Further Delineation of Clinical Phenotype of ZMYND11 Variants in Patients with Neurodevelopmental Dysmorphic Syndrome.

Intellectual disability with speech delay and behavioural abnormalities, as well as hypotonia, seizures, feeding difficulties and craniofacial dysmorphism, are the main symptoms associated with pathogenic variants of the ZMYND11 gene. The range of clinical manifestations of the ZMYND phenotype is constantly being expanded by new cases described in the literature. Here, we present two previously unreported paediatric patients with neurodevelopmental challenges, who were diagnosed with missense variants in the ZMYND11 gene. It should be noted that one of the individuals manifested with hyperinsulinaemic hypoglycaemia (HH), a symptom that was not described before in published works. The reason for the occurrence of HH in our proband is not clear, so we try to explain the origin of this symptom in the context of the ZMYND11 syndrome. Thus, this paper contributes to knowledge on the range of possible manifestations of the ZMYND disease and provides further evidence supporting its association with neurodevelopmental challenges.

Foot drop in children with newly diagnosed type 1 diabetes: three case reports.

Summary: The etiology of foot drop is diverse from various diseases to mechanic injuries and includes neuropathy of the peroneal nerve. Peroneal neuropathy might also be one of the forms of diabetic neuropathy, very rarely reported as the first sign of diabetes. We describe three cases of children with newly diagnosed type 1 diabetes (TID) who developed unilateral peroneal nerve palsies and tibial nerve palsies, presenting clinically as a foot drop. In two of our cases, the symptoms of foot drop occurred shortly after starting treatment for severe diabetes ketoacidosis. In the third patient, food drop was a reason for the initial medical consultation, but eventually, TID was diagnosed. The presented cases highlight that neuropathy can be observed not only as a chronic complication of T1D, but it can also appear at the time of disease manifestation. The incorrect position of the lower limb during a keto coma may contribute to the development of neuropathy. Learning points: Neuropathy can be observed not only as a chronic complication of type 1 diabetes (T1D), but it can also appear at the time of disease manifestation. The incorrect position of the lower limb causing external pressure during a keto coma may contribute to the development of neuropathy. It is important to examine the glycemia in patients with acute peroneal neuropathy, as this kind of peripheral neuropathy can be associated with newly diagnosed T1D. Normalization of glycemia might lead to rapid neuronal recovery.

Prevalence of haplotype DQ2/DQ8 and celiac disease in children with type 1 diabetes.

Type 1 diabetes (T1D) and celiac disease (CD) coexist very often. Identification of the human leukocyte antigen (HLA) DQ2/DQ8 can confirm the genetic predisposition to CD. Negative result of this test allows to exclude CD with a high probability. It was suggested that in individuals with higher risk of CD, including T1D patients, the implementation of genetic testing should reduce the number of patients requiring systematic immunological screening. The aim of this study was to analyze the prevalence of different haplotypes predisposing to CD in children and adolescents with previously diagnosed T1D. MATERIAL AND METHODS: A retrospective analysis was performed on 166 T1D children (91 girls) in whom HLA DQ2/DQ8 alleles were tested. In 9.6% CD was also diagnosed. RESULTS: In 12.7% both HLA DQ2/DQ8 were negative. In 87.3% patients HLA DQ2 and/or DQ8 was positive, including 27.7% patients with both haplotypes DQ2.5 and DQ8 positive. In all CD patients the disease predisposing alleles were positive, while none of the HLA DQ2/DQ8 negative children were diagnosed with CD. CONCLUSIONS: The prevalence of HLA DQ2.5 and the HLA DQ2.5 / HLA DQ8 configuration is higher in patients with T1D, and CD compared to children with T1D alone. The combination of HLA DQ2 and HLA DQ8 most significantly increases the risk of developing CD. The group of HLA DQ2/DQ8 negative patients with improbable CD diagnosis, is relatively small. Most of T1D patients HLA DQ2/DQ8 positive need further regular antibody assessment. In patients with T1D, who are at high risk of developing CD, genetic testing may be considered to select those who require further systematic serological evaluation. Due to its retrospective nature, the study was not registered in the database of clinical trials and the Clinical trial registration number is not available.

To increase body height and muscle strength - one medicine for two diseases? Case report of a boy with Silver-Russell syndrome and Duchenne muscular dystrophy.

The coexistence of 2 genetic diseases can mutually modify their course. We describe the case of a 10-year-old boy with Sliver-Russell syndrome (SRS) and Duchenne muscular dystrophy (DMD). The patient's short stature, which is part of the clinical picture of both diseases, has been additionally aggravated by the steroid therapy, which is necessary to delay the progression of DMD. From the age of 9 years, the patient was treated with recombinant human growth hormone (rhGH) for 18 months. The following study discusses whether rhGH therapy in a child with SRS and DMD may alleviate or worsen the course of DMD, and how it affects carbohydrate metabolism disorders.

MRI Protocol for Pituitary Assessment in Children with Growth or Puberty Disorders-Is Gadolinium Contrast Administration Actually Needed?

The aim of this study was to assess the diagnostic value of non-contrast pituitary MRI in children with growth or puberty disorders (GPDs) and to determine the criteria indicating the necessity to perform post-contrast examination. A retrospective study included re-analysis of 567 contrast-enhanced pituitary MRIs of children treated in a tertiary reference center. Two sets of sequences were created from each MRI examination: Set 1, including common sequences without contrast administration, and Set 2, which included common pre- and post-contrast sequences (conventional MRI examination). The differences in the visibility of pituitary lesions between pairs of sets were statistically analyzed. The overall frequency of Rathke's cleft cysts was 11.6%, ectopic posterior pituitary 3.5%, and microadenomas 0.9%. Lesions visible without contrast administration accounted for 85% of cases. Lesions not visible before and diagnosed only after contrast injection accounted for only 0.18% of all patients. Statistical analysis showed the advantage of the antero-posterior (AP) pituitary dimension over the other criteria in determining the appropriateness of using contrast in pituitary MRIs. The AP dimension was the most significant factor in logistic regression analysis: OR = 2.23, 95% CI, 1.35-3.71, p-value = 0.002, and in ROC analysis: AUC: 72.9% with a cut-off value of 7.5 mm, with sensitivity/specificity rates of 69.2%/73.5%. In most cases, the use of gadolinium-based contrast agent (GBCA) in pituitary MRI in children with GPD is unnecessary. The advantages of GBCA omission include shortening the time of MRI examination and of general anesthesia; saving time for other examinations, thus increasing the availability of MRI for waiting children; and acceleration in their further clinical management.

Alpha-1 Acid Glycoprotein and Podocin mRNA as Novel Biomarkers for Early Glomerular Injury in Obese Children.

INTRODUCTION: Obesity, which is a serious problem in children, has a negative impact on many organs, including kidneys, and obesity-related glomerulopathy (ORG) is an increasingly common cause of ESKD (end-stage kidney disease) in adults. Early-detected and -treated glomerular lesions are reversible, so it is important to find a useful marker of early damage. The study aimed to evaluate the albumin-to-creatinine ratio (ACR), urinary alpha-1-acid glycoprotein (α1-AGP), and mRNA of podocyte-specific proteins as indicators of glomerular injury and their relationship with the degree of obesity and metabolic disorders. MATERIALS AND METHODS: A total of 125 obese children and 33 healthy peers were enrolled. Patients were divided into two groups, depending on SDS BMI values. ACR, α1-AGP, mRNA expression of nephrin, synaptopodin, podocin, and C2AP protein in urine sediment were measured. RESULTS: ACR values did not differ between groups and were within the normal range. α1-AGP and mRNA expression were significantly higher in obese children compared with controls. mRNA expression of the remaining podocyte proteins was similar in both groups. No significant differences concerning all examined parameters were found depending on the degree of obesity. There was a positive significant correlation between α1-AGP and ACR. CONCLUSIONS: Increased α1-AGP before the onset of albuminuria suggests its usefulness as a biomarker of early glomerular damage in obese children. An increased podocin mRNA expression also indicates podocyte damage and may be linked to ORG development. The lack of increase in expression of other podocyte proteins suggests that podocin mRNA may be a more specific and sensitive biomarker. The degree of obesity has no impact on the tested parameters, but further studies are needed to confirm it.

Disturbances in the intraventricular conduction system in teenagers with type 1 diabetes. A pilot study.

Body Surface Potential Mapping (BSPM) is a multi-electrode synchronous method for examining electrocardiographic records on the patients' body surface that allows the assessment of changes in the heart conduction system. The aim of the study was to visualize and evaluate changes in the intraventricular system in adolescents with T1D. PATIENTS AND METHODS: Inclusion criteria: age > 12 years, T1D duration >3 years, HbA1c >8%. EXCLUSION CRITERIA: diagnosis of autonomic neuropathy, heart structural defects, heart failure. BSPM data were processed into map plotting to illustrate differences in ventricular activation time (VAT, isochron lines). RESULTS: 33 teenagers (20 boys), mean age 15.0 ± 2.1 years, T1D from 6.8 ± 4.1 years were included. Mean HbA1c was 9.6 ± 2.0%. In the standard ECG recording abnormalities were not present. The distribution of isolines on the group-mean map plotted for T1D patients only initially resembles the course of isolines on the group-map for normal subjects (N = 30), in whom the electrical impulse stimulating the heart ventricles passes through the atrio-ventricular node, then symmetrically excites the branches of His bundle and finally the Purkinje fibers. In T1D patients, after proper onset of intraventricular stimulation, the isolines reflecting the both ventricles reach higher time values, which indicates problems in the propagation of the ventricular depolarization.

Clinical evaluation of 31 children with pituitary insufficiency in the course of the pituitary stalk interruption syndrome. The unexpected growth without growth hormone in 2 children.

INTRODUCTION: The pituitary stalk interruption syndrome (PSIS) is one of the complex -forms of congenital pituitary insufficiency. Symptoms resulting from insufficiency of the pituitary gland, in spite of the inborn character of the disease, may appear at various stages of life. The aim of this paper was to present clinical presentation in 31 patients with PSIS confirmed radiologically. RESULTS: In the whole study population during first examination 25.8% children were diagnosed with combined pituitary hormone deficiency (CPHD). During the endocrinological observation (median follow-up 5.1 years, range 0.513.2) of the above-mentioned group 74.2% subjects were diagnosed with CPHD, while 25.8% patients with isolated growth hormone deficiency (GHD). Two children with initially short stature were confirmed with GHD. As a result of the parents' decision, growth hormone therapy was either not started or discontinued. During further follow-up, however, the children achieved normal height. CONCLUSIONS: Children with PSIS present a diverse clinical picture and should be observed because of the risk of further pituitary disorders. In the differential diagnosis of hypoglycemia in the neonatal period and in infancy, hypopituitarism should be considered. The phenomenon of normal growth in patients with confirmed growth hormone deficiency has been observed, although is not fully understood.

Hyperosmolar hyperglycaemic state (HHS) as the first manifestationof type 2 diabetes in a child.

Hyperglycaemic hyperosmolar state (HHS) may occur in young patients with type 1 and type 2 diabetes and in infants with hyperglycaemia. Hyperglycaemic hyperosmolar state is characterised by extremely high glucose concentration, which, by increasing osmotic diuresis, intensifies dehydration. Hyperglycaemic hyperosmolar state criteria include the following: plasma glucose > 600 mg/dl, venous pH > 7.25, sodium bicarbonate > 15 mmol/l, slight ketonuria, plasma osmolality > 320 mOsm/kg, and impairment of consciousness (aggression, unconsciousness, convulsions). We describe the case of a 13-year-old patient with severe obesity (at presentation body mass > 120 kg, BMI > 40 kg/m2), who developed HHS (glycaemia 647 mg/dl, pH 7.18, pCO2 96.5 mmHg, BE - 5.0 mmol/l, HCO3 35.2 mmol/l; Na 167 mmol/l, plasma osmolarity 370 mOsm/kg) in the course of pneumonia and newly diagnosed type 2 diabetes (HbA1c 15.5%, C-peptide 2.63 ng/ml). In the follow-up, due to the hypoglycaemia, insulin was discontinued, metformin was administered at a dose of 2 g/day, with a further reduction to 500 mg/day, together with physical rehabilitation and a low-calorie diet. Weight reduction during 6 months of observation was approximately 37 kg. Due to breathing disorders occurring at night, the girl still needs breathing assistance (CPAP).

Polymorphism of the FTO Gene Influences Body Weight in Children with Type 1 Diabetes without Severe Obesity.

The objective was to compare the impact of clinical and genetic factors on body mass index (BMI) in children with type 1 diabetes (T1DM) without severe obesity. A total of 1,119 children with T1DM (aged 4-18 years) were qualified to take part in the study. All children were genotyped for variants of FTO, MC4R, INSIG2, FASN, NPC1, PTER, SIRT1, MAF, IRT1, and CD36. Results. Variants of FTO showed significant association with BMI-SDS in the T1DM group. The main factors influencing BMI-SDS in children with T1DM included female gender (P = 0.0003), poor metabolic control (P = 0.0001), and carriage of the A allele of the FTO rs9939609 gene (P = 0.02). Conclusion. Our research indicates, when assessing, the risk of overweight and obesity carriage of the A allele in the rs9939609 site of the FTO gene adds to that of female gender and poor metabolic control. This trial is registered with ClinicalTrials.gov (NCT01279161).

[Adipocytokines concentration and metabolic parameters in obese children]. / Ocena stezen adipocytokin oraz parametrów metabolicznych u dzieci z otyloscia

INTRODUCTION: Adipose tIssue secretes metabolically active proteins. AIM OF THE STUDY: 1. To evaluate the prevalence of insulin resistance (IR) and metabolic syndrome (MS) in obese children as well as to measure plasma hormones concentrations: leptin, adiponectin, resistin in obese adolescents. 2. To assess the relationship between the studied adipocytokines and markers of metabolic syndrome. MATERIAL AND METHODS: The study was carried out in 79 obese children, 10-18 years old, (mean 14.3n1.9 years) and 35 normostenic healthy children (mean age 14.6n2.37 years) as a control group. In all children adiponectin, leptin, resistin, lipid profile (triglycerides and HDL cholesterol) were estimated and plasma glucose and insulin levels were measured during the oral glucose tolerance test (OGTT). HOMA-IR was calculated. RESULTS: MS was diagnosed in 28/78 of children (36% of subjects), IR in 54/79 patients (68% of subjects). There were higher concentrations of leptin and resistin (p <0.0001) and lower of adiponectin (p <0.05) in obese children in comparison to normostenic children. In obese girls with IR a higher concentration of leptin was observed comparing to obese girls without IR (p <0.05). A lower concentration of adiponectin was present in patients with IR and MS (p <0.05). There were no correlations between resistin concentration and IR level nor insulin concentration observed. CONCLUSIONS: 1. A sex-related relationship between plasma leptin and IR was observed. 2 Hypoadiponectinemia was connected with IR and other metabolic disorders typical for the metabolic syndrome, independently of BMI. 3. There were no statistically significant correlations between the resistin concentration and IR nor metabolic disorders, which might contradict the hypothesis of the role of resistin in the pathogenesis of insulin resistance in humans.

The effect of a one-year weight reduction program on serum uric acid in overweight/obese children and adolescents.

BACKGROUND: Hyperuricemia may underlie obesity and related disorders, but the impact of weight reduction and metformin on serum uric acid (sUA) in Caucasian children/adolescents is unknown. METHODS: One hundred and thirteen children/adolescents were enrolled (83 completed) into 1-year weight reduction program (diet+exercise) without or with metformin. Anthropometric and biochemical measurements were conducted at baseline and at the end of follow-up (13 ± 3 months). RESULTS: sUA decreased in 86% females and 67% males. Significantly more patients substantially (≥ 10%) reduced their sUA than body mass index (BMI)%. In females, sUA decreased regardless of type of intervention, but more markedly in the metformin group, and ΔsUA correlated positively with ΔBMI%, ΔWHtR (waist-to-height ratio), Δinsulin, ΔHOMA (homeostasis model of assessment), and Δtriglycerides/high density lipoprotein (HDL), but correlated negatively with baseline sUA, HOMA, insulin, and triglycerides/HDL. Of these, metformin treatment, baseline sUA, and ΔBMI% were independent predictors of sUA reduction, explaining 77% of data variability. In males, sUA reduction was significant in the metformin group only, and negatively correlated with ΔWHR (waist-to-hip ratio), ΔWHtR, Δleptin, baseline sUA, and waist circumference. Of these, baseline sUA and ΔBMI% were independent predictors of sUA reduction, explaining 69% of data variability. Except for sUA, females reduced their BMI%, waist circumference, triglycerides, triglycerides/HDL and increased HDL, while males reduced total cholesterol. CONCLUSIONS: A longitudinal weight reduction program encompassing diet/exercise with or without metformin was more efficient in reducing sUA than weight and its effect on sUA and other metabolic parameters differed between genders. Weight loss did not condition sUA reduction, which was strongly dependent on baseline levels. The sUA reducing effects of metformin may contribute to its effects on blood pressure-lowering and endothelial function-improving properties in females.

Gender-specific association of serum uric acid with metabolic syndrome and its components in juvenile obesity.

BACKGROUND: Hyperuricemia has been implicated in the pathogenesis of obesity and related metabolic abnormalities. Studies on the association between serum uric acid (sUA) and metabolic syndrome (MetS) in juvenile obesity are scant. The effect of gender has not been evaluated. METHODS: sUA (uricase method), anthropometric and biochemical indices were measured in gender-stratified children/adolescents consisting of 113 overweight/obese and 71 lean individuals. RESULTS: In males, sUA was significantly elevated in overweight as well as obese patients. sUA was strongly associated with obesity indices and reflected sexual development, decreases in high density lipoprotein-cholesterol, and moderately, the number of MetS components. Waist circumference (WC) and Tanner stage explained 40% of sUA variability. Controlling for body mass index (BMI) and other MetS components, sUA was associated with abdominal obesity, explaining 30% of variability in WC. In females, sUA was significantly increased in obesity, high blood pressure (BP), and MetS and corresponded with the number of MetS components, indices of glucose metabolism, triglycerides (TG), and the atherogenecity index. Insulin-resistance (IR) (homeostasis model assessment; HOMA) and high BP explained 29% of sUA variability, whereas sUA, while controlling for BMI, age, and other MetS components, was associated with hypertriglyceridemia, hyperglycemia, high BP, and abdominal obesity. IR mediated the associations with high TG and glucose. CONCLUSIONS: The association between sUA and MetS components in juvenile obesity is gender-specific, with females being related more closely and to more metabolic abnormalities. It may explain why, despite its lower concentrations, sUA is an independent predictor of mortality from all causes and from vascular diseases exclusively in females. Our findings may help in identifying metabolic abnormalities which may possibly be targeted by reducing sUA in males and females.

[Complex analysis of the physical metabolic and genetic state in children of mothers with type 1 diabetes]. / Kompleksowa ocena rozwoju fizycznego oraz stanu metabolicznego i genetycznego u dzieci matek z cukrzyca typu 1 -- obserwacja kilkuletnia.

BACKGROUND: Complex assessment of the development, clinical and immunological state of children born by mothers with type 1 diabetes, in the years 1998-2000. MATERIALS AND METHODS: Material examined were 30 newborns, and subsequently 25 in the first, 30 children at 5-6 years of life. In newborns and in the 5-6 years the antibodies: IA-2A, IAA, ICA, anti GAD, insulin (IRI), peptide C were determined. In the first year HbA(1c), TSH, antigens HLA DQA1 and DQB1 were determined, in the 5th-6th years of life, the level of antibodies anti endomizium. RESULTS: Developmental anomalies in newborns were found in 6, in 3 in first and in the 5th-6th years in 4 children. Systemic infections were found in 6, hypoxia and prematurity in 12 newborns. A positive titer of anti GAD in 15, ICA in 18, IA-2A in 8, IAA in 18 newborns. In the first year of life, anti GAD in 2, in the 5-6th years in 4 children. In one child anti GAD was found during three examinations. In the case of this positive titer of antibodies, the allele DQB1*0302 was present. Allel DQB1*0302 was present in 28% of children, allele DQA1*0301 was absent. Mean levels of IRI afterbirth and in the first year of life were: 23.6 and 9.7 uIU/ml and peptide C 1.25 and 0.92 ng/ml. Mean levels of HbA(1c) in the first and 5th yrs of life were: x 6.2%, TSH 2.45 uIU/ml and 3.4 uIU/ml. Pathological values of antibodies anti endomizium were found in 4 children, biopsy of the small intestine confirmed coeliac disease. A normal body mass was seen in 9 newborns in 16 in the first, and 14 children 5-6 years of age. Deficiency in body mass was found in 2 newborns and 3 children in the first and 5-6th yrs. Macrosomia was found in 8 newborns in group I and 3 in group II. Overweight was found in 5 children in the first year and 9 in 5-6th yrs of life. None of the children have developed diabetes. CONCLUSIONS: 1. Children of mothers with type 1 diabetes should be monitored by an outpatient clinic for diabetic patients. 2. Children of mothers with diabetes should have determined regularly immunological markers for diabetes and other autoimmunological disease.