Rituximab Treatment as Second-Line Therapy in Glucocorticoid Nonresponsive Graves' Orbitopathy: A Nonrandomized, Controlled, Interventional Study.

Objective: In moderate-to-severe Graves' orbitopathy, rituximab is recommended as second-line therapy in patients nonresponsive to intravenous glucocorticoids. We aimed to evaluate rituximab as early second-line therapy, as data are scarce and contradictory.

Methods: In this nonrandomized, controlled, interventional study, patients with Graves' orbitopathy started on intravenous glucocorticoids.

Genome sequencing differentiates a paracentric inversion from a balanced insertion enabling more accurate preimplantation genetic testing.

Introduction: Distinguishing paracentric inversions (PAIs) from chromosomal insertions has traditionally relied on fluorescent in situ hybridization (FISH) techniques, but recent advancements in high-throughput sequencing have enabled the use of genome sequencing for such differentiation. In this study, we present a 38-year-old male carrier of a paracentric inversion on chromosome 2q, inv (2)(q31.2q34), whose partner experienced recurrent miscarriages.

Novel findings in a Swedish primary familial brain calcification cohort.

Introduction: Brain calcifications are frequent findings on imaging. In a small proportion of cases, these calcifications are associated with pathogenic gene variants, hence termed primary familial brain calcification (PFBC). The clinical penetrance is incomplete and phenotypic variability is substantial.

Psychiatric complications in Graves' disease.

Background: Mood disorders are common in Graves' disease despite treatment. The pathogenic mechanisms involved are unknown and so is whether previous psychiatric disease influences these symptoms.

Methods: This is a longitudinal study conducted in Sweden on 65 women with newly diagnosed Graves' disease and 65 matched controls.

The relationship between mental fatigue, depression, and cognition in Graves' disease.

Objective: Mental fatigue, depression, anxiety, and cognitive complaints are common in Graves' disease (GD). Our aims were to assess the relationship between these variables in patients with GD during both hyperthyroidism and a long stable euthyroidism.

Methods: A prospective longitudinal case-control study where 65 premenopausal women diagnosed with GD and 65 matched controls were assessed twice with 15 months in between.

Multi-omics analysis reveals multiple mechanisms causing Prader-Willi like syndrome in a family with a X;15 translocation.

Prader-Willi syndrome (PWS; MIM# 176270) is a neurodevelopmental disorder caused by the loss of expression of paternally imprinted genes within the PWS region located on 15q11.2. It is usually caused by either maternal uniparental disomy of chromosome 15 (UPD15) or 15q11.

A Longitudinal Study of Medial Temporal Lobe Volumes in Graves Disease.

Context: Neuropsychiatric symptoms are common features of Graves disease (GD) in hyperthyroidism and after treatment. The mechanism behind these symptoms is unknown, but reduced hippocampal volumes have been observed in association with increased thyroid hormone levels.

Objective: This work aimed at investigating GD influence on regional medial temporal lobe (MTL) volumes.

Biallelic mutations in WRAP53 result in dysfunctional telomeres, Cajal bodies and DNA repair, thereby causing Hoyeraal-Hreidarsson syndrome.

Approximately half of all cases of Hoyeraal-Hreidarsson syndrome (HHS), a multisystem disorder characterized by bone marrow failure, developmental defects and very short telomeres, are caused by germline mutations in genes related to telomere biology. However, the varying symptoms and severity of the disease indicate that additional mechanisms are involved. Here, a 3-year-old boy with HHS was found to carry biallelic germline mutations in WRAP53 (WD40 encoding RNA antisense to p53), that altered two highly conserved amino acids (L283F and R398W) in the WD40 scaffold domain of the protein encoded.

From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability.

Background: Since different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.

Methods: We analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n = 68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n = 156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.

Structural brain changes in hyperthyroid Graves' disease: protocol for an ongoing longitudinal, case-controlled study in Göteborg, Sweden-the CogThy project.

Introduction: Cognitive impairment and reduced well-being are common manifestations of Graves' disease (GD). These symptoms are not only prevalent during the active phase of the disease but also often prevail for a long time after hyperthyroidism is considered cured. The pathogenic mechanisms involved in these brain-derived symptoms are currently unknown.

The cerebellar phenotype of Charcot-Marie-Tooth neuropathy type 4C.

Background: Friedreich ataxia (FRDA) is the most common familial ataxia syndrome in Central and Southern Europe but rare in Scandinavia. Biallelic mutations in SH3 domain and tetratricopeptide repeats 2 ( cause Charcot-Marie-Tooth disease type 4C (CMT4C), one of the most common autosomal recessive polyneuropathies associated with early onset, slow disease progression and scoliosis. Beyond nystagmus reported in some patients, neither ataxia nor cerebellar atrophy has been documented as part of the CMT4C phenotype.

Genomic screening in rare disorders: New mutations and phenotypes, highlighting ALG14 as a novel cause of severe intellectual disability.

We have investigated 20 consanguineous families with multiple children affected by rare disorders. Detailed clinical examinations, exome sequencing of affected as well as unaffected family members and further validation of likely pathogenic variants were performed. In 16/20 families, we identified pathogenic variants in autosomal recessive disease genes (ALMS1, PIGT, FLVCR2, TFG, CYP7B1, ALG14, EXOSC3, MEGF10, ASAH1, WDR62, ASPM, PNPO, ERCC5, KIAA1109, RIPK4, MAN1B1).

Role of iodine-containing multivitamins during pregnancy for children's brain function: protocol of an ongoing randomised controlled trial: the SWIDDICH study.

Introduction: Iodine is essential for normal brain development. Moderate and severe fetal iodine deficiency results in substantial to serious developmental delay in children. Mild iodine deficiency in pregnancy is associated with neurodevelopmental deficits in the offspring, but evidence from randomised trials is lacking.

The clinical utility of PGD with HLA matching: a collaborative multi-centre ESHRE study.

Study Question: Has PGD-HLA been successful relative to diagnostic and clinical efficacy?

Summary Answer: The diagnostic efficacy of PGD-HLA protocols was found lower in this study in comparison to published PGD-HLA protocols and to that reported for general PGD by ESHRE (78.5 vs 94.1% and vs 92.

Delineation of two intracranial areas and the perpendicular intracranial width is sufficient for intracranial volume estimation.

Objectives: The aim of the present study is to determine if the delineation of one or two optimally chosen intracranial areas (ICA) is enough to achieve adequate estimates of intracranial volume (ICV) in magnetic resonance imaging.

Methods: The correlations of 62 fully delineated ICVs with four types of ICV estimates were calculated. The estimate types were: (1) a single midsagittal ICA, (2) single ICA multiplied by the intracranial width perpendicular to the ICA, (3) sum of two ICAs multiplied by the perpendicular intracranial width and (4) shape-preserving piecewise cubic interpolation using two ICAs.

Paroxysmal Kinesigenic Dyskinesia.

Background: Paroxysmal kinesigenic dyskinesia (PKD) is a rare condition associated with heterozygous mutations in the proline-rich transmembrane protein 2 () gene.

Phenomenology Shown: In this article we illustrate the phenomenology of PKD in a male previously misdiagnosed with Tourette's syndrome.

Educational Value: Regardless of the underlying phenotype, PKD is highly responsive to some antiepileptic drugs.

A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders.

Objective: De novo mutations contribute significantly to severe early-onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred.

Methods: We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction.

Meiotic segregation analyses of reciprocal translocations in spermatozoa and embryos: no support for predictive value regarding PGD outcome.

Translocation heterozygotes have an increased risk of producing gametes with unbalanced chromosome content. This often leads to reproductive problems such as infertility, repeated miscarriages or birth of an affected child. To increase the chances of having a healthy live-born child, translocation heterozygotes often opt for preimplantation genetic diagnosis (PGD).

Clinical and molecular consequences of disease-associated de novo mutations in SATB2.

Purpose: To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability.

Methods: Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production.