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

Impact of Lower Screening TSH Cutoff Level on the Increasing Prevalence of Congenital Hypothyroidism

Lower cutoff levels in screening programs have led to an increase in the proportion of detected cases of transient hypothyroidism, leading to an increase in the overall prevalence of primary congenital hypothyroidism (CH) in several countries. We have performed a retrospective evaluation on the data from 251,008 (96.72%) neonates screened for thyroid-stimulating hormone (TSH) level in dried blood spot specimens taken 48 h after birth, between 2002 and 2015, using the DELFIA method. A TSH value of 15 mIU/L whole blood was used as the cutoff point until 2010 and 10 mIU/L thereafter. Primary CH was detected in 127 newborns (1/1976) of which 81.1% had permanent and 18.9% had transient CH. The prevalence of primary CH increased from 1/2489 before 2010 to 1/1585 thereafter (p = 0.131). However, the prevalence of permanent CH increased only slightly (p = 0.922), while the transient CH prevalence showed an 8-fold increase after lowering the TSH cutoff level (p < 0.001). In cases of permanent CH, we observed a lower prevalence of thyroid dysgenesis (82.7% vs. 66.7%) and a higher prevalence of a normal in situ thyroid gland (17.3% vs. 33.3%), for the period with a lower TSH cutoff value. Our findings support the impact of a lower TSH cutoff on the increasing prevalence of congenital hypothyroidism

Testicular adrenal rest tumors in boys with 21-hydroxylase deficiency, timely diagnosis and follow-up

Background: Testicular adrenal rest tumors (TARTs) are found in 30–94% of adult males with congenital adrenal hyperplasia (CAH). We sought to explore TART appearance through yearly ultrasound examination of testes in young boys with CAH, and its association with metabolic control and genetic mutations. Methods: Twenty-five boys with 21-hydroxylase deficiency in the age group 4–18 years diagnosed during the period 2001–2016 were included in the study. ACTH, 17-hydroxyprogesterone, androstenedione and testosterone were measured at 4-month intervals. Growth and BMI were assessed at the time of evaluation. PCR/ACRS method was used for CYP21A2 gene analysis. Testicular ultrasound examination was performed yearly. Results: TARTs were detected by ultrasound in 8 children at the age of 6–16 years (13.2 years average). Five had salt-wasting form, two had simple virilizing form and one had non-classic form of CAH. Significant differences in the17OHP and androstenedione levels were detected between the boys, adherent and non-adherent to therapy. Inadequate metabolic control was not different in boys with and without TART (11/17 and 5/8 respectively). No significant difference was detected in the distribution of genetic mutations or adherence to therapy between patients with and without TARTs. One patient had a mutation not reported thus far in TART and another developed leukemia. Conclusion: TART is not rare in young boys with CAH, irrespective of the specific mutation or metabolic control. Ultrasound screening helps timely diagnosis and adjustment of therapy

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

Regional Variation in the Incidence of Congenital Hypothyroidism in Macedonia

The incidence of congenital hypothyroidism (CH) is increasing in different areas around the world. Potential causes include changes in population ethnic composition, environmental factors, changing screening program methodology and lowering of TSH cutoff levels. The incidence of CH in different regions of Macedonia has not been evaluated before. A total of 251,008 newborns from all eight regions in the country have been screened between 2002 and 2015, by measurement of the thyroid-stimulating hormone (TSH) from blood spots, sampled 48–72 h after birth, using the DELFIA assay. Overall CH incidence confirmed at birth was 1/1976. The highest CH incidence was observed in the Vardar region (1/970), while the Eastern region had the lowest incidence (1/4202; p=0.021). In the other regions, the following CH incidence was detected: Northeastern 1/1459, Pelagonia 1/1627, Polog 1/1444, Skopje 1/2430, Southwestern 1/3226, and Southeastern 1/1843. Interestingly, in the Vardar region, 4.44% of the screened newborns had a TSH concentration > 5 mIU/L, as an indicator of regional iodine deficiency, compared to the Eastern region where 1.66% of newborns had a TSH > 5 mIU/L. The higher CH incidence in some of the regions may be due to increasing exposure to environmental toxic agents and/or deficient iodine intake. Further research into the potential environmental determinants of increased CH risk is warranted

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