Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome.

Mutations in FGFR1 have recently been associated with Hartsfield syndrome, a clinically distinct syndromic form of holoprosencephaly (HPE) with ectrodactly, which frequently includes combinations of craniofacial, limb and brain abnormalities not typical for classical HPE. Unrelated clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. FGFR1 is a principal cause for these less severe diseases as well. Here we demonstrate that of the nine FGFR1 mutations recently detected in our screen of over 200 HPE probands by next generation sequencing, only five distinct mutations in the kinase domain behave as dominant-negative mutations in zebrafish over-expression assays. Three FGFR1 mutations seen in HPE probands behave identical to wild-type FGFR1 in rescue assays, including one apparent de novo variation. Interestingly, in one HPE family, a deleterious FGFR1 allele was transmitted from one parent and a loss-of-function allele in FGF8 from the other parent to both affected daughters. This family is one of the clearest examples to date of gene:gene synergistic interactions causing HPE in humans.

Newborn screening in southeastern Europe.

The aim of our study was to assess the current state of newborn screening (NBS) in the region of southeastern Europe, as an example of a developing region, focusing also on future plans. Responses were obtained from 11 countries. Phenylketonuria screening was not introduced in four of 11 countries, while congenital hypothyroidism screening was not introduced in three of them; extended NBS programs were non-existent. The primary challenges were identified. Implementation of NBS to developing countries worldwide should be considered as a priority.

Health-related quality of life and metabolic control in children with type 1 diabetes mellitus in Bosnia and Herzegovina.

The primary objective of the study was to examine the relationship between generic and disease-specific HRQOL scores and metabolic control in children with Type 1 Diabetes Mellitus (T1DM). This cross-sectional study included 65 consecutive children between ages 5 and 18 years with T1DM. According to their values of glycosylated hemoglobin (HbA(1C)), the children were assigned to one of two groups. In Group 1 (N = 21) were the children with HbA(1C) values < 8% (good to moderate metabolic control) and Group 2 (N = 44) were children with > 8% (poor metabolic control). To evaluate generic and disease-specific HRQOL scores in children with T1DM in relation to metabolic control, we used the PedsQL 4.0 Generic Core Scales and the PedsQL 3.0 Diabetes Module. The patients in Group 1, by pediatric patient self-report and parent proxy-report, had statistically better disease-specific HRQOL scores on the diabetes symptoms, treatment barriers, treatment adherence and worry domains in comparison with Group 2. We also found significant correlations between the total generic HRQOL scores and HbA(1C) for both parent proxy-reports' Spearman's coefficient of rank correlation rho = -0.257; p = 0.0412 and pediatric patients' Spearman's coefficient of rank correlation rho = -0.269; p = 0.0313. The current findings suggest that poor glycemic control in children with T1DM is associated with lower generic and disease-specific HRQOL scores in developing and transitional countries.

Current Status of Newborn Screening in Southeastern Europe.

Significant part of Southeastern Europe (with a population of 76 million) has newborn screening (NBS) programs non-harmonized with developed European countries. Initial survey was conducted in 2013/2014 among 11 countries from the region (Albania, Bulgaria, Bosnia and Herzegovina (BIH), Croatia, Kosovo, Macedonia, Moldova, Montenegro, Romania, Serbia, and Slovenia) to assess the main characteristics of their NBS programs and their future plans. Their cumulative population at that time was ~52,5 million. At that time, none of the countries had an expanded NBS program, while phenylketonuria screening was not introduced in four and congenital hypothyroidism in three of 11 countries. We repeated the survey in 2020 inviting the same 11 countries, adding Cyprus, Greece, Hungary, and Malta (due to their geographical position in the wider region). The aims were to assess the current state, to evaluate the change in the period, and to identify the main obstacles impacting the implementation of expanded NBS and/or reaching a wider population. Responses were collected from 12 countries (BIH-Federation of BIH, BIH-Republic of Srpska, Bulgaria, Croatia, Greece, Hungary, Kosovo, North Macedonia, Malta, Montenegro, Romania, Serbia, Slovenia) with a population of 68.5 million. The results of the survey showed that the regional situation regarding NBS only modestly improved in this period. All of the surveyed countries except Kosovo screened for at least congenital hypothyroidism, while phenylketonuria was not screened in four of 12 countries. Croatia and Slovenia implemented an expanded NBS program using tandem mass spectrometry from the time of last survey. In conclusion, the current status of NBS programs in Southeastern Europe is very variable and is still underdeveloped (or even non-existent) in some of the countries. We suggest establishing an international task-force to assist with implementation and harmonization of basic NBS services where needed.

Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010.

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together.

A novel CLCN5 mutation in a boy with Bartter-like syndrome and partial growth hormone deficiency.

Dent disease is an X-linked recessive disorder affecting the proximal tubule and is characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis/nephrolithiasis with a variable number of features of Fanconi syndrome. It is most often associated with mutations in CLCN5, which encodes the endosomal electrogenic chloride/proton exchanger ClC-5. Renal acidification abnormalities are only rarely seen in Dent disease, whereas the hypokalemic metabolic alkalosis associated with hyperreninemic hyperaldosteronism (Bartter-like syndrome) has been reported in only one patient so far. We report on a 5-year-old boy with Dent disease caused by mutation in CLCN5 gene, c.1073G>A, who presented with hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism persisting over the entire follow-up. No mutations were found in NKCC2, ROMK, NCCT, or ClC-Kb genes. In addition, the patient exhibited growth failure associated with partial growth hormone (GH) deficiency. Coexistence of Bartter-like syndrome features with LMWP should prompt a clinician to search for Dent disease. The Bartter syndrome phenotype seen in Dent disease patients may represent a distinct form of Bartter syndrome, the exact mechanism of which has yet to be fully elucidated. Growth delay that persists in spite of appropriate therapy should raise suspicion of other causes, such as GH deficiency.

Glycemic control in diabetic children: role of mother's knowledge and socioeconomic status.

The aim of this study is to investigate the role of mother's knowledge and socioeconomic status (SES) of the family on glycemic control in diabetic children. Our sample was taken from successive admissions to the outpatient's diabetes clinics in Tuzla, Bosnia and Herzegovina. Diabetes knowledge was assessed using the Michigan Diabetes Research and Training Center Diabetes Knowledge Test. Glycemic control was assessed by glycosylated hemoglobin (HbA(1C)). The mother's demographics were obtained by self-report. To categorize families' SES, parents' level of education, and current employment were recorded and analyzed using the Hollingshed two-factor index of social position. As expected, higher mother's knowledge was significantly associated with lower HbA(1C) (r = -0.2861705, p = 0.0442). Also, a significant correlation was found between the families' SES and HbA(1C) levels (r = 0.4401921; p = 0.0015). Mothers with more knowledge have children with better metabolic control, and low SES is significantly associated with higher levels of HbA1c. Improvement of mothers' knowledge and family SES may improve glycemic control and ultimately decrease acute and chronic complications of diabetes in children.

Neonatal screening for congenital hypothyroidism in the Federation of Bosnia and Herzegovina: eight years' experience.

This report demonstrates the prevalence of primary congenital hypothyroidism (CH) in the Federation of Bosnia and Herzegovina and summarizes the laboratory data. Neonatal thyroid-stimulating hormone (TSH) was measured in whole blood drawn between the 3rd and 5th days of life and spotted on filter paper using the fluorometric assay. Among the 87,061 neonates, 22 had CH, 13 dysgenetic forms, and nine with thyroids in situ. No differences were found between the two types in terms of TSH and total T4 concentrations. However, thyroglobulin was significantly lower in patients with dysgenetic thyroid tissue (p=0.0023). We conclude that the prevalence of CH in the Federation of Bosnia and Herzegovina is 1:3,957 newborns.

Untreated congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) is an inherited metabolic disease caused by the deficiency of one of the enzymes necessary for cortisol synthesis. With carefully supervised medical treatment, CAH patients have the capacity for normal puberty and fertility. We report on a 12.4-year-old female who, because of the early interruption of treatment, developed progressive virilization with reduced final height and altered psycho-social orientation to male. One of the reasons for interrupting replacement therapy in our case was the difficult social and economic status of the family, who lived for many years without basic medical care.

Clinical and molecular genetic findings in a 6-year-old Bosnian boy with triple A syndrome.

The triple A syndrome is a rare autosomal recessive disease that is characterised by the triad of adrenocorticotropin (ACTH)-resistant adrenal insufficiency, achalasia and alacrima. In most patients, neurological and dermatological abnormalities are associated features. We report on the first Bosnian patient with triple A syndrome. Endocrine investigation confirmed primary adrenal insufficiency at the age of 5.8 years. Two months later, achalasia was diagnosed, and in the presence of alacrima, the patient satisfies the diagnostic criteria of triple A syndrome. In addition, a large number of associated neurological and dermatological features were present in this patient. Moreover, he has dysmorphic facial features, which have not been previously described in triple A syndrome. Triple A syndrome was confirmed by molecular analysis, revealing a nonsense mutation p.W84X in the AAAS gene. The parents are both heterozygous carriers of the mutation. The affected twin brother unfortunately died from hypoglycaemic shock, despite a normal cortisol rise in an ACTH stimulation test. Further, triple A syndrome patients carrying the identical homozygous p.W84X mutation have to be studied to assess a genotype-phenotype relationship for this mutation.

Maternal and neonatal urinary iodine excretion and neonatal TSH in relation to use of antiseptic during caesarean section in an iodine sufficient area.

AIM: To evaluate the influence of topical iodine-containing antiseptics on neonatal TSH in full-term infants born by Caesarean section in an iodine sufficient area. POPULATION AND METHODS: Urinary iodide excretion (UIE) was estimated in 86 mothers on the second day after delivery by Caesarean section and their 86 full-term neonates. The mothers were divided into two groups according to the use of antiseptic to prepare Cesarean sections: 42 mothers who were prepared with povidone-iodine (Isosept, Bosnalijek) comprised the study group, and 47 mothers who were prepared with alcoholic solution (Skinsept color, Ecolab) formed the control group. Neonatal TSH was measured in whole blood drawn between day 3 and 5 of life, spotted on filter paper using a sensitive fluorometric assay (Delfia). RESULTS: Maternal and neonatal UIE were significantly higher (p < 0.05) in the study group compared to the control group. No significant difference was found for neonatal TSH. CONCLUSION: Our data suggest that perinatal iodine exposure of full-term neonates who were born by Caesarean section in an iodine sufficient area did not influence neonatal TSH, although median UIE was higher, suggesting optimal iodine intake during pregnancy. Further research is needed to define a critical value of urinary iodine concentrations in full-term neonates in an iodine sufficient area that may lead to the impairment of thyroid function.

Iodine nutrition status of pregnant women in an iodine-sufficient area.

BACKGROUND: Iodine is necessary for the synthesis of thyroid hormones, which play a decisive role in the development of the brain during fetal and early postnatal life. OBJECTIVE: To evaluate whether prophylaxis with 20 to 30 mg of iodine per kilogram of salt is enough to ensure optimal iodine nutrition during pregnancy in an iodine-sufficient area. METHODS: A cross-sectional study of pregnant women was conducted in 2007. The urinary iodine concentration (UIC) was measured in 300 randomly selected women in Tuzla, Bosnia, and Herzegovina, in all three trimesters of pregnancy. RESULTS: The median UIC of the pregnant women was 142 microg/L, ranging from 27 to 1,080 microg/L. The median UIC of the pregnant women in each trimester of pregnancy who were not restricting their salt intake was consistent with adequate iodine nutrition, as defined by the World Health Organization Technical Consultation, whereas the median UIC of women who were restricting their salt intake was insufficient. CONCLUSIONS: Pregnant women in the urban area of Tuzla had adequate iodine status except for those with restricted salt intake, which presents an increased risk to the mother as well to as the unborn child. Women in the rural area of Tuzla were found to be iodine-deficient, regardless of whether they had restricted their salt intake or not. However, for those pregnant women who have been advised to restrict their salt intake and who thus face the risk of iodine deficiency, the use of salt with higher concentrations of iodine could be advised.

High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis.

OBJECTIVE: Thyroid dyshormonogenesis is a genetically heterogeneous group of inherited disorders in the enzymatic cascade of thyroid hormone synthesis that result in congenital hypothyroidism (CH). Thyroid peroxidase gene (TPO) mutations are one of the most common causes of thyroid dyshormonogenesis. The aim of this study was to identify TPO gene defects in a cohort of patients with thyroid dyshormonogenesis from Slovenia, Bosnia, and Slovakia. DESIGN AND METHODS: Forty-three patients with permanent CH and orthoptic thyroid glands from 39 unrelated families participated in the study. Mutational analysis of the TPO gene and part of its promoter consisted of single-stranded conformation polymorphism analysis, sequencing, and restriction fragment length polymorphism (RFLP) analysis. RESULTS: TPO gene mutations were identified in 46% of participants. Seven different mutations were identified, four mutations of these being novel, namely 613C > T (R175X), 1519_1539del (A477_N483del), 2089G > A (G667S), and 2669G > A (G860R). Only a single allele mutation was identified in 65% of the TPO mutation carriers. CONCLUSIONS: The results showed a higher prevalence of TPO gene mutations in thyroid dyshormonogenesis when compared with published studies. The high percentage of single allele mutations implied possible intronic or regulatory TPO gene mutations or monoallelic expression.

[Clinical and laboratory characteristics at onset of type 1 diabetes mellitus in children]. / Klinicke i laboratorijske odlike dijabetesa tipa 1 u djece u vrijeme postavljanja dijagnoze.

The aim was to describe the clinical and laboratory characteristics of diabetes mellitus type 1 at its onset. The hospital records at Tuzla pediatric hospital were analysed of 109 children aged 0-14 who presented with diabetes between 1990 and 2005. The data base was divided into three age groups: 0-4.9, 5-9.9 and 10-14 years - referred to hereafter as the younger, middle and older age groups. We found the duration of symptoms prior to diagnosis to be significantly shortest in the younger age group. Polyuria, polydipsia and weight loss were the main presenting symptoms in all age groups. The median blood glucose value was 26.0 mmol/L and the pH value was 7.30. The incidence of diabetic ketoacidosis of 48.0% and the median HbA 1c value of 10.7% at diagnosis indicate that disease was not recognised long before diagnosis. Since our desire is to avoid the development of ketoacidosis, it is necessary to educate people who are in permanent contact with children about the symptoms of diabetes type 1. This could to a certain degree prevent the presentation of the life-threatening condition of diabetic ketoacidosis, if the occurrence of diabetes cannot be prevented.

Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism.

The cyclic adenosine monophosphate (cAMP) intracellular signaling pathway mediates the physiological effects of several hormones and neurotransmitters, acting by the activation of G-protein coupled receptors (GPCRs) and several downstream intracellular effectors, including the heterotrimeric stimulatory G-protein (Gs), the cAMP-dependent protein kinase A (PKA), and cAMP-specific phosphodiesterases (PDEs). Defective G-protein-mediated signaling has been associated with an increasing number of disorders, including Albright hereditary osteodistrophy (AHO) and pseudohypoparathyroidism (PHP), a heterogeneous group of rare genetic metabolic disorders resulting from molecular defects at the GNAS locus. Moreover, mutations in PRKAR1A and PDE4D genes have been recently detected in patients with acrodysostosis (ACRDYS), showing a skeletal and endocrinological phenotype partially overlapping with AHO/PHP. Despite the high detection rate of molecular defects by currently available molecular approaches, about 30% of AHO/PHP patients still lack a molecular diagnosis, hence the need to screen patients negative for GNAS epi/genetic defects also for chromosomal regions and genes associated with diseases that undergo differential diagnosis with PHP. According to the growing knowledge on Gsα-cAMP signaling-linked disorders, we investigated our series of patients (n = 81) with a clinical diagnosis of PHP/AHO but negative for GNAS anomalies for the presence of novel genetic variants at PRKAR1A and PDE4D genes. Our work allowed the detection of 8 novel missense variants affecting genes so far associated with ACRDYS in 9 patients. Our data further confirm the molecular and clinical overlap among these disorders. We present the data collected from a large series of patients and a brief review of the literature in order to compare our findings with already published data; to look for PRKAR1A/PDE4D mutation spectrum, recurrent mutations, and mutation hot spots; and to identify specific clinical features associated with ACRDYS that deserve surveillance during follow-up. © 2016 American Society for Bone and Mineral Research.

Clinical presentation of primary congenital hypothyroidism: experience before mass screening.

Primary congenital hypothyroidism is a common preventable cause of mental retardation. Neonatal thyroid screening is highly successful in early diagnosis and the improvement of developmental prognosis in the hypothyroid neonate. However, rarely cases could be missed, so doctors must be aware of the earl symptoms and signs of hypothyroidism. Therefore, the purpose of this study was to emphasize the presenting clinical features of primary congenital hypothyroidism at the age of diagnosis. The study population included 17 children with primary congenital hypothyroidism who attended the Department of Pediatrics, University Clinical Center Tuzla between 1986 and 1999. The diagnosis of all patients was confirmed by serum thyroid function tests (T4 and TSH). Of the 17 patients 10 (58.8%) were diagnosed in the first three months of life and 3 of them (17.6%) between fourth and sixth month of life. Four children (23.5%) were diagnosed after the age of six months. In the first three months of life hypothermia, constipation, jaundice, poor feeding, hoarse cry, macroglossia and hypoactivity were the moste common symptoms. Among the 17 patients with primary congenital hypothyroidism 5 of them (29.4 %) were diagnosed to have disgenetic thyroid tissue and 12 (70.6%) as having dyshormonogenesis. TSH and T4 levels were higher in patients in whom thyroid tissue was dysgenetic as comapared with those with dyshormonogenesis but the difference was not statistically significant (p > 0.05). Now it is expected that neonatal screening program in Bosnia and Herzegovina Federation will contribute to the detection of primary congenital hypothyroidism in early days of life. However, until an effective screening test is not yet routine in whole country, paediatricians should consider the diagnosis of hypothyroidism whenever it is clinically suggested.

Thyroid volume measurement by ultrasound in schoolchildren from mildly iodine-deficient area.

Thyroid size was estimated by ultrasound and physical examination in 480 schoolchildren (238 boys and 242 girls), 7-14 years old, living in Tuzla Canton. By physical examination goiter was found in 13.5% (n=65) of subjects. When compared with the upper limits of the reference thyroid volumes reported by WHO and ICCIDD, goiter by ultrasonography was found in 12.9% (n=62) of all subjects. All goitrous children had a diffuse goiter. The differences in mean thyroid volumes between groups with and without goiter detected by physical examination were significant in all age groups (p<0.05). The results of ultrasound examinations correlate well with palpatory findings and show higher values for the thyroid volume in children with goiter. It generally confirms the values of the findings by palpation, even in areas with mild iodine deficiency.

Effect of family disintegration on age at menarche.

OBJECTIVE: The aim of this study was to determine the effect of psychosocial factors on the age at menarche of girls in Federation of Bosnia and Herzegovina (FBH). SUBJECTS AND METHODS: A cross-sectional study was conducted from September 2002 to May 2003 in all Cantons of the FBH. The random stratified sample included 19.803 girls aged 9.0 to 17.5 years. Data were collected using the status quo method. Probit analysis was used to estimate median age at menarche and 95% confidence intervals. RESULTS: The present study shows that menarche occurred significantly earlier (p<0.05) in girls from dysfunctional families (median: 12.99 years, 95% confidence interval: 12.93-13.05) than in girls who grew up in intact families (median: 13.04 years, 95% confidence interval: 13.01-13.07). Analyzing separately the impact of each of family stressors on age at menarche, we found that menarcheal age was significantly lower in girls from single-mother families, whose parents are divorced, whose one parent is died and where alcoholism in family is present than in girls from intact families. Maturation was found to be earlier in girls from dysfunctional families then in those from intact families after the influence of place of residence and sibship size was eliminated. CONCLUSION: From our research we can conclude that the girls from dysfunctional families reached earlier age at menarche than their peers who grew up in normal families, and that this effect did not disappear after controlling for socioeconomic variables.