencing. Results: Analysis of 295 children diagnosed with tumors of the LFS/LFL spectrum identified the p.R337H mutation in 9/11 (81,8%) children with ADR (including a homozygous p.R337H individual) and in 2/2 (100%) children with CPC. All individuals had loss of heterozygosity in the tumor and in all cases the mutant allele occurred on the same founder haplotype. One hundred fourth-six (49,5%) patients had a cancer FH in first or second degree relatives, 47 (16,0%) had a FH of breast cancer and 49 (16,6%) had FH of LFL consistent with Chompret and/or Birch criteria. Conclusions: These results confirm the strong association of p.R337H with ADR and CPC. A FH consistent with LFL syndrome is present in a high proportion of children diagnosed with tumors of the LFS/LFL spectrum in Southern Brazil. Financial support: FIPE-HCPA, CAPES, FAPERGS and Glaxo Smith Kline.

Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population

ObjectiveTo evaluate the actual impact of MEFV mutations on clinical manifestations associated with fever attacks in Caucasian children with periodic fever.Methods113 children carrying MEFV mutations (44 with mutations in two...