Diagnostic Value of Circulating Cell-free DNA in Patients With Papillary Thyroid Cancer.

AIM: We investigated whether the occurrence and development of papillary thyroid cancer (PTC) might be predicted using levels of circulating cell-free DNA (cfDNA). MATERIALS AND METHODS: The peripheral blood samples were collected from 68 patients with PTC, 31 patients with nodular goiter (NG), and 86 healthy controls (HC). The concentration of cfDNA was measured by qPCR using three primer sets: ß-actin99, ß-actin394 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in plasma samples. RESULTS: It was demonstrated that plasma ß-actin99 and ß-actin394 in the PTC group were significantly higher compared to HC (p<0.05 and p<0.001, respectively). The cfDNA integrity index was significantly higher in the PTC patients compared to HC and NG (p<0.001, p<0.05, respectively). The cfDNA concentration in the NG group was significantly higher than in the PTC (p<0.05 and p<0.001, respectively). Moreover, in most PTC patients with suppressed thyroglobulin, the ß-actin394 and cfDNA integrity index was significantly decreased after surgery (p<0.05 and p<0.001, respectively). ROC analysis revealed that cfDNA integrity index can be used as a potential marker in distinguishing PTC from HC (AUC 0.901, p<0.001) and NG (AUC 0.629, p<0.05). CONCLUSION: Increased concentration of cfDNA ß-actin99 and ß-actin394 may be a valuable biomarker that differentiates PTC patients from HC. Also, an increased cfDNA integrity index may be a suitable parameter which differentiates PTC patients from NG and HC.

Serum Cystatin C as a Biomarker for Early Diabetic Kidney Disease and Dyslipidemia in Young Type 1 Diabetes Patients.

Background and objectives: This study aimed to assess the clinical significance of serum cystatin C in the early diagnosis of renal injury and its association with dyslipidemia in young T1D patients. Materials and Methods: A total of 779 subjects were evaluated for kidney function by estimating glomerular filtration rate (eGFR) based on serum creatinine (eGFRcreat) and cystatin C (eGFRcys). Results: The median age of study subjects was 16.2 years (2.1;26.4), diabetes duration-5.3 years (0.51;24.0). The median of HbA1c was 8% (5.2;19.9) (64 mmol/mol (33.3;194)); 24.2% of participants had HbA1c < 7% (53 mmol/mol). Elevated albumin excretion rate was found in 13.5% of subjects. The median of cystatin C was 0.8 mg/L (0.33;1.71), the median of creatinine-63 µmol/L (6;126). The median of eGFRcys was lower than eGFRcreat (92 mL/min/1.73 m2 vs. 101 mL/min/1.73 m2, p < 0.001). A total of 30.2% of all patients were classified as having worse kidney function when using cystatin C vs. creatinine for eGFR calculation. Linear correlations were found between cystatin C and HbA1c, r = -0.088, p < 0.05, as well as cystatin C and HDL, r = -0.097, p < 0.01. Conclusions: This study showed that cystatin C might be used as an additional biomarker of early kidney injury in young patients with T1D.

Colorimetric and Electrochemical Screening for Early Detection of Diabetes Mellitus and Diabetic Retinopathy-Application of Sensor Arrays and Machine Learning.

In this review, a selection of works on the sensing of biomarkers related to diabetes mellitus (DM) and diabetic retinopathy (DR) are presented, with the scope of helping and encouraging researchers to design sensor-array machine-learning (ML)-supported devices for robust, fast, and cost-effective early detection of these devastating diseases. First, we highlight the social relevance of developing systematic screening programs for such diseases and how sensor-arrays and ML approaches could ease their early diagnosis. Then, we present diverse works related to the colorimetric and electrochemical sensing of biomarkers related to DM and DR with non-invasive sampling (e.g., urine, saliva, breath, tears, and sweat samples), with a special mention to some already-existing sensor arrays and ML approaches. We finally highlight the great potential of the latter approaches for the fast and reliable early diagnosis of DM and DR.

Papillary Thyroid Carcinoma Tissue miR-146b, -21, -221, -222, -181b Expression in Relation with Clinicopathological Features.

We analyzed miR-146b, miR-21, miR-221, miR-21, and miR-181b in formalin fixed paraffin-embedded papillary thyroid carcinoma (PTC) tissue samples of 312 individuals and evaluated their expression relationship with clinicopathological parameters. A higher expression of miR-21 was related to unifocal lesions (p < 0.011) and autoimmune thyroiditis (0.007). miR-221, miR-222 expression was higher in the PTC tissue samples with extrathyroidal extension (p = 0.049, 0.003, respectively). In a group of PTC patients with pT1a and pT1b sized tumors, the expression of miR-146b, miR-21, miR-221, and miR-222 in PTC tissue samples was lower than in patients with pT2, pT3, and pT4 (p = 0.032; 0.0044; 0.003; 0.001; 0.001, respectively). Patients with lymph node metastases had higher expression of miR-21, -221, -222, and -181b (p < 0.05). A high expression of miR-146b, miR-21, miR-221 panel was associated with decreased overall survival (OS) (Log rank p = 0.019). Univariate analysis revealed that presence of metastatic lymph nodes and high expression of miR-146b, miR-21, and miR-221 panels were associated with increased hazard of shorter OS. After multivariate analysis, only sex (male) and age (≥55 years) emerged as independent prognostic factors associated with shorter OS (HR 0.28 (95% CI 0.09-0.86) and HR 0.05 (95% CI 0.01-0.22), respectively). In conclusion, 5 analyzed miRs expression have significant relations to clinicopathologic parameters so further investigations of these molecules are expedient while searching for prognostic PTC biomarkers.

Plasma-Derived miRNA-222 as a Candidate Marker for Papillary Thyroid Cancer.

We analyzed five miRNA molecules (miR-221; miR-222; miR-146b; miR-21; miR-181b) in the plasma of patients with papillary thyroid cancer (PTC), nodular goiter (NG) and healthy controls (HC) and evaluated their diagnostic value for differentiation of PTC from NG and HC. Preoperative PTC plasma miRNA expression (n = 49) was compared with plasma miRNA in the HC group (n = 57) and patients with NG (n = 23). It was demonstrated that miR-221; miR-222; miR-146b; miR-21 and miR-181b were overexpressed in preoperative PTC plasma samples compared to HC (p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.002; respectively). The upregulation in tumor tissue of these miRNAs was consistent with The Cancer Genome Atlas Thyroid Carcinoma dataset. A significant decrease in miR-21; miR-221; miR-146b and miR-181b expression was observed in the plasma of PTC patients after total thyroidectomy (p = 0.004; p = 0.001; p = 0.03; p = 0.036; respectively). The levels of miR-222 were significantly higher in the preoperative PTC compared to the NG group (p = 0.004). ROC curve (receiver operating characteristic curve) analysis revealed miR-222 as a potential marker in distinguishing PTC from NG (AUC 0.711; p = 0.004). In conclusion; circulating miR-222 profiles might be useful in discriminating PTC from NG.

Association of MicroRNA Expression and BRAFV600E Mutation with Recurrence of Thyroid Cancer.

Many miRNAs and cancer-related mutations have been proposed as promising molecular markers of papillary thyroid carcinoma (PTC). However, there are limited data on the correlation between miRNA expression, BRAFV600E mutation, and PTC recurrence. Therefore, to evaluate the potential of BRAFV600E mutation and five selected miRNAs (-146b, -222, -21, -221, -181b) in predicting PTC recurrence, these molecular markers were analyzed in 400 formalin-fixed, paraffin-embedded PTC tissue specimens. The expression levels of miRNAs were measured using qRT-PCR. It was demonstrated that expression levels of all analyzed miRNAs are significantly higher in recurrent PTC than in non-recurrent PTC (p < 0.05). Moreover, higher expression levels of miR-146b, miR-222, miR-21, and miR-221 were associated with other clinicopathologic features of PTC, such as tumor size and lymph node metastases at initial surgery (p < 0.05). No significant differences in the frequency of BRAFV600E mutation in recurrent PTC and non-recurrent PTC were determined. Our results suggest that miRNA expression profile differs in PTC that is prone to recurrence when compared to PTC that does not reoccur after the initial surgery while BRAFV600E mutation frequency does not reflect the PTC recurrence status. However, the prognostic value of the analyzed miRNAs is rather limited in individual cases as the pattern of miRNA expression is highly overlapping between recurrent and non-recurrent PTC.

Sex Hormones, Gonad Size, and Metabolic Profile in Adolescent Girls Born Small for Gestational Age with Catch-up Growth.

STUDY OBJECTIVE: To characterize and compare sex hormone concentrations, and uterine and ovarian volumes in adolescent girls born small for gestational age (SGA) who had experienced catch-up growth and girls born at a size appropriate for gestational age (AGA), and to investigate the association between these parameters and glucose metabolism, perinatal factors, and early growth. DESIGN: A prospective, longitudinal, observational study from birth until adolescence. SETTING: Mean age at final assessment was 12.7 ± 0.1 years. PARTICIPANTS: We followed 55 girls (20 SGA, 35 AGA). INTERVENTIONS AND MAIN OUTCOME MEASURES: Sex hormone concentrations (gonadotropins, estradiol, testosterone, and sex hormone binding globulin) were analyzed, and the oral glucose tolerance test conducted. Uterine and ovarian sizes were assessed using pelvic ultrasound. RESULTS: Uterine and ovarian volumes were smaller in SGA-born compared with AGA-born girls (P = .013 and P = .039, respectively). SGA girls had lower sex hormone binding globulin levels (P = .039) and higher testosterone levels (P = .003), free androgen index (P < .001), and glycemia 2 hours post glucose load (P = .005) compared with AGA-born girls. Birth weight and early infancy height velocity explained 37.4% of variation in ovarian volume (P = .004), and body mass index at birth, increase in peripheral skinfold thickness during second year of life, and early childhood height velocity explained 43.2% of variation in testosterone levels in adolescence (P = .006). CONCLUSION: SGA-born girls who experienced catch-up growth remain at risk of biochemical hyperandrogenism in adolescence, and have reduced uterine and ovarian volumes, which might influence future reproductive function. Ovarian size and androgen levels in adolescence might be influenced by early growth and subcutaneous fat deposition.

Thirty-Five Years of Thyroid Cancer Experience in a Paediatric Population: Incidence Trends in Lithuania between 1980 and 2014.

BACKGROUND: Thyroid cancer (TC) is a rare condition in children. It may be associated with radiation, iodine deficiency or familial inheritance. AIMS: The objectives of this study were to analyse the prevalence and incidence trends over 3 decades and clinical features of TC in the paediatric population in Lithuania. METHODS: We reviewed all TC cases diagnosed in children aged less than 18 years during the period 1980-2014 using medical records from 3 main hospitals in Lithuania where such TC cases are managed. RESULTS: During the 35-year period (1980-2014) there were 57 cases (45 females) of TC in children in Lithuania. The mean age at the time of diagnosis was 14.51 ± 0.52 years. The crude incidence rate of TC ranged from 0 to 0.93 cases per 100,000 children per year and the mean annual increase was 5.26% (p < 0.001). Papillary carcinoma was the most common histological type (73.7%). No association was found between the incidence of TC and the reported areas of radioactive contamination after the Chernobyl accident. In total, 8.8% of patients had secondary TC after initial radiotherapy of a primary oncologic disease. CONCLUSION: The incidence of TC in the Lithuanian paediatric population between 1980 and 2014 ranged from 0 to 0.93 cases per 100,000 children per year and there was a 5.26% annual increase (p < 0.001), most probably related to the increased use of ultrasound testing.

Factors Associated with the Prevalence of Thyroid Nodules and Goiter in Middle-Aged Euthyroid Subjects.

The aim of the present study was to determine associations of thyroid hormone levels and different metabolic parameters and anthropometric measurements with volume of nodular and nonnodular thyroid as well as with prevalence of goiter and thyroid nodules in middle-aged euthyroid subjects. Methods. The study consisted of 317 euthyroid subjects aged 48-49 from the Kaunas Cardiovascular Risk Cohort study. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), and antithyroid peroxidase antibody (ATPO) levels, as well as anthropometric and metabolic parameters and smoking information, were evaluated. Results. In subjects with and without thyroid nodules, thyroid volume correlated with components of metabolic syndrome, body mass index (BMI), smoking, and TSH levels. In the nonnodular thyroid group, thyroid volume was also positively related to serum insulin and HOMA-IR, whereas a negative correlation between thyroid volume and leptin was identified in the nodular thyroid group. The goiter was identified in 12.3% of subjects. Female gender, thyroid nodules, smoking, BMI, and levels of TSH were independent predictors for goiter. Thyroid nodules were found in 31.2% of participants. Female gender, higher TSH levels, and thyroid volume were independent risk factors for thyroid nodules. Conclusions. Female gender, thyroid nodules, smoking, BMI, and TSH levels were identified as potential predictors of goiter. Female gender, TSH levels, and thyroid volume predicted the presence of thyroid nodules.

A description of clinician reported diagnosis of type 2 diabetes and other non-type 1 diabetes included in a large international multicentered pediatric diabetes registry (SWEET).

BACKGROUND: Although type 1 diabetes (T1D) remains the most frequent form of diabetes in individuals aged less than 20 years at onset, other forms of diabetes are being increasingly recognized. OBJECTIVES: To describe the population of children with other forms of diabetes (non-type 1) included in the multinational SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) database for children with diabetes. METHODS: Cases entered in the SWEET database are identified by their physician as T1D, type 2 diabetes (T2D) and other types of diabetes according to the ISPAD classification. Etiologic subgroups are provided for other types of diabetes. Descriptive analyses were tabulated for age at onset, gender, daily insulin doses, and hemoglobin A1c (A1C) for each type and subtype of diabetes and when possible, values were compared. RESULTS: Of the 27 104 patients included in this report, 95.5% have T1D, 1.3% T2D, and 3.2% other forms of diabetes. The two most frequent etiologies for other forms of diabetes were maturity onset diabetes of the young (MODY) (n = 351) and cystic fibrosis-related diabetes (CFRD) (n = 193). The cause was unknown or unreported in 10% of other forms of diabetes. Compared with T1D, children with T2D and CFRD were diagnosed at an older age, took less insulin and had lower A1C (all P < .0001). CONCLUSION: In centers included in SWEET, forms of diabetes other than type 1 remain rare and at times difficult to characterize. Sharing clinical information and outcome between SWEET centers on those rare forms of diabetes has the potential to improve management and outcome.

The effect of a drospirenone-containing combined oral contraceptive on female sexual function: a prospective randomised study.

OBJECTIVES: The study investigated the effects on female sexual function of a progestogen-containing combined oral contraceptives (COCs) with an antiandrogenic profile taken in a continuous regimen. METHODS: In this prospective randomised single-institution study, 80 healthy women with a monogamous partner and an active sexual life were randomised into two groups for a period of 3 months. Women in the exposed group (n = 40) took a COCs containing 30 µg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) in a 21/7 regimen. Women in the control group (n = 40) used either a barrier contraceptive method (BCM) or a natural family planning method (NFPM). Participants were asked to complete a set of validated questionnaires to assess sociodemographic variables and measure Female Sexual Function Index (FSFI). RESULTS: The total FSFI score (p < 0.0001), as well as the desire (p = 0.04) and arousal (p = 0.03) scores, were significantly lower in the COCs group after 3 months of hormonal contraceptive use compared with baseline. Women using BCM or NFPM showed an improvement in total FSFI score (p = 0.02). Hormonal contraception with DRSP increased the likelihood of worse sexual function in the desire (odds ratio [OR] 2.47; 95% confidence interval [CI] 1.22, 4.98; p = 0.01) and arousal domains (OR 2.85; 95%CI 1.34, 5.93; p = 0.005) and in total FSFI score (OR 2.01; 95%CI 1.45, 2.79; p < 0.001). The results remained statistically significant even after adjustment for smoking status. CONCLUSIONS: The study found evidence that women taking a combined EE/DRSP COCs for 3 months may have a worsening of sexual function as measured by FSFI.

Predictive Factors of Development of Graves' Ophthalmopathy for Patients with Juvenile Graves' Disease.

Background. Due to low incidence of Graves' ophthalmopathy (GO) among children, the manifestation is poorly analyzed, posing a risk to late identification of insidious disease. Purposes. To identify predictive factors that may influence the development of GO in pediatric and young patients with Graves' disease (GD). Methods. A cross-sectional study of patients newly diagnosed with pediatric or juvenile GD during 2002-2012 was conducted at the Hospital of Lithuanian University of Health Sciences. Ocular evaluation was based on European Group on Graves' Orbitopathy survey. The ocular manifestations were analyzed in relation to demographic, environmental, and clinical factors. Results. In total, 130 patients with juvenile GD were included; 29.2% had GO. Median age at GD onset was 17 yrs (IQR 4-29). Main symptoms of GO were eyelids retraction (73.7%), proptosis (65.8%), injection of conjunctiva (42.1%), and eyeball motility disturbance (21.1%). Major significant and independent risk factors for GO development were high initial concentration of FT4 (OR = 5.963), TTHAb (OR = 6.358), stress (OR = 6.030), and smoking (OR = 7.098). Conclusion. The major factors that could influence GO development were smoking, stress, and increased levels of initial TRAb, FT4. Slight proptosis, retraction of eyelids, and conjunctive injection were found as predominant ophthalmological symptoms in juvenile GO.

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations.

Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.

Prevalence of overweight/obesity in relation to dietary habits and lifestyle among 7-17 years old children and adolescents in Lithuania.

BACKGROUND: Until recently increasing prevalence of overweight and obesity among pediatric population in Europe and worldwide contributes to major well-known risks for metabolic consequences in later life. The aim of this study was to determine the prevalence of overweight/obesity among children and adolescents in Lithuania and assess its association with energy balance related behaviors as well as familial demographic and socioeconomic factors. METHODS: Cross-sectional study included 3990 7-17 years old schoolchildren from 40 schools of Kaunas region, Lithuania. Study participants underwent anthropometric measurements. Body mass index (BMI) was evaluated according to International Obesity Task Force (IOTF) criteria for children and adolescents. Children and adolescents and their parents filled in the questionnaires on parental sociodemographic characteristics, dietary habits, TV watching time, and family socioeconomic status. RESULTS: The prevalence of underweight, overweight, and obesity among boys and girls was 6.9 and 11.7 % (P < 0.05), 12.6 and 12.6 % (P > 0.05), and 4.9 and 3.4 % (P < 0.05), respectively. Obesity was significantly more prevalent in the 7-9 years old group (6.7 and 4.8 % in boys and girls, respectively, P < 0.05). Lower meals frequency and breakfast skipping were directly associated with overweight/obesity (P < 0.05); however, physical inactivity was not associated with higher BMI. Children's overweight/obesity was directly associated with lower paternal education and unemployment (OR 1.30, P = 0.013 and OR 1.56, P = 0.003, respectively). CONCLUSIONS: The prevalence of overweight and obesity among 7-17 years old Lithuanian children and adolescents was more prevalent in younger age, still being one of the lowest across the European countries. Meals frequency, breakfast skipping, paternal education and unemployment as well as a family history of arterial hypertension were found to be associated with children's and adolescents' overweight/obesity.

Early development of endocrine and metabolic consequences after treatment of central nervous system tumors in children.

BACKGROUND AND OBJECTIVE: Survival after childhood cancer has dramatically improved during last few decades, implying the need for evaluation and correction of late consequences of the disease and its treatment. The aim of this study was to characterize endocrine and metabolic late effects after treatment of brain tumors in children. MATERIALS AND METHODS: Late complications were analyzed in 51 children treated for brain tumors at the Hospital of Lithuanian University of Health Sciences during 2000-2011. Data on late endocrine and metabolic effects were collected from medical records. Most frequently patients suffered from low-grade glioma (n=17, 33.3%) and medulloblastoma (n=13, 25.5%). The majority (n=42, 82.4%) of the patients underwent surgery; 29 (56.9%) received radiotherapy (RT); 26 (51.0%), chemotherapy; and 17 (33.4%), combined treatment. RESULTS: The median follow-up was 21 months (range 0.25-10.6 years). Most common endocrine consequence was low serum insulin-like growth factor (IGF-I) levels (58.3%), found on average in 30.7 months after cancer treatment. Short stature was observed in 34.6% (mean time to development, 47.7 months), and hypothyroidism in 40.7% of patients (mean time to development, 63.6 months). Low bone mineral density was found in 50.0% of the cases after 44.5 months and overweight in 30.0% after 49.9 months of follow-up. CONCLUSIONS: Survivors of brain tumors suffer from numerous endocrine and metabolic consequences, majority of them developing within the first 5 years after brain tumor therapy. An active follow-up aiming for early diagnosis and therapy is essential for improvement of quality of life in these patients.

Congenital hyperinsulinism.

Hyperinsulinism is the most common cause of hypoglycemia in infants. In many cases conservative treatment is not effective and surgical intervention is required. Differentiation between diffuse and focal forms and localization of focal lesions are the most important issues in preoperative management. We present a case of persistent infancy hyperinsulinism. Clinical presentation, conservative treatment modalities, diagnostic possibilities of focal and diffuse forms, and surgical treatment, which led to total recovery, are discussed.

High prevalence of PROP1 defects in Lithuania: phenotypic findings in an ethnically homogenous cohort of patients with multiple pituitary hormone deficiency.

CONTEXT: PROP1 gene mutations cause multiple pituitary hormone deficiency (MPHD). OBJECTIVE: We sought to expand experience with PROP1 mutation carriers by studying a large cohort of Lithuanian patients. PATIENTS AND METHODS: Sixty-seven MPHD patients were tested for PROP1 defects. Perinatal and postnatal data were obtained from medical records. Hormonal investigations, pituitary imaging, and GH therapy were provided in a single center in Kaunas, Lithuania. RESULTS: A biallelic PROP1 gene mutation was found in 47 subjects (70.1%), of which 46 were homozygous for 296delGA. Positive finding rate among MPHD and population prevalence of PROP1 defects in Lithuania (15.8 per million) were the highest reported to date. Patients' birth lengths/weights were normal. Testicular retention was noted in 31% of boys. Median height SD scores declined over years 1-5: -1.56, -2.34, -3.43, -3.52, and -3.70. Mid-parental height predicted severity of growth retardation at diagnosis (r2=0.30; P=.0001). Deficiencies of GH, TSH, ACTH, and FSH/LH were diagnosed in 44/44, 44/44, 19/44, and 22/44 subjects at median age of 5.5, 5.6, 13.1, and 15.0 years, respectively. Pituitary height ranged from 16.6 mm (+20.2 SD) to 1.4 mm (-15.5 SD) and declined with age (r2=0.27, P=.001). GH replacement (dose 0.027 mg/kg/d) led to height velocities 12.2; 9.1; 6.9; 6.8; 6.7; 5.6; and 5.7 cm/y (medians) at years 1-7 and final height SD scores (17 patients) -0.98±1.77 (-1.04±1.41 below target height; P=.008 vs 0). CONCLUSIONS: High prevalence of PROP1 defects in Lithuania is due to 296delGA mutation, suggesting a founder effect.

Puberty in children born small for gestational age.

Small for gestational age (SGA) children are more prone to have precocious pubarche and exaggerated precocious adrenarche, an earlier onset of pubertal development and menarche, and faster progression of puberty than children born of appropriate for gestational age (AGA) size. The majority of studies investigating the onset of puberty in children born SGA and AGA established that, although puberty begins at an appropriate time (based on chronological age and actual height) in SGA children, onset is earlier relative to AGA children. Evaluating pubertal growth in SGA children, a more modest bone age delay from chronological age at the onset of puberty and more rapid bone maturation during puberty compared to AGA children were reported. Peak height velocity in adolescence is reached at an earlier pubertal stage and lasts for a shorter period in children born SGA than in those born AGA. These differences lead to an earlier fusion of the growth plates and a shorter adult height. The pathophysiological mechanism underlying the unique pubertal growth pattern of children born SGA remains unclear. However, it seems that this is not only related to birth weight, gestational age, adiposity or obesity, but that there may also be an influence of rapid weight gain in early childhood on pubertal onset: excess weight gain in childhood may be related to central adiposity, decreased insulin sensitivity, and increased IGF-I levels and might thus predispose to precocious pubarche.

Carcinoma of two parathyroid glands caused by a novel MEN1 gene mutation - a rare feature of the MEN 1 syndrome.

Multiple endocrine neoplasia type 1 (MEN 1) is a rare syndrome inherited in an autosomal dominant pattern, characterized by combinations of tumors of the parathyroid glands, pituitary gland, and pancreatic islet cells and more rare tumors of endocrine organs and nonendocrine tissues. Germline mutations in the MEN1 gene are responsible for the MEN 1 syndrome, leading to an inactive form of menin protein. Benign lesions of the parathyroid glands are characteristic in patients with the MEN 1 syndrome; however, patients can develop parathyroid carcinomas very rarely. This report presents a clinical case of the MEN 1 syndrome: a 39-year-old woman underwent surgery for carcinoma of two parathyroid glands as well as was treated for pituitary prolactinoma, which caused infertility, and malignant insulinoma; the patient had multiple subcutaneous lipomas as well. Genetic analysis revealed a novel germline mutation in the MEN1 gene - a nucleotide insertion at codon 43 in exon 2 (c.129insA), which caused the occurrence of the MEN1 syndrome. The clinical case of the MEN 1 syndrome presented here is relevant in gathering the data on etiopathogenesis of not only MEN 1 syndrome, but an extremely rare pathology - parathyroid carcinoma - as well.

Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects.

BACKGROUND/AIMS: Defects of the PROP1 gene are the most prevalent genetic cause of combined pituitary hormone deficiency. Previous observations in affected patients have shown pituitary size ranging from hypoplasia to overt pituitary mass and evolution of size over the lifespan. METHODS: We evaluated pituitary size and morphology in PROP1-mutation carriers who originated from Central and Eastern Europe. We analyzed 112 pituitary magnetic resonance imaging (MRI) scans from 82 patients (42 males) aged 2.5-72.7 (median 16.6) years from 60 kindreds. RESULTS: Among the 120 independent PROP1 alleles, the most prevalent mutations were delGA301/302 (99 alleles) and delA150 (13 alleles). Median pituitary height at first MRI was 4.7 mm (range 1.0-20.7) and median volume was 127.6 mm(3) (range 7.5-3,087.0). Pituitary size did not differ between sexes and did not correlate with hormonal phenotype, but significantly decreased with increasing age. However, evaluation of individual values suggested a biphasic mode with increasing volume during childhood, peak in adolescence, and subsequent regression in adulthood. CONCLUSION: Although pituitary size was increased in a number of PROP1-deficient patients, none of them suffered permanent damage from pituitary mass; therefore, any proposed surgery should be postponed as long as possible and ultimately may not be necessary due to the self-limiting nature of the pituitary enlargement.