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Nonclassical 21-hydroxylase deficiency ( NC21O HD) manifests with various degrees of post natal virilization. The length of CAG repeats of the androgen receptor gene (AR) is inversely correlated to activity of the human androgen receptor (AR) and affects phenotype of several androgendependent disorders. The aim of the study was to investigate the associations between CAG repeat length and the phenotype of females with NC21OHD. CAG repeat length and AR inactivation were assessed in females with NC21OHD, and related to their clinical presentation. CAG repeat length and AR inactivation were assessed in 119 females with NC21OHD. Biallelic mean (BAM) of the CAG repeat length and the weighted BAM (WBAM) were related to various clinical parameters. Age at diagnosis and age of menarche positively correlated with BAM (r = 0.22, p = 0.02, and r = 0.23, p = 0.01, respectively). A shorter ( < 25) BAM was associated with younger age at diagnosis (14.8 vs. 21.4 years, p < 0.01), at adrenarche (8.1 vs. 10.2 years, p < 0.01) and gonadarche (9.9 vs. 11.2 years, p < 0.01), and higher corrected height standard deviation score at diagnosis (0.77 vs. 0.15, p = 0.01). Precocious pubarche and precocious puberty were more frequent in these with the shorter BAM. Results of WBAM were similar. The CAG repeat length of the AR gene contributes to the clinical diversity of the phenotype in females with NC21OHD. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe a proband with features of type 2 diabetes who was found to have concomitant maturity-onset diabetes of the young (MODY) and the consequent multigeneration genetic analysis. DESIGN: Familial genetic analysis. SETTING: Tertiary university medical center. PARTICIPANTS: The proband was a 13.5-yr-old boy with marked non-ketotic hyperglycemia, obesity, systolic hypertension, and insulin resistance. His mother, maternal aunt, grandmother, and great grandmother had diabetes; his father was obese and had early ischemic heart disease. INTERVENTIONS: Clinical examination, laboratory work-up, and DNA study. Outcome measures: Mutation in hepatocyte nuclear factor-1alpha gene, the most common cause of MODY. Results: The proband showed elevated C-peptide level and was negative for beta-cell antibodies. On genetic analysis for MODY, the 291fsinsC mutation was identified in all affected family members. A younger sister who was obese but had no signs of impaired glucose tolerance was also tested on the basis of these findings and was found to have the same mutation. CONCLUSIONS: The patient, who presented with apparent type 2 diabetes, had concomitant MODY 3, inherited from his mother's side, and some features of type 2 diabetes secondary to marked obesity. This combination probably caused an earlier and more severe presentation of the disease and had significant implications for medical management. A search for MODY mutations should be considered in patients with a history of diabetes in three generations of one side of the family, even those in whom the clinical picture resembles type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: The Israeli Yemenite Jewish community has displayed an exceptionally rapid increase in the frequency of type 1 diabetes, having the highest rate of all Israeli ethnic groups. We studied the role of the environment, in relation to the nature and frequency of HLA class II genes, to evaluate its possible involvement in the development of diabetes.Research Design and Methods: We interviewed 196 elderly Yemenite women, who had immigrated to Israel as adults, in programmed encounters about signs and symptoms of type 1 diabetes, infant feeding customs, and infectious diseases in Yemen. We also performed HLA oligotyping of DRB1, DQA1, and DQB1 genes in 120 unrelated Yemenite Jews, including 44 type 1 diabetic patients and 76 healthy control subjects, and used these data in correspondence analysis comparing Yemenites with different Israeli ethnic groups.Results: Interviews indicated that early exposure to cow's milk was very common in Yemen. However, none of the women could recall classical presentations of diabetes. HLA oligotyping showed that gene frequencies of non-Asp-57 (of the HLA-DQB chain) in the patients (0.94) and control subjects (0.6) were similar to those of other populations with a known high incidence of type 1 diabetes. Correspondence analysis revealed that Yemenite Jews are genetically distinct from other ethnic groups in Israel.Conclusions: The genetic distinctiveness of Yemenite Jews may explain their unusually high incidence of type 1 diabetes in Israel. Despite the presence of highly susceptible diabetogenic HL4 class II genes in this community, early exposure to cow's milk did not cause phenotypic expression of diabetes in Yemen. This finding suggests that in this population, either cow's milk does not play a crucial role in triggering diabetes, or environmentally conferred protection, such as frequent infectious disease in Yemen, was dominant. [ABSTRACT FROM AUTHOR]

Describes a study to examine the effect of age at the start of iron chelation therapy on gonadal function in Beta-thalassemia major. Background; Methods; Results; Conclusions.

Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare cause of adrenocortical insufficiency, especially in children, and may be an underestimated cause of neonatal death. Early postnatal diagnosis may prevent hypoglycemic seizures, Addisonian crises, and death. There are also occasional reports of prenatal diagnosis of IAD by findings on the maternal triple-marker screen (TMST), a combined serum analyte test that measures levels of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol for the detection of Down syndrome and open neural-tube defects. An isolated low estriol level is usually correlated with compromised uteroplacental perfusion and frequently associated with fetal death. A low estriol level in the context of normal fetal sonography and growth, after exclusion of placental sulfatase deficiency and Smith-Lemli-Opitz syndrome, should raise the suspicion of deficient fetal steroidogenesis, which leads to decreased production of adrenal dehydroepiandrosterone sulfate.We describe 2 brothers with adrenal insufficiency resulting from IAD. The parents are first cousins whose first son is healthy. During the pregnancy of the second son, who died at the age of 7 weeks as a result of presumed cardiomyopathy, a low estriol level on the TMST was ignored because of a normal fetal ultrasound. In the third pregnancy, a low level was found again, and the mother was referred to our tertiary center. Ultrasonography revealed no abnormalities, and karyotype was normal. Normal levels of steroid sulfatase activity and 7-dehydrocholesterol ruled out X-linked ichthyosis and Smith-Lemli-Opitz syndrome, respectively. Postnatally, basal and stimulated cortisol and ACTH levels were low. Other pituitary functions were normal, suggesting the diagnosis of IAD. The patient was treated with a stress dose of hydrocortisone on day 2 of life, which was tapered to a maintenance dose. At the time of this writing, he was 7 months old, with normal growth and development.Recently, loss-of-function mutations in the human TPIT gene were detected in autosomal recessive IAD. TPIT is a cell-restricted T-box transcription factor that is important for the terminal differentiation of pituitary corticotrophs. Therefore, we performed molecular analysis of the TPIT gene, which revealed a new mutation (IVS4+1G>A) that affects the first nucleotide of the splice site at the 5' end of the fourth intron. This stop codon probably leads to loss of TPIT function by nonsense-mediated mRNA decay, as it does for other TPIT nonsense mutations.We recommend that pregnant women with an isolated low estriol level of unexplained etiology be referred for additional evaluation by a multidisciplinary team that includes a geneticist and pediatric endocrinologist. Prompt ACTH testing in the first postnatal days will allow for early diagnosis. The immediate institution of glucocorticoid therapy, with proper instructions for stress management, can prevent unnecessary neonatal death secondary to an easily treatable disease. [ABSTRACT FROM AUTHOR]