Two novel mutations in seven Czech and Slovak kindreds with familial neurohypophyseal diabetes insipidus-benefit of genetic testing.

UNLABELLED: Familial neurohypophyseal diabetes insipidus (FNDI) is a rare hereditary disorder with unknown prevalence characterized by arginine-vasopressin hormone (AVP) deficiency resulting in polyuria and polydipsia from early childhood. We report the clinical manifestation and genetic test results in seven unrelated kindreds of Czech or Slovak origin with FNDI phenotype. The age of the sign outset ranged from 2 to 17 years with remarkable interfamilial and intrafamilial variability. Inconclusive result of the fluid deprivation test in three children aged 7 and 17 years old might cause misdiagnosis; however, the AVP gene analysis confirmed the FNDI. The seven families segregated together five different mutations, two of them were novel (c.164C > A, c.298G > C). In addition, DNA analysis proved mutation carrier status in one asymptomatic 1-year-old infant. CONCLUSIONS: The present study together with previously published data identified 38 individuals with FNDI in the studied population of 16 million which predicts a disease prevalence of 1:450,000 for the Central European region. The paper underscores that diagnostic water deprivation test may be inconclusive in polyuric children with partial diabetes insipidus and points to the clinical importance and feasibility of molecular genetic testing for AVP gene mutations in the proband and her/his first degree relatives. WHAT IS KNOWN: • At least 70 different mutations were reported to date in about 100 families with neurohypophyseal diabetes insipidus (FNDI), and new mutations appear sporadically. What is New: • Two novel mutations of the AVP gene are reported • The importance of molecular testing in children with polyuria and inconclusive water deprivation test is emphasized.

Fabry Disease in Slovakia: How the Situation Has Changed over 20 Years of Treatment.

Fabry disease (FD, OMIM#301500) is a rare inborn error of the lysosomal enzyme α-galactosidase (α-Gal A, EC 3.2.1.22) and results in progressive substrate accumulation in tissues with a wide range of clinical presentations. Despite the X-linked inheritance, heterozygous females may also be affected. Hemizygous males are usually affected more severely, with an earlier manifestation of the symptoms. Rising awareness among health care professionals and more accessible diagnostics have positioned FD among the most-common inherited metabolic diseases in adults. An early and correct diagnosis of FD is crucial with a focus on personalised therapy. Preventing irreversible destruction of vital organs is the main goal of modern medicine. The aim of this study was to offer a complex report mapping the situation surrounding FD patients in Slovakia. A total of 48 patients (21 males, 27 females) with FD are registered in the Centre for Inborn Errors of Metabolism in Bratislava, Slovakia. In our cohort, we have identified three novel pathogenic variants in five patients. Three patients presented with the frameshift mutation c.736delA, and two others presented with the missense mutations c.203T>C, c.157A>C. Moreover, we present a new clinical picture of the pathogenic variant c.801+1G>A, which was previously described and associated with the renal phenotype.

Risk factors of post-surgery complications in children with thyroid cancer.

INTRODUCTION: Thyroid cancer in children is a hot topic because of the large clinical heterogeneity and the risk of severe complications. We aimed to study 1. The frequency, 2. Etiology, and 3. Risk factors of post-surgery complications of thyroid cancer. MATERIAL AND METHODS: A retrospective analysis including risk factors for post-surgery complications of patients treated for thyroid malignancies in years 2006-2018 was performed. RESULTS: Over a period of 12 years 22 patients with thyroid malignancy (68% female; 12.6 ±â€¯4.0 years of age, median follow-up 6 years) were identified. Histologically, 12 (55%) patients had papillary carcinoma. Six patients (27.3%) had multiple endocrine neoplasia type 2 (MEN2) syndrome, 3 (13.7%) patients had medullary carcinoma and 1 patient had follicular carcinoma. Neck lymph node metastases were diagnosed in 8 (36.4%), distant metastases in 6 (27.3%), and both locations were involved in 4 (18.2%) patients. Six (27.3%) children had surgical complications: 1 child had unilateral vocal cord paralysis and transient hypoparathyroidism and 5 had transient hypoparathyroidism. The higher risk of surgery complications in forward stepwise logistic regression was associated in with distant metastases (R2 = 0.584, OR 52.63, p = 0.010). CONCLUSIONS: Postoperative complications were significantly associated with presence of distant metastases. Favorable results were observed in with children with MEN2 syndrome.

CTLA-4 gene polymorphisms predispose to autoimmune endocrinopathies but not to celiac disease.

OBJECTIVES: The aim of the study was to determine the association of two CTLA-4 gene polymorphisms (CT60, +49 A/G) with Hashimoto thyroiditis (HT), type 1 diabetes mellitus (T1DM) and celiac disease (CD) as well as with the occurrence of multi-organ involvement by autoimmunity in children. METHODS: Genotyping was done by RFLP analysis in Slovak children with HT (n=63) and CD (n=120) and both Slovak and Slovene children with T1DM (n=320) and healthy controls (n=231). RESULTS: We found a significant association of the G allele of the CT60 polymorphism with HT (p<0,0005) in the Slovak population and T1DM in both Slovak (p<0.01) and Slovene populations (p<0.005). The G allele of the +49A/G polymorphism was significantly, though less strongly, associated with T1DM (p<0.05) and HT (p<0.05). Distribution of genotypes of CTLA-4 gene polymorphisms in CD patients did not differ significantly from controls. None of the polymorphisms was associated with multi-organ involvement by autoimmunity. CONCLUSION: The G allele of both examined CTLA-4 gene polymorphisms predisposes to HT and T1DM, but not to CD. No association with multi-organ involvement was found. The GG genotype of the CT60 polymorphism may identify CD patients at an increased risk for concomitant T1DM and HT. Further studies to assess the predictive value of CTLA-4 polymorphisms for the co-occurrence of HT and T1DM in CD patients are needed.

The prevalence of melanocortin-4 receptor gene mutations in Slovak obese children and adolescents.

Melanocortin-4 receptor (MC4R) deficiency is the most frequent monogenic form of obesity. The contribution of MC4R mutations to the Slovak population has not been investigated as yet. We screened the coding sequence of the MC4R gene in a cohort of 210 Slovak obese children and adolescents. We identified four different mutations in four patients, giving a mutation detection rate of 0.95%. Of these, three were missense mutations previously identified and characterized by other research groups (p.R7C, p.S127L and p. R305W, respectively). One was a novel nonsense mutation p.W174* detected in a severely obese 7-year-old boy. This mutation was further analyzed in family segregation analysis and exhibited variable penetrance. Two known amino acid polymorphisms (p.V103I and p.I251L) were also identified in seven subjects of our cohort group. We also performed multifactorial statistical analysis to determine the influence of genotypes on standard biochemical blood markers. No significant influence was observed in carriers of DNA variants on tested parameters. We conclude that rare heterozygous MC4R mutations contribute to the onset of obesity only in a few cases in the Slovak population.

Thyroid function and ioduria in infants after cardiac surgery: comparison of patients with primary and delayed sternal closure.

OBJECTIVES: Thyroid hormone alterations after cardiac surgery may be aggravated by the use of iodine antiseptics. We evaluated thyroid function and ioduria in infants with delayed sternal closure (DSC) who are exposed to povidone-iodine for sternal wound protection and compared them with findings in infants after primary sternal closure. DESIGN: Prospective clinical study. SETTING: Pediatric cardiac intensive care unit. PATIENTS: Ninety-three infants after cardiac surgery using cardiopulmonary bypass, 60 of them with primary sternal closure and 33 of them with delayed sternal closure. MEASUREMENTS AND MAIN RESULTS: Thyroid hormones were studied in patients with primary sternal closure immediately after surgery, 5 days and 19 days after surgery, in patients with DSC immediately after surgery, immediately after sternal closure, and 2 wks after sternal closure. Ioduria was evaluated on the first, third, and fifth postoperative days after cardiac surgery with primary sternal closure and immediately after DSC. In both groups of patients, low total triiodothyronine, total thyroxine, thyroxine-binding globulin levels, high reverse triiodothyronine levels, and normal free triiodothyronine, free thyroxine, and thyroid-stimulating hormone levels were recorded immediately after surgery. Concentrations of total triiodothyronine and thyroid-stimulating hormone were lower in the patients with DSC. Five days after primary sternal closure and 2 wks after DSC, all thyroid hormone levels were normal for age. Ioduria after DSC was higher than ioduria after primary sternal closure. CONCLUSIONS: Patients with DSC compared with patients with primary sternal closure display more profound thyroid suppression in the immediate postoperative period. The use of povidone-iodine adhesive drapes with single povidone-iodine mediastinal irrigation in patients with DSC is associated with significant iodine absorption but no significant thyroid dysfunction.

Evaluation of lipid and glucose metabolism and cortisol and thyroid hormone levels in obese appropriate for gestational age (AGA) born and non-obese small for gestational age (SGA) born prepubertal Slovak children.

AIM: Obesity is the major determinant of metabolic syndrome. Being born small for gestational age (SGA) may be co-responsible. We aimed at evaluating the association between 1. obesity and 2. being born SGA and the presence of endocrine-metabolic abnormalities in prepubertal Slovak children. METHODS: The study included 98 children, aged 3-10.9 years: 36 AGA-born obese children (OB), 31 SGA-born children (SGA) and 31 appropriate for gestational age born non-obese children (AGA). Fasting serum levels of glucose, total cholesterol, LDL, HDL, triglycerides, fT4, TSH, cortisol and insulin were determined. HOMA-IR was calculated. Personal data about birth weight and length and family history were collected. Actual anthropometric measurement was done. RESULTS: In every group, high prevalence of positive family history of metabolic disorder was found. In comparison with AGA children, OB children were taller (p<0.01) with higher body mass index (BMI) (p<0.001), and had increased insulin levels and homeostasis model assessment for insulin resistance (HOMA-IR) (p<0.001), decreased high-density lipoprotein (HDL) (p<0.001), and a trend to higher cortisol levels (p=0.069) was noted. SGA-born children were shorter (p<0.001), with BMI comparable to the AGA group. They had higher glucose levels (p<0.001), a trend to decreased HDL levels (p=0.085) and increased fT4 levels (p<0.001). A three-fold higher occurrence of metabolic abnormalities was present in obese children and twice more metabolic abnormalities were present in SGA-born children in comparison with AGA-born children. CONCLUSIONS: SGA-born children are more prone to developing endocrine-metabolic abnormalities than non-obese children born AGA, but they are at less risk than obese AGA-born children. We should provide specialized care for obese children already in prepubertal age and pay attention to SGA-born children.

Treatment of Pathological Bone Fractures in a Patient with McCune-Albright Syndrome.

McCune-Albright syndrome is a rare genetic disorder with typical skeletal and endocrine manifestations. The disease course is complicated by recurrent fractures resulting from polyostotic fibrous dysplasia and the treatment is thus primarily directed at the reduction of the risk of fractures. However, due to the complex mechanism of the skeletal damage the standard antiporotic therapeutics are ineffective. We report here a case of a 31-year-old female, diagnosed with the McCune-Albright syndrome in early childhood. She was suffering from extensive bone involvement, complicated by recurrent fractures despite the treatment with bisphosphonates. In addition, the disease course was complicated by the impairment of several endocrine functions-precocious puberty, hyperestrogenism, and hyperthyroidism for which a total thyroidectomy was performed. During the operation, two enlarged parathyroid glands were removed. This resulted in severe hypocalcaemia in the postoperative period with a need for supplementation with very high calcium and vitamin D doses. After this episode, the patient has remained free of fractures. We discuss here the corrected thyroid function, the supplementation with unconventionally high doses of vitamin D and calcium, and the termination of bisphosphonates treatment as presumable factors contributing to the reduced fracture risk in this patient.

Thyroid hormone status after cardiac surgery in infants with delayed sternal closure and continued use of cutaneous povidone-iodine.

OBJECTIVE: The aim of this prospective study was to examine whether providone-iodine used for sternal wound protection in infants with delayed sternal closure (DSC) influences the thyroid function. PATIENTS AND METHODS: Thyroid hormones (see bellow) and thyroxine binding globulin (TBG) were estimated by radioimmunoassay and ioduria by mass spectrometry in 20 infants in whom cutaneous povidone-iodine was continuously applied on the skin for 1-7 days before DSC after open heart surgery. RESULTS: In the early postoperative period the median levels of total triiodothyronine (TT3), total thyroxine (TT4) and thyroxine-binding globulin (TBG) were below the lower limit of normal, while these of reverse triiodothyronine (rT3) were above normal. The median levels of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) were normal. Two weeks after the sternal closure, the levels of TT3, TT4 and TBG increased significantly (P < 0.001), while these of rT3 decreased, but not significantly. The levels of TSH increased (P < 0.001), being above normal in 7 patients. Four weeks after the sternal closure, TSH levels remained markedly increased in 4 infants. These patients were considered to be hypothyroid and were started on thyroxine replacement therapy. Such replacement treatment was withdrawn at a median age of 6.5 months (range 5-8 months). Urinary iodine concentration on the last day of povidone-iodine exposure was several times higher (P < 0.001) than that in the control group of healthy infants. CONCLUSIONS: Transient hypothyroidism was found in four of 20 infants with DSC who were exposed to povidone-iodine. It is suggested to monitor TSH level in these patients, optimally at 4 weeks after closure of the sternum, when findings may show true hypothyroidism.