[Show abstract][Hide abstract] 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; · 1.59 Impact Factor
[Show abstract][Hide abstract] 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; · 1.59 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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. · 2.30 Impact Factor
[Show abstract][Hide abstract] 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. · 4.20 Impact Factor
[Show abstract][Hide abstract] 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 08/2008; 146A(13):1718-24. · 2.30 Impact Factor
[Show abstract][Hide abstract] 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. · 1.64 Impact Factor
[Show abstract][Hide abstract] 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. · 2.30 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: We describe a female affected by diaphragmatic hernia and nasopharyngeal teratoma. The case is compared with one already reported and possible diagnoses discussed. These cases appear to represent a new syndrome.