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 (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.

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.

Objective - We aim to emphasize the importance of extensive endocrine workup in cases of pituitary masses. Case report - We report on a case of pituitary thyrotrophic hyperplasia in a 12-year-old girl who was thought to have a pituitary macroadenoma with suprasellar extension. The main complaint was headache, while other symptoms of hypothyroidism were present, but weren't recognised. Hormonal testing revealed low total thyroxine (<12.8 nmol/l) and high TSH (310.5 mIU/l) levels, and hyperprolactinemia (prolactin level at 1680 mIU/l). Based on the clinical history, laboratory data, and MRI, a diagnosis of pituitary hyperplasia secondary to primary hypothyroidism, consequent to chronic autoimmune thyroiditis, was made. Therapy with levothyroxine was initiated at 50 I¼g/day and gradually increased to 75 I¼g daily. After three months of thyroxine replacement, she was clinically and biochemically euthyroid. A follow-up MRI, 4 months after thyroxine replacement was initiated, showed complete resolution of the mass, and normal pituitary gland. Conclusion - Primary hypothyroidism should be considered in the differential diagnosis of pituitary masses. Multidisciplinary assessment in these cases will help to avoid delays in diagnosis and prevent unnecessary surgery.

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.

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.

This is a brief review of the hyperphenylalaninemia and their classifi cation. The classical phenylketonuria is described in some details, along with procedures for treatment and follow up of patients. The other forms of hyperphenylalaninemia are briefl y reviewed, with some more details of the form due to tetrahydrobiopterin defi ciency. In addition, the procedures for the analysis of the results of neonatal screening for phenylketonuria are delineated.

AIM This study was to evaluate the impact of the family socioeconomic status (SES) on health-related quality of life (HRQOL) in children with type 1 diabetes mellitus (T1DM). METHODS The cross-sectional study included 65 consecutive children T1DM between ages 5 and 18 years and their mothers. The control group was formed by random selection by matching each patient with one or two healthy control subjects. To evaluate generic HRQOL in children with T1DM we used the PedsQL™ 4.0 Generic Core Scales which include both a parent proxy-report and a child self-report with age-appropriate versions. To categorize the families' SES, the parents' education level and current employment were recorded and analyzed using the Hollingshed two-factor index of social position. None of the diabetic children in the sample came from families of upper social classes, so we categorized our diabetic children into the lower and middle social classes. RESULTS Physical health (P=0.02), social functioning (P=0.04), and school activities (P=0.0003) were lower in T1DM children with middle SES families than in controls from middle SES families. Parental reports revealed statistically significantly poorer HRQOL in children from low SES families in total scale score (P=0.005) and in terms of physical (P=0.0126), and psychosocial health (P=0.0246) as compared with the control group with lower SES. Also the parental proxy reports for middle scores of family SES were statistical significantly lower in the total score (P=0.0001), psychosocial health (P=0.0001), emotional functioning (P=0.0006), and school functioning (P=0.0001) compared with the middle group of the control. CONCLUSION The current findings suggest that low and middle SES of families in children with T1DM is associated with lower generic HRQOL as compared to control children with similar SES of families.

No abstract available.