Federica Natacci

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano, Lombardy, Italy

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Publications (23)72.27 Total impact

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    ABSTRACT: There are between 5,000 and 8,000 distinct rare diseases (RDs) affecting 6-8% of the population, most of which are caused by genetic defects. Many are highly complex, childhood-onset, multi-system disorders that are often associated with developmental disability, and require lifelong, highly specialized care and support. As larger numbers of children with previously fatal RDs survive into adulthood, they encounter significant challenges in transitioning from family-centered, developmentally focused, multidisciplinary pediatric care to a less supportive adult healthcare system that is often unfamiliar with these conditions. This paper discusses the challenges of the transition from pediatric to adult health care in two groups of patients with multisystem genetic RDs (neurofibromatosis 1 [NF1] and Williams-Beuren syndrome [WBS]), and analyzes strategies for making the process easier for patients with and without developmental disabilities. Our findings show that there are still no guidelines in national healthcare programs on how to transition RD adolescents with and without developmental disabilities, and only a few pediatric centers have implemented the elements of transition in their general practice. Evidence regarding programs to facilitate transition is inconclusive and the transition from pediatric medicine to adult medicine for RDs remains a major challenge. However, transition requires both time and personnel, which are difficult to find in periods of fiscal austerity. Nevertheless, we should strongly advocate for governments investing more into transition infrastructure or they will face increased long-term social and economic costs due to poor treatment compliance, disengagement from services, increased genetic risks, and higher rates of disease-related complications. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2013; 161(7). DOI:10.1002/ajmg.a.35982 · 2.05 Impact Factor
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    ABSTRACT: Few cases of mosaicism involving a normal cell line and an unbalanced autosomal translocation have been reported so far. No cases of partial trisomy 13 and partial monosomy 8 mosaicism have been published. The authors report a new patient with partial trisomy 13 and partial monosomy 8 mosaicism due to an unbalanced translocation (13/8). A postzygotic mitotic exchange of nonhomologous chromatids followed by the loss of one of the translocated chromatids has been hypothesized as the potential underlying mechanism. Although a clear correlation of the clinical features of the patient with his chromosomal abnormality can be challenging, dysmorphic features, hyperactive behavior, moderate developmental delay, and tonic-clonic seizures can be interpreted as secondary to the particular genotype of the patient. These findings should be taken into account in the diagnostic process of patients presenting with multiple congenital anomalies and/or mental retardation conditions.
    Journal of child neurology 04/2013; 28(11). DOI:10.1177/0883073813483571 · 1.67 Impact Factor
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    American Journal of Medical Genetics Part A 02/2013; 161(2). DOI:10.1002/ajmg.a.35720 · 2.05 Impact Factor
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    ABSTRACT: Congenital myasthenic syndromes are inherited disorders caused by various defects in neuromuscular transmission. Although the typical presentation is fatigable weakness with prominent cranial involvement, neonates can lack these hallmark manifestations, and in those with choline acetyltransferase gene mutations, basal electrophysiological testing can yield negative findings. The authors report the case of a male infant presenting at birth with oculomotor and bulbofacial weakness, hypotonia, clubfoot, and severe respiratory insufficiency. Electromyography showed myogenic signs, and basal repetitive nerve stimulation yielded negative findings. Since age 6 months, the infant had progressively improved, acquiring autonomous respiration. Prolonged subtetanic repetitive nerve stimulation disclosed a marked decremental response compatible with suspected congenital myasthenic syndrome with episodic apnea. Genetic testing identified 2 novel choline acetyltransferase mutations (R470X, F580C). Keeping a high clinical suspicion of this rare condition and undertaking early comprehensive electrophysiological assessments including prolonged repetitive nerve stimulation (10 Hz for 5 minutes) can expedite the diagnosis.
    Journal of child neurology 01/2013; 29(3). DOI:10.1177/0883073812470000 · 1.67 Impact Factor
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    ABSTRACT: The term "position effect" is used when the expression of a gene is deleteriously affected by an alteration in its chromosomal environment even though the integrity of the protein coding sequences is maintained. We describe a patient affected by epilepsy and severe neurodevelopment delay carrying a balanced translocation t(15;16)(p11.2;q12.1)dn that we assume caused a position effect as a result of the accidental juxtaposition of heterochromatin in the euchromatic region. FISH mapped the translocation breakpoints (bkps) to 15p11.2 within satellite III and the 16q12.1 euchromatic band within the ITFG1 gene. The expression of the genes located on both sides of the translocation were tested by means of real-time PCR and three, all located on der(16), were found to be variously perturbed: the euchromatic gene NETO2/BTCL2 was silenced, whereas VPS35 and SHCBP1, located within the major heterochromatic block of chromosome 16q11.2, were over-expressed. Pyrosequencing and chromatin immunoprecipitation of NETO2/BTCL2 and VPS35 confirmed the expression findings. Interphase FISH analysis showed that der(16) localised to regions occupied by the beta satellite heterochromatic blocks more frequently than der(15). To the best of our knowledge, this is the first report of a heterochromatic position effect in humans caused by the juxtaposition of euchromatin/heterochromatin as a result of chromosomal rearrangement. The overall results are fully in keeping with the observations in Drosophila and suggest the occurrence of a human heterochromatin position effect associated with the nuclear repositioning of the der(16) and its causative role in the patient's syndromic phenotype.
    Molecular Cytogenetics 04/2012; 5:16. DOI:10.1186/1755-8166-5-16 · 2.66 Impact Factor
  • Annales d Endocrinologie 04/2012; 73(2):152. DOI:10.1016/j.ando.2012.03.020 · 0.66 Impact Factor
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    ABSTRACT: To investigate in a large sample of consecutive patients with neurofibromatosis type 1 (NF1) the possibility of including the presence of choroidal abnormalities detected by near-infrared reflectance (NIR) as a new diagnostic criterion for NF1. Cross-sectional evaluation of a diagnostic test. Ninety-five consecutive adult and pediatric patients (190 eyes) with NF1, diagnosed based on the National Institutes of Health (NIH) criteria. Controls included 100 healthy age- and gender-matched control subjects. Confocal scanning laser ophthalmoscopy was performed for each subject, investigating the presence and the number of choroidal abnormalities. Sensitivity, specificity, and diagnostic accuracy for the different cutoff values of the criterion choroidal nodules detected by NIR compared with the NIH criteria. Choroidal nodules detected by NIR imaging were present in 79 (82%) of 95 of the NF1 patients, including 15 (71%) of the 21 NF1 pediatric patients. Similar abnormalities were present in 7 (7%) of 100 healthy subjects, including 2 (8%) of the 25 healthy pediatric subjects. The highest accuracy was obtained at the cutoff value of 1.5 choroidal nodules detected by NIR imagery. Sensitivity and specificity of the examination at the optimal cutoff point were 83% and 96%, respectively. Diagnostic accuracy was 90% in the overall population and 83% in the pediatric population. Both of these values were in line with the most common NIH diagnostic criteria. Choroidal abnormalities appearing as bright patchy nodules detected by NIR imaging frequently occurred in NF1 patients. The present study shows that NIR examination to detect choroidal involvement should be considered as a new diagnostic criterion for NF1.
    Ophthalmology 09/2011; 119(2):369-75. DOI:10.1016/j.ophtha.2011.07.046 · 6.17 Impact Factor
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    ABSTRACT: Williams-Beuren syndrome (WBS) is a multisystem disorder that requires ongoing management by a primary care physician familiar with the natural history and specific medical problems associated with the condition. While the natural history of the disease during infancy is well known, data about the adult WBS population have been published only in the last few years, and show a wide range of medical, neurological, and psychiatric problems. We investigated 45 young adult WBS patients (mean age 23 years, range 17-39 years) using a well-coordinated team which included a cardiologist, a nephrologist, an ophthalmologist, an endocrinologist, a gastroenterologist, orthodontist, and orthopedist. Here we describe the clinical features and medical complications in this cohort of patients. Most patients demonstrated a high frequency of multiple organ systems complications, in particular, abnormal body habitus; cardiovascular disease, and hypertension; sensorineural hearing loss; gastrointestinal symptoms including diverticular disease and abnormal glucose tolerance. We offer some suggestions for clinical monitoring which we propose will be useful in the overall care of adults with WBS.
    American Journal of Medical Genetics Part A 02/2011; 155A(2):353-9. DOI:10.1002/ajmg.a.33819 · 2.05 Impact Factor
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    ABSTRACT: It is not unusual for patients with "rare" conditions, such as skeletal dysplasias, to remain undiagnosed until adulthood. In such cases, a pregnancy may unexpectedly reveal hidden problems and special needs. A 28 year old primigravida was referred to us at 17 weeks for counselling with an undiagnosed skeletal dysplasia with specific skeletal anomalies suggesting the collagen 2 disorder, spondyloperipheral dysplasia (SPD; MIM 156550). She was counselled about the probability of dominant inheritance and was offered a prenatal diagnosis by sonography. US examination at 17, 18 and 20 weeks revealed fetal macrocephaly, a narrow thorax, and shortening and bowing of long bones. The parents elected to continue the pregnancy. At birth the baby showed severe respiratory distress for four weeks which then resolved. Mutation analysis of both mother and child revealed a hitherto undescribed heterozygous nonsense mutation in the C-propeptide coding region of COL2A1 confirming the diagnosis of SPD while reinforcing the genotype-phenotype correlations between C-propeptide COL2A1 mutations and the SPD-Torrance spectrum. This case demonstrates the importance of a correct diagnosis even in adulthood, enabling individuals affected by rare conditions to be made aware about recurrence and pregnancy-associated risks, and potential complications in the newborn.
    Orphanet Journal of Rare Diseases 02/2011; 6:7. DOI:10.1186/1750-1172-6-7 · 3.96 Impact Factor
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    ABSTRACT: Neurofibromatosis type 1 (NF1) is a developmental and cancer predisposing syndrome resulting from haploinsufficiency or alteration in neurofibromin, a multifunctional protein that acts in various signaling pathways affecting morphogenetic processes and cell proliferation. Neurofibromin deficiency deregulates Ras/Raf/MEK/ERK and Ras/PI3K/AKT/PKB/mTOR signaling networks and intersected pathways including the cAMP-dependent protein kinase A (PKA) and the Rho-cofillin which acts on actin cytoskeleton reorganization, cell motility and adhesion. As the neurofibromin-mediated pathways are associated with biological effects depending on the cell lineage, deregulation induced by NF1 mutation clearly has cell type-specific effects. This review summarizes our increasing knowledge of NF1 as a disease rooted in defective developmental mechanisms that can also influence the potential for malignant growth. The cardinal features of NF1 patients, at birth and during life involve the cardiovascular, connective/skeletal and central nervous systems, as they reflect the NF1 mutation sensitivity of cell lineages committed to specifying these systems during embryonic development. A switch to neoplastic transformation may also occur in both the prenatal and postnatal life in cancer initiating cells of defined lineages, with the cooperation of a genetically and epigenetically modified tumor microenvironment. We emphasize how much of our current knowledge of the pathomechanisms of NF1 clinical signs and cancer has come from engineered mouse models and in vitro primary cells and cell lines exposed to inhibitors of signaling molecules. Advances in our knowledge of the developmental defects primed by the loss neurofibromin should reveal further associations between given NF1 mutations and tissue-specific symptoms, thus improving the clinical management of the patients.
    Current Molecular Medicine 08/2009; 9(5):634-53. DOI:10.2174/156652409788488801 · 3.61 Impact Factor
  • Clinical dysmorphology 02/2009; 18(1):45-8. DOI:10.1097/MCD.0b013e328317c867 · 0.42 Impact Factor
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    ABSTRACT: OPHN1 mutations cause a syndromic form of mental retardation (MR) characterized by cerebellar hypoplasia, early hypotonia, motor and speech delay, with occasional seizures and strabismus. Here we report on a familial chromosome duplication spanning about 800 Kb of Xq12q13.1, associated with MR and a distinctive phenotype in the affected male, but not in his heterozygous mother. The parents were healthy and non-consanguineous with a history of three pregnancies. The first resulted in the birth of a boy with MR, motor impairment and seizures. The second pregnancy was terminated because of trisomy 18. At the time of the third, the first affected boy was analyzed by array-CGH, which revealed a 800 Kb duplication at Xq12q13.1, encompassing three genes, including OPHN1. This mutation was inherited from his healthy mother and was not present in any of the three maternal brothers. To our knowledge this is the first report of a clinical phenotype associated with duplication of Xq12q13.
    American Journal of Medical Genetics Part A 07/2008; 146A(13):1718-24. DOI:10.1002/ajmg.a.32365 · 2.05 Impact Factor
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    ABSTRACT: We present the case of a monozygotic twin pregnancy discordant for phenotype and karyotype. A chorionic villus sample was performed at the 11th week of gestation in a primigravida because of cystic hygroma detected by ultrasound in one twin of a monochorionic, biamniotic pregnancy. Rapid testing by means of quantitative fluorescence polymerase chain reaction and conventional karyotyping, obtained by both short- and long-term culture, revealed a homogeneous monosomy X (45,X). Amniocentesis was performed separately for both twins before termination and showed an homogeneous monosomy X in one sample and a 46,X,del(X)(p11.1) karyotype in the other one. Postmortem fetal tissues culture confirmed the discordant karyotype between the two embryos. Placental samples obtained after termination revealed the cell line which was not detected at chorionic villus sampling. Based on this and previous reports, we suggest that in cases of a phenotypic discordance detected at ultrasound in the first trimester, it is advisable to perform a karyotype analysis on amniocytes because it better reflects fetal constitution rather than chorionic villi or lymphocytes in case of heterokaryotipic monosomy X monochorionic twins.
    Twin Research and Human Genetics 07/2008; 11(3):352-6. DOI:10.1375/twin.11.3.352 · 1.92 Impact Factor
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    ABSTRACT: We describe a sib recurrence for achondroplasia with parents of average stature. The three sibs shared the paternal allele and all carried the same causal mutation in the fibroblast growth factor receptor 3 gene (FGFR3): G > A nt1138 (Gly380Arg). We were able to identify this mutation on sperm DNA confirming paternal germinal mosaicism. Our family shows that a more precise definition of the recurrence risk is feasible using this approach, based on a single DNA test, which could be offered in selected cases.
    American Journal of Medical Genetics Part A 03/2008; 146A(6):784-6. DOI:10.1002/ajmg.a.32228 · 2.05 Impact Factor
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    ABSTRACT: Our purpose is to describe the prenatal manifestation of Norman-Roberts syndrome and to expand the knowledge of the fetal phenotype of this rare condition. The recurrence in two sibs might contribute to the hypothesis of a recessive condition. Three cases are presented in which the diagnosis was suggested by a prenatal ultrasound examination and confirmed by pathology of the fetuses, after termination of pregnancy. The major sign was the ultrasound detection of microcephaly at the 22nd and 23rd week of gestation. Fetal Magnetic Nuclear Resonance, the pathological examination with histological studies, was applied to arrive at the diagnosis of Norman-Roberts syndrome. To the best of our knowledge, this is the second description of prenatal cases of Norman-Roberts syndrome. The combined clinical and pathological data is a contribution that might help to increase the identification of this rare condition and to correctly define the risk of its recurrence.
    Prenatal Diagnosis 06/2007; 27(6):568-72. DOI:10.1002/pd.1728 · 2.51 Impact Factor
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    ABSTRACT: We report the case of a young boy with fine hair, mild nail dysplasia, blocked nasolacrimal ducts, absence of central incisors, bilateral oligodactyly of feet and anal stenosis. His father showed the same spectrum of anomalies with mild expression. He had mild nail dysplasia, blocked nasolacrimal ducts, inferior dental cysts with consequent premature tooth loss, frequent dental decays consequent to enamel abnormality and cutaneous syndactyly of the second and third right toe. The acro-dermato-ungual-lacrimal-tooth syndrome was suspected and molecular analysis of the P63 gene was performed, but no mutation was found. Although P63 gene analysis was negative, we think that both cases show clinical overlap with the acro-dermato-ungual-lacrimal-tooth syndrome and confirm the wide expression of this condition, even in the same family.
    Clinical Dysmorphology 11/2006; 15(4):239-41. DOI:10.1097/01.mcd.0000220618.01144.6d · 0.42 Impact Factor
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    ABSTRACT: The presence in the conceptus of a Robertsonian translocation predisposes to UPD formation, mainly by post-zygotic events of chromosome abnormality rescue. This is due to the increased risk of generating aneuploid zygotes because the rearranged chromosome and the respective homologues are prone to non-disjunction errors. Given this, carriers and karyotypically normal individuals conceived from a parent with a Robertsonian translocation are at risk for UPD. Abnormal phenotypes due to an imprinting effect have been found to be associated with UPD 14 and 15. The aim of the study was to refine, at the time of prenatal diagnosis, the risk for UPD 14 and 15 in a population with Robertsonian translocations involving these chromosomes. Sixty-five cases of familial and de novo heterologous Robertsonian translocations involving chromosomes 14 and 15 and 18 fetuses with a normal karyotype, but conceived by a Robertsonian translocation carrier were prenatally studied to investigate the presence of UPD for chromosomes 14 and 15. Of the 65 Robertsonian translocation carriers, one fetus with a de novo der(14;21) showed maternal UPD 14. None of the 18 fetuses with a normal karyotype had UPD. Our data, combined with other previous prenatal investigations provide a general risk estimate for UPD 14 and 15 of 0.6%. Nevertheless, combining our data and those previously reported, all three fetuses with UPD had a de novo Robertsonian translocation, thus suggesting a risk of UPD formation of about 3% for this specific group of translocation carriers.
    Prenatal Diagnosis 12/2004; 24(12):997-1000. DOI:10.1002/pd.961 · 2.51 Impact Factor
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    ABSTRACT: Quantitative fluorescent polymerase chain reaction (QF-PCR) has recently entered the field of prenatal diagnosis to overcome the need to culture fetal cells, hence to allow rapid diagnosis of some selected chromosomal anomalies. We reviewed the studies on the accuracy of QF-PCR in detecting chromosomal anomalies at prenatal diagnosis. Overall, 22 504 samples have been analysed. The detection rate of aneuploidies of the selected chromosomes (13, 18 and 21, and X and Y) was 98.6% (95% confidence interval 97.8-99.3). QF-PCR might play a major role and be considered a valid alternative to the full karyotype. Being less expensive, and almost entirely automated, more women could undergo invasive prenatal diagnosis without significant increase in health expenditure. By using QF-PCR as a stand-alone test, the chances of non diagnosing the commonest, and the only chromosome anomalies which do increase in frequency with maternal age, are approximately one in 150 abnormal karyotypes, or one in 10-30 000 samples, based on the age distribution. These error rates might be deemed acceptable, although most structural chromosomal anomalies will be missed. At present, women are rarely informed about the full spectrum of the conditions which might be diagnosed via amniocentesis or chorionic villous sampling. Some of these anomalies might be acceptable, in view of their limited or uncertain clinical relevance, and decision analysis might, in the majority of cases, confine the full karyotype to selected women who have specific indications.
    Human Reproduction Update 01/2004; 10(6):541-8. DOI:10.1093/humupd/dmh046 · 8.66 Impact Factor
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    ABSTRACT: The underestimates of NF1 gene mutations in neurofibromatosis 1 (NF1) have been attributed to the large size of the NF1 gene, the considerable frequency of gross deletions and the common occurrence of splicing defects that are only detectable by cDNA analysis. We here report on a patient with severe NF1 showing at RT-PCR analysis the expected fragment from exon 4b to 8 together with a shortened one with the in-frame skipping of exon 7. Sequencing of the corresponding genomic fragment revealed a G-->A transition and a C-->A transversion at nucleotide positions 57 and 58 of the 174-bp long exon 7, neither of which was present in the proband's parents or 50 healthy controls. No other variation was found in the entire NF1 coding sequence. The use of previously established sequence matrices for the scoring of putative ESE motifs showed that the adjacent silent and missense mutations are located within highly conserved overlapping stretches of seven nucleotides with a close similarity to the ESE-specific consensus sequences recognised by the SC35 and SF2/ASF SR proteins. The combined occurrence of both consecutive alterations decreases the motif score for both SF2/ASF and SC35 below their threshold levels. As the aberrant transcript is consistently expressed, a protein lacking 58 amino acids is predicted. Thus the contiguous internal exon 7 mutations are suggested to cause exon 7 skipping as a result of the mis-splicing caused by abrogation of functional ESEs.
    Human Genetics 11/2003; 113(6):551-4. DOI:10.1007/s00439-003-1009-2 · 4.52 Impact Factor
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    ABSTRACT: A child and his mother were found to be mosaic for a small supernumerary marker chromosome (SMC) that was identified and characterized by means of fluorescent in situ hybridization. The marker chromosome was derived from the pericentromeric region of chromosome 2; the involvement of proximal 2q was determined by YAC probes. The proband was referred because of psychotic illness and mild mental retardation, whereas his mother presented only minor dysmorphisms. There are only a few published reports concerning SMC(2) or proximal 2q trisomy. We reviewed the previously reported cases in an attempt to establish genotype-phenotype correlations, which are particularly important when SMCs are identified in prenatal diagnosis.
    American Journal of Medical Genetics 08/2002; 111(3):319-23. DOI:10.1002/ajmg.10537 · 3.23 Impact Factor

Publication Stats

247 Citations
72.27 Total Impact Points

Institutions

  • 2007–2013
    • Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
      • Endocrinology and Diabetology
      Milano, Lombardy, Italy
  • 1998–2011
    • University of Milan
      • • Department of Biology and Genetics for Medical Sciences
      • • Faculty of Medicine
      Milano, Lombardy, Italy
  • 2003–2004
    • Istituti Clinici di Perfezionamento
      Milano, Lombardy, Italy
  • 2002
    • GENOMA Molecular Genetics Laboratory
      Roma, Latium, Italy
  • 2001
    • I.R.C.C.S. Istituto Auxologico Italiano
      • Laboratorio di Citogenetica
      Milano, Lombardy, Italy