Biomedical subjects

N Krone

Publications and source records attributed to N Krone.

10 recordsLinked to original sources

PubMed2006

Absence of exercise-induced leptin suppression associated with insufficient epinephrine reserve in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency suffer from glucocorticoid and mineralocorticoid deficiency. They have insufficient epinephrine reserves and increased basal leptin levels and are often insulin resistant. In healthy subjects, an inhibitory effect of acute catecholamine elevation on the leptin plasma concentrations has been reported. However, it is not yet known how leptin levels respond to exercise in CAH patients. METHODS: We performed a cycle ergometer test in six CAH patients to measure the response of plasma leptin, glucose and the catecholamines, epinephrine (E) and norepinephrine (N), as well as their respective metabolites, metanephrine (M) and normetanephrine (NM), to intense exercise. RESULTS: Baseline leptin concentrations in CAH patients were not different from those of controls. Leptin levels decreased significantly with exercise in healthy controls, whereas they remained unchanged in CAH patients. In contrast to controls, CAH patients showed no rise of plasma glucose. Basal and stimulated E and M levels were significantly lower in CAH patients compared to controls. Baseline and stimulated N and NM levels were comparable, showing a significant rise after exercise. Peak systolic blood pressure and peak heart rate in both groups were comparable. CONCLUSION: CAH patients do not manifest exercise-induced leptin suppression. The most probable reason for this is their severely impaired epinephrine stress response. In addition, epinephrine deficiency is leading to secondary changes in various catecholamine dependent metabolic pathways, e. g., energy balance. Although obvious clinical sequelae are so far unknown, the catecholamine-deficient state and the resulting hyperleptinemia might contribute to the severity of the disease in CAH.

Adolescent↗

PubMed2006

Three novel point mutations of the CYP21 gene detected in classical forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) [OMIM 201 910] is a group of autosomal recessive disorders most commonly due to 21-hydroxylase deficiency and presenting with a wide range of clinical manifestations. A limited number of inactivating pseudogene-derived mutations account for the majority of 21-hydroxylase gene ( CYP21) mutations, additional rare mutations can be found in single families and small populations. We found three novel CYP21 mutations in CAH patients suffering from the classical form of the disease, of which one is a frameshift mutation (1353-1354insA) leading to a premature termination codon (K277K, Q228A...E294X), one results in a premature stop codon (2551C>T, R444X), and one is a missense mutation (2609T>C; P463L). The frameshift and premature stop mutations can be predicted to result in a CYP21 protein without any residual enzyme activity. To determine the functional consequences of the P463L mutation, the IN VITRO enzyme activity was studied in COS-7 cells and revealed a reduced 21-hydroxylase activity of 2.6+/-0.8 (SD)% for the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol and of 3.0+/-0.5 % for the conversion of progesterone to 11-deoxycorticosterone (DOC). We conclude that functional analyses of unknown mutations provide information on the disease severity and should be always performed when novel CYP21 mutations are detected. Knowledge of the residual 21-hydroxylase function improves both genetic counselling and individual clinical management in CAH patients.

Adrenal Hyperplasia, Congenital↗

PubMed2006

Initially elevated TSH and congenital central hypothyroidism due to a homozygous mutation of the TSH beta subunit gene: case report and review of the literature.

Congenital central hypothyroidism (CCH) is a rare disease which can be caused by mutations in the gene for the thyrotropin (TSH) beta subunit ( TSHB). The diagnosis is usually delayed because the TSH serum levels in these patients are not elevated leading to a negative result in the neonatal TSH screening. Herein, we report a 2-year-old girl with CCH due to a mutation in the TSHB gene, in whom the unusual finding of an initially elevated TSH level complicated the diagnostic workup. The proposita, who had a supposedly normal TSH screening result, is a German girl of non-consanguineous parents. At 5 weeks of age, her thyroid function tests showed peripheral hypothyroidism with a moderately increased TSH (23.8 microIU/ml) so that thyroid hormone substitution was initiated. At the age of 2 years, the administration of TRH failed to increase the TSH serum concentrations, which prompted TSH measurements with two different assay systems. Variable TSH levels ranging from not detectable low to elevated were found so that central hypothyroidism due to a mutation in the TSHB gene was suspected. This was confirmed by molecular analysis of the TSHB gene, which identified a homozygous deletion (delta 313 T) in the coding sequence. This mutation has been found in the German population before and may be a founder mutation. We conclude that depending on the assay system variable TSH serum levels in individuals with mutations in the TSHB gene may complicate the diagnostic workup.

Child, Preschool↗

PubMed2004

Congenital adrenal hyperplasia - how to improve the transition from adolescence to adult life.

Congenital adrenal hyperplasia (CAH) is caused by a defect in the biosynthesis of cortisol that results in maximal activity of the hypothalamic-pituitary adrenal axis with hyperplasia of the adrenals and hyperandrogenism due to the accumulation of androgen precursors. In the salt-wasting subtype of the disorder, which accounts for appr. 75 % of patients with classical CAH, patients are unable to synthesise sufficient amounts of aldosterone and are prone to life-threatening salt-losing crises, whereas the simple virilising form is predominantly characterized by clitoris hypertrophy and posterior labial fusion. In addition, a non-classical variant can be discerned which in most cases is diagnosed at the time of puberty or early adolescence when hirsutism and menstrual irregularities may occur. The vast majority of CAH patients have 21-hydroxylase deficiency (90 - 95 %). Less common forms, such as 11beta-hydroxylase deficiency, will not be discussed in this review. Unfortunately, a considerable number of CAH patients is lost to regular and competent follow-up once they move out of paediatric care. This is most probably the result of insufficient co-operation between paediatric and adult endocrinologists at the time of transition from adolescence to adulthood. Furthermore, there is a lack of clinical guidance regarding psychosexual development in these patients. In this overview we will focus on special aspects of CAH treatment in adolescence and adulthood, and report on our 10-year experience with a transfer system for endocrine patients from paediatric to internal medical care, known as the "Kieler Modell". For practical purposes, we here provide charts for follow-up of CAH patients that can be adapted for use in any endocrine outpatient clinic.

Adolescent↗

PubMed2003

Chromatographic system for the simultaneous measurement of plasma 18-hydroxy-11-deoxycorticosterone and 18-hydroxycorticosterone by radioimmunoassay: reference data for neonates and infants and its application in aldosterone-synthase deficiency.

A new chromatographic system for the steroid precursor separation and a sensitive radioimmunoassay system for the subsequent measurement of 18-hydroxy-11-deoxycorticosterone and 18-hydroxycorticosterone has been developed. 18-Hydroxy-11-deoxycorticosterone and 18-hydroxycorticosterone were extracted with methylene chloride and separated from cross-reacting steroids by Sephadex LH-20 column chromatography. Anti-18-hydroxy-11-deoxycorticosterone and anti-18-hydroxycorticosterone antibodies raised in rabbits were used. The lower detection limit of the assay is 0.03 nmol/l and 0.128 nmol/l for 18-hydroxy-11-deoxycorticosterone and 18-hydroxycorticosterone, respectively. Normal values for this assay in 128 healthy neonates and infants aged 0-5 months were established as a basis for the early hormonal diagnosis of aldosterone synthase deficiency types I and II. Its application for the diagnosis of aldosterone synthase deficiency is demonstrated in two patients with homozygous mutation/deletion in the encoding CYP11B2 gene.

18-Hydroxycorticosterone↗

PubMed2001

CYP21 mutations in simple virilizing congenital adrenal hyperplasia.

We studied the functional and structural effects of two unique missense mutations in CYP21 found in patients with simple virilizing congenital adrenal hyperplasia. The rare variants L300F and V281G were found in two girls who were each hemizygous for one of the mutations. Functional analysis after expression in COS-1 cells revealed that the mutant enzymes had reduced enzymatic activity for conversion of both 17-hydroxyprogesterone (L300F 9.5%, V281G 3.9% of normal) and progesterone (L300F 4.4%, V281G 3.9% of normal). Both mutant enzymes had an increased degradation in mammalian COS-1 cells compared to the normal protein, although the L300F variant affected the degradation pattern to a greater extent. Our data indicate that the residue L300 is important in maintaining normal structure of the 21-hydroxylase enzyme whereas mutations affecting V281 most likely cause impaired enzyme activity by interfering with a specific function(s) of the protein.

17-alpha-Hydroxyprogesterone↗

PubMed2001

Mothers with congenital adrenal hyperplasia and their children: outcome of pregnancy, birth and childhood.

OBJECTIVES: Fertility rates in women with congenital adrenal hyperplasia (CAH) are reported to be poor, but few data are available. We assessed rates and course of pregnancy, mode of delivery and long-term outcome of offspring from women with CAH. DESIGN: A large cohort of women with CAH due to 21-hydroxylase deficiency had initially been diagnosed and followed at one centre. Those women who had given birth were contacted. Information was gathered from hospital records, direct patient contact, structured questionnaire and the Documentation of Pregnancy and Preventive Care Booklets. RESULTS: Between 1978 and 1998, 18 women with CAH (one salt wasting, 12 simple virilizing, five nonclassical) had given birth to 31 children (18 females, 13 males). Delivery was by Caesarean section in 16 out of the 31 children. None of the female newborns was masculinized. Twenty-nine children were born at term, five children were small for gestational age (SGA). Postnatal development was basically normal in all children; 18 are now older than 10 years, seven are between 5 and 10 years old, six are less than 5 years old. CONCLUSIONS: Fertility is reduced in females with CAH, especially those with the severe or salt wasting phenotype. In those women with CAH who do conceive, course and outcome of pregnancy is mostly uneventful, although the rate of SGA offspring may be increased. Psychomotor and somatic long-term development of the children was within normal limits.

Adrenal Hyperplasia, Congenital↗

PubMed2000

Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders. CAH is most often caused by deficiency of steroid 21-hydroxylase. The frequency of CYP21-inactivating mutations and the genotype-phenotype relationship were characterized in 155 well defined unrelated CAH patients. We were able to elucidate 306 of 310 disease-causing alleles (diagnostic sensitivity, 98.7%). The most frequent mutation was the intron 2 splice site mutation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7%) and large gene conversions (7.1%). Five point mutations were detected that have not been described in other CAH cohorts. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted functional consequences and compared to the clinical phenotype. The positive predictive value for null mutations (ppv(null)) was 100%, as all patients with these mutations had a salt-wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null mutation), the ppv(A) to manifest with salt-wasting CAH was 90%. In group B predicted to result in simple virilizing CAH (I172N in homozygous or compound heterozygous form with a more severe mutation), ppv(B) was 74%. In group C (P30L, V281L, P453S in homozygous or compound heterozygous form with a more severe mutation), ppv(C) was 64.7% to exhibit the nonclassical form of CAH, but 90% when excluding the P30L mutation. Thus, in general, a good genotype-phenotype relationship is shown in patients with either the severest or the mildest mutations. A considerable degree of divergence is observed within mutation groups of intermediate severity. As yet undefined factors modifying 21-hydroxylase gene expression and steroid hormone action are likely to account for these differences in phenotypic expression.

Adrenal Hyperplasia, Congenital↗

PubMed1999

A novel frameshift mutation (141delT) in exon 1 of the 21-hydroxylase gene (CYP21) in a patient with the salt wasting form of congenital adrenal hyperplasia. Mutation in brief no. 255. Online.

Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disease with a wide range of clinical manifestation. In 90-95% of the cases it is caused by 21-hydroxylase deficiency (OMIM #201910) due to mutations of the CYP21 gene (GDB Accession #M12792). In most cases the CYP21-inactivating point mutations are transferred by apparent gene conversions from CYP21P to CYP21. In only a few cases point mutations have been described, which are not present in the pseudogene. Using Southern blot analysis and DNA sequencing we have identified a novel mutation (141delT) of the CYP21 gene in a patient suffering from the salt wasting form of CAH. This results in a premature termination of a truncated protein at amino acid position 51 (L51X), which is likely to result in an enzyme with no activity. This novel mutation has not been reported to occur in the CYP21P alleles and it was not found in the CYP21P alleles in this CAH family.

Adrenal Hyperplasia, Congenital↗

PubMed1998

Comprehensive analytical strategy for mutation screening in 21-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease with a wide range of clinical manifestations. It is most often caused by deficiency of steroid 21-hydroxylase, reflecting any of a wide range of mutations in the 21-hydroxylase (CYP21) gene. A major challenge in molecular diagnostics of CAH is the high homology between the CYP21 gene and the CYP21P pseudogene and the phenomenon of apparent gene conversion, which inactivates the functional gene. In this study we devised an improved stepwise diagnostic procedure involving nonradioactive Southern blotting and direct DNA sequencing. This strategy led to a successful elucidation of the molecular cause of the disease in 181 out of 182 unrelated alleles in a total of 91 clinically and biochemically characterized patients. We were able to identify all classical known disease-causing mutations of the 21-hydroxylase gene and a novel nonsense mutation (bp 670, A-->C, Y97X). Our method also allows the reliable, secure diagnosis of the heterozygous configuration and may therefore be used for pre-, peri-, and postnatal diagnosis of CAH, even when informative data of the index patient are lacking. Furthermore, it can be used to confirm the diagnosis of CAH in newborns detected in 17-hydroxyprogesterone screening programs.

Adrenal Hyperplasia, Congenital↗