Pelvic and breast ultrasound abnormalities and associated metabolic disturbances in girls with premature pubarche due to adrenarche.

OBJECTIVE: Premature adrenarche (PA) has been suggested as a risk factor for future health problems, such as metabolic syndrome and early menarche. However, not all girls with PA have these features and it is not certain who will develop them. We propose that these abnormalities might be identified earlier, even before they are visible. DESIGN: Case-control study. SETTING: Tertiary care hospital. PARTICIPANTS: Forty-eight girls with premature pubarche due to PA and age (mean age 7.6 ± 1.0 years), weight, body mass index (BMI), birth weight and gestational age-matched 49 girls with no palpable breast tissue. MEASUREMENTS: Early pubertal pelvic and breast ultrasonographic changes and their associations with obesity and metabolic parameters were evaluated. Blood samples were collected, breast and pelvic ultrasound examinations were performed and bone ages were assessed. RESULTS: Girls with PA were taller and their bone ages were higher (p = .049 and p = .005). Fasting blood glucose, insulin, triglycerides, high-density lipoprotein and low-density lipoprotein cholesterol were not different between the groups. Luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol were not different either. Ultrasonography revealed breast gland tissue in 30% of girls with PA and 5% of controls (p = .006). Uterine volume and endometrial thickness were higher in girls with PA (p = .03 and p = .04). Endometrial thickness was positively associated with serum insulin levels in the whole study group and after adjusting for age, diagnosis, BMI, mean ovarian volume and LH, FSH, estradiol levels, this association remained with a borderline p-value (R2 = 0.486, p = .050). CONCLUSIONS: We found early changes in uterus and breast glands of girls with PA and endometrial thickness was positively associated with insulin levels.

Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community.

OBJECTIVE: In this study, we aimed to investigate the genetic background of thyroid dyshormonogenesis (TDH). CONTEXT: Thyroid dyshormonogenesis comprises 10-15% of all cases of congenital hypothyroidism (CH), which is the most common neonatal endocrine disorder, and might result from disruptions at any stage of thyroid hormone biosynthesis. Currently seven genes (NIS, TPO, PDS, TG, IYD, DUOX2 and DUOXA2) have been implicated in the aetiology of the disease. DESIGN: As TDH is mostly inherited in an autosomal recessive manner, we planned to conduct the study in consanguineous/multi-case families. PATIENTS: One hundred and four patients with congenital TDH all coming from consanguineous and/or multi-case families. MEASUREMENTS: Initially, we performed potential linkage analysis of cases to all seven causative-TDH loci as well as direct sequencing of the TPO gene in cases we could not exclude linkage to this locus. In addition, in silico analyses of novel missense mutations were carried out. RESULTS: TPO had the highest potential for linkage and we identified 21 TPO mutations in 28 TDH cases showing potential linkage to this locus. Four of 10 distinct TPO mutations detected in this study were novel (A5T, Y55X, E596X, D633N). CONCLUSIONS: This study underlines the importance of molecular genetic studies in diagnosis, classification and prognosis of CH and proposes a comprehensive mutation screening by new sequencing technology in all newly diagnosed primary CH cases.

TSHR is the main causative locus in autosomal recessively inherited thyroid dysgenesis.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and results in mental retardation if untreated. Eighty-five percent of CH cases are due to disruptions in thyroid organogenesis and are mostly sporadic, but about 2% of thyroid dysgenesis is familial, indicating the involvement of genetic factors in the aetiology of the disease. In this study, we aimed to investigate the Mendelian (single-gene) causes of non-syndromic and non-goitrous congenital hypothyroidism (CHNG) in consanguineous or multi-case families. Here we report the results of the second part (n=105) of our large cohort (n=244), representing the largest such cohort in the literature, and interpret the overall results of the whole cohort. Additionally, 50 sporadic cases with thyroid dysgenesis and 400 unaffected control subjects were included in the study. In familial cases, first, we performed potential linkage analysis of four known genes causing CHNG (TSHR, PAX8, TSHB, and NKX2-5) using microsatellite markers and then examined the presence of mutations in these genes by direct sequencing. In addition, in silico analyses of the predicted structural effects of TSHR mutations were performed and related to the mutation specific disease phenotype. We detected eight new TSHR mutations and a PAX8 mutation but no mutations in TSHB and NKX2-5. None of the biallelic TSHR mutations detected in familial cases were present in the cohort of 50 sporadic cases. Genotype/phenotype relationships were established between TSHR mutations and resulting clinical presentations. Here we conclude that TSHR mutations are the main detectable cause of autosomal recessively inherited thyroid dysgenesis. We also outline a new genetic testing strategy for the investigation of suspected autosomal recessive non-goitrous CH.

A Homozygous TPO Gene Duplication (c.1184_1187dup4) Causes Congenital Hypothyroidism in Three Siblings Born to a Consanguineous Family.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disease, and germ-line mutations in the TPO gene cause the inherited form of the disease. Our aim in this study was to determine the genetic basis of congenital hypothyroidism in three affected children coming from a consanguineous Turkish family. Because CH is usually inherited in autosomal recessive manner in consanguineous/multicase families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First, we investigated the potential genetic linkage of the family to any known CH locus, using microsatellite markers, and then screened for mutations in linked-gene by conventional sequencing. The family showed potential linkage to the TPO gene and we detected a homozygous duplication (c.1184_1187dup4) in all cases. The mutation segregated with disease status in the family. This study confirms the pathogenicity of the c.1184_1187dup4 mutation in the TPO gene and helps establish a genotype/phenotype correlation associated with this mutation. It also highlights the importance of molecular genetic studies in the definitive diagnosis and accurate classification of CH.