Search

Schilbach-Rott syndrome (SRS, OMIM% 164220) is a disorder of unknown aetiology that is characterised by hypotelorism, epichantal folds, cleft palate, dysmorphic face, hypospadia in males and mild mental retardation in some patients. To date, 5 families and 17 patients have exhibited this phenotype, and recurrence in two of these families suggests an autosomal dominant inheritance. SRS overlaps with a mild form of holoprosencephaly (HPE), but array-CGH analysis and sequencing of some HPE-related genes (SEPT9, SHH and TWIST) did not reveal any variants in at least one family. Herein, we investigated by array-CGH analysis a 11-year-old female patient and her father, both exhibiting the typical SRS phenotype, disclosing in the daughter-father couple the same microduplication of chromosome 9q22.32q22.33 [arr[hg19]9q22.32 (98,049,611_98,049,636) x3,9q22.33 (99,301,483_99,301,508)x3], involving eight genes, including PTCH1. The duplication segregated with the disease, since it was not found in the healthy paternal grandparents of the proband. The gain-of-function variants of the PTCH1 gene are responsible for a mild form of HPE. This is the first genetic variant found in SRS. This finding reinforces the hypothesis that SRS belongs to the HPE clinical spectrum and suggests to perform array-CGH in patients with SRS phenotype and, if negative, to consider a potential benefit from sequencing of HPE-related genes.

OBJECTIVE To assess the usefulness, feasibility, and limitations of pedicled multifidus muscle flaps (PMMFs) for the treatment of inaccessible dural tears during spine surgery. METHODS The technique of PMMF harvesting was investigated together with relevant anatomy. We prospectively evaluated 8 patients treated with the PMMF technique between January 2017 and December 2019. Results were compared with a retrospective series of 9 patients treated with a standard technique between January 2014 and December 2016. Inclusion criteria were inaccessible dural tear or dural tear judged not amenable to direct repair because of tissue loosening. Exclusion criteria were surgical treatment of intradural disease. Clinical and demographic data of all patients were collected. Clinical evaluations were performed according to American Spinal Injury Association criteria and Oswestry Disability Index. Preoperative and postoperative computed tomography was performed in all patients. The primary end point was wound healing (cerebrospinal fluid leakage, infection, and fluid collection); secondary end points were neurologic outcome and complications. RESULTS Control group: 1 death as a result of wound infection secondary to cerebrospinal fluid fistula and 2 patients needed lumbar subarachnoid drain; neurologic outcome: 3 patients improved and 6 were unchanged. Flap group: no wound-related complications were observed; neurologic outcome: 3 patients improved and 5 were unchanged. No flap-related complications were described. Flap harvesting was feasible in all cases, with an average 20 minutes adjunctive surgical time. CONCLUSIONS The PMMF technique was feasible and safe; in this preliminary experience, its use is associated with lower complications as a result of dural tears but larger series are needed to confirm its effectiveness.

Rational: Intestinal lymphangiectasia (IL) is a rare disease characterized by dilatation and rupture of intestinal lymphatic channels leading to protein-losing enteropathy. IL is classified as primary and secondary types. Patient concerns: A 3-month-old girl born at term from vaginal delivery with an APGAR score of 10/10 and birth weight of 4.310 g (>97° percentile) was admitted to our hospital because of increasing abdominal tenderness and diarrhea. At first examination, she presented an abdominal circumference of 60 cm, edema of the lower extremities and vulva, and facial dysmorphisms (hypertelorism, flat nasal bridge, flat mid-face). Diagnosis: Once admitted, ultrasonography showed a large amount of ascites, while blood laboratory investigations revealed severe hypoproteinemia, hypoalbuminemia and hypogammaglobulinemia. Lymphoscintigraphy with 99m-Tc-nanocolloid demonstrated abnormal leakage of the tracer in the abdomen as evidence of IL. To detect a possible secondary, exams were performed and demonstrated positive antibody titres for CMV-IgM and IgG in blood and CMV-DNA positivity in blood, urine, saliva, maternal milk, and gastric and duodenal biopsies. Genetic investigations identified the genomic variant c.472C>T of the CCBE1 gene, coding for a protein variant (p.Arg158Cys), in homozygosity. Interventions: Total parenteral nutrition was started and continued for a total of 18 days, then gradually bridged by enteral nutrition with a special formula. In addition, antiviral therapy for CMV infection was added first with intravenous ganciclovir for 14 days, resulting in the disappearance of blood viral load after 7 days of therapy and then with valganciclovir per os for another 30 days. Outcomes: The clinical course of the child gradually improved. A few days after starting treatments, lower extremities and vulvar edema disappeared, and abdominal circumference gradually decreased to a stable value of 38 cm, without any ultrasonographic signs of ascites left. Moreover, serum albumin and IgG rose to normal values after 3 months (4.3 g/dL and 501 mg/dL, respectively). Lessons: This case suggests that in presence of IL both primary and secondary causes should be evaluated. On the other hand, genetic diagnosis is crucial not only for diagnosis but also for prognosis in HS. Life expectancy and quality could deeply vary among different gene mutations and protein variants of the same gene. Further studies and case reports are needed to better understand the clinical meaning of these genetic results and the role of CMV as trigger of IL.

Acrofrontofacionasal Dysostosis type 1 (AFFND1) is an extremely rare, autosomal recessive syndrome, comprising facial and skeletal abnormalities, short stature and intellectual disability. We analyzed an Indian family with two affected siblings by exome sequencing and identified a novel homozygous truncating mutation in the Neuroblastoma-Amplified Sequence (NBAS) gene in the patients' genome. Mutations in the NBAS gene have recently been associated with different phenotypes mainly involving skeletal formation, liver and cognitive development. The NBAS protein has been implicated in two key cellular processes, namely the non-sense mediated decay and the Golgi-to-Endoplasmic Reticulum retrograde traffic. Both functions were impaired in HEK293T cells overexpressing the truncated NBAS protein, as assessed by Real-Time PCR, Western blot analysis, co-immunoprecipitation, and immunofluorescence analysis. We examined the expression of NBAS protein in mouse embryos at various developmental stages by immunohistochemistry, and detected expression in developing chondrogenic and osteogenic structures of the skeleton as well as in the cortex, hippocampus and cerebellum, which is compatible with a role in bone and brain development. Functional genetics in the zebrafish model showed that depletion of endogenous z-nbas in fish embryos results in defective morphogenesis of chondrogenic cranial skeletal elements. Overall, our data point to a conserved function of NBAS in skeletal morphogenesis during development, support the hypothesis of a causative role of the mutated NBAS gene in the pathogenesis of AFFND1 and extend the spectrum of phenotypes associated with defects in this gene.

A consistent percentage of patients with metastatic non-small cell lung cancer (NSCLC) derives no or only marginal benefit from immunotherapy (IO). Since serum sodium has been linked to both prognosis in NSCLC and modulation of immune cells activity, we aimed to assess the association between low baseline serum sodium concentration (≤ 135 mEq/L) and clinical outcomes of patients with metastatic NSCLC treated with IO. We included metastatic NSCLC patients treated with checkpoint inhibitors in our department from April 2013 to April 2018 with available baseline serum sodium concentration. Demographics, clinical and pathological characteristics were collected. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional-hazards model. Of 197 patients included, 26 (13%) presented low baseline serum sodium concentration. Patients in the low sodium cohort experienced a poorer disease control rate (OR 0.36; 95% CI, 0.15–0.86; Wald test P = .02), median overall survival (OS) (2.8 vs. 11.6 months; HR 3.00; 95% CI, 1.80–4.80; P

Rubinstein–Taybi syndrome (RSTS) is a rare, clinically heterogeneous disorder characterized by cognitive impairment and several multiple congenital anomalies. The syndrome is caused by almost private point mutations in the CREBBP (~55% of cases) and EP300 (~8%) genes. The CREBBP mutational spectrum is variegated and characterized by point mutations (30–50%) and deletions (~10%). The latter are diverse in size and genomic position and remove either the whole CREBBP gene and its flanking regions or only an intragenic portion. Here, we report 14 novel CREBBP deletions ranging from single exons to the whole gene and flanking regions which were identified by applying complementary cytomolecular techniques: fluorescence in situ hybridization, multiplex ligation-dependent probe amplification and array comparative genome hybridization, to a large cohort of RSTS patients. Deletions involving CREBBP account for 23% of our detected CREBBP mutations, making an important contribution to the mutational spectrum. Genotype–phenotype correlations revealed that patients with CREBBP deletions extending beyond this gene did not always have a more severe phenotype than patients harboring CREBBP point mutations, suggesting that neighboring genes play only a limited role in the etiopathogenesis of CREBBP-centerd contiguous gene syndrome. Accordingly, the extent of the deletion is not predictive of the severity of the clinical phenotype.

Here, we describe a child, born from consanguineous parents, with clinical features of SHORT syndrome, high IGF1 levels, developmental delay, CNS defects, and marked progeroid appearance. By exome sequencing, we identified a new homozygous c.2201G>T missense mutation in the IGF1R gene. Proband's parents and other relatives, all heterozygous carriers of the mutation, presented with milder phenotype including high IGFI levels, short stature, and type 2 diabetes. Functional studies using patient's cell lines showed a lower IGF1R expression that leads to the alteration of IGF1R-mediated PI3K/AKT/mTOR downstream pathways, including autophagy. This study defines a clinically recognizable incomplete dominant form of SHORT syndrome, and provides relevant insights into the pathophysiological and phenotypical consequences of IGF1R mutations.

Background: The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. Patients and results: Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported SUCLG1 patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients. Median survival was 20 years for SUCLA2 and 20 months for SUCLG1. Notable clinical differences between the two groups were hepatopathy, found in 38 % of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14 % of cases with SUCLG1 mutations. Long survival, to age 20 years or older, was reported in 12 % of SUCLA2 and in 10 % of SUCLG1 patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69 % of SUCLA2 and 80 % of SUCLG1 patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found. Conclusions: To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.

Mutations of the MED12 gene have been reported mainly in males with FG (Opitz-Kaveggia), Lujan-Fryns, or X-linked Ohdo syndromes. Recently, a different phenotype characterized by minor anomalies, severe intellectual disability (ID), and absent language was reported in female and male patients belonging to the same family and carrying a frameshift MED12 mutation (c.5898dupC). Here, we report on two brothers and their niece affected by severe and mild ID, respectively, where whole exome sequencing combined with variant analysis within a panel of ID-related genes, disclosed a novel c.2312T>C (p.Ile771Thr) MED12 mutation. This variant, which has not been reported as a polymorphism, was not present in a third unaffected brother, and was predicted to be deleterious by five bioinformatic databases. This finding together with the phenotypic analogies shared with the carriers of c.5898dupC mutation suggests the existence of a fourth MED12-related disorder, characterized by severe ID, absent or deficient language and, milder, clinical manifestation in heterozygotes. We have reviewed the literature on MED12 heterozygotes, their clinical manifestations, and discuss the possible biological causes of this condition. (C) 2016 Wiley Periodicals, Inc.

Malformations of the cerebral cortex are an important cause of developmental disabilities and epilepsy. Neurological disorders caused by abnormal neuronal migration have been observed to occur with mutations in tubulin genes. The α- and β-tubulin genes encode cytoskeletal proteins, which play a role in the developing brain. TUBA1A mutations are associated with a wide spectrum of neurological problems, which are characterized by peculiar clinical details and neuroradiologic patterns. This manuscript describes the case of a nine-year-old girl with microcephaly, mild facial dysmorphisms, epileptic seizures, and severe developmental delay, with a de novo heterozygous c.320A>G [p.(His 107 Arg)] mutation in TUBA1A gene, and the clinical aspects and neuroimaging features of “lissencephaly syndrome” are summarized. This case shows that TUBA1A mutations lead to a variety of brain malformations ranging from lissencephaly with perisylvian pachygyria to diffuse posteriorly predominant pachygyria, combined with internal capsule dysgenesis, cerebellar dysplasia, and callosal hypotrophy. This peculiar neuroradiological pattern, in combination with the usually severe clinical presentation, suggests the need for future molecular studies to address the mechanisms of TUBA1A mutation-induced neuropathology.

Context Familial isolated hypoparathyroidism (FIH) is a genetically heterogeneous disorder due to mutations of the calcium-sensing receptor (CASR), glial cells missing-2 (GCM2), guanine nucleotide binding protein α11 (GNA11), or parathyroid hormone (PTH) genes. Thus far, only four cases with homozygous and two cases with heterozygous mutations in the PTH gene have been reported. Objective To clinically describe an FIH family and identify and characterize the causal gene mutation. Design Genomic DNA of the family members was subjected to CASR, GCM2, GNA11, and PTH gene mutational analysis. Functional assays were performed on the variant identified. Participants Six subjects of a three-generation FIH family with three affected individuals having severe hypocalcemia and inappropriately low serum PTH. Results No mutations were detected in the CASR, GCM2, and GNA11 genes. A heterozygous variant that segregated with the disease was identified in PTH gene exon 2 (c.41T>A; p.M14K). This missense variant, in the hydrophobic core of the signal sequence, was predicted in silico to impair cleavage of preproPTH to proPTH. Functional assays in HEK293 cells demonstrated much greater retention intracellularly but impaired secretion into the medium of the M14K mutant relative to wild type. The addition of the pharmacological chaperone, 4-phenylbutyric acid, led to a reduction of cellular retention and increased accumulation in the cell medium of the M14K mutant. Conclusions We report a heterozygous PTH mutation in an FIH family and demonstrate accumulation of the mutant intracellularly and its impaired secretion. An accurate genetic diagnosis in such hypoparathyroid patients is critical for appropriate treatment and genetic counseling.

Genetic testing strategies and counseling in cystic fibrosis (CF) can be problematic due to its extreme allelic heterogeneity and the difficult clinical interpretation of rare variants. Since in a previous survey of Italian CF patients, Umbria (a small region with about 900,000 inhabitants) was excluded due to the low number of chromosomes tested (

Many conditions can compromise facial symmetry, resulting in an impairment of the affected person from both esthetic and functional points of view. For these reasons, a detailed, focused, and objective evaluation of facial asymmetry is needed, both for surgical planning and for treatment evaluation. In this study, we present a new quantitative method to assess symmetry in different facial thirds, objectively defined on the territories of distribution of trigeminal branches. A total of 70 subjects (40 healthy controls and 30 patients with unilateral facial palsy) participated. A stereophotogrammetric system and the level of asymmetry of the subjects' hemi-facial thirds was evaluated, comparing the root mean square of the distances (RMSD) between their original and mirrored facial surfaces. Results show a high average reproducibility of area selection (98.8%) and significant differences in RMSD values between controls and patients (p = 0.000) for all of the facial thirds. No significant differences were found on different thirds among controls (p > 0.05), whereas significant differences were found for the upper, middle, and lower thirds of patients (p = 0.000). The presented method provides an accurate, reproducible, and local facial symmetry analysis that can be used for different conditions, especially when only part of the face is asymmetric.

The most frequent causes of Intellectual Disability (ID)/Autism Spectrum Disorders (ASDs) are chromosomal abnormalities, genomic rearrangements and submicroscopic deletions coupled with duplications. We report here on an 11-year-old girl showing autism, macrocephaly, and facial dysmorphism, in which array-CGH showed a de novo microdeletion of ∼114 Kb in the 14q11.2 chromosomal region, involving the SUPT16H, CHD8, and RAB2B genes. Four patients with ID and/or ASD and/or macrocephaly with overlapping deletions have been previously described: three showed very large rearrangements (>1 Mb), while one had a microdeletion of ∼101 Kb, largely overlapping the one reported herein. The minimal critical region, considering present and previous cases, contains the SUPT16H and CHD8 genes. Notably, recent studies also disclosed CHD8 heterozygous loss-of-function mutations in patients with ASD and macrocephaly. Our finding shows the presence of a recurrent microdeletion associated with a clinically recognizable phenotype, and further on underlines the pivotal role of CHD8 gene in the pathogenesis of the disorder.

We report on a 9-year-old female patient with facial anomalies and developmental delay, heterozygous for three de novo rearrangements: a paracentric inversion of chromosome 7, an apparently balanced translocation between chromosome 1 and 7, involving the same inverted chromosome 7, detected by standard cytogenetic analysis [46,XX, der(7) inv(7)(q21.1q32.1)t(1;7)(q23q32.1)]; and a 2p16.1 deletion, spanning about 3.5 Mb of genomic DNA, shown by SNP-array analysis [arr 2p16.1 (56,706,666-60,234,485)x1 dn]. Clinical features and cytogenetic imbalance in our patient were similar to those reported in five published cases, suggesting that this genomic region is prone to recombination and its hemizygosity results in a distinct although variable spectrum of clinical manifestations.

Richieri-Costa et al. [1985, 1992] and Guion-Almeida andRichieri-Costa[2003]reportedthreesetsofsibswithshortstature,intellectual disability, hypertelorism, ulcerated corneae, bilateralpolar cataracts, iris atrophy, microphthalmia, notched/bifid nasaltip, cleft lip and palate, poly-syndactyly of fingers, camptodactyly,and hypoplasia of the distal phalanges, short metacarpals andhypoplastic toenails, hip dislocation, hypoplastic fibulae, tarsalanomalies, and tibio-talar subluxation. Normal chromosomesand parental consanguinity suggested autosomal recessive inher-itance of this rare syndrome known as ‘‘acrofrontofacionasaldysostosistype1’’(AFFND1)(OMIM:201180).Toourknowledgethe condition has been reported only in these three Brazilianfamilies.Here, we report on two sisters of Indian origin showing amultiple congenital anomalies/intellectual disability syndromewhich strongly fits with the diagnosis of AFFND1.Thepatientswereborntohealthy,non-consanguineousparentswho also had one spontaneous miscarriage, and other two healthychildren,aboyandagirl.Theproposita,a12-year-oldgirl,wasbornatterm,afteranuneventfulpregnancy.Herbirthweightwas2,120g(

The Authors report a new family with spondylo-costal dysplasia in which three members in three generation are affected. The genetic heterogeneity of the condition and its implication in genetic counseling is discussed.

ContextElevated blood pressure (BP) measured at the physician's office may reflect true hypertension or white coat hypertension (WCH). The prognostic value of WCH among pregnant women is unknown.ObjectiveTo assess the prognostic value of WCH in pregnancy.DesignProspective cohort study conducted between September 1994 and October 1997.SettingCommunity hospital.PatientsWomen without preexisting hypertension and not treated with antihypertensive drugs and with high (n = 148) or normal (n = 106) office BP (high office BP was defined as ≥140 mm Hg systolic and/or ≥90 mm Hg diastolic) matched for gestational age during their third trimester of pregnancy. All women underwent 24-hour noninvasive BP monitoring, and women without hypertension on 24-hour monitoring (125/74 mm Hg or less for average 24-hour BP) with office hypertension were classified as having WCH. Women were followed up through the end of pregnancy.Main Outcome MeasuresDuration of pregnancy, gestational hypertension, preeclampsia or eclampsia, cesarean delivery, placental and neonatal weight, and length of maternal and neonatal hospital stays for those with and without elevated office BP.ResultsAfter application of exclusion criteria, data for 7 women were removed from the analysis. For the remaining subjects, in the group with elevated BP, prevalence of WCH was 29.2% (42/144). Duration of pregnancy was similar in the normotensive and WCH groups (39.6 vs 39.8 weeks;P = .50), but shorter (38.3 weeks; P

In 15 subjects affected by "severe" obesity, some functional parameters were measured: glycemia, insulinemia, lacticidemia, uricemia, triglyceridemia, following oral load of fructose (100 gms), and separately, of glucose (100 gms). The analysis of the results obtained revealed a trend significantly different in the two cases in the glycemic and insulinemic profiles, whereas no statistically significant variations were observed with reference to the trend of the other parameters taken into consideration.

The aim of the present study was to investigate the possible normalizing effect of antioxidants on certain parameters indicative of oxidative stress in Down's syndrome (DS). The study was performed in pediatric patients with DS with proven redox imbalance, who were advised to take a dietary supplementation composed of alpha-lipoic acid and L-cysteine for several treatment cycles (one treatment cycle = 30 days dietary supplementation plus 30 days wash-out). Serum thiol groups, serum total and septic reactive oxygen species (ROS) and total antioxidant status of serum were determined before and after dietary supplementation, using commercially available kits. In all the evaluable patients (n = 20), after 3.8 +/- 1.1 treatment cycles, thiol group serum concentrations and total antioxidant status of serum significantly increased (p0.0001 for both parameters) in comparison with basal values, while serum total and septic ROS significantly decreased (p0.0001 for both parameters). On the basis of these results it is impossible to demonstrate the clinical effects of the biochemical normalization obtained in patients with DS after supplying alpha-lipoic acid and L-cysteine. These data suggest that delaying the clinical expression of redox imbalance in patients with DS might be feasible by normalizing their redox balance.