Androgen Receptor CAG Repeat Length in Relation to Phenotype Among Females with Nonclassical 21-Hydroxylase Deficiency.

Nonclassical 21-hydroxylase deficiency (NC21OHD) 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 androgen-dependent 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.

[Androgen receptor polymorphism in relation to medical conditions characterized by hyper/hypoandrogenism].

An androgen receptor (AR) is a transcription factor consisting of four functional regions. The transactivation region contains a highly polymorphic area characterized by a variable number of CAG trinucleotide repeats encoding a polyglutamine tract. Several in vitro studies demonstrated a negative linear relation between the lengths of CAG repeats and relative AR transactivations. Numerous clinical studies then sought associations between the described polymorphism and clinical parameters of various medical conditions characterized by hyper/hypoandrogenism. In this article, we describe some of those interesting associations. We believe such links should be investigated in any medical condition involving androgens as a key element in its pathogenesis.

Effect of polymorphism in insulin locus and HLA on type 1 diabetes in four ethnic groups in Israel.

This study examined a possible association of the insulin (INS) gene with type 1 diabetes (T1D) in patients and controls from four ethnic groups in Israel. We analyzed the distribution of -23HphI single nucleotide polymorphism (SNP) T/A alleles that correspond to INS variable number of tandem repeat short class I alleles (26-63 repeats) and class III alleles (141-209 repeats), respectively. The -23HphI T/T genotype was found to be positively associated with T1D in three Jewish groups (Yemenites: 93.9% patients vs 68.8% controls, P = 0.0002; Ashkenazi: 80.6% vs 50.8%, P < 10(-4); Ethiopians: 75% vs 40.5%, P = 0.002). The Yemenite healthy controls have the highest frequency of T allele from all Jewish groups studied (83.5% vs 68.8% in Ashkenazi and 64.3% in Ethiopians). The high frequency of a susceptibility allele in the Yemenites is in line with the high incidence of T1D in this population. No association was observed between T1D and the INS gene in Israeli Arabs studied (70.6% vs 66.7%). Variable incidence of T1D among different ethnicities in Israel is largely attributed to heterogeneous genetics. Human leukocyte antigen (HLA) results of our previous studies describing the susceptibility and protective haplotypes were used for combined analysis to determine possible interaction between the HLA and INS loci. Only in the Ashkenazi group such interaction was presented with statistical significance.

Growth without growth hormone and similar dysmorphic features in three patients with sporadic combined pituitary hormone deficiencies.

BACKGROUND/AIMS: Mutations in the HESX1 gene are associated with a broad spectrum of phenotypes: septo-optic dysplasia, midline defects, pituitary abnormalities with consequent hypopituitarism, isolated growth hormone (GH) deficiency or combined pituitary hormone deficiencies (CPHD). This study examined the prevalence of mutations in the HESX1 gene in patients with CPHD. PATIENTS/METHODS: Sixty patients with sporadic CPHD without septo-optic dysplasia were screened for mutations in HESX1. RESULTS: Three patients were found to be heterozygous for the same Asn125Ser variant in the HESX1 gene. In all 3, panhypopituitarism was presented in the neonatal period, manifested by severe hypoglycemia and neonatal jaundice in 2 patients and respiratory distress in 1. Remarkable findings from physical examination included coarse face; prominent, large, low-set ears; and skeletal abnormalities. Magnetic resonance imaging, performed in 2 patients, revealed a hypoplastic anterior and ectopic posterior pituitary without other midline anomalies. Despite persistent GH deficiency and undetectable levels of insulin-like growth factor 1, all patients had normal linear growth along the 10-25th percentile without GH therapy. CONCLUSION: The present study expands the clinical picture of HESX1 mutations by demonstrating that patients heterozygous for Asn125Ser may have a severe endocrinologic and neuroradiologic phenotype and similar dysmorphic features appearing very early in life.

Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsalpha.

OBJECTIVE: Pseudohypoparathyroidism type Ia (PHP-Ia) is a hereditary disorder characterized by resistance to multiple hormones that work via cAMP such as PTH and TSH, accompanied by typical skeletal features including short stature and brachydactyly, termed Albright hereditary osteodystrophy (AHO). In affected kindreds, some members may have AHO but not hormone resistance; they are termed as pseudopseudohypoparathyroidism (PPHP). The molecular basis for the disorder is heterozygous inactivating mutation of the Gsalpha gene. In affected families, subjects with both PHP-Ia and PPHP have the same Gsalpha mutations. The skeletal features common to PPHP and PHP-Ia are presumably caused by tissue-specific Gsalpha haploinsufficiency. Other features that distinguish between PPHP and PHP-Ia, such as the multihormone resistance, are presumably caused by tissue-specific paternal imprinting of Gsalpha. This suggests that major differences in phenotype between PHP-Ia and PPHP point to specific tissues with Gsalpha imprinting. One such major difference may be cognitive function in PHP-Ia and PPHP. DESIGN: Description of a large family with PHP-Ia and PPHP. PATIENTS: Eleven affected subjects with PHP-Ia or PPHP in one family. MEASUREMENTS: Cognitive impairment (CI) was defined by a history of developmental delay, learning disability and the Wechsler intelligence scale. RESULTS: CI occurred only in the five PHP-Ia but not in the six PPHP subjects. Hypothyroidism which occurred in all PHP-Ia subjects was apparently not the cause of CI as it was mild, and was treated promptly. Analysis of additional Israeli cases, and the published cases from the literature, all with documented Gsalpha mutations, revealed that CI is prevalent in PHP-Ia [60 of 77 subjects (79%)] but not in PPHP [3 of 30 subjects (10%)] (P < 1 x 10(-6)). CONCLUSION: We suggest that Gsalpha is imprinted in the brain.

Four novel mutations, including the first gross deletion in TCF1, identified in HNF-4alpha, GCK and TCF1 in patients with MODY in Israel.

Maturity onset diabetes of the young (MODY) is characterized by a primary defect in insulin secretion with non-ketotic hyperglycemia, monogenic autosomal dominant mode of inheritance, age at onset less than 25 years, and lack of autoantibodies. The aim of this study was to characterize the genetic basis of MODY in different ethnic groups in the Israeli population. Fifty-nine unrelated Israeli patients with MODY were assessed for mutations in the three common MODY genes: hepatocyte nuclear factor (HNF)-4alpha, glucokinase (GCK), and transcription factor 1 (TCF1). Overall, 11 mutations in 12 unrelated families were found (20.3% of patients), for a relative frequency of 1.7% for MODY1, 8.5% for MODY2, and 10.1% for MODY3. Four mutations were novel, including the first gross deletion ever described in the TCF1 gene. The low overall mutation frequency found here may suggest the involvement of other, yet unidentified, genes in the etiology of MODY in Israel.

Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia.

CONTEXT: Because many women with 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) carry at least one allele affected by a severe mutation of CYP21, they are at risk for giving birth to infants with classic adrenal hyperplasia (CAH). OBJECTIVE: Our objective was to determine the frequency of CAH and NCAH infants born to mothers with 21-OH-deficient NCAH. DESIGN AND SETTING: We conducted an international multicenter retrospective/prospective study. PATIENTS AND METHODS: The outcome of 203 pregnancies among 101 women with 21-OH-deficient NCAH was reviewed. The diagnosis of 21-OH-deficient NCAH was established by a basal or post-ACTH-stimulation 17-hydroxyprogesterone level of more than 10 ng/ml (30.3 nmol/liter). When possible, genotype analyses were performed to confirm CAH or NCAH in the offspring. RESULTS: Of the 203 pregnancies, 138 (68%) occurred before the mother's diagnosis of NCAH and 65 (32%) after the diagnosis. Spontaneous miscarriages occurred in 35 of 138 pregnancies (25.4%) before the maternal diagnosis of NCAH, and in only four of 65 pregnancies (6.2%) after the diagnosis (P < 0.002). Four (2.5%; 95% confidence interval, 0.7-6.2%) of the 162 live births were diagnosed with CAH. To date, 24 (14.8%; 95% confidence interval, 9.0-20.6%) children, 13 girls and 11 boys, have been diagnosed with NCAH. The distribution of NCAH children and their mothers varied significantly by ethnicity (P < 0.0001, for both). CONCLUSIONS: The risk of a mother with 21-OH-deficient NCAH for giving birth to a child affected with CAH is 2.5%; at least 14.8% of children born to these mothers have NCAH.

Clinical characteristics and diabetes associated autoantibodies in patients with both type 1 diabetes mellitus and asthma.

OBJECTIVE: Type 1 diabetes mellitus (DM1) and asthma are mediated by opposite arms of the cellular immune system, namely T helper (Th)1 and Th2 CD4+ cells, respectively. It is not known whether their coexistence affects their clinical manifestations. METHODS: The number of asthma exacerbations, frequency of hypoglycemic events, HbA1c levels, diabetes associated autoantibody status and diabetes associated late complications were determined in three paired groups of patients (n = 11) matched by gender and age: DM1 and asthma, asthma only, and DM1 only. RESULTS: Patients with both diseases had a higher prevalence of hypoglycemic events per month compared to patients with DM1 only: 5.67 +/- 4.27 vs 1.45 +/- 2.06, respectively (p = 0.008). The co-existence of the two diseases did not modify the remaining clinical and laboratory parameters. CONCLUSION: Patients with both DM1 and asthma have similar clinical characteristics to patients with only one of these diseases apart from a higher rate of hypoglycemic events compared to patients with DM1 without asthma.

The Long-Term Outcome of Boys With Partial Androgen Insensitivity Syndrome and a Mutation in the Androgen Receptor Gene.

BACKGROUND: In boys with suspected partial androgen insensitivity syndrome (PAIS), systematic evidence that supports the long-term prognostic value of identifying a mutation in the androgen receptor gene (AR) is lacking. OBJECTIVE: To assess the clinical characteristics and long-term outcomes in young men with suspected PAIS in relation to the results of AR analysis. METHODS: Through the International Disorders of Sex Development Registry, clinical information was gathered on young men suspected of having PAIS (n = 52) who presented before the age of 16 years and had genetic analysis of AR. RESULTS: The median ages at presentation and at the time of the study were 1 month (range, 1 day to 16 years) and 22 years (range, 16 to 52 years), respectively. Of the cohort, 29 men (56%) had 20 different AR mutations reported. At diagnosis, the median external masculinization scores were 7 and 6 in cases with and without AR mutation, respectively (P = .9), and median current external masculinization scores were 9 and 10, respectively (P = .28). Thirty-five men (67%) required at least one surgical procedure, and those with a mutation were more likely to require multiple surgeries for hypospadias (P = .004). All cases with an AR mutation had gynecomastia, compared to 9% of those without an AR mutation. Of the six men who had a mastectomy, five (83%) had an AR mutation. CONCLUSIONS: Boys with genetically confirmed PAIS are likely to have a poorer clinical outcome than those with XY DSD, with normal T synthesis, and without an identifiable AR mutation. Routine genetic analysis of AR to confirm PAIS informs long-term prognosis and management.

Type 1 diabetes environmental factors and correspondence analysis of HLA class II genes in the Yemenite Jewish community in Israel.

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.

Sexual precocity in boys: accelerated versus slowly progressive puberty gonadotropin-suppressive therapy and final height.

The indication for GnRH analog treatment in boys with central sexual precocity is based mainly on the age of onset of puberty. Our aim was to determine whether the rate of pubertal progression should also be taken into consideration. Included in the study were 81 boys with central sexual precocity: 27 with true precocious puberty (onset at <9 yr) and 54 with early puberty (onset at 9-10.5 yr). At the time of analysis, all had completed puberty, and 66 (22 central precocious puberty, 44 early puberty) had achieved final height. Progression of puberty (Tanner stage 2 to 3) was accelerated (0.5-1.32 yr) in 42 boys (16 central precocious puberty, 26 early puberty) and slow (1.7-2.9 yr) in 39 (11 central precocious puberty, 28 early puberty). The boys with accelerated puberty had significantly elevated T levels (central precocious puberty and early puberty, P < 0.001), faster growth rate (change in height SD score/duration: central precocious puberty, P < 0.05; early puberty, P < 0.01), and faster bone maturation rate (change in bone age/duration: central precocious puberty, P < 0.05; early puberty, P < 0.001). All 42 boys with accelerated puberty were treated with GnRH analog for 2.3-4.2 yr; the duration to completion of puberty and the height gain after therapy was discontinued were similar for the boys with central precocious puberty and early puberty. The 39 boys with slow puberty received no treatment and had a prolonged course of puberty (central precocious puberty, 5.05 +/- 0.3 yr; early puberty, 4.72 +/- 0.77 yr; average normal, 3.5 yr). The final height achieved in the 35 (11 central precocious puberty, 24 early puberty) untreated boys was within the range of their respective target height. The 31 (11 central precocious puberty, 20 early puberty) treated boys also achieved their genetic target height. Predictions based on the Bayley-Pinneau method at Tanner stage 3 for all boys and at discontinuation of therapy for treated boys overestimated the achieved final height (P < 0.001). In conclusion, boys with sexual precocity, whether central precocious puberty or early puberty, may have either accelerated or slow pubertal development. The decision to institute suppressive therapy should be based also on the rate of pubertal progression. Treatment should be offered only to those (either central precocious puberty or early puberty) with accelerated growth and bone maturation rates and rapid increase in T levels. Suppression therapy apparently converts accelerated puberty into nonsustained slow puberty and probably prevents compromised final height.

Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients.

The course of Graves' thyrotoxicosis in 7 prepubertal children (6.4+/-2.4 yr) was compared with that in 21 pubertal (12.5+/-1.1 yr) and 12 postpubertal (16.2+/-0.84 yr) patients. In the prepubertal group the main complaints were weight loss and frequent bowel movements (86%), whereas typical symptoms (irritability, palpitations, heat intolerance, and neck lump) occurred significantly less often (P < 0.01). The most prominent manifestation at diagnosis was accelerated growth and bone maturation: their height SD score was significantly greater than that of the pubertal and postpubertal patients (2.6+/-0.7 us. 0.15+/-0.65 and 0.15+/-0.9, respectively, P < 0.001), and their bone age to chronological age ratio was 1.39+/-0.35 compared with 0.98+/-0.06 in the pubertal children (P = 0.02). T3 levels were also significantly higher than in the other two groups (9.9+/-2.9 nmol/L vs. 6.32+/-1.9 nmol/L and 6.02+/-2.0 nmol/L, P = 0.01). All patients were initially prescribed antithyroid drugs (ATDs). Overall, adverse reactions to ATDs occurred in 35%, with a higher rate among the prepubertal children (71%) than the pubertal (28%) and postpubertal (25%) patients (P = 0.08). Major adverse reactions were noted in two children, both prepubertal. Remission was achieved in 10 patients (28%). Although the rate of remission did not differ among the three groups, time to remission tended to be longer in the prepubertal children (P = 0.09). In conclusion, thyrotoxicosis has an atypical presentation and more severe course in prepubertal children. Considering their adverse reactions to ATD, overall low remission rate, and long period to remission, definitive treatment should be considered earlier in this age group.

Standard and low-dose short adrenocorticotropin test compared with insulin-induced hypoglycemia for assessment of the hypothalamic-pituitary-adrenal axis in children with idiopathic multiple pituitary hormone deficiencies.

Insulin-induced hypoglycemia (IIH) is the gold standard test for assessment of the integrity of the hypothalamic-pituitary-adrenal (HPA) axis, but it may be hazardous. We sought to determine whether the standard (250 micrograms) or low-dose (1 microgram/1.73 m2) short ACTH test can replace IIH in patients with idiopathic multiple pituitary hormone deficiencies (MPHD). Three groups of subjects were studied: 1) control group, children with early or accelerated puberty and no other evidence of adrenal or pituitary pathology (n = 13, age 10.1 +/- 2.2 yr, 3 males); 2) patients with idiopathic hypothalamic pituitary insufficiency and either isolated GH deficiency or MPHD and preserved HPA function (n = 20, age 13.7 +/- 4.4 yr, 13 males); and 3) MPHD patients with impaired HPA axis function (n = 10, age 16.8 +/- 4.8 yr, 9 males). IIH and the 250 micrograms and 1 microgram/1.73 m2 ACTH tests were performed in groups 2 and 3; group 1 underwent only the ACTH tests. Pass peak cortisol level was defined as 520 nmol/L. No significant difference was noted between the standard and low-dose tests in the 30-min cortisol response to ACTH. Basal and peak cortisol levels attained on both ACTH tests were similar in groups 1 and 2 and significantly lower in group 3 (P < 0.0001). Both the 250 and 1 microgram ACTH tests were highly correlated with IIH (r = 0.71, P < 0.0001 for the 250 micrograms, r = 0.7, P < 0.0001 for the 1 microgram, n = 30), and both demonstrated high sensitivity (90% each) and specificity (100% and 90%, respectively) compared with IIH. We conclude that in idiopathic MPHD patients, both the standard and low-dose ACTH tests are equivalent to IIH in detecting HPA insufficiency. We suggest that they can replace IIH as a screening test for the integrity of the HPA axis in children with suspected MPHD.

Neonatal pig islets induce a lower T-cell response than adult pig islets in IDDM patients.

BACKGROUND: Pancreatic pig islets may provide a substitute in the future for difficult to obtain human islets for transplantation in insulin-dependent diabetes millitus (IDDM) patients. However, the immune response to xenografts may significantly hamper this approach. Because neonatal tissue is believed to be less immunogenic, we examined whether the T-cell response to neonatal pig islets differs from the response to adult islets. METHODS: The T-cell proliferative response to different concentrations of sonicated neonatal and adult pig islets, as well as to insulin and mitogens, was tested in 21 recent onset IDDM patients and 21 healthy controls. We determined the presence of various circulating islet autoantibodies and their association with the T-cell response in IDDM patients. RESULTS: In the IDDM patients, sonicated adult pig islets (at 1 microg protein/ml) induced a significantly higher frequency (12 of 21 vs. 1 of 21, p<0.001) and magnitude (2.58+/-0.44 vs. 1.38+/-0.13, p<0.02) of positive T-cell responses than neonatal islets at the same concentration. Similar results were obtained with a 10-fold higher concentration of islet sonicate. There was no significant association between the individual T-cell responses and the presence of circulating autoantibodies in IDDM patients. CONCLUSION: These results indicate that neonatal pig islets induce a lower T-cell reactivity than adult islets, suggesting that the neonatal tissue may be immunologically more suitable for future islet xenotransplantation.

Type 1 diabetes in Jewish Ethiopian immigrants in Israel: HLA class II immunogenetics and contribution of new environment.

The interrelationship between human leukocyte antigen immunogenetics and environmental factors and their contribution to the emergence of type 1 diabetes (T1D) were studied in Jewish immigrants from Ethiopia in Israel. This community displays high incidence of T1D, and is unique both by its ethnic segregation and its rapid exposure to a new environment after the immigration. The study population consisted of 152 Ethiopian Jews living in Israel, 33 with T1D and 119 unrelated controls. Human leukocyte antigen class II susceptible and protective alleles in the Jewish Ethiopian patients were similar to those in patients of other ethnic groups in Israel and in non-Jewish Ethiopian patients, with a few exceptions. Three haplotypes were markedly associated with diabetes in Jewish Ethiopian patients: DRB1*0301 DQA1*05 DQB1*02 (OR 4.4, p < 0.001); DRB1*0404 DQA1 03 DQB1*0302 (OR 19.2, p = 0.006), and DRB1*0405 DQA1*03 DQB1*0302 (OR 87.8, p < 0.001). The highly susceptible allele DRB1*0301 was more common in the general Ethiopian population (25.2%) than in all other ethnic groups in Israel, which may render this community prone to the disease. The age at onset of disease in patients with two susceptible haplotypes was negatively correlated with the duration of living in Israel (r = -0.621, p = 0.04). We concluded that ongoing exposure of genetically predisposed immigrants from Ethiopia to diabetogenic environmental factors eventually leads to a high incidence of overt diabetes in this ethnic group.

Immunogenetics of HLA class II in Israeli Ashkenazi Jewish, Israeli non-Ashkenazi Jewish, and in Israeli Arab IDDM patients.

The distribution of HLA class II alleles and genotypes in IDDM patients was examined in the three main Israeli ethnic groups: Ashkenazi Jews, non-Ashkenazi Jews, and Arabs. Molecular sequence specific oligonucleotide probe analysis was performed for DRB1, DQA1, and DQB1 genes. The DRB1*03011, DQA1*05 DQB1*02/DRB1*0402, DQA1*03, DQB1*0302 genotype was found to be the main susceptibility genotype in all three groups, with differences in the degree of association. In addition to DRB1*0402 (more frequent among Ashkenazi Jews), DRB1*0405, another subtype of DRB1*04, was found to be more prevalent among non-Ashkenazi Jews and Arabs. Many alleles were found to be negatively associated with insulin dependent diabetes mellitus (IDDM). This could be a result of the high frequency of susceptible alleles, or of linkage disequilibrium to a primary negatively associated allele. The strongest negative association was observed for DQB1*0301 in all three ethnic groups. The alleles DRB1*1401, DRB1*1501, DQB1*05031, DQB1*0602, and DQB1*0609 were not detected in any of the 202 IDDM patients, and are probably either strongly protective or in linkage with such alleles. Despite the differences found between the three ethnic groups, an overall analysis shows that the DRB1*04 alleles that account for susceptibility to IDDM in the Israeli population (DRB1*0402 and *0405) are the same as those responsible for susceptibility to IDDM in a number of other Mediterranean populations. In contrast, the susceptible allele in most Caucasian populations is DRB1*0401. It is noteworthy that the susceptible alleles DRB1*0402/05 for Mediterranean and DRB1*0401 for Caucasian populations are also frequent in the respective healthy populations. These findings support the results obtained in other studies, which point to a genetic relationship between the Israeli and Mediterranean populations.

HLA class II immunogenetics of IDDM in Yemenite Jews.

The association between HLA-DR and DQ and insulin dependent diabetes mellitus (IDDM) was analyzed in 47 patients and 76 controls of Yemenite Jewish origin. The IDDM susceptibility alleles DRB1*03011, DQA1*0501, DQB1*02 and DRB1*0402, DQA1*0301, DQB1*0302 found in Caucasians had a very strong predisposing effect also in the Yemenite IDDM group. The DRB1*07, DQA1*0201 and DQB1*02 alleles were found to have a strong negative association with IDDM. None of the patients carried DRB1*07 and DQA1*0201 compared with healthy controls (43.7%). Our analysis revealed that the DRB1*03011 DQA1*0501 DQB1*02/DRB1*04 DQA1*03 DQB1*0302 heterozygous genotype confers the highest susceptibility (59.6% in patients vs. 0% in controls). The homozygous DRB1*03 and DRB1*04 genotypes were also found to be positively associated with the disease. 81% of the patients compared to 1.3% of controls carried the susceptibility alleles on both haplotypes. In conclusion, the development of IDDM in Yemenite Jews is strongly dependent on the presence of the susceptibility HLA alleles and on the absence of the DRB1*07 haplotype. The Yemenite Jewish group is uniquely homogenous with regard to genetic susceptibility factors involved in the process of IDDM, and may thus be an ideal model for further genetic studies.

Non-classical 21-hydroxylase deficiency in infancy and childhood: the effect of time of initiation of therapy on puberty and final height.

OBJECTIVE: To review the characteristics of children with non-classical 21-hydroxylase deficiency (NC-21-OHD) diagnosed during infancy and childhood, and to evaluate the relationship of pubertal and bone age maturation at initiation of glucocorticoid therapy with the course of puberty and final height. DESIGN: We retrospectively compared the course of puberty, growth pattern and final height in two groups of patients: group A (two males, six females), hydrocortisone (HC) treatment 7.5-15 mg/m2 per 24 h, initiated > or = 1 year before onset of true puberty and group B (seven females), treatment started with the first signs of true puberty present. PARTICIPANTS: Thirteen girls and two boys with NC-21-OHD diagnosed at age range 0.5-10.6 years were followed-up for 9.0 +/- 3.8 years (mean +/- S.D). Therapy with HC was initiated because of signs of hyperandrogenism, accelerated growth and bone maturation, or true precocious puberty. The HC dose was adjusted according to linear growth and basal plasma androgen levels. RESULTS: Puberty and peak height velocity developed significantly earlier in the girls of group B: gonadarche at 7.9 +/- 1.4 years and peak height velocity at 9.2 +/- 1.4 years vs 10.2 +/- 0.4 years (P = 0.002) and 11.5 +/- 0.7 years (P = 0.006) in group A. Menarche, however, occurred only slightly earlier in group B (12.0 +/- 1.1 vs 12.8 +/- 0.5 years, P = 0.068). All eight children in group A achieved a final height within the range of their mean parental height standard deviation scores (SDS) in comparison with only 1/7 in group B (P = 0.0014). Seven of eight patients who started therapy before a bone age of 9 years achieved a final height within the parental height SDS range, compared with 2/7 who started therapy later (P = 0.041). The final height SDS was significantly better for group A (0.05 +/- 0.19, mean +/- S.E.M.) than group B (-1.63 +/- 0.23, P = 0.0007), even when adjusted for a significant effect of the mean parental height SDS (A. -0.63 +/- 0.28; B, -0.89 +/- 0.31, P = 0.0245, ANCOVA). CONCLUSION: Every child with signs of excess androgen activity or early puberty should be studied for the possibility of NC-21-OHD. Screening programs for populations with a high frequency of the gene for NC-21-OHD would facilitate early diagnosis and treatment. Pubertal stage and bone age at the introduction of therapy dictate height prognosis. Initiation of therapy before puberty with careful follow-up and HC dose adjustment can assure the achievement of genetic adult height.

Combined clonidine-short-ACTH test for the simultaneous assessment of growth hormone reserve and hypothalamic-pituitary-adrenal axis integrity in children.

OBJECTIVE: To determine the feasibility of using the combined oral clonidine and the short-ACTH test instead of the sometimes dangerous insulin-induced hypoglycemia test as a screening procedure, for the simultaneous assessment of growth hormone reserve and hypothalamic-pituitary-adrenal axis integrity in children with growth retardation. DESIGN: Evaluative study. METHOD: Seventy-three children (52 males) aged 11+/-3 years with attenuated growth (group 1) were tested by combined clonidine (150 microg/m(2)) and short-ACTH test (either the standard 250 microg or the low-dose 1 microg/1. 73 m(2)). Thirty-one children received no pretreatment (nonprimed) (subgroup 1NP), and 42 were primed with ethynylestradiol 40 microg/m(2)/day two days before testing (subgroup 1P). The control group for the short-ACTH test (group 2) consisted of 42 children and adolescents (13 males) aged 12+/-3 years with early or accelerated puberty or premature closure of epiphyses, who received ACTH only (21 standard, 21 low-dose) with no evidence of adrenal or pituitary pathology. The peak GH response was compared between the primed and the nonprimed group 1 subjects, and the cortisol levels were compared between the combined test subgroups and the controls. The peak pass level for growth hormone was 10 ng/ml; the peak pass level for cortisol was 520 nmol/l. RESULTS: Sixty-four of the 73 children in group 1 (87.7%) showed a growth hormone level of >/=10 ng/ml on the first stimulation test, including 26/31 (84%) nonprimed and 38/42 (90.5%) primed. Of the 9 patients who failed the first clonidine test, 4 also failed the second, primed test, including 1/5 nonprimed patients (20%) and 3/4 primed patients (75%). This yielded a GH deficiency/insufficiency rate of 5.5% and a rather low false-positive rate of 13.3% (4/30) for the nonprimed subjects and 2. 6% (1/39) for the primed subjects. Peak 30-min cortisol in response to ACTH stimulation was similar in the patients who underwent the 250 microg or the 1 microg test within each group (subgroup 1NP, subgroup 1P and group 2); therefore, the results for the two tests were considered together. Compared with group 2, subgroup 1NP patients had a similar 30-min cortisol response (P=NS), and subgroup 1P patients had a much higher response (P<0.05) (group 2=690+/-145 nmol/l, subgroup 1NP=772+/-195 nmol/l, subgroup 1P=934+/-209 nmol/l). However, there was no significant difference in the increment in cortisol response between the three groups. CONCLUSIONS: Our results suggest that the combined clonidine-short-ACTH test is a reliable and safe tool for the simultaneous assessment of growth hormone reserve and hypothalamic-pituitary-adrenal axis integrity in children.