Silvia S. Costa

Fragile X Premutation Is a Significant Risk Factor for Premature Ovarian Failure: The International Collaborative POF in Fragile X Study—Preliminary Data

The preliminary results of an international collaborative study examining premature menopause in fragile X carriers are presented. A total of 760 women from fragile X families was surveyed about their fragile X carrier status and their menstrual and reproductive histories. Among the subjects, 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. Sixty-three (16%) of the premutation carriers had experienced menopause prior to the age of 40 compared with none of the full mutation carriers and one (0.4%) of the controls. Based on these preliminary data, there is a significant association between fragile X premutation carrier status and premature menopause.

Fusarium Infection in Hematopoietic Stem Cell Transplant Recipients

To characterize the epidemiology and prognostic factors of invasive fusariosis in hematopoietic stem cell transplant (HSCT) recipients, the records of HSCT recipients from 9 hospitals (7 in Brazil and 2 in the United States) were retrospectively reviewed. Sixty-one cases were identified: 54 in allogeneic HSCT recipients and 7 in autologous HSCT recipients. The incidence of fusariosis among allogeneic HSCT recipients varied between a range of 4.21-5.0 cases per 1000 in human leukocyte antigen (HLA)--matched related transplant recipients to 20.19 cases per 1000 in HLA-mismatched transplant recipients. The median time period between transplantation and diagnosis of fusariosis was 48 days. Among allogeneic HSCT recipients, a trimodal distribution was observed: a first peak before engraftment, a second peak at a median of 62 days after transplantation, and a third peak >1 year after transplantation. The actuarial survival was 13% (median, 13 days). Persistent neutropenia was the single prognostic factor for death identified by multivariate analysis.

Premature ovarian failure is associated with maternally and paternally inherited premutation in Brazilian families with fragile X.

To the Editor: Strong evidence has been produced that indicates FMR1 premutation as a risk factor for premature ovarian failure (POF) (Cronister et al. 1991; Schwartz et al. 1994; Vianna-Morgante et al. 1996, 1999; Murray et al. 1998; Uzzielli et al. 1999). The most extensive survey was a collaborative study engaging nine centers in different countries that showed that 16% of women with premutation suffered POF compared with 0.4% of their noncarrier relatives (Allingham-Hawkins et al. 1999). In a recent study of Dutch families with fragile X, Hundscheid et al. (2000) disclosed a parent-of-origin effect of the premutation such that POF occurred with a significant frequency only in women who inherited the premutation from their fathers. We investigated parental origin of the premutation and occurrence of POF in 113 female carriers in families with fragile X, ascertained through mentally retarded patients. In these families, women aged ⩾25 years who had been tested for the fragile X mutation were interviewed personally by one of us (A.M.V.-M.) about their menstrual, gynecological, and reproductive histories, after appropriate informed consent. Those who had undergone hysterectomy or oophorectomy were not included in the study. POF was defined as spontaneous cessation of menstruation at age <40 years, for at least 1 year. Part of the present sample was included in our previous study of the frequency of POF in fragile X carriers (Vianna-Morgante et al. 1999). Parental origin of the premutation could be determined in 59/113 women: 27 of the premutations were maternally inherited (MIP) and 32 were paternally inherited (PIP). The 27 women with a MIP belonged to 21 sibships (average 1.29 daughters, range 1–3 daughters), and the 32 women with a PIP belonged to 19 sibships (average 1.68 daughters, range 1–5 daughters). Age at examination did not differ between the two groups (medians: MIP, 36.83; PIP, 38.875; P=.5328 [Mann-Whitney test]). Among women with a MIP, five had experienced POF, and it occurred in nine women with a PIP, a difference that was not statistically significant (P=.5411 [Fisher’s exact test]). Age at menopause in the two groups did not differ either (medians: MIP, 38 [n=9]; PIP, 35 [n=13]; P=1.0 [Mann-Whitney test]) but were significantly lower than age at menopause among 50 of their relatives who carried normal alleles (median age: 51 years [n=9]; P=.0014 [Kruskal Wallis test]). These results are summarized in table 1. Table 1 Characteristics of Women Carrying an FMR1 PIP or MIP and Their Noncarrier Relatives In conclusion, our data do not support the hypothesis of a parent-of-origin effect of the FMR1 premutation on ovarian function such that only the paternally inherited premutation is significantly associated with POF. The association of POF with PIP and MIP in one pedigree as shown by Vianna-Morgante et al. (1996) further denies an effect confined to paternally inherited premutation. The finding of a possible genomic imprinting effect, reported by Hundscheid et al. (2000), may be peculiar to the Dutch population. Otherwise the difference between theirs and the present survey may be the result of an undiagnosed ascertainment bias. Data on other populations are urgently needed, if only considering their implications for genetic counseling.

Microduplication of the ICR2 Domain at Chromosome 11p15 and Familial Silver-Russell Syndrome

Silver–Russell syndrome (SRS) is characterized by severe intrauterine and postnatal growth retardation in association with a typical small triangular face and other variable features. Genetic and epigenetic disturbances are detected in about 50% of the patients. Most frequently, SRS is caused by altered gene expression on chromosome 11p15 due to hypomethylation of the telomeric imprinting center (ICR1) that is present in at least 40% of the patients. Maternally inherited duplications encompassing ICR1 and ICR2 domains at 11p15 were found in a few patients, and a microduplication restricted to ICR2 was described in a single SRS child. We report on a microduplication of the ICR2 domain encompassing the KCNQ1, KCNQ1OT1, and CDKN1C genes in a three‐generation family: there were four instances of paternal transmissions of the microduplication from a single male uniformly resulting in normal offspring, and five maternal transmissions, via two clinically normal sisters, with all the children exhibiting SRS. This report provides confirmatory evidence that a microduplication restricted to the ICR2 domain results in SRS when maternally transmitted.

Can we decrease amphotericin nephrotoxicity

Amphotericin B (AmB) is considered the drug of choice for the treatment of systemic fungal infections. Nephrotoxicity is a major complication associated with its use, and appears to be related to higher cumulative doses, diuretic use, abnormal serum creatinine at baseline, and the use of concomitant nephrotoxic drugs. The two major hypotheses for the pathogenesis of AmB-related nephrotoxicity are direct effects of the drug on epithelial cell membranes and vasoconstriction. During the last few years, some randomized trials have tested different strategies to reduce AmB-induced renal toxicity. These strategies include sodium supplementation, low-dose dopamine, slower infusion rates, the administration of AmB in lipid emulsions, and in lipid formulations. The results of these trials showed that the lipid formulations of AmB significantly reduce nephrotoxicity. Unfortunately, these agents are costly, restricting their use to patients with a high risk of developing renal failure.

Fully mutated and gray-zone FRAXA alleles in Brazilian mentally retarded boys

We used a non-isotopic polymerase chain reaction (PCR) technique for fragile X syndrome diagnosis to screen 256 mentally retarded boys who were selected randomly from special schools. Patients identified as pre- or full-mutation carriers were further investigated by Southern blot analysis with the StB12.3 probe. The PCR-based test identified five boys with the expanded allele and 17 other patients as carriers of either premutated or gray-zone alleles. The full mutation was confirmed in four cases after Southern blotting and a fifth patient carried a normal allele. Of the 17 patients identified with a premutation allele by PCR, one individual was diagnosed as mosaic by Southern blotting, 12 individuals displayed fragments of 2.90 kb or 2.85 kb, and the remaining four individuals showed apparently normal-sized fragments. However, sizing of these 16 alleles by further PCR analysis showed them to be in the gray-zone range (40-60 repeats). Therefore, the frequency of the full mutation in this cohort of mentally retarded boys was close to 2% (5/256). The prevalence of gray-zone alleles among those mentally impaired boys who did not carry the full mutation was 6.4% (16/251) and, although more than twice the prevalence of these alleles among a cohort of unaffected Brazilian males 2.8% (71251), the difference did not reach statistical significance.

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

BACKGROUND The etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders. OBJECTIVE To analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause. PATIENTS AND METHODS A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature. RESULTS In 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation. CONCLUSION Pathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.

A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation

Point mutations in the SYNGAP1gene were described recently as arelativelyfrequentcauseofmentalretardation,presentinabout3%of nonsyndromic individuals with mental retardation [Hamdanet al., 2009]. We ascertained a carrier of a deletion encompassingSYNGAP1 among 300 patients with mental retardation studied by1Mb array-comparative genomic hybridization (a-CGH). Data onthe patient were deposited in the DECIPHER database (Databaseof Chromosomal Imbalances and Phenotype in Humans usingEnsembl Resources, http://www.sanger.ac.uk/PostGenomics/decipher).Informed consent for publishing results and photos was obtainedfrom the patient’s legal guardians.The boy (DECIPHER USP002265) was the only child of non-consaguineous healthy parents, and no other cases of mentalimpairment were known among first- or second-degree relatives.He was born at term by caesarean; his birth weight was 3,315 g(between 25th and 50th centiles) and length 47cm ( 3rd centile).Motor development was considered slightly delayed: he sat upwithout support at 6

Premature ovarian failure (POF) in Brazilian fragile X carriers

The gynecological and reproductive histories of 193 women from fragile X families were surveyed. Among the 101 carriers of the premutation, 14 experienced premature menopause, contrarily to their 37 fully mutated and 55 noncarrier female relatives. Although premature menopause showed a tendency to cluster in certain fragile X families, as a group, the premutated women experienced menopause earlier than noncarriers. This suggests that premature menopause may be the extreme effect of a spectrum of ovarian anomalies associated with the fragile X premutation.

DXS548/FRAXAC1 haplotypes in fragile X chromosomes in the Brazilian population.

In order to investigate the origin of the fragile X mutation in the Brazilian population, we assessed the size of the microsatellite markers DXS548, FRAXAC1 and FRAXAC2 in 72 X chromosomes from unrelated affected males and 64 control chromosomes. We found a significantly different distribution of alleles between fragile X and controls for loci DXS548 and FRAXAC1, but no apparent linkage disequilibrium was detected for the sequence FRAXAC2. The most frequent DXS548/FRAXAC1 haplotypes in affected males were haplotypes 204/158 bp (2-1) and 196/152 bp (6-4). These findings are in accordance with the proposed two main mutational pathways for the generation of FMR-1 alleles that predispose to instability and hyperexpansion.