Search

The Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are 2 rare but clinically well-described diseases caused by de novo heterozygous sequence variants in the KAT6B gene. Both phenotypes are characterized by significant global developmental delay/intellectual disability, hypotonia, genital abnormalities, and patellar hypoplasia/agenesis. In addition, congenital heart defects, dental abnormalities, hearing loss, and thyroid anomalies are common to both phenotypes. This broad clinical overlap led some authors to propose the concept of KAT6B spectrum disorders. On the other hand, some clinical features could help to differentiate the 2 disorders. Furthermore, it is possible to establish a genotype-phenotype correlation when considering the position of the sequence variant along the gene, supporting the notion of the 2 disorders as really distinct entities.

Whole exome sequencing (WES) has made the identification of causative SNVs/InDels associated with rare Mendelian conditions increasingly accessible. Incorporation of softwares allowing CNVs detection into the WES bioinformatics pipelines may increase the diagnostic yield. However, no standard protocols for this analysis are so far available and CNVs in non-coding regions are totally missed by WES, in spite of their possible role in the regulation of the flanking genes expression. So, in a number of cases the diagnostic workflow contemplates an initial investigation by genomic arrays followed, in the negative cases, by WES. The opposite workflow may also be applied, according to the familial segregation of the disease. We show preliminary results for a diagnostic application of a single next generation sequencing panel permitting the concurrent detection of LOH and variations in sequences and copy number. This approach allowed us to highlight compound heterozygosity for a CNV and a sequence variant in a number of cases, the duplication of a non-coding region responsible for sex reversal, and a whole-chromosome isodisomy causing reduction to homozygosity for a WFS1 variant. Moreover, the panel enabled us to detect deletions, duplications, and amplifications with sensitivity comparable to that of the most widely used array-CGH platforms.

Prader-Willi syndrome is a complex condition caused by lack of expression of imprinted genes in the paternally derived region of chromosome 15 (15q11q13). A small number of patients with Prader-Willi phenotype have been discovered to have narrow deletions, not encompassing the whole critical region, but only the SNORD116 cluster, which includes genes codifying for small nucleolar RNAs. This kind of deletion usually is not detected by the classic DNA methylation analysis test. We present the case of a male patient with a mild Prader-Willi phenotype and a small deletion including SNORD116, diagnosed by methylation-sensitive multiplex ligation-dependent probe amplification (MLPA. The patient showed neonatal hypotonia, hyperphagia, obesity, central hypogonadism, hypothyroidism, strabismus. Stature and intellectual development are within the normal range. The presence of macrocephaly, observed in other cases of SNORD116 deletions as well, is uncommon for the classic phenotype of the syndrome.

The genetic basis of Rubinstein-Taybi syndrome (RSTS), a rare, sporadic, clinically heterogeneous disorder characterized by cognitive impairment and a wide spectrum of multiple congenital anomalies, is primarily due to private mutations in CREBBP (approximately 55% of cases) or EP300 (approximately 8% of cases). Herein, we report the clinical and the genetic data taken from a cohort of 46 RSTS patients, all carriers of CREBBP point mutations. Molecular analysis revealed 45 different gene alterations including 31 inactivating (21 frameshift and 10 nonsense), 10 missense and 4 splicing mutations. Bioinformatic tools and transcript analyses were used to predict the functional effects of missense and splicing alterations. Of the 45 mutations, 42 are unreported and 3 were described previously. Recurrent mutations maybe a key tool in addressing genotype-phenotype correlations in patients sharing the same defects (at the genomic or transcript level) and specific clinical signs, demonstrated here in two cases. The clinical data of our cohort evidenced frequent signs such as arched eyebrows, epicanthus, synophrys and/or frontal hypertrichosis and broad phalanges that, previously overlooked in RSTS diagnosis, now could be considered. Some suggested correlations between organ-specific anomalies and affected CREB-binding protein domains broaden the RSTS clinical spectrum and perhaps will enhance patient follow-up and clinical care.

Primary pachydermoperiostosis (PDP) is a rare syndrome, characterized by digital clubbing, periostosis, and pachydermia. We have evaluated biochemical bone turnover markers, including components of interleukin-6 (IL-6) and osteoprotegerin/receptor activator of nuclear factor (NF)-?B ligand (OPG/RANKL) systems, in an 18-year-old man affected by primary PDP. The acute phase of the disease was characterized in our patient by high serum levels of IL-6 and RANKL. The observed high serum levels of these parameters are associated with increased values in markers of bone resorption (degradation products of C-terminal telopeptides of type-I collagen and urinary hydroxyproline/creatinine ratio) and reduced serum levels of bone alkaline phosphatase, a marker of bone formation. Serum levels of osteotrophic hormones were in the normal range. Our data suggest that, despite the radiographic findings, the acute phase of primary PDP is characterized by increased bone resorption, probably mediated by IL-6 and RANKL. Read More: http://informahealthcare.com/doi/abs/10.1080/03009740701772457

Electroencephalography is potentially more secure and privacy-compliant than traditional biometric identifiers. A related video can be seen here: http://youtu.be/5f0zflJRnvc. It depicts four maps representing the spatial distribution on the scalp of an EEG signal in time for the four bands Delta, Theta, Alpha, and Beta. Another related video can be seen here: http://youtu.be/X34pUw-4z_8. It depicts the spatial distribution on the scalp of an EEG amplitude spectral density (top) for frequencies ranging in the [1, 30] Hz interval (bottom).

The urinary benzene metabolite trans,trans-muconic acid (MA) was determined in 144 children living in Campania (Italy): 92 from Naples (1,300,000 inhabitants), designated as an urban source, and compared to 52 from Pollica (300 inhabitants), considered a rural, background exposure for benzene. The children participating in the study were tested by an anonymous questionnaire about the possible sources of exposure to benzene. Quantifiable levels of MA were found in 63% of the urine samples analyzed. Setting the value of nondetectable urinary samples at 7 microg/L MA, a value that is one-half of the instrument detection limit of 14 microg/L, the mean urinary concentration levels were 98.7+/-81.0 microg/L and 48.4+/-71.7 microg/L in Naples and Pollica, respectively; adjustment of these values to creatinine clearance resulted in MA levels of 141.2+/-145.4 microg/L in Naples and 109.8+/-133.2 microg/L in Pollica. Passive smoke exposure did not significantly affect urinary MA levels, but proximity of the home to traffic increased urine MA content. Data show that MA can be utilized as a biomarker for exposure; however, a clear-cut association to benzene requires personal monitoring and control of dietary sorbic acid.

An improvement of the method commonly used for the determination of ivermectin is proposed. An automatic system is used for the solid-phase extraction column purification stage in order to provide more efficient and fast sample preparation, prior to separation and quantification by HPLC. Some tests were performed to obtain recovery and repeatability data. The mean recovery for spiked samples (five replicates twice at three concentration levels) was more than 90% in the concentration range 7.5-30 ng g-1. The tests for accuracy (five replicates at three concentration levels) gave a standard error of -2.0% at the highest and -19.2% at the lowest concentration. Concerning repeatability data (five replicates twice at three concentration levels), in the concentration range 7.5-30 ng g-1 the RSD varied from 9.29 to 2.15%. The described method was used in a survey on the presence of ivermectin in food-producing animals in two regions of southern Italy; no positives out of 250 liver samples were found.

We present a case of ultrasonographic prenatal diagnosis at 24 weeks of femur-fibula-ulna (FFU) complex. To our knowledge, this is the first report of an early prenatal diagnosis of FFU.

In this paper the use of brain waves as a biometric identifier is investigated. Among the very different protocols that can be used to acquire the electroencephalogram signal (EEG) of an individual we rely on a very simple one: closed eyes in resting conditions. A database of 48 healthy subjects, collected by the authors at the neurophysiology laboratory of the IRCCS Fondazione Santa Lucia, Roma, Italy, has been used for the experiments. Signals acquired from triplets of electrodes have been employed in the experimentations. In more detail, ten different triplets have been used separately in the experiments in order to speculate about the most suitable triplet to capture the occurring phenomena. Feature vectors constituted by the reflection coefficients of a six order AR model have been extracted for each used channel thus giving rise to a feature vector of length eighteen. A polynomial regression based classification is then employed. This analysis has been performed for three different frequency bands for each of the ten different triplet under analysis. The obtained genuine acceptance rate is of 96.08%.

We describe a dominant point mutation in the COL1A1 gene causing extremely severe osteogenesis imperfecta (OI type II/III) which was detected in the dermal fibroblasts of a proband, diagnosed by ultrasonography at 24 weeks of gestation. Type I collagen secretion was reduced and pro alpha 1(I) chains were overmodified. The mutation was localised in one COL1A1 allele by chemical cleavage of mismatched bases in normal cDNA/proband's mRNA heteroduplexes, and identified by cloning and sequencing. A G-to-A transition which causes the substitution of Gly-415 with serine in the alpha 1(I) triple helical domain was found. The same mutation was detected in the father's spermatozoa and lymphocytes. Mosaicism in the father's germline explains the occurrence in the family of two additional OI pregnancies, which were documented by X-ray and ultrasound investigations.

The aim of this study was to elucidate if the TV commercials that were remembered by the subjects after their observation within a documentary elicited particular brain activity when compared to the activity generated during the observation of TV commercials that were forgotten. High resolution EEG recordings were performed in a group of 10 healthy subjects with the steady state somatosensory evoked potentials (SSSEPs) technique, in which a series of light electrical stimulation at the left wrist were delivered at the frequency of 20 Hz. The brain activity was indexed by the phase delay of the EEG spectral responses at 20 Hz with respect to the stimulus delivering and evaluated at the scalp level as well as at the cortical surface using several regions of interest coincident with the Brodmann areas (BAs). Results suggest that the cerebral processes involved during the observation of TV commercials that were remembered by the population examined (RMB dataset) are generated by the posterior parietal cortices and the prefrontal areas, rather bilaterally. These results are compatible with previously results obtained in literature by using MEG and fMRI devices during similar experimental tasks. High resolution EEG is able to summarize, with the use of SSSEPs methodologies, the behavior of the estimated cortical networks subserving the proposed memory tasks. It is likely that such tool could play a role in the next future for the investigation of the neural substrates of the human behavior in decision-making and recognition tasks.

A fluorescence in situ hybridization (FISH) study was performed in 56 patients with short stature of unknown cause in order to establish the role of deletion of the SHOX gene in this population. FISH analysis was carried out on metaphase spreads and interphase lymphocytes from blood smears using a probe specific for the SHOX gene. Deletion of SHOX was found in four patients (7.1%). No skeletal abnormalities were detected in these patients either at the physical examination or at X-rays of the upper and lower limbs. Present results indicate that SHOX plays an important role also in short stature of unknown cause, and FISH analysis appears as an easy, appropriate, and inexpensive method for the detection of SHOX deletion.

The possibility of using automated equipment for solid phase extraction of isoniazid from milk has been investigated. This equipment provides two noteworthy advantages: it shortens the time of analysis and avoids SPE column plugging, stabilizing flow rates. After setting the correct programme on software controlling the equipment, some validation parameters have been determined to obtain recovery and repeatability data. The mean recovery for spiked samples resulted in the range 75-95%, the standard error ranged from -5 to -20% while the RSD varied from 2 to 22%. Therefore the method can be considered reliable and fast.

Overgrowth Syndromes (OS) – Beckwith-Wiedeman (BW), Simpson-Golabi-Behmel, Perlman, Sotos, Weaver (WS), Proteus, KlippelTrenaunay and some other heterogeneous conditions – are characterized by an excessive prenatal and postnatal growth. As some of them have a poor prognosis, a correct prenatal diagnosis is essential. So far, just a few of prenatal diagnosis of OS have been reported, mostly regarding the BW one. We report the first prenatal diagnosis of Weaver syndrome, in a low risk pregnancy, detected as early as the 22 weeks’ gestation, in a G2 P1 28-year-old Caucasian woman. Parents were non related. The patient was referred to our tertiary centre because of a presumptive diagnosis of BW syndrome, that was excluded because there was neither omphalocele nor macroglossia. 2D US scan was performed with an Hitachi Logos machine (Esaote), and the images were further elaborated in a 3D freehand mode. The 2D scan showed a single living fetus with all the biometric parameters above the 99◦ centile for gestational age. The fetus showed as well: broadening of long bones epiphyses; external male genitalia with micropenis; enlarged hyperechogenic kidneys with severe hydronephrosis; camptodactyly with clinodactyly of fifth digits; enlarged liver; long, everted and broad upper lip.; large ears; enlarged plica nucalis > 9 mm; polyhydramnios. Amniocentesis showed a normal male, 46XY, karyotype. 3D surface rendering images better defined the 2D findings, especially as for the fetal profile, hands and kidneys was concerning, allowing us to postulate a prenatal diagnosis of Weaver syndrome. After extensive genetic counselling, parents opted for pregnancy termination, and a stillborn fetus weighing 788 g was delivered. Dismorphological, X-Ray and necroscopic examination confirmed the prenatal diagnosis of WS. We believe that 3D scan is helpful in making an accurate prenatal diagnosis in case of OS, permitting parents to decide in order to pregnancy termination.

Height is the result of interactions of several factors including those of genetic origin. About 3% of people have short stature and in most of them the cause is unknown.1 Recently, the SHOX gene (short stature homeobox containing gene), mapped on the pseudoautosomal region (PAR1) of the X and Y chromosomes, has been specifically associated with the short stature of patients with Turner syndrome or with Leri-Weill dyschondrosteosis (LWD).2–7 Few data have been reported on the relationship between SHOX mutations and idiopathic short stature. Rao et al 2 reported one change among 91 patients with idiopathic short stature, and Binder et al 8 found a mutation in one out of 68 patients. The largest study was recently published by Rappold et al ,9 who found a frequency of 2.4% of SHOX mutations using fluorescence in situ hybridisation (FISH) on 150 patients and single strand conformational polymorphism analysis (SSCP) on 750 patients. We report a study carried out on 56 patients with short stature of unknown origin detecting SHOX mutations in seven (12.5%) by using FISH and direct sequencing analyses. ### Patients Fifty-six patients, 33 females and 23 males, with a mean age of 12.2 years (range 5-18 years) entered this study. All patients were unrelated, coming from different regions of central and southern Italy. In order to exclude patients with dyschondrosteosis or other diseases associated with short stature, we used the following criteria: (1) height at or below the 3rd centile; (2) absence of obvious skeletal abnormalities on physical examination; (3) absence of other diseases on physical examination and routine analyses; (4) normal bone age; (5) normal hGH values using a polyclonal in house RIA (lower detection limit 0.1 ng/μl, mean intra-assay coefficient of variation 6.9%, and mean interassay coefficient 9.5%); and (6) normal karyotype in 16 metaphases …

VATER association is an acronym for vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and renal anomalies. It is rare and sporadic and with no recognized teratogen or chromosomal abnormality. A mitochondrial DNA disorder has been suggested. To date a few of prenatal diagnosis of VATER association have been reported in literature. We report a case of VATER association diagnosed as earlier as the 20th week of gestation associated with a number of fetal anomalies. The consultant, a 33-year old Caucasian woman, gravida3, para1, was referred to our prenatal diagnosis unit because of a previous US scan showing a single vessel umbilical cord, an omphalomesenteric cyst, hypoplasia of left cerebellar hemisphere, ectasia of the aortic arch, a suspicious of anal atresia, sacral anomalies. Normal female foetal karyotype, 46 XX, obtained by amniocentesis, was found. The 20th-week scan confirmed the previous diagnosis but the cerebellar hypoplasia showing as well a coarctation of the descending aorta, a mild bilateral renal pyelectasis with a dysplastic appearance, a diagnosis of sacral agenesia was made. Genitalia was definitively ambiguous with an hypertrophic tuberculum ending with an anechoic cyst showing gross variation during the scan as for the urethrocele. Stomach was not detected during the all US examination. Even tough, due to the earlier of the gestational week, there were no signs of tracheoesophageal fistula, on the basis of the US scan a diagnosis of VATER syndrome associated with ambiguous genitalia was made. After prenatal and genetic counselling parents decided for pregnancy termination at 20 weeks of gestation. Dismorphological and X-ray examination confirmed the US diagnosis and necroscopy further detected an esophageal atresia. This case confirm that the VATER association can be readily diagnosed in utero, and that prenatal diagnosis can contribute to clinical decisions regarding pregnancy.

Chondrodysplasia with snail-like pelvis (Schnechenbecken dysplasia) is a rare distinct, lethal, short-limbed dwarfism. We describe the clinical and radiological features of a new case in an Italian family.

We describe a case of semi-lethal chondrodysplasia with skeletal manifestations, detectable at birth, typical of the round femoral inferior epiphysis dysplasia (RFIED) or 'Glasgow' variant. Immunological abnormalities and Hirschsprung disease, so far described only in cartilage hair hypoplasia (CHH), were documented during the first months of life in our patient. These findings confirm the hypothesis that RFIED is a form of CHH with early infantile onset.

Total haemoglobin and methaemoglobin concentration in blood was analyzed in sea bass (Dicentrarchus labrax) exposed for 18 h to 150 mg/l NO2-N in sea water. Observations of recovery mechanisms carried out for 24 days following the nitrite exposure showed that, after a rapid disappearance of methaemoglobinaemia, a strong anaemia occurred, due to a drop in the total haemoglobin concentration. Complete recovery from this anaemia occurred only after 24 days. The mechanism of recovery from nitrite intoxication is discussed with a view to devising treatment that might help to minimize losses at fish-farming facilities.

We describe three patients, originating from three different Italian localities, affected by the cardio-facio-cutaneous (CFC) syndrome. In addition to a varying degree of mental retardation, these patients present characteristics consisting of a peculiar face with bitemporal frontal constriction and other anomalies involving the eyes, nose, ears, hair, skin, and heart that are consistent with this diagnosis.

This retrospective cohort study was planned to determine whether recommendations to take folic acid have in fact lessened the risk of neural tube defects. Recommendations typically include eating a healthy diet and takingfolic acid supplements when planning pregnancy or throughout the childbearing years. In a few countries, including the United States, flour is fortified so that much of the population will receive at least a small supplemental amount of folic acid. Many governments promote the use of supplements because folic acid is inexpensive, safe, and easy to use. The authors acquired information on more than 13 million births from 13 birth defects registries in Norway that monitored rates of neural tube defects from 1988 to 1998. Cases of anencephaly and spina bifida totaled 8636. Rates of defects were stable during the 10-year monitoring interval in most areas. There were no evident changes in rates of defects after local recommendations were issued. Comparable findings were obtained when analyzing anencephaly and spina bifida separately and combined. Folic acid use in Europe is, in general, low; in Norway, it is approximately 10%. In China, intensive educational efforts and a high rate of planned pregnancies probably are responsible for the effectiveness of a public health campaign to promote the use of folic acid supplements. Rates of folic acid use generally follow economic and educational trends. Fortifying flour with folic acid holds promise for delivering some folic acid to a large part of the population, crossing social and economic barriers. Blood folate levels have increased rapidly where this practice is followed. It is estimated that thousands of neural tube defects occurring since 1992 could have been prevented.

The analysis of 236 Italian patients with Paget's bone disease showed higher clinical severity and greater frequency of neoplastic degeneration among patients who live or descend from individuals living in the Campania region (southern Italy). A prevalent involvement of the spine and the skull, the sites preferentially involved in giant cell tumors complicating Paget's disease, was also shown in familial cases from this geographical region. Introduction: The Campania region in southern Italy has been recently indicated as a high prevalence area for Paget's disease of bone (PDB), and most pagetic families with multiple occurrence of neoplasms in affected members were from this geographical region. Materials and Methods: We evaluated the PDB epidemiological characteristics in 125 patients from Campania in comparison with 111 patients from other Italian regions. Twenty-three patients from Campania and 26 patients from other Italian areas had at least one first-degree relative affected by PDB (familial cases). The remaining patients made up the sporadic cases. Results: Among subjects from Campania, the patients in the familial group tended to come from larger families and showed at diagnosis higher serum total alkaline phosphatase, larger extension of disease, and earlier mean age with respect to patients with PDB of the sporadic group. The skull, spine, and humerus were the sites preferentially involved in the familial cases. In contrast, no such differences were observed between familial and sporadic PDB cases among patients from the other geographical areas, except for a lower age at diagnosis. An increased PDB clinical severity was finally observed in the PDB cohort from Campania in comparison with patients from other Italian regions. Neoplastic degeneration of pagetic bones (osteosarcoma and giant cell tumor) was exclusively observed in patients with polyostotic PDB from Campania. Conclusions: We showed a higher clinical severity of PDB with occurrence of neoplastic degeneration in the high prevalence area of Campania, with its maximum expression in cases with familial disease. This peculiar pattern might be traced to genetic predisposition and/or to the abnormal impact of a still undefined environmental trigger.

The authors describe a new sign by postmortem autopsy of thesubtype 2 of Pfeiffer s and the possibility of prenatal diagnosis