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Background: The Sforzesco brace is a very rigid push-up brace effective in adolescent idiopathic scoliosis (AIS). We recently developed a new Sforzesco brace based on modularity (the Modular Italian brace—MI brace) that could allow standardization, facilitating global expertise diffusion, increased modifiability and adaptability, and cost savings due to longer brace life. We aimed to compare the short-term results of the two braces. Methods: The retrospective study included 231 consecutive AIS treated with a MI brace (N = 53) or Sforzesco brace (N = 178). The main outcome was the first 6-month follow-up out-of-brace radiograph Cobb angle change. Secondary outcomes included the in-brace Cobb degrees and aesthetics (TRACE), prominence (angle of trunk rotation and mm), kyphosis, and lordosis changes. Results: The two groups were similar at baseline, apart from more immature patients in MI brace. Both braces reduced the Cobb angle (−6° out-of-brace; −16° in-brace) without differences between groups. All secondary outcomes improved, apart from a statistically and clinically insignificant 3° kyphosis reduction. The MI brace participants were 4.9 times more likely to improve the Cobb angle than the Sforzesco brace (OR = 4.92; 95%CI 1.91–12.64; p = 0.001). Conclusions: These findings suggest that the MI-brace can be safely used instead of the classical Sforzesco brace. However, further studies of different designs and longer follow-ups are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Neurodevelopmental disorders comprise a clinically and genetically heterogeneous group of conditions that affect 2%-5% of children and represents a public health challenge due to complexity of the etiology. Only few patients with unexplained syndromic and non-syndromic NDDs receive a diagnosis through first-tier genetic tests as array-CGH and the search for FMR1 CGG expansion. The aim of this study was to evaluate the clinical performance of a targeted next-generation sequencing (NGS) gene panel as a second-tier test in a group of undiagnosed patients with NDDs. Method: A 221-gene next-generation sequencing custom panel was designed and used to analyze a cohort of 338 patients with a broad spectrum of NDDs (202 males and 136 females) including Intellectual Disability (ID), Autism Spectrum Disorders (ASD), Epilepsy, language and motor disorders. Results: A molecular diagnosis was established in 71 patients (21%) and a de novo origin was present in 38 (64.4%) of the available trios. The diagnostic yield was significantly higher in females than in males (29.4% vs. 15.3%; p = 0.0019) in particular in ASD (36.8% vs. 7.6%; p = 0.0026) and Epilepsy (38.9% vs. 14.4% p = 0.001). The most involved genes were SLC2A1, SCN1A, ANKRD11, ATP1A2, CACNA1A, FOXP1, and GNAS altered in more than two patients and accounting for the 19.7% of the diagnosis. Conclusion: Our findings showed that this NGS panel represents a powerful and affordable clinical tool, significantly increasing the diagnostic yield in patients with different form of NDDs in a cost- and time-effective manner without the need of large investments in data storage and bioinformatic analysis. [ABSTRACT FROM AUTHOR]

Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin that predisposes to seizures, focal neurological deficits and fatal intracerebral hemorrhage. It may occur sporadically or in familial forms, segregating as an autosomal dominant condition with incomplete penetrance and highly variable expressivity. Its pathogenesis has been associated with loss-of-function mutations in three genes, namely KRIT1 (CCM1), CCM2 and PDCD10 (CCM3), which are implicated in defense mechanisms against oxidative stress and inflammation. Herein, we screened 21 Italian CCM cases using clinical exome sequencing and found six cases (~29%) with pathogenic variants in CCM genes, including a large 145–256 kb genomic deletion spanning the KRIT1 gene and flanking regions, and the KRIT1 c.1664C>T variant, which we demonstrated to activate a donor splice site in exon 16. The segregation of this cryptic splicing mutation was studied in a large Italian family (five affected and seven unaffected cases), and showed a largely heterogeneous clinical presentation, suggesting the implication of genetic modifiers. Moreover, by analyzing ad hoc gene panels, including a virtual panel of 23 cerebrovascular disease-related genes (Cerebro panel), we found two variants in NOTCH3 and PTEN genes, which could contribute to the abnormal oxidative stress and inflammatory responses to date implicated in CCM disease pathogenesis. [ABSTRACT FROM AUTHOR]

We introduced pelvis semi-rigid material (ethylene vinyl acetate) (Free-Pelvis) to improve the comfort and adaptability of very rigid braces (VRBs) for adolescents with idiopathic scoliosis (AIS), but this can also negatively impact the corrective forces on the trunk. Study Design: This was a matched retrospective cohort study. The inclusion criteria were AIS, age 10–16, VRB 23 h/day, X-rays available, primary curve 36°–65°, and angle of trunk rotation 7–23°. The cases were Sforzesco VRB with Free-Pelvis (FPB). The controls included classical Sforzesco VRB matched for Risser (range 0/4), menarche age (10/15), weight (33.5/83 kg), height (140/180 cm), BMI (13.5/29 kg/sqm), aesthetics (TRACE 4/12), plumbline distances (S1: −60/35; C7 + L3: −10/115 mm), and referred brace use (22/24 h/day). Statistics: predictors of the results have been tested with linear and logistic regression according to the outcome variable type. We performed logistic regression for improved vs. worsened. The explanatory variable was brace type. We included 777 VRB and 25 FPB, age 13 ± 1, 47° ± 8° Cobb, and 11% men. The few baseline statistical differences were not clinically relevant. We achieved in-brace corrections of 15.2° ± 7.7° and 17.4° ± 6.5° for VRB and FPB, respectively (p = 0.21); out-of-brace corrections at 5 ± 2 months were 7.8° ± 0.2° for VRB and 8.1° ± 1.3° for FPB (p = 0.83). The type of brace did not influence the Cobb angle at either time interval or affect the odds of improvement. Free-Pelvis innovation, introduced to improve comfort and adaptability, does not change the in-brace or short-term results of classical VRB and consequently can be safely applied. [ABSTRACT FROM AUTHOR]

Abnormal NIPT results, contrasting with normal fetus development, could disclose maternal malignancy, and this possibility should always be explained during pretest counseling. In this case, a complete diagnostic assessment is recommended and should be managed by a multidisciplinary team to define the best timing for diagnostic procedures, delivery, and treatment. [ABSTRACT FROM AUTHOR]

The 22q11.2 microdeletion syndrome (22q11.2 DGS) is characterized by an extreme intrafamilial and interfamilial variability. The main clinical features are congenital heart defects, palatal abnormalities, learning disability, facial dysmorphisms and immune deficiency. In 85–90% of cases, the 22q11.2 DGS is caused by a heterozygous ~3-Mb deletion, including the TBX1 gene, considered one of the major genes responsible for heart defects. Individuals with atypical deletions with at least one breakpoint outside low copy repeats have been reported. Our patient is a child presenting tetralogy of Fallot (TOF) with an atypical 22q11.2 deletion proximal to the critical DiGeorge region. The rearrangement was inherited from the healthy mother and spanned ~642–970 kb, encompassing DGCR6 and PRODH, two novel possible candidate genes for conotruncal heart defects. [ABSTRACT FROM AUTHOR]

The TSC1 and TSC2 gene products interact to form the tuberous sclerosis complex (TSC), an important negative regulator of the mechanistic target of rapamycin complex 1 (TORC1). Inactivating mutations in TSC1 or TSC2 cause TSC, and the identification of a pathogenic TSC1 or TSC2 variant helps establish a diagnosis of TSC. However, it is not always clear whether TSC1 and TSC2 variants are inactivating. To determine whether TSC1 and TSC2 variants of uncertain clinical significance affect TSC complex function and cause TSC, in vitro assays of TORC1 activity can be employed. Here we combine genetic, functional, and structural approaches to try and classify a series of 15 TSC2 VUS. We investigated the effects of the variants on the formation of the TSC complex, on TORC1 activity and on TSC2 pre‐mRNA splicing. In 13 cases (87%), the functional data supported the hypothesis that the identified TSC2 variant caused TSC. Our results illustrate the benefits and limitations of functional testing for TSC. [ABSTRACT FROM AUTHOR]

A 4-year-old girl was referred to the geneticist with a history of ataxia associated with intention tremor of the hands, strabismus and hypermetropy. Her symptoms presented about 2 years earlier with inability to walk unaided and lower limbs hypotonia. Cognitive functions were normal. Brain MRI showed a cerebellar and vermian hypoplasia with enlargement of both the cerebrospinal fluid spaces and the IV brain ventricle. Family history was unremarkable. A genetic screening using a 42-gene panel for hereditary ataxia/spastic paraparesis identified a de novo c.1438C>T - p.(Arg480Trp) missense change in the SPTBN2 gene (NM_006946.2). This variant is reported to be associated with congenital ataxia, later evolving into ataxia and intellectual disability. This case further supports the existence of a specific SPTBN2 p.(Arg480Trp)- associated phenotype, with a de novo recurrence of this variant in the heterozygous state. [ABSTRACT FROM AUTHOR]

Introduction: The EXIST-2 (NCT00790400) study demonstrated the superiority of everolimus over placebo for the treatment of renal angiomyolipomas associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (LAM). This post hoc analysis of EXIST-2 study aimed to assess angiomyolipoma tumor behavior among patients who submitted to continued radiographic examination following discontinuation of everolimus in the noninterventional follow-up phase. Methods: For patients who discontinued everolimus at the completion of extension phase for reasons other than angiomyolipoma progression, a single CT/MRI scan of the kidney was collected after 1 year of treatment discontinuation. Changes from baseline and from the time of everolimus discontinuation in the sum of volumes of target angiomyolipoma lesions were assessed in the non-interventional follow-up phase (data cutoff date, November 6, 2015). Results: Of the 112 patients who received ≥1 dose of everolimus and discontinued treatment by the end of extension phase, 34 (30.4%) were eligible for participation in the non-interventional follow-up phase. Sixteen of 34 patients were evaluable for angiomyolipoma tumor behavior as they had at least one valid efficacy assessment (i.e. kidney CT/MRI scan) after everolimus discontinuation. During the non-interventional follow-up phase, compared with baseline, two patients (12.5%) experienced angiomyolipoma progression (angiomyolipoma-related bleeding [n = 1], increased kidney volume [n = 1]). Five patients out of 16 (31.3%) experienced angiomyolipoma progression when compared with the angiomyolipoma tumor assessment at everolimus discontinuation. The median (range) percentage change in angiomyolipoma tumor volume (cm3) from baseline was −70.56 (−88.30; −49.64) at time of everolimus discontinuation (n = 11), and −50.55 (−79.40; −23.16) at week 48 (n = 7) after discontinuation of everolimus. One patient death was reported due to angiomyolipoma hemorrhage. Conclusions: Angiomyolipoma lesions displayed an increase in volume following discontinuation of everolimus in patients with renal angiomyolipoma or sporadic LAM associated with TSC, but there was no evidence of rapid regrowth. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Karyotyping and aCGH are routinely used to identify genetic determinants of major congenital malformations (MCMs) in fetal deaths or terminations of pregnancy after prenatal diagnosis. Pathogenic rearrangements are found with a variable rate of 9-39% for aCGH. We collected 33 fetuses, 9 with a single MCM and 24 with MCMs involving 2-4 organ systems. aCGH revealed copy number variants in 14 out of 33 cases (42%). Eight were classified as pathogenic which account for a detection rate of 24% (8/33) considering fetuses with 1 or more MCMs and 33% (8/24) taking into account fetuses with multiple malformations only. Three of the pathogenic variants were known microdeletion syndromes (22q11.21 deletion, central chromosome 22q11.21 deletion, and TAR syndrome) and 5 were large rearrangements, adding up to >11 Mb per subject and comprising strong phenotype-related genes. One of those was a de novo complex rearrangement, and the remaining 4 duplications and 2 deletions were 130-900 kb in size, containing 1-7 genes, and were classified as variants of unknown clinical significance. Our study confirms aCGH as a powerful technique to ascertain the genetic etiology of fetal major congenital malformations. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Bracing could be efficacious, given good compliance and quality of braces. Recently the SOSORT Brace Treatment Management Guidelines (SBTMG) have highlighted the perceived importance of the professional teams surrounding braced patients. Purpose: To verify the impact of a complete rehabilitation team in the adolescent patient with bracing. Materials and methods: Design. Initial cross-sectional study, followed by a retrospective case-control study. Population: Thirty-eight patients (15.8 ± 1.6 years; 26 females; 10 hyperkyphosis, 28 scoliosis of 29.2 ± 7.9° Cobb) extracted from a single orthotist database (between January 1, 2008 and September 1, 2009) and treated by the same physician; brace wearing at least 15 hours/day for a minimum of 6 months; age 10 or more. Treatment: Braces: Sforzesco, Sibilla, Lapadula or Maguelone. Exercises: SEAS. Methods: Two questionnaires filled in blindly by patients: SRS-22 and one especially developed and validated with 25 questions on adherence to treatment. Groups (main risk factor): TEAM (private institute: satisfied 44/44 SOSORT criteria; grade of teamwork, "excellent") included 13 patients and NOT 25 (National Health Service Rehabilitation Department: 35/44 SOSORT criteria respected; grade, "insufficient"). Results: TEAM was more compliant to bracing than NOT (97 ± 6% vs. 80 ± 24%) and performed nearly double the exercises (38 ± 12 vs. 20 ± 13 minutes/session). The self-reduction of bracing was significant in NOT (from 16.8 ± 3.7 to 14.8 ± 4.9 hours/day, , P<0.05); TEAM showed a significant reduction in the difficulties due to bracing (from 8.9 ± 1.4 to 3.5 ± 2.0 in 12 months on a 10-point scale, P<0.05). Pain was perceived by 55% of NOT versus 7% of TEAM (P < 0.05). The populations did not differ at the baseline studied outcomes. The absence of a good team surrounding the patient increases by five times the risk of reduced compliance to bracing (odds ratio OR 5.5 - 95% confidence interval 95CI 3.6-7.4), along with more than 15 times that of QoL problems (OR 15.7 - 95CI 13.6-17.9) and pain (OR 16.8 - 95CI 14.5-19.1). Conclusions: Provided the limits of this first study on the topic, the SBTMG seems to be important for brace treatment, influencing pain, QoL and compliance (and so, presumably, final results). Future studies on the topic are advisable. [ABSTRACT FROM AUTHOR]

The TWIK-related spinal cord potassium channel (TRESK) is encoded by KCNK18, and variants in this gene have previously been associated with susceptibility to familial migraine with aura (MIM #613656). A single amino acid substitution in the same protein, p.Trp101Arg, has also been associated with intellectual disability (ID), opening the possibility that variants in this gene might be involved in different disorders. Here, we report the identification of KCNK18 biallelic missense variants (p.Tyr163Asp and p.Ser252Leu) in a family characterized by three siblings affected by mild-to-moderate ID, autism spectrum disorder (ASD) and other neurodevelopment-related features. Functional characterization of the variants alone or in combination showed impaired channel activity. Interestingly, Ser252 is an important regulatory site of TRESK, suggesting that alteration of this residue could lead to additive downstream effects. The functional relevance of these mutations and the observed co-segregation in all the affected members of the family expand the clinical variability associated with altered TRESK function and provide further insight into the relationship between altered function of this ion channel and human disease. [ABSTRACT FROM AUTHOR]

Congenital sensorineural hearing loss may occur in association with inborn pigmentary defects of the iris, hair, and skin. These conditions, named auditory-pigmentary disorders (APDs), represent extremely heterogeneous hereditary diseases, including Waardenburg syndromes, oculocutaneous albinism, Tietz syndrome, and piebaldism. APDs are part of the neurocristopathies, a group of congenital multisystem disorders caused by an altered development of the neural crest cells, multipotent progenitors of a wide variety of different lineages, including those differentiating into peripheral nervous system glial cells and melanocytes. We report on clinical and genetic findings of two monozygotic twins from a large Albanian family who showed a complex phenotype featured by sensorineural congenital deafness, severe neuropsychiatric impairment, and inborn pigmentary defects of hair and skin. The genetic analyzes identified, in both probands, an unreported co-occurrence of a new heterozygous germline pathogenic variant (c.2484 + 5G > T splicing mutation) in the KIT gene, consistent with the diagnosis of piebaldism, and a heterozygous deletion at chromosome 15q13.3, responsible for the neuropsychiatric impairment. This case represents the first worldwide report of dual locus inherited syndrome in piebald patients affected by a complex auditory-pigmentary multisystem phenotype. Here we also synthesize the clinical and genetic findings of all known neurocristopathies characterized by a hypopigmentary congenital disorder.

Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS.