Maria Dracopoulou

Carotid Atherosclerosis in Adolescents and Young Adults With IDDM: Relation to urinary endothelin, albumin, free cortisol, and other factors

OBJECTIVE To investigate 1) alterations of carotid intimal-plus-medial thickness (IMT) in subjects with IDDM and 2) the relation of IMT to indexes of diabetic angiopathy and to risk factors of atherosclerosis. RESEARCH DESIGN AND METHODS IMT was assessed by ultrasound B-mode imaging in 39 subjects with IDDM (23 male, 16 female young adults aged 17.5 ± 5.2 years, diabetes duration 8.8 ± 5.9) and in 22 control subjects (healthy siblings of the IDDM subjects) of comparable age. Urinary endothelin (UET1) and urinary free cortisol (UFC) were determined by radioammunoassay (RIA), urinary albumin by nephelometry, HbA1c by high-performance liquid chromatography (HPLC), and plasma renin by immunoradiometric assay (IRMA). RESULTS The IMT values were greater in IDDM subjects than in control subjects (0.49 ± 0.1 mm, 0.44 ± 0.09 mm, respectively; P = 0.048) and greater in IDDM male subjects than in control male subjects (0.52 ± 0.09 and 0.44 ± 0.06 mm, respectively; P = 0.015), with no difference between IDDM and control female subjects. The IMT values were greater in diabetic male subjects than in female subjects (0.52 ± 0.09 and 0.45 ± 0.1 mm, respectively; P = 0.017). In IDDM subjects, but not in control subjects, there was a positive correlation of IMT to urinary albumin (P = 0.008), systolic blood pressure (P = 0.023), UET1 (P = 0.016), UFC (P = 0.002), and BMI (P = 0.021). Multiple regression analysis demonstrated that in IDDM subjects the variable that interacts independently with IMT was the BMI (P = 0.001). CONCLUSIONS IMT, an index of atherosclerosis (macroangiopathy), is increased in IDDM subjects quite early (already in adolescence), and it is positively related to urinary albumin, UET1, blood pressure, and UFC.

Gonadoblastoma in a patient with del(9)(p22) and sex reversal: report of a case and review of the literature.

Studies of distinct clinical prototypes have significantly contributed to our understanding of evolutionary abnormalities and their association with neoplasia. We describe a phenotypic female, aged 20 years at report, who was examined as an infant for developmental retardation. The clinical characteristics of the 9p- syndrome were present and the external genitalia were those of a normal female. The karyotype was 46XY,del(9)(p22). The parental karyotypes were normal. No SRY deletion or mutation was detected. Sonography showed the presence of a uterus. Basal luteinizing hormone values were normal; follicle stimulating hormone values were high (40 IU/L). Stimulation with human chorionic gonadotropin did not produce any rise in testosterone. The gonads were removed and histologic analysis disclosed dysgenetic gonads with gonadoblastoma in situ. This case constitutes the fourth case of gonadoblastoma developing in an individual with 9p- syndrome and sex reversal. This and analogous prototypes point to a locus (or loci) on the short arm of chromosome 9, which either constitutes a nonspecific suppressor gene or a gonadoblastoma suppressor gene. An alternative hypothesis would be that a gonad not normally differentiated is more prone to gonadoblastoma development without any specific gene involvement.

Low TSH congenital hypothyroidism : identification of a novel mutation of the TSH beta-subunit gene in one sporadic case (C85R) and of mutation Q49stop in two siblings with congenital hypothyroidism

Isolated congenital hypothyroidism resulting from mutation of the TSH ß-subunit gene, has rarely been reported. In the present article, we report a new mutation (C85R) in exon 3 of the TSH ß-subunit gene in one sporadic case and the mutation Q49stop in two siblings with congenital hypothyroidism. The novel mutation is a T to C transition at codon 85, resulting in a change of cysteine to arginine (C85R) of the ß-subunit. Because the cysteine residues of all glycoproteins are highly conserved, this mutation is expected to result in conformational changes of the ß-subunit, rendering it incapable to form a functional heterodimer with the α-subunit. The second mutation described is a C to T transition resulting in a premature stop at codon 49 (Q49stop), leading to the formation of a truncated protein. Although the two siblings reported herein carried the same mutation, they had slightly modified clinical and biochemical phenotype. The mutation C85R and the previously described E11stop have, thus far, exclusively been detected in Greek patients. The Q49stop mutation initially detected in Greek patients was subsequently identified in an Egyptian girl and most recently in two Turkish siblings. These three reports possibly indicate the presence of a mutational hot spot on the TSH ß-subunit gene. Hence, with the novel mutation herein reported, a total of five mutations of the TSH ß-subunit gene are recognized as a cause of low-TSH congenital hypothyroidism worldwide.

Elevated coagulation and inflammatory markers in adolescents with a history of premature adrenarche

Females with a history of premature adrenarche are at high risk of developing polycystic ovary syndrome (PCOS) and features of the metabolic syndrome later in life. Coagulation disorders, subclinical inflammation, and oxidative stress have been reported in patients with PCOS and metabolic syndrome. These factors were studied in a group of adolescents with a history of premature adrenarche. This is a cross-sectional study that determined the biochemical-hormonal profile and indices of inflammation, coagulation, and oxidative stress in 45 adolescent girls with a history of premature adrenarche and 19 age- and body mass index-matched controls. Girls with premature adrenarche had hyperandrogenism and higher indices of insulin resistance than controls. They also had significantly higher C-reactive protein (0.76 +/- 0.65 vs 0.41 +/- 0.31 mg/L, P = .0001) and plasminogen activator inhibitor 1 (37.6 +/- 24.7 vs 24.47 +/- 4.6 ng/mL, P = .034), and lower tissue plasminogen activator values in comparison with controls (3.5 +/- 1.5 vs 5.2 +/- 2.12 ng/mL, P = .0019). Both C-reactive protein(r = 0.545, P = .0001) and plasminogen activator inhibitor 1 (r = 0.36, P = .04) were positively correlated with oxidative stress, whereas tissue plasminogen activator was positively correlated (r = 0.37, P = .02) with total antioxidant status. None of these factors was correlated with androgens or indices of insulin resistance. Adolescent girls with a history of premature adrenarche display metabolic deviations usually encountered in subjects with PCOS and metabolic syndrome, such as subclinical inflammation and fibrinolytic abnormalities.

Long-term Clinical Data and Molecular Defects in the StAR Gene in Five Greek Patients.

CONTEXT Steroidogenic acute regulatory (STAR) gene mutations lead to adrenal and gonadal failure. Interesting, though as yet unexplained, features are the formation of ovarian cysts and the potential presence of CNS findings. OBJECTIVE To report biochemical, genetic, and long-term clinical data in five Greek patients from four different families with STAR gene defects (three 46,XX and two 46,XY). METHODS AND RESULTS All patients presented in early infancy with adrenal insufficiency. The STAR gene mutation c.834del11bp, detected in three of our patients, completely alters the carboxyl end of the STAR protein and has not thus far been described in other population groups. These three patients belong to three separate families, possibly genetically related, as they live in different villages located in a small region of a Greek island. However, their interrelationship has not been proven. A second mutation, p.W250X, detected in our fourth family, was previously described only in two Serbian patients. Ovarian cysts were detected ultrasonographically in our 46,XX patients and seemed to respond to a low dose of a contraceptive. The histology of an excised ovarian cyst was diagnosed as a corpus luteum (CL) cyst. In two out of the four patients who had undergone brain magnetic resonance imaging, asymptomatic Chiari-1 malformation was observed. CONCLUSIONS The occurrence of STAR gene mutation c.834del11bp in three families living in a restricted geographic region could indicate either a founder effect or simply reflect a spread of this defect in a highly related population. The ovarian histological findings suggest that ovarian cysts detected ultrasonographically in 46,XX individuals with STAR gene defects may be CL cysts. The Chiari-1 malformation in two of our patients may be part of the STAR gene mutation phenotype. Nevertheless, more data are needed to confirm or disprove the existence of specific CNS pathology in patients with STAR gene mutations.

The Dilemma of Sex Reassignment in an Adolescent with 17β-HSD-3 Deficiency Raised as a Female: Ten-Year Follow-Up

A number of patients with defective differentiation of the genital system, described in the literature by various terminologies (Dacou-Voutetakis, 2007; Hughes et al., 2006), wish to have sex reassignment in adolescence or adulthood. One of the disorders prompting the request for sex reassignment after childhood is the deficiency of 17b-hydroxysteroid dehydrogenase-3 (17b-HSD-3) caused by mutations in the HSD17B3 gene. The enzyme 17b-HSD-3 is involved in the terminal phase of testicular steroidogenesis and specifically catalyzes the conversion of androstenedione (A) to testosterone (T). Persons with this defect have near-normal or ambiguous female external genitalia at birth due to the absence of testosterone and dihydrotestosterone when the external genitalia differentiate (Gooren, 2002). Individuals with 17b-HSD-3 deficiency are considered as females and are raised as girls. At puberty, however, they become virilized as a result of an increase in T and dihydrotestosterone levels due to the action of 17b-HSD-isoenzymes and peripheral conversion of A to T (Sobel & Imperato-McGinley, 2004). In a recent review dealing with these patients, the opinion expressed was that genital appearance at birth does not determine psychosexual outcome and that the general appearance of the child in combination with masculine behavior are stronger determinants for the development of male gender identity (Cohen-Kettenis, 2005). In the present report, we describe an XY individual with 17b-HSD-3 deficiency raised as female, the dilemmas arising at age 17 years when the question of sex reassignment was seriously considered, as well as her follow-up of 10 years post-feminizing surgery of the external genitalia. The patient, currently 27-years-old, is the fourth oldest of five children of a family living in a rural area of a small Greek island. The family does not belong to any specific religious group. At birth, no abnormality of the external genitalia was identified. Shortly thereafter, however, the mother questioned the appearance of the external genitalia but refused testing in Athens as recommended by the local pediatrician. The patient attended primary school up to the 6th grade but was unable to learn reading, writing, and arithmetic, similar to her mother and one brother and in contrast to two other children of the family. A school for children with special needs was not available in the area at that time. Quite early, the patient started to work at the family farm located some distance away from home, caring for sheep and other animals and thus living a rather isolated life. At the age of 8 years, the patient was brought by her father to our hospital but after a few consultations they left, stating that they would come back later ‘‘after finishing with jobs on the farm.’’ At that time, the patient had the appearance of a normal girl and presented only mild clitoral enlargement without hypertrichosis. With the girl’s onset of puberty, however, the pediatrician noted evidence of virilization. One member of our team (CDV), accompanied by the local pediatrician, visited the M. Liakopoulou (&) Child Psychiatry Department, ‘‘Aghia Sophia’’ Children’s Hospital, Athens University School of Medicine, Athens 11527, Greece e-mail: mliakopo@otenet.gr