Phenotype variability and different genotype of four patients with thyroid hormone resistance syndrome due to variants in the THRB gene.

BACKGROUND:   Resistance to thyroid hormone (RTH) is a rare dominantly inherited disorder mainly due to variants in the THRB gene leading to decreased end-organ responsiveness to thyroid hormones. CASE REPORT: Clinical and molecular characteristics of four patients with RTH are described. Four patients with various phenotypes were studied; two prepubertal boys and two adults (one male and one female). Sequencing analysis of the THRB was performed. All individuals had persistently elevated free thyroxine and/or free triiodothyronine associated with non-suppressed thyroid-stimulating hormone (TSH), and all had non-autoimmune goiters of various sizes. In both adults, antithyroid drugs were previously administered without successful suppression of the thyroid hormones. The 27-year-old female had resting tachycardia as the only symptom. The 35-year-old male had a degree of cognitive impairment and was initially diagnosed with atrial fibrillation. The eight-year-old boy was diagnosed with attention deficit disorder and had resting tachycardia. The oldest boy (age nine years) underwent thyroid function tests as a part of the investigation for obesity and learning difficulties. Direct sequencing analysis of the THRB gene showed three previously reported variants: p.His435Leu (c.1304A>T) in the 35-year-old male, p.Pro453Thr (c.1357C>A) in the oldest boy, and p.Arg438Cys (c.1312C>T) variant in the other two patients. CONCLUSIONS: Various phenotypes characterize common variants in the THRB gene, asymptomatic, thyroid hormone deprivation symptoms, or thyroid hormone excess symptoms. RTH should be suspected in both adults and children with elevated thyroid hormones and not suppressed TSH. A prompt molecular diagnosis and genetic counseling could prevent unnecessary tests and inappropriate treatments. HIPPOKRATIA 2019, 23(3): 135-139.

Genetic defects of the CYP21A2 gene in girls with premature adrenarche.

OBJECTIVES: To seek evidence on the prevalence of CYP21A2 genetic defects and consequences in girls with premature adrenarche (PA). METHODS: The study included 59 girls diagnosed with PA. Direct DNA sequencing and MLPA analysis were performed to identify mutations in CYP21A2 gene. RESULTS: Twelve girls were diagnosed with non-classic congenital adrenal hyperplasia (NC-CAH) based on stimulated 17-hydroxyprogesterone (17-OHP) levels and the presence of two mutations in CYP21A2, 19 were heterozygotes. The most frequent mutations detected were the mild p.Val281Leu and p.Pro453Ser. Higher levels of mean stimulated 17-OHP were found in the carriers of the p.Val281Leu mutation. The detection rate for two CYP21A2 mutations was higher in girls with PA than in adult females with hyperandrogenemia in our studied population. A notable increased allelic frequency for the known p.Asn493Ser polymorphism was observed in the pool of the 28 girls with PA in whom no mutation was identified. CONCLUSIONS: In girls with PA, the frequency of the underlying CYP21A2 genetic defects is similar to that observed in other populations. The carrier status is likely a contributing factor in the genotype-phenotype correlation in NC-CAH. However, polymorphisms and other genes may be implicated in the clinical manifestation of the disease.

Effects of growth hormone on heart structure and function in adolescence.

Until recently, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) were considered to control only linear growth. Apart from growth effect, GH has additional important physiological functions in the human body influencing several metabolic processes, body composition, muscle strength, and bone mineral density. In adolescence, where the majority of these physiological functions reach a zenith, GH plays a crucial role. The ability of GH to trigger cardiac muscle growth by direct and indirect effects plays a pivotal role in the physiology of the heart. Patients with childhood or adulthood onset of GH deficiency are exposed to increased risk for cardiovascular morbidity. GH treatment may have beneficial effect on the cardiovascular system in GH deficient adolescents. On the other hand discontinuation of GH treatment in these patients may result in the accumulation of relevant cardiovascular risk factors such as increase in body and abdominal fat and LDL and total cholesterol concentrations. No potential adverse cardiac effects of GH therapy have been so far demonstrated in short stature patients with normal GH secretion. Nevertheless, no evidence of heart hypertrophy or cardiomypathy has been documented in adolescents with GH excess has been reported in adults. Nonetheless, normalization of GH and IGF-1 levels in such patients is essential in order to arrest cardiovascular disease later in life.

Genetic defects in the cyp21a2 gene in heterozygous girls with premature adrenarche and adolescent females with hyperandrogenemia.

UNLABELLED: Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder primarily caused by mutants in the CYP21A2 gene. Heterozygosity for CYP21A2 mutations in females increases their risk of clinically manifesting hyperandrogenism and the present study was designed to seek evidence on the prevalence and consequences of heterozygous CYP21A2 mutations in children with premature adrenarche and adolescents with hyperandrogenemia. The hormonal response to ACTH was evaluated in 17 girls with clinical signs of premature adrenarche and 17 adolescent females with hyperandrogenemia, along with direct DNA sequencing and MLPA analysis for mutations in the CYP21A2 gene. The suspicion of heterozygote state was based on the median plasma 17-OHP before and 60 minutes after ACTH stimulation. All 34 patients were identified as carriers of CYP21A2 mutations. The most frequent mutations among this cohort of carriers were the mild p.V281L (52.9%), followed by p.Q318stop (20.6%), p.V304M (8.9%), p.P482S (5.9%), p.P453S (5.9%), large deletion/conversion exons 1-4 (2.9%) and large deletion/conversion exons 6-8 (2.9%). Higher values of stimulated 17-OHP levels were found in the carriers of the p.V281L mutation compared with carriers of other mutations (mean=21.9 nmol/L vs 17.0 nmol/L). This finding supports the already identified notion that carriers of the mild p.V281L are at higher risk for hyperandrogenism than carriers of severe mutations. IN CONCLUSION: a. Females with premature adrenarche and hyperandrogenemia are likely to bear heterozygous CYP21A2 mutations, therefore systematic evaluation of 17-OHP values in combination with the molecular testing of CYP21A2 gene is beneficial, b. carriers of the mild p.V281L, are at higher risk of androgen excess compared to carriers of other types of mutations.

Outcome and management of pregnancy in women with thalassaemia in Cyprus.

We describe the management and clinical outcome of pregnancies among 100 Greek Cypriot women with thalassaemia: 88 with thalassaemia major and 12 with thalassaemia intermedia. A total of 152 successful pregnancies and 161 deliveries were included. All patients had endocrine assessment and frequent ferritin measurements. Multiple successful pregnancies included 7 twins and 1 triple pregnancy. Pregnant thalassaemics required significantly larger amount of total blood transfusion during pregnancy. There was a statistically significant increase in the ferritin levels during pregnancy, and levels remained significantly higher after pregnancy. Most pregnancies resulted in delivery of full-term healthy babies, and obstetric complications were rare, although some problems were encountered.

Outcome and management of pregnancy in women with thalassaemia in Cyprus

We describe the management and clinical outcome of pregnancies among 100 Greek Cypriot women with thalassaemia: 88 with thalassaemia major and 12 with thalassaemia intermedia. A total of 152 successful pregnancies and 161 deliveries were included. All patients had endocrine assessment and frequent ferritin measurements. Multiple successful pregnancies included 7 twins and 1 triple pregnancy. Pregnant thalassaemics required significantly larger amount of total blood transfusion during pregnancy. There was a statistically significant increase in the ferritin levels during pregnancy, and levels remained significantly higher after pregnancy. Most pregnancies resulted in delivery of full-term healthy babies, and obstetric complications were rare, although some problems were encountered

Efficacy of combined treatment with growth hormone and gonadotropin releasing hormone analogue in children with poor prognosis of adult height.

OBJECTIVE: This study was conducted to study the role of combination therapy of growth hormone and Gonadotropin-releasing hormone (GnRH) analogues in girls with idiopathic central precocious puberty (CPP) or idiopathic short stature (ISS). METHODS: Five girls with CPP (median age 9.1 y, pubertal stage 2-3) (3 of them previously treated with GnRH analogue (GnRHa) for 16.2 +/- 0.3 months) and 8 girls with ISS (median age 11.4 y, pubertal stage 2-3) (previously treated with GH for 10.95 +/- 1.42 months), were treated with recombinant human GH (0.33 mg/kg/week) and GnRHa (3.75 mg/28 days) for 22 months. RESULTS: Height of girls with CPP improved from - 1.3 to - 0.2 SDS and height for BA from - 2.1 to - 0.6 SDS (P = 0.042). Predicted adult height (PAH) improved from - 3.1 to - 0.6 SDS (P = 0.042). In girls with ISS only PAH improved from - 3.0 to - 1.5 SDS (P = 0.025). CONCLUSION: Combined treatment improves height and PAH in CPP. Height in ISS is also improved however not significantly.