A novel BRCA2 pathogenic variant c.7094_7100del (p.His2365LeufsTer9) in an Italian family with hereditary breast cancer.

BACKGROUND: Breast cancer is the most common type of malignancy and the foremost cause of tumor-related death in women. The two most well-known genes linked to hereditary breast cancer are BRCA1 (MIM#113705) and BRCA2 (MIM#600185). Germline mutations in the tumor-suppressor genes are found in a proportion of this group. CASE REPORT: Family history of breast and ovarian cancer, early-onset breast cancer, and ethnicity constitute the basic criteria for identifying cases affected by BRCA1 or BRCA2 mutations. This study reports a novel BRCA2 pathogenic variant c.7094_7100del (p.His2365LeufsTer9), identified in a family from Basilicata, Italy, with a history of hereditary breast cancer. Genetic tests are available to predict the risk of developing cancer, particularly in cases of hereditary cancer, the predisposition to cancer, and the target organs. CONCLUSIONS: The identification of this variant expands the spectrum of BRCA2 mutations associated with hereditary breast cancer and highlights the importance of genetic testing and counseling for families with a history of breast cancer.

7q35q36.3 deletion and concomitant 20q13.2q13.33 duplication in a newborn: familiar case.

OBJECTIVE: Array-CGH is a powerful tool in identifying and characterizing complex genomic rearrangements smaller than 5-10 megabase (Mb), for which classical cytogenetic approaches are not sensitive enough. The use of Array-CGH has increased of 10-20% the detection rate of unbalanced cryptic rearrangements, such as deletions and/or duplications. PATIENTS AND METHODS: We present here the first report of a patient with 7q35q36.3 microdeletion and concomitant 20q13.2q13.33 microduplication detected by array-CGH and confirmed by reiterative FISH experiments associated with dysmorphism, development delay, Long QT syndrome (LQTS), complex congenital heart disease, pulmonary hypertension, hypotonia, respiratory distress, cognitive deficit. RESULTS: We proved that this unbalanced rearrangement was due to an adjacent-1 segregation that occurred in the mother, carrier of a balanced translocation between chromosomes 7 and 20. The same unbalanced rearrangements were also found in the proband's maternal uncle, who had been given a clinical diagnosis of Dandy-Walker/Rubinstein-Taybi syndromes in the past. Given the above-mentioned observations, the proband's uncle is not affected by Dandy-Walker/Rubinstein-Taybi syndromes, but by a genomic syndrome highlighted by array-CGH. CONCLUSIONS: The Array-CGH allowed us to understand that the loss of several genes is expressed with clinical manifestations due to the concomitance of several syndromes, each related to the malfunction of a "specific disease gene". For these reasons, the genotype-phenotype correlation in these cases is more complex. This study confirms that the array-CGH is useful in identifying pathologies that were considered idiopathic until a few years ago.

16p11.2 microdeletion syndrome: a case report.

BACKGROUND: The recurrent ∼ 600 kb 16p11.2 microdeletion is among the most commonly known genetic etiologies of autism spectrum disorder, overweightness, and related neurodevelopmental disorders. CASE PRESENTATION: Our patient is a 2-year-old white girl from the first pregnancy of a non-consanguineous healthy young white couple (father 33-years old and mother 29-years old). Our patient and her parents' DNA were analyzed by comparative genomic hybridization-array platform. Comparative genomic hybridization-array analysis highlighted a ∼ 600 kb deletion in 16p11.2 region. It has a segregant nature, since it was found in the mother and in her 2-year-old daughter. The microdeletion was confirmed by fluorescence in situ hybridization analysis. CONCLUSIONS: The presented clinical case is worthy of note since the observed microdeletion is often associated with a clinical phenotype tending to overweightness, but the proband (female) was hospitalized due to poor height and weight development, and anorexia. Moreover, the segregant nature of the observed genomic abnormality has to be noted, as well as the phenotypic variability between the mother and daughter. The case described here enriches the phenotypical spectrum linked to the 16p11.2 microdeletion. For these reasons, in the presence of a suspected genetic pathology it is fundamental to study the proband from the clinical point of view, to extend the clinical observation to the parents, and to provide a good family anamnesis. In this way, it is possible to reveal the presence of a familial genetic pathology whose phenotypical outcomes can be highly variable among the members of a family.

Prevention of neural tube defects and maternal gestational diabetes through the inositol supplementation: preliminary results.

OBJECTIVE: Our study aims to demonstrate that the use in the preconceptional period until the 24th week of pregnancy of inositol and folic acid, first of all, preserves the product of conception from neural tube defects (NTDs) and then, thanks to inositol supplementation, it possibly counteracts and prevents the onset of maternal gestational diabetes (GDM). PATIENTS AND METHODS: We have collected data derived from pregnant women arrived at our laboratory, from January 2014 to January 2016, with no family history of type 2 diabetes and hypertension. The first group (n = 68 women) was treated from the preconceptional period until the 24th week of pregnancy with 1.75 g/day myo-inositol, 250 mg/day D-chiro-inositol, 12.5 mg/day Zinc pidolate, 100 mg/day methylsulfonylmethane, 120 mg/day Vitamin C and 400 mcg/day (6S)-5-methyltetrahydrofolic acid. The control group (n = 72) was only treated with 400 mcg/day folic acid. The main outcome measure was the prevalence of maternal GDM. Secondary outcome measures were the prevalence of NTDs and fetal macrosomia. RESULTS: A significant difference was found regarding body mass index (BMI), fasting oral glucose tolerance test (OGTT), after 1-h-glucose OGTT, 2-h-glucose OGTT, glycated hemoglobin (HbA1c) and serum folate, between the two groups. Five infants, in the control group, weighted greater than 4 kg. Moreover, we found a positive correlation between HbA1c and OGTT at the 24th week of pregnancy. CONCLUSIONS: This study shows the efficacy of preconceptional supplementation of inositol to reduce the risk of the onset of GDM and to confirm the importance of folic acid supplementation to avoid NTDs development. Moreover, the positive correlation between HbA1c and OGTT may be useful to consider the use of HbA1c as a single tool for GDM prevention and diagnosis in selected woman in pregnancy.

Biochemical and molecular characterization of von Willebrand disease type 2N in a pregnant patient who gave birth under analgesia with remifentanil.

von Willebrand 's disease (vWD) is the commonest inherited bleeding disorder. Although in literature there are some cases reported of epidural analgesia for labor pain in pregnancies with Von Willebrand's disease, the technique is not free from risk of neurolocal complications. Authors reported a case of spontaneous labor in a pregnant woman with type II vWD, delivered under local analgesia administered through a continuous intravenous infusion of remifentanil integrated by boli. A 34-year-old woman at the 39th week of her second pregnancy was admitted for an active labor of a single fetus in cephalic presentation. The patient had been diagnosed with type II vWD by a hematologist during her first pregnancy. The patient coagulation panel was as follows: a reduction of VIIIth factor concentration (21 percent); a normal value of vWD functional assay; an increase of vWf:Ag (antigen) and a reduction of XIth factor. During labor she was put on remifentanil in PCA (patient controlled analgesia), administered with slow boli followed by continuous infusions at increasing doses. The woman delivered a female fetus weighing 3,550 g, in vertex presentation, in left anterior occipital position, with an A.P.G.A.R. of 8 at the first minute and 9 at the fifth minute. The total duration of labor was 3 hours and 10 minutes. The patient was satisfied with analgesia in labor. The bleeding during and after delivery was regular. In the authors ' opinion, it is important to know that an alternative to epidural analgesia can be used in order to avoid the risk of neurological complications in labor pain for patients with type II Von Willebrand's disease.

Salvage utilization of selective and super selective embolization in emergency by use of a-magnetic coil and nano-particles in gynecology.

INTRODUCTION: Pelvic arteries embolization (PAE) can be described as an obstetric procedure effective in emergencies, to use especially in managing uncontrollable acute uterine hemorrhage, if resistant to medical therapy. This procedure leads to immediate control of hemorrhages and restores cardiovascular status, especially in critical patients. PAE can be used as an alternative to removing organs. PURPOSE OF STUDY: To utilize the PAE in local anesthesia for management of acute uterine hemorrhage for cervical myoma in a critical patients, a fertile woman with concomitant cardiovascular stroke and in high-dosage of antithrombosis therapy, with severe anemia. MATERIAL ANDS METHODS: This procedure was used in an University affiliated Hospital, by a selective catheterization of the left hypogastric artery with an a-magnetic coil and super-selective catheterization of the right uterine artery, instilling a mixture of micro-particles and an absorbable haemostatic gelatin. RESULTS: Authors have successfully completed this procedure in 40 minutes in local anaesthesia, showed by stopping of iodated contrast fluid in vascular myoma network, with subsequent cervical myomectomy, whilst preserving uterus. CONCLUSION: PAE allows, through super-selective catheterization of both uterine arteries or selective catheterization of hypogastric arteries, to instill a mixture of micro-particles, absorbable haemostatic gelatins or endovascular coils, mixed with iodated contrast fluid and, thereby, to stop bleeding. This procedure leaded to an immediate control of hemorrhages and restores cardiovascular status, as an alternative to removing organs.

Importance of molecular biology in the characterization of beta-thalassemia carriers.

OBJECTIVES: The term beta-thalassemia includes all those hereditary disturbances of the hemoglobin (Hb), transferred trough a recessive autosomal mechanism, due to a reduced or else defective synthesis of beta globin sequences. The aim of this paper is to highlight as sometimes the only biochemical diagnosis is not exhaustive and a molecular diagnostic widening is necessary to detect the genetic deficiency that is the reason of the beta-thalassemic trait. CASE REPORT AND RESULTS: To improve this theory the following clinical case is reported: a 29 years old girl that was 11 weeks pregnant addressed us to receive the prenatal screening test related to the first three-month pregnancy period. The biochemical and hematological tests highlighted that Mrs. D.F. was a carrier of the beta-thalassemic trait, (MCV 63fl decrease, MCH 30pg, HbA2: 4.4 increase, HbF:1.5 increase, red blood cells 5.92 x 10(6)/ul and Hb 12.4 g/dl), that has been confirmed trough our molecular analysis (genotype: beta+IVS1.110 G --> A in heterozigosys). More difficult to be realized was the case of Mr. B.A.: he showed an uncertain hematological picture labeled as "compatible with a alpha-thalassemia picture" (MCV 62.9fl decrease, MCH 21.4pg decrease, HbA2: 2.7, HbF: 1.0, red blood cells 5.33 x10(6)/ul, Hb 11.4 g/dl decrease). This picture revealed difficult to be understood because of the regularity of HbA2 (2.7%) that was in contrast with the value of the MCV (62.9). In situation like this only the molecular diagnosis allows correctly highlighting the specific typology of thalassemia the subject is carrier of. As a matter of fact the molecular analysis excluded the possibility that Mr. B.A. was a alpha-thalassemia carrier and pointed out that he was a healthy carrier of beta-thalassemia (genotype beta degrees 39C --> T in heterozigosys). In the light of what has been explained above, the couple has been informed about risks to beget child suffering from beta-thalassemia and together with the married couple has been decided to work out a prenatal diagnosis through a sample of chorionic villus. DISCUSSION AND CONCLUSIONS: The identification of these particular cases fixes important implications about the prenatal diagnosis approach. The correct characterization of the healthy carrier is absolutely necessary with a subsequent study in depth of the partner's situation. It is important to highlight the importance of a careful study of hematological parameters and a widespread and correct information about clinical implication connected to the complications of the beta-thalassemia. As to this subject, the molecular study of the defect of the gene let to point out couples that run the risk of beta-thalassemia and to develop an exhaustive and correct information about the possibility to beget children suffering from beta-thalassemia. If two carrier partners wish to have children they can chose among the following possibilities: they can be well informed about the risk and accept the possibility to beget a child suffering from beta-thalassemia, they can give up the idea of having children or they can decide to beget children however but to avoid the possibility that the same suffers of thalassemia they can ask for a prenatal diagnosis.

Androgen insensitivity syndrome (or Morris syndrome) and other associated pathologies.

BACKGROUND: The androgen insensitivity syndrome (AIS) is a disease connected with the inactivation of AR due to a mutation that inactivate male sexual differentiation, and causes a spectrum of phenotypic anomalies having as a common aspect the loss of reproductive characteristics. PATIENTS: In this paper the clinical, endocrinological and molecular features of three patients are reported. The first case concerns a 17 years old patient, the second an infant suffering from inguinal hernia that has been surgically corrected when he was 3 months old and finally the third case concerns a 57 years old woman. RESULTS: All the subjects had a common primary amenorrhea and a following pelvic echography highlighted the absence of internal genital organs and the presence of a dead-end vagina. All the patients are characterized by a normal male karyotype and present on the short arm of the Y chromosome the SRY gene. Moreover, FISH revealed the presence of androgen receptor gene on the X chromosome and the SRY gene on the Y one. The automatic sequencing of the genes for the androgen receptor (AR) shows that each subject has a mutation in the gene for the androgen receptor (AR). These mutations are associated with complete androgen insensivity syndrome (CAIS). All the cases of study exhibited a negative family history for CAIS. CONCLUSION: This study confirms the need to perform a pelvic examination by means of echography in pre-pubertal and pubertal age to highlight the normality of the internal genitalia (uterus and ovaries). If a primary amenorrhea is checked, the karyotyping is compulsory. If a Morris's syndrome is suspected, it is of critical importance to find the rudimentary male gonads (by means of MRI, pelvic echography, laparoscopy) and surgically remove them to prevent the onset of malignancies (teratoblastoma, gonadoblastoma). Once the considered disease has been identified, a continuous psychological help can be considered useful for the patient and the family.

Stickler syndrome in Pierre-Robin sequence prenatal ultrasonographic diagnosis and postnatal therapy: two cases report.

The Pierre-Robin Syndrome (PRS) is a rare congenital abnormality, with an approximately 1/30,000 estimated rate, characterized by the presence of the combination of mandibular hypoplasia (micrognathia or small jaw), glossoptosis (retrusion of the tongue into the pharyngeal airway) and, often, a posterior cleft of the secondary palate. It may be an isolated occurrence or part of a more complex syndrome and it is associated with long-term respiratory, nutritional, and developmental difficulties. Stickler syndrome (SS) is a rare autosomal dominant connective tissue disorder estimated to affect approximately 1/7500 newborns. It is diagnosed clinically and, at present, there is no consensus on a minimal clinical diagnostic criterion. The most frequent diagnosis in patients with syndromic Pierre Robin sequence is Stickler syndrome, which may be complicated by congenital high myopia and substantial risk of retinal detachment. However, cases of Stickler syndrome with probable visual complications are rarely identified among this group of patients by members of the cleft team. The patient had an acute unilateral hydrops, with a monolateral keratoconus. The ocular abnormalities included: severe myopia, abnormalities of the vitreous, and high risk of retinal detachment (with subsequent blindness). We report two extremely rare cases of prenatal diagnosis of PRS and SS, prematurely identified by prenatal ultrasonography and successively managed by oculists ophthalmogists.