Predictors of the clinical severity of T1DM presentation at diagnosis in children and adolescents with type 1 diabetes mellitus (T1DM).

PURPOSE: We aimed to assess factors associated with the presence and severity of ketoacidosis (DKA) at pediatric type 1 diabetes (T1DM) diagnosis, in relation to pancreatic, associated and familial autoimmunity. METHODS: Antibodies against pancreatic beta-cells, organ specific autoantibodies (thyroid, celiac, and parietal) and family history of autoimmunity were retrospectively evaluated in 116 T1DM patients aged 11.9 ± 4.6 (mean ± SD) years, with disease duration 7.62 ± 3.67 years (mean ± SD). RESULTS: Most patients (67.2%) presented with DKA at diagnosis. Younger children (< 2 years) had tenfold risk of DKA, compared to older children (12.1-15 years) (OR = 10.8, 95% CI: 1.0-116.9, P = 0.05). Fasting c-peptide levels were lower in the DKA group (OR = 0.26, 95% CI = 0.07-0.89, P = 0.033). The number of anti-pancreatic antibodies at disease onset did not show any significant correlations with the presence (p = 0.889) or severity of DKA (p = 0.863). All patients with multiple autoimmunity (> 2 autoimmune diseases plus T1DM) presented with DKA. Familial autoimmunity acted protectively against DKA manifestation (OR = 0.40, 95% CI = 0.16-1.0, P = 0.051). CONCLUSIONS: Among newly diagnosed T1DM patients, 67.2% presented with DKA. Younger age, lower c-peptide and the presence of associated autoimmunity were predictive factors of the presence and severity of DKA at diagnosis. High degree of suspicion, due to family history, may prevent DKA development and severity.

Combined exome analysis and exome depth assessment achieve a high diagnostic yield in an epilepsy case series, revealing significant genomic heterogeneity and novel mechanisms.

OBJECTIVES: Genetics of epilepsy are highly heterogeneous and complex. Lesions detected involve genes encoding various types of channels, transcription factors, and other proteins implicated in numerous cellular processes, such as synaptogenesis. Consequently, a wide spectrum of clinical presentations and overlapping phenotypes hinders differential diagnosis and highlights the need for molecular investigations toward delineation of underlying mechanisms and final diagnosis. Characterization of defects may also contribute valuable data on genetic landscapes and networks implicated in epileptogenesis. METHODS: This study reports on genetic findings from exome sequencing (ES) data of 107 patients with variable types of seizures, with or without additional symptoms, in the context of neurodevelopmental disorders. RESULTS: Multidisciplinary evaluation of ES, including ancillary detection of copy number variants (CNVs) with the ExomeDepth tool, supported a definite diagnosis in 59.8% of the patients, reflecting one of the highest diagnostic yields in epilepsy. CONCLUSION: Emerging advances of next-generation technologies and 'in silico' analysis tools offer the possibility to simultaneously detect several types of variations. Wide assessment of variable findings, specifically those found to be novel and least expected, reflects the ever-evolving genetic landscape of seizure development, potentially beneficial for increased opportunities for trial recruitment and enrollment, and optimized, even personalized, medical management.

Familial autoimmunity in pediatric patients with type 1 diabetes (T1D) and its associations with the severity of clinical presentation at diabetes diagnosis and with coexisting autoimmunity.

PURPOSE: The aim was to evaluate the impact of familial autoimmunity on the age and severity of type 1 diabetes (T1D) presentation and on the coexistence of other autoimmune diseases. METHODS: We retrospectively evaluated the medical records of 121 children/adolescents (male: 63) followed in our Diabetic Clinic from 2002 to 2016. RESULTS: Seventy-six patients (62.8%) had at least one relative with an autoimmune disease, Hashimoto's thyroiditis (49.5%) and T1D (22.3%) being the commonest. Children with familial autoimmunity were younger at T1D diagnosis (mean age ± SD) (6.766 ± 3.75). Median fasting c-peptide levels at presentation were not related to familial autoimmunity. Patients with familial autoimmunity more often exhibited GADA autoantibody positivity at diagnosis. The larger the number of the patient's relatives diagnosed with an autoimmune disease, the higher were the patient's GADA levels (Spearman's rho test = 0.19, p = 0.049). Children with a first-degree relative with autoimmunity had a coexisting autoimmune disorder at a significantly higher percentage (p = 0.016). Family history of autoimmunity was negatively associated with the presence of diabetic ketoacidosis (DKA) (p = 0.024). Patients with a relative with T1D less frequently exhibited DKA at diagnosis (12.8 vs. 87.2%, p = 0.003). The presence of DKA was associated with younger age (p = 0.05) and lower c-peptide levels (p = 0.033). CONCLUSIONS: Familial autoimmunity was present in 62.8% of children with T1D, autoimmune thyroiditis and T1D being the two most frequent familial autoimmune diseases. Familial autoimmunity reduced the risk of DKA at diagnosis, but these patients were younger and had higher levels of pancreatic autoantibodies and a greater risk of developing additional autoimmune diseases.

Growth Hormone Deficiency due to p.(Gln467Argfs*64) Mutation in the ARID1B Gene in a Girl with Coffin-Siris Syndrome.

Introduction: Coffin-Siris syndrome (CSS) (MIM #135900) is an extremely rare genetic multisystemic disorder characterized by aplasia or hypoplasia of the upper phalanx of the fifth finger, moderate to severe cognitive and/or developmental delay, and characteristic facial features (thick lashes, hypertrichosis of the trunk, sparse hair). Congenital anomalies of the brain, kidney, and heart have been described but are less consistent across patients. Case presentation: We report a case of a 12-year-5-month-old girl with the clinical features of CSS, severe scoliosis, and epilepsy. Growth hormone deficiency was diagnosed at the age of 9 years. Recombinant human growth hormone (rhGH) treatment was started that resulted in a significant improvement of the growth velocity up to 5.4 cm/year (>90-97th centile). Next-generation sequencing identified a mutation in the ARID1B gene. Discusion: Despite its phenotypic heterogeneity, key features of CSS have become clearer and along with molecular diagnosis, a further global approach to improve the care of these individuals is enabled. Appropriate therapies for this population are needed to optimize growth and intellectual potentials.

Predictors of associated and multiple autoimmunity in children and adolescents with type 1 diabetes mellitus.

PURPOSE: Type 1 diabetes mellitus (T1DM) is an autoimmune condition characterised by the presence of antipancreatic antibodies. The autoimmune process is also directed against other organs, most frequently against the thyroid gland, intestinal mucosa, and gastric parietal cells. METHODS: Our investigation included 121 children with T1DM with a mean age±standard deviation of 11.99±4.63 years (range, 2.0-20.0 years). We explored the frequency of associated autoimmunity; the presence of predictive factors such as current age, sex, and severity at diabetes diagnosis; T1DM duration; and family history of autoimmunity. RESULTS: Associated autoimmunity was present in 28.9% of T1DM patients. Children with associated autoimmunity were older at diabetes diagnosis (p=0.009) and had a longer diabetes duration compared to children without associated autoimmunity (p=0.044). Adolescents aged 12-20 years had a statistically significant higher chance of developing thyroid autoimmunity compared to children aged 1-5 years (p=0.019). Multiple autoimmunity (MA), T1DM, and 2 or more autoimmune diseases were present in 5.8% of the study population. All children with MA presented with ketoacidosis at diabetes diagnosis and had a higher percentage of familial autoimmunity (p=0.042). The familial autoimmunity of these patients most frequently affected ≥3 relatives (p=0.026) and was more frequently diagnosed before 5 years of age (p=not significant). CONCLUSION: Associated autoimmunity was present in almost one-third of T1DM patients. Significant associations with associated autoimmunity were longer diabetes duration, female sex, older age at diabetes diagnosis, and glutamic acid decarboxylase positivity. Predictors of MA were age <5 years at T1DM diagnosis, the presence of diabetic ketoacidosis at diagnosis, and a significant family history of autoimmunity.

Novel Hemizygous Missense Variant of Spermine Synthase (SMS) Gene Causes Snyder-Robinson Syndrome in a Four-Year-Old Boy.

Snyder-Robinson syndrome (SRS) is an extremely rare X-linked intellectual disability syndrome (MRXSSR; MIM #309583). The main clinical features of SRS include psychomotor delay, hypotonia, and asthenic-type body habitus - reduced body weight and bone abnormalities (osteoporosis, fractures, kyphoscoliosis). We report a case of SRS with a hemizygous missense variant in the SMS gene,c.334C>G (p.Pro112Ala), in a 4-year-old boy, who initially developed hypotonia, delayed motor skills, and subsequently epilepsy. This variant in SMS was found to be de novo. To the best of our knowledge, this novel SMS gene variant has never been previously reported in disease-related variation databases, such as ClinVar or HGMD.