Prevalence of congenital hypothyroidism in North Macedonia: data from a newborn screening program conducted for twenty years.

BACKGROUND: Congenital hypothyroidism (CH) is a common endocrine disorder that can be treated if timely detected by newborn screening, optimizing the developmental outcome in affected children. In the present study, we analyze the data of the national newborn thyroid screening program in North Macedonia collected over twenty years, including the CH prevalence as well as its geographical and ethnic variations. METHODS: The thyroid-stimulating hormone (TSH) was measured on a filter paper blood spot sample using the DELFIA fluoroimmunometric assay. A TSH value of 15 mIU/L whole blood was used as the cutoff point until 2010 and 10 mIU/L thereafter. RESULTS: Out of 377,508 screened live births, a total of 226 newborns with primary CH were detected, providing an overall prevalence of 6.0 per 10,000. Lowering the TSH cutoff led to an apparently increased prevalence of the transient CH, from 0.2 to 2.4 per 10,000 live births (p < 0.0001) with an impact on the overall prevalence of primary CH (from 4.0 to 7.1 per 10,000, p=0.0001). Taking ethnicity into account, the significantly highest primary CH prevalence of 11.3 per 10,000 live births was observed among the Roma neonates, with a predominance of permanent CH (75.5%). There were also regional differences in the prevalence of primary CH. The highest primary CH prevalence of 11.7 per 10,000 live births was observed in the Vardar region, together with the highest regional prevalence of the transient CH (3.2 per 10,000). The highest prevalence of permanent CH was observed in the Pelagonia region (6.6 per 10,000) where the largest percentage of the Roma population lives. CONCLUSIONS: The overall CH prevalence is high in North Macedonia, with substantial ethnic and geographical variations. Further analysis to elucidate the causes for the significant variations in the CH prevalence including environmental factors is warranted.

Collodion phenotype remains a challenge for neonatologists: A rare case of self-healing collodion baby.

We report a unique case of self-healing collodion baby (CB) that was successfully managed despite the risk of potentially serious complications. Self-healing CB is a rare and distinct outcome of collodion phenotype occurring in approximately 10% of the cases. The outcome depends on the initial assessment and adequate multidisciplinary approach.

Neonatal lupus erythematosus-a rare syndrome of transient autoimmunity.

Neonatal lupus erythematosus (NLE) is a rare autoimmune disease due to a passive transfer of maternal autoantibodies to the fetus. The clinical spectrum is variable and includes skin lesions, cardiac, hematological, or hepatobiliary disorders. We report an NLE case presenting with skin eruption that was initially considered as tinea.

Thyroid function and dysfunction in preterm infants-Challenges in evaluation, diagnosis and therapy.

Thyroid hormone levels have a crucial role for optimal brain development from gestation through the first 2 postnatal years. However, thyroid hormones vary with gestational age, and their levels vary between term and preterm infants. Preterm newborns are prone to thyroid dysfunction which is now more frequently observed with the advances of neonatal care and improved survival of extremely premature infants. Thus, hypothyroxinaemia of prematurity associated with delayed TSH elevation is very common in low birth weight premature infants most likely due to the immaturity of the hypothalamic-pituitary thyroid axis. Furthermore, postnatal illness, medications and iodine status may contribute to the thyroid dysfunction or affect the interpretation of the thyroid function tests. Despite available guidelines, timing of screening and optimal treatment of thyroid dysfunction in premature infants remains controversial. Furthermore, it is unknown whether untreated thyroid dysfunction in premature babies affects neurodevelopmental outcome. In the vast majority of preterm infants, hypothyroxinaemia is transient; however, permanent hypothyroidism due to thyroid dysgenesis or enzyme defects might also occur. Therefore, careful monitoring of thyroid function and long-term follow-up is needed to assess an appropriate therapeutic approach. This article reviews thyroid physiology in preterm infants, the influences of gestation and other neonatal conditions on thyroid function tests, optimal timing of screening and possible predictors to differentiate transient hypothyroxinaemia from permanent hypothyroidism.

A novel 9 bp deletion (c.1271_1279delGTGCCCGCG) in exon 10 of CYP21A2 gene causing severe congenital adrenal hyperplasia.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of adrenal steroidogenesis with a broad spectrum of clinical presentations, ranging from the severe classical salt-wasting (SW) and simple-virilizing (SV) form, to the mild nonclassical form. A large variety of CYP21A2 genotypes in correlation with phenotype have been described. MATERIALS AND METHODS: DNA samples from a 14-day-old male newborn with clinical and laboratory signs of SW CAH and family members were subjected for molecular analysis of the nine most common point CYP21A2 mutations by ACRS/PCR method. Direct DNA sequencing of the whole CYP21A2 gene was performed to detect the second mutant allele in the patient. The in silico predicting analysis and the crystal structure analysis of the mutated CYP21A2 protein have been performed. RESULTS: Molecular analysis confirmed that the patient was compound heterozygote carrying p.Q318X mutation inherited from the mother and a novel c.1271_1279delGTGCCCGCG (p.G424_R426del) variant in exon 10 inherited from the father. The in silico predicting software tools classified the novel mutation as pathogenic. Crystal structure analysis showed that the three residues affected by the novel in-frame deletion form several hydrogen bonds that could lead to impaired stability and function of the CYP21A2 protein. These findings were concordant with the patient's phenotype. The need of several molecular methods to elucidate the genotype in this patient has also been discussed. CONCLUSIONS: A novel 9 bp deletion in CYP21A2 gene with predicted pathogenic effect on the enzyme activity was detected in neonatal patient causing severe SW CAH.

Genetics of Gland-in-situ or Hypoplastic Congenital Hypothyroidism in Macedonia.

Neonatal screening in Macedonia detects congenital hypothyroidism (CH) with an incidence of 1 in 1,585, and more than 50% of cases exhibit a normally located gland-in-situ (GIS). Monogenic mutations causing dyshormonogenesis may underlie GIS CH; additionally, a small proportion of thyroid hypoplasia has a monogenic cause, such as TSHR and PAX8 defects. The genetic architecture of Macedonian CH cases has not previously been studied. We recruited screening-detected, non-syndromic GIS CH or thyroid hypoplasia cases (n = 40) exhibiting a spectrum of biochemical thyroid dysfunction ranging from severe permanent to mild transient CH and including 11 familial cases. Cases were born at term, with birth weight >3,000 g, and thyroid morphologies included goiter (n = 11), thyroid hypoplasia (n = 6), and apparently normal-sized thyroid. A comprehensive, phenotype-driven, Sanger sequencing approach was used to identify genetic mutations underlying CH, by sequentially screening known dyshormonogenesis-associated genes and TSHR in GIS cases and TSHR and PAX8 in cases with thyroid hypoplasia. Potentially pathogenic variants were identified in 14 cases, of which four were definitively causative; we also detected digenic variants in three cases. Seventeen variants (nine novel) were identified in TPO (n = 4), TG (n = 3), TSHR (n = 4), DUOX2 (n = 4), and PAX8 (n = 2). No mutations were detected in DUOXA2, NIS, IYD, and SLC26A7. The relatively low mutation frequency suggests that factors other than recognized monogenic causes (oligogenic variants, environmental factors, or novel genes) may contribute to GIS CH in this region. Future non-hypothesis-driven, next-generation sequencing studies are required to confirm these findings.

Diagnostic re-evaluation of congenital hypothyroidism in Macedonia: predictors for transient or permanent hypothyroidism.

BACKGROUND: Diagnostic re-evaluation is important for all patients with congenital hypothyroidism (CH) for determining the etiology and identifying transient CH cases. Our study is a first thyroxine therapy withdrawal study conducted in Macedonian CH patients for a diagnostic re-evaluation. We aimed to evaluate the etiology of CH, the prevalence of transient CH and identify predictive factors for distinguishing between permanent (PCH) and transient CH (TCH). MATERIALS AND METHODS: Patients with CH aged >3 years underwent a trial of treatment withdrawal for 4 weeks period. Thyroid function testing (TFT), ultrasound and Technetium-99m pertechnetate thyroid scan were performed thereafter. TCH was defined when TFT remained within normal limits for at least 6-month follow-up. PCH was diagnosed when TFT was abnormal and classified according the imaging findings. RESULTS: 42 (55%) patients had PCH and 34 (45.0%) patients had TCH. Thyroid agenesia was the most prevalent form in the PCH group. Patients with TCH had lower initial thyroid-stimulating hormone (TSH) values (P < 0.0001); higher serum thyroxine levels (P = 0.0023) and lower mean doses of levothyroxine during treatment period (P < 0.0001) than patients with PCH. Initial TSH level <30.5 IU/mL and levothyroxine dose at 3 years of age <2.6 mg/kg/day were a significant predictive factors for TCH; sensitivity 92% and 100%, specificity 75.6% and 76%, respectively. CONCLUSION: TCH presents a significant portion of patients with CH. Initial TSH value and levothyroxine dose during treatment period has a predictive role in differentiating TCH from PCH. Earlier re-evaluation, between 2 and 3 years age might be considered in some patients requiring low doses of levothyroxine.

Prevalence of Functional Gastrointestinal Disorders in Children and Adolescents in the Mediterranean Region of Europe.

BACKGROUND & AIMS: Little is known about the prevalence of functional gastrointestinal disorders (FGIDs) in children from the Mediterranean area of Europe. We aimed to assess the prevalence of FGIDs in children and adolescents in this region. METHODS: We collected data on 13,750 children (4-18 years old) enrolled in the Mediterranean-European Area Project, a school-based health study performed in Croatia, Greece, Israel, Italy, Jordan, Lebanon, Macedonia, Serbia, and Spain. Data were collected from March to June and in September of 2016. We analyzed data from 6602 students 4 to 10 years old (group A; mean age, 7.7 ± 1.9 y), and 7148 subjects 11 to 18 years old (group B; mean age, 13.8 ± 2.1 y). Children with FGIDs were identified based on answers to questionnaires on pediatric gastrointestinal symptoms, selected based on Rome III criteria. RESULTS: In group A, the prevalence of FGIDs was 20.7%. The most frequent disorders were functional constipation (11.7%), irritable bowel syndrome (IBS, 4%), aerophagia (3.5%), and abdominal migraine (3.1%). The prevalence of abdominal migraine was significantly higher in girls than in boys (P = .007). In group B, the overall prevalence of FGIDs was 26.6%. The most frequent disorders were functional constipation (13.1%), abdominal migraine (7.8%), aerophagia (6.3%), and IBS (5.6%). In group B, FGIDs had a higher prevalence among girls than boys (P < .001). In both groups, we found significant differences in the prevalence of specific disorders among specific countries. CONCLUSIONS: In an analysis of data on children 4 to 18 years old from the Mediterranean-European Area Project, we found FGIDs to be more frequent in girls. Functional constipation, aerophagia, abdominal migraine, and IBS are the most common disorders. However, the prevalence of FGIDs varies significantly among countries.

Submental thyroid ectopy might cause subclinical hypothyroidism in early childhood.

OBJECTIVE: Thyroid ectopy is a rare condition resulting from abnormal embryologic development and migration of the gland. Sublingual is the most common thyroid ectopy; all other ectopic thyroid locations occur very rare. There are no reports in the literature that describe the clinical course of patients with congenital hypothyroidism due to thyroid ectopy. METHODS AND RESULTS: We present a child with congenital hypothyroidism detected on neonatal screening which had a subclinical course during follow-up. Scintigraphy revealed submental thyroid ectopy, a rare ectopic location and no orthotopic thyroid gland. CONCLUSION: Our case is unique because of the rare ectopic thyroid location but also of the unexpected clinical course; however, further thyroid monitoring is required for the therapy adjustment and detection of any changes in the ectopic tissue.

Vesicoureteral Reflux Detected with (99m)Tc-DTPA Renal Scintigraphy during Evaluation of Renal Function.

BACKGROUND: Radionuclide techniques, as direct radionuclide cystography and (99m)Tc-DMSA scintigraphy, have been used in evaluation of vesicoureteral reflux (VUR) and reflux nephropathy (RN) in children. Dynamic (99m)Tc-DTPA scintigraphy is reserved for evaluation of differential renal function and obstruction in children, where hydronephrosis is detected by ultrasonography (US) pre- or postnatally. CASE REPORT: Six year old boy was prenatally diagnosed with bilateral hydronephrosis. Postnatal, severe bilateral VUR was detected by voiding urethrocytography. US and (99m)Tc-DTPA scintigraphy performed in the first month of life showed small left kidney that participated with 2% in the global renal function. Bilateral cutaneous ureterostomy has been performed in order to obtain good renal drainage and promote optimal renal growth. Twelve months later, classic antireflux procedure was done. Control (99m)Tc-DTPA scintigraphy, 5 ys after antireflux surgery, revealed persisting radioactivity during the diuretic phase, in the left kidney that indicated antireflux procedure failure with VUR reappearance. CONCLUSION: (99m)Tc-DTPA scintigraphy is the first method of choice for long-term monitoring of individual kidney function in children with VUR and other congenital urinary tract anomalies. Additionally, it can be used as indirect radionuclide cystography when rising of radioactivity in the kidney region, during the diuretic phase can indicate presence of VUR.

Frequency of thyroid status monitoring in the first year of life and predictors for more frequent monitoring in infants with congenital hypothyroidism.

BACKGROUND: The essential role of thyroid hormones for normal brain development during a critical period of life is well established. Neonatal screening programs for congenital hypothyroidism (CH) enable early detection of patients and attainment of euthyroid status as quickly as possible. Adequate and accurate monitoring of thyroid function is necessary. In the study we aimed to determine the periodicity of thyroid function testing in the first year of life (3-month intervals versus <3-month intervals monitoring). METHODS: We retrospectively analyzed charts of CH children from Macedonia detected on neonatal screening during a 3-year period (2011-2014). Needs for monthly thyroid monitoring were defined according to the recommendations: a dose change within a month of a previous control, values of T4/FT4 not in the upper half of the reference range, and a high or very low thyroid-stimulating hormone (TSH) value. RESULTS: Monthly thyroid testing was indicated in more than a third of CH patients during the first year of life. Children who needed more frequent monitoring intervals had a higher initial value of TSH (p=0.032) and a lower value of T4 (p=0.038) than those requiring less frequent monitoring. The sex, birth weight, age of treatment onset, initial L-thyroxine dose, and L-thyroxine dose at 1-year of age in our study were not predictive factors for more frequent thyroid monitoring. CONCLUSIONS: Children with severe hypothyroidism at birth are potential candidates for more frequent thyroid monitoring during the first year of life, although the individual patient approach should not be avoided as variations in TSH values are very common.

Diagnostic approach in children with unusual symptoms of acquired hypothyroidism. When to look for pituitary hyperplasia?

BACKGROUND: Pituitary hyperplasia secondary to primary longstanding hypothyroidism has been reported in the literature in adults and rarely in children. METHODS: Here we present the clinical presentation and diagnostic procedures in eight children with pituitary hyperplasia due to autoimmune thyroiditis, highlighting common findings, such as growth delay, fatigue or gaining weight, but also exceptional findings such as pericardial effusion, rhabdomyolysis, isolated hypertrichosis, and Van Wyk-Grumbach syndrome, which have rarely or never been described. RESULTS AND CONCLUSIONS: Surprisingly no thyroid enlargement was detected. We discuss the unusual presenting signs of autoimmune thyroiditis that should raise the suspicion of pituitary hyperplasia. We suggest that a more elaborate clinical assessment and even modification of the diagnostic approach to autoimmune thyroiditis is needed in order to avoid its serious complications.

Evaluation of Neonatal Hemolytic Jaundice: Clinical and Laboratory Parameters.

BACKGROUND: Neonatal jaundice that occurs in ABO or Rhesus issoimunisation has been recognized as one of the major risk factors for development of severe hyperbilirubinemia and bilirubin neurotoxicity. AIM: Aim of our study was to investigate clinical and laboratory parameters associated with hemolytic jaundice due to Rh and ABO incompatibility and compare results with the group of unspecific jaundice. MATERIAL AND METHODS: One hundred sixty seven (167) neonatal hyperbilirubinemia cases were included in the study, 24.6% of which presented with ABO/Rhesus type hemolytic jaundice, and the rest with unspecific jaundice. Evaluation included: blood count, reticulocites, serum bilirubin, aminotransferases, blood grouping, and Coombs test, also the day of bilirubin peak, duration of the hyperbilirubinemia, and additional bilirubin measurements. RESULTS: We showed significantly lower mean values of hemoglobin, erythrocytes and hematocrit and significantly higher values of reticulocytes in the group of ABO/Rh incompatibility compared to the group of jaundice of unspecific etiology; also an earlier presentation and a higher-grade jaundice in this group. CONCLUSIONS: The laboratory profile in ABO/Rh isoimmunisation cases depicts hemolytic mechanism of jaundice. These cases carry a significant risk for early and severe hyperbilirubinemia and are eligible for neurodevelopmental follow-up. Hematological parameters and blood grouping are simple diagnostic methods that assist the etiological diagnosis of neonatal hyperbilirubinemia.

Unique concurrent appearance of two rare conditions in a young girl: central precocious puberty due to hypothalamic hamartoma and uncommon type of diabetes.

Hypothalamic hamartomas (HH) are rare congenital nonneoplastic lesions of the tuber cinereum, which usually present as precocious puberty of central origin in young girls and respond well to treatment with long acting gonadotropin releasing hormone (GnRH) analogs. No association of this condition with diabetes mellitus of any form has been reported so far. On the other hand, diabetes mellitus in children and adolescents, when it is not autoimmune type 1 diabetes, is difficult to classify. We present a girl with early onset of central precocious puberty at the age of 8 months, due to hypothalamic hamartoma. Treatment with depot of a GnRH analog for a period of 9 years and 8 months was successful, and her puberty continued 6 months after the discontinuation of triptorelin. At the age of 9 years 6 months, the girl presented with diabetes. She was negative for islet, GAD and IA2 antibodies and her insulinemia and C-peptide remained within normal limits during the 2 years of follow-up. Her metabolic control is excellent with a combination of metformin and a low-dose of mixed insulin. To our knowledge, this is the first description of the simultaneous appearance of these two endocrinological conditions.

Coagulopathy as initial manifestation of concomitant celiac disease and cystic fibrosis: a case report.

INTRODUCTION: Celiac disease and cystic fibrosis have many common manifestations, such as malabsorption, steatorrhea and growth failure, and were for many years recognized as one clinical entity. Since their recognition as two separate diseases, their co-existence in a patient has been described sporadically; around 20 cases have been described in the literature. Taking into consideration the incidences of the two diseases, the chance of them occurring together is one in 2,000,000 in the general population. CASE PRESENTATION: We describe the case of a five-year-old boy of Turkish ethnicity with both celiac disease and cystic fibrosis, who presented initially with a skin hemorrhage. The diagnosis of celiac disease was made with a positive serum anti-tissue transglutaminase antibody test and the presence of HLA-DQ2 heterodimer, and confirmed on histology with small intestinal villous atrophy. A positive sweat test confirmed the diagnosis of associated cystic fibrosis.To the best of our knowledge there has been no previous report of this rare presentation of associated celiac disease and cystic fibrosis. CONCLUSION: The clinical significance of this case is the consideration of malabsorption with both celiac disease and cystic fibrosis in patients who present with unexplained coagulopathy.