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Biomedical subjects

M I New

Publications and source records attributed to M I New.

At least 37 records · Page 2Linked to original sources
PubMed1999

Steroid disorders in children: congenital adrenal hyperplasia and apparent mineralocorticoid excess.

Our research team and laboratories have concentrated on two inherited endocrine disorders, congenital adrenal hyperplasia (CAH) and apparent mineralocorticoid excess, in thier investigations of the pathophysiology of adrenal steroid hormone disorders in children. CAH refers to a family of inherited disorders in which defects occur in one of the enzymatic steps required to synthesize cortisol from cholesterol in the adrenal gland. Because of the impaired cortisol secretion, adrenocorticotropic hormone levels rise due to impairment of a negative feedback system, which results in hyperplasia of the adrenal cortex. The majority of cases is due to 21-hydroxylase deficiency (21-OHD). Owing to the blocked enzymatic step, cortisol precursors accumulate in excess and are converted to potent androgens, which are secreted and cause in utero virilization of the affected female fetus genitalia in the classical form of CAH. A mild form of the 21-OHD, termed nonclassical 21-OHD, is the most common autosomal recessive disorder in humans, and occurs in 1/27 Ashkenazic Jews. Mutations in the CYP21 gene have been identified that cause both classical and nonclassical CAH. Apparent mineralocorticoid excess is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, and low to undetectable levels of potassium, renin, and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11beta-hydroxysteroid dehydrogenase type 2. In 1998, we reported a mild form of this disease, which may represent an important cause of low-renin hypertension.

Adrenal Hyperplasia, Congenital↗
PubMed1999

Intrauterine growth retardation associated with maternal uniparental disomy for chromosome 6 unmasked by congenital adrenal hyperplasia.

We report the first case of maternal uniparental disomy for chromosome 6 (UPD6mat) ascertained through congenital adrenal hyperplasia (CAH), which arose because of reduction to homozygosity of an autosomal recessive mutation. This case suggests that UPD6mat is associated with intrauterine growth retardation (IUGR). A case of paternal UPD (involving only the short arm of chromosome 6) ascertained as CAH has previously been reported, but was not stated to have IUGR. Our patient was born with IUGR followed by extraordinarily good catch-up growth. She had a history of a marked lag in motor development. She presented at 2.65 y of age with pubarche of 3 mo duration, clitoral enlargement, and an advanced bone age. Simple virilizing CAH was diagnosed by elevations of plasma 17-hydroxyprogesterone and testosterone. Mutation analysis showed that the CAH was due to homozygosity for the 1172N exon 4 mutation. When parental DNA was examined, the mother was found to be heterozygous for the uncommon exon 4 mutation, while the father had no detectable mutations. DNA microsatellite analysis was subsequently performed on the patient and parents using polymorphic markers spanning the entire chromosome 6. Seven markers were informative for inheritance of a single maternal allele and absence of paternal alleles in the proband. Analysis of microsatellite markers from other chromosomes confirmed biparental inheritance at these loci. This combination of findings is diagnostic of UPD6mat. The only other reported case of UPD6mat was discovered serendipitously when genotyped for renal transplantation; this patient had a history of IUGR. Since both cases of UPD6mat had IUGR, the phenotype appears to include IUGR as well as the potential to unmask an autosomal recessive trait.

Adrenal Hyperplasia, Congenital↗
PubMed1999

Congenital adrenal hyperplasia (21-hydroxylase deficiency) without demonstrable genetic mutations.

Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency (21-OHD) is the most common inherited defect of adrenal steroid biosynthesis. At least 36 mutations in the CYP21 gene, which is mapped to chromosome 6p21.3, have been described. We performed genetic analysis of the CYP21 gene in a patient with classic 21-OHD CAH and her family. The entire exonic coding regions and intronic regions, as well as the -1 kb 5' upstream promoter region, were thoroughly sequenced and analyzed. Despite extensive sequencing, no mutation was found in this 3.7 kb area. The 11beta-hydroxylase defect, closely mimicking the clinical and biochemical phenotype of classic 21-OHD, was excluded by directly sequencing 2.6 kb covering the entire coding of the CYP11B1 gene. Herein we describe a phenotypically and hormonally affected patient with classic simple virilizing 21-OHD CAH who lacks a mutation in the entire CYP21 gene and coding region of the CYP11B1 gene.

Adrenal Hyperplasia, Congenital↗
PubMed1999

Resistance to several steroids in two sisters.

A 14-yr-old native American girl from the Iroquois Nation was referred as a potential patient with the syndrome of apparent mineralocorticoid excess. Instead, her evaluation revealed resistance to glucocorticoids, mineralocorticoids, and androgens, but no resistance to vitamin D or thyroid hormones. She lacked Cushingoid features despite significantly high cortisol levels. Menstruation was regular, and there was no clinical evidence of masculinization despite high serum androgen levels in the male range. The patient's sister had similar clinical features. Partial resistance to exogenous glucocorticoid and mineralocorticoid administration was well demonstrated in both patients. It is proposed that these patients represent the first cases of partial resistance to multiple steroids, possibly due to a coactivator defect.

Adolescent↗
PubMed1999

Prevalence of mild apparent mineralocorticoid excess in Mennonites.

UNLABELLED: We have studied an unusual patient with mild low-renin hypertension due to a homozygous mutation in the HSD11B2 gene (PNAS 95:10200-10205, 1998). The patient came from an inbred Mennonite family, and though the mutation identified her as an AME patient, she had a normal birth weight and did not demonstrate the typical features of AME, such as hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and in many cases nephrocalcinosis. Biochemically, typical patients with AME have abnormal cortisol metabolites and an exceedingly diminished ability to convert [11-3H]cortisol to cortisone. In this patient with mild AME, the conversion of cortisol to cortisone was 58% compared to 0 to 6% in typical AME patients, while the normal conversion is 90 to 95%. Molecular analysis of the HSD11B2 gene of this patient showed a homozygous mutation in codon 227 (P227L). We studied this Mennonite population for the prevalence of the P227L mutation. Our hypothesis was that this mild form of AME would be prevalent in the somewhat inbred Mennonite population to which the patient belongs. Our proposed study was 1) to determine if there are other cases of this mild form of AME, and 2) to establish the heterozygote frequency of the mutation in the Mennonites. RESULTS: We did not detect any additional cases of mild AME. We detected 15 carriers of the P227L mutation out of 445 Mennonites, resulting in a heterozygote frequency of 0.03. CONCLUSION: Since this is an inbred population, the chance of two heterozygotes marrying would be 0.001, which is 1 in 1000 people. This population is known to have large families and therefore the possibility of having an affected child is high. The population consists of 2000 members and we have discovered one affected patient. Thus, there might be one other patient in this population.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Prenatal diagnosis and treatment of 11beta-hydroxylase deficiency congenital adrenal hyperplasia resulting in normal female genitalia.

Congenital adrenal hyperplasia (CAH) consists of autosomal recessive disorders of cortisol biosynthesis, which in the majority of cases result from 21-hydroxylase deficiency. Another enzymatic defect causing CAH is 11beta-hydroxylase deficiency. In both forms, the resulting excessive androgen secretion causes genital virilization of the female fetus. For over 10 yr female fetuses affected with 21-hydroxylase deficiency have been safely and successfully prenatally treated with dexamethasone. We report here the first successful prenatal treatment with dexamethasone of an affected female with 11beta-hydroxylase deficiency CAH. The family had two girls affected with 1beta-hydroxylase deficiency born with severe ambiguous genitalia who were both homozygous for the T318M mutation in the CYP11B1 gene, which codes for the 11beta-hydroxylase enzyme. In the third pregnancy in this family, the female fetus was treated in utero by administering dexamethasone to the mother, starting at 5 weeks gestation. The treatment was successful, as the newborn was not virilized and had normal female external genitalia. A second family with two affected sons was also studied in preparation for a future pregnancy. We report a novel 1-bp deletion in codon 394 (R394delta1) in the CYP11B1 gene in this family.

Adrenal Hyperplasia, Congenital↗
PubMed1998

A genetic defect resulting in mild low-renin hypertension.

Severe low-renin hypertension has few known causes. Apparent mineralocorticoid excess (AME) is a genetic disorder that results in severe juvenile low-renin hypertension, hyporeninemia, hypoaldosteronemia, hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and in many cases nephrocalcinosis. In 1995, it was shown that mutations in the gene (HSD11B2) encoding the 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11beta-HSD2) cause AME. Typical patients with AME have defective 11beta-HSD2 activity, as evidenced by an abnormal ratio of cortisol to cortisone metabolites and by an exceedingly diminished ability to convert [11-3H]cortisol to cortisone. Recently, we have studied an unusual patient with mild low-renin hypertension and a homozygous mutation in the HSD11B2 gene. The patient came from an inbred Mennonite family, and though the mutation identified her as a patient with AME, she did not demonstrate the typical features of AME. Biochemical analysis in this patient revealed a moderately elevated cortisol to cortisone metabolite ratio. The conversion of cortisol to cortisone was 58% compared with 0-6% in typical patients with AME whereas the normal conversion is 90-95%. Molecular analysis of the HSD11B2 gene of this patient showed a homozygous C-->T transition in the second nucleotide of codon 227, resulting in a substitution of proline with leucine (P227L). The parents and sibs were heterozygous for this mutation. In vitro expression studies showed an increase in the Km (300 nM) over normal (54 nM). Because approximately 40% of patients with essential hypertension demonstrate low renin, we suggest that such patients should undergo genetic analysis of the HSD11B2 gene.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Normal external genitalia in a female with classical congenital adrenal hyperplasia who was not treated during embryogenesis.

Classical congenital adrenal hyperplasia (CAH) results from an inherited enzymatic defect in cortisol synthesis and more than 90 per cent of cases are due to 21-hydroxylase deficiency. The androgen excess associated with this condition typically results in ambiguous external genitalia in affected females. It has been shown that prenatal treatment with dexamethasone is successful in preventing or reducing genital ambiguity in affected females. Rather than treating with dexamethasone, some couples choose to terminate the pregnancy when an affected fetus is prenatally diagnosed. We report a female with classical CAH who was born with normal external genitalia, although maternal treatment with dexamethasone did not begin until 16 weeks' gestation.

Adrenal Hyperplasia, Congenital↗
PubMed1998

DAX1 mutations map to putative structural domains in a deduced three-dimensional model.

The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1.

Adrenal Glands↗
PubMed1998

Diagnosis and management of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia is a family of inborn errors of steroidogenesis, each characterized by a specific enzyme deficiency that impairs cortisol production by the adrenal cortex, and can lead to sexual ambiguity in both genetic males and females. The enzymes most often affected are 21-hydroxylase, 11 beta-hydroxylase, and 3 beta-hydroxysteroid dehydrogenase, and less often, 17 alpha-hydroxylase/17, 20-lyase and cholesterol desmolase. Decreased production of cortisol results in increased pituitary secretion of adrenocorticotropic hormone. The elevated adrenocorticotropic hormone stimulates both the accumulation of precursor steroids in the impeded pathways and excessive steroid synthesis in other adrenal biosynthetic pathways unaffected by the enzyme deficiency. Correct identification of the enzyme affected is achieved by the observation of clinical syndromes reflecting distinct hormonal patterns, and it is measured quantitatively as low levels of cortisol and other adrenal steroids, as well as increased levels of steroids proximal to the blocked step. Many of the corresponding genes for the described enzymes have been isolated and characterized, and specific mutations causing many cases of congenital adrenal hyperplasia have been identified. These advances have important implications for early prenatal diagnosis and prenatal treatment.

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

Examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess.

Apparent mineralocorticoid excess (AME) is a genetic disorder causing pre- and postnatal growth failure, juvenile hypertension, hypokalemic metabolic alkalosis, and hyporeninemic hypoaldosteronism due to a deficiency of 11 beta-hydroxysteroid dehydrogenase type 2 enzyme activity (11 beta HSD2). The 11 beta HSD2 enzyme is responsible for the conversion of cortisol to the inactive metabolite cortisone and therefore protects the mineralocorticoid receptors from cortisol intoxication. Several homozygous mutations are associated with this potentially fatal disease. We have examined the phenotype, biochemical features, and genotype of 14 patients with AME. All of the patients had characteristic signs of a severe 11 beta HSD2 defect. Birth weights were significantly lower than those of their unaffected sibs. The patients were short, underweight, and hypertensive for age. Variable damage of one or more organs (kidneys, retina, heart, and central nervous system) was found in all of the patients except one. The follow-up studies of end-organ damage after 2-13 yr of treatment in six patients demonstrated significant improvement in all patients. The urinary metabolites of cortisol demonstrated an abnormal ratio with predominance of cortisol metabolites, i.e. tetrahydrocortisol plus 5 alpha-tetrahydrocortisol/tetrahydrocortisone was 6.7-33, whereas the normal ratio is 1.0. Infusion of [11-3H]cortisol resulted in little release of tritiated water, indicating the failure of the conversion of cortisol to cortisone. Thirteen mutations in the HSD11B2 gene have been previously published, and we report three new genetic mutations in two patients, one of whom was previously unreported. All of the patients had homozygous defects except one, who was a compound heterozygote. Our first case had one of the most severe mutations, resulting in the truncation of the enzyme 11 beta HSD2, and died at the age of 16 yr while receiving treatment. Three patients with identical homozygous mutations from different families had varying degrees of severity of clinical and biochemical features. Due to the small number of patients with identical mutations, it is difficult to correlate genotype with phenotype. In some cases, early and vigilant treatment of AME patients may prevent or improve the morbidity and mortality of end-organ damage such as renal or cardiovascular damage and retinopathy. The outcome of treatment in more patients may establish the efficacy of treatment.

Adolescent↗
PubMed1997

Prenatal diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency) in Croatia.

We report on the prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase in 20 at-risk pregnancies (16 salt-wasting and 4 simple virilizing families). We have diagnosed 3 affected fetuses (2 males and 1 female), 3 healthy homozygotes (2 males and 1 female), and 14 healthy heterozygotes (7 females and 7 males). These data were collected over 4 years. In 16 fetuses, the diagnosis was made with measurements of 17-hydroxyprogesterone (17-OHP) and delta-4-androstenedione (delta) in amniotic fluid (AF), human leukocyte antigen (HLA) typing of amniotic cells, as well as karyotypes between the 16th and 18th weeks of gestation. In 4 fetuses, DNA analysis of amniotic cells was also performed. In 3 pregnancies in which affected fetuses were suspected (on the basis of HLA typing and measurements of 17-OHP and delta concentrations in AF), the fetuses were electively aborted between the 17th to 19th weeks of gestation by parental decision. In all aborted fetuses, diagnosis was confirmed with HLA typing, autopsy findings of hyperplastic adrenal glands, and ambiguous genitalia in female fetuses. Postnatal diagnosis was confirmed in healthy fetuses with HLA typing and serum measurements of 17-OHP concentrations, and in 4 of them with DNA analysis. In 3 of the 4 families, DNA analyses revealed the following mutations: in Family 1, the index case mutation was Intron 2, Exon 3/Exon 6, and the fetus was Normal/Exon 6; in Family 2, the index case mutation was Ex1 Int2 Ex3/ Int2, and the fetus was Ex1 Int2 Ex3/Normal; and in Family 3, the index case mutation was Ex8(356)/Ex8(356), and the fetus was Ex8(356)/ Normal. We also report one case of prenatal diagnosis and treatment. Dexamethasone 0.5 mg BID (20 micrograms/kg/d) was given starting at 6th week of gestation. Prenatal diagnosis suggested, but did not prove, that the female fetus was a heterozygote as the fetus lacked the paternal mutation Ex8(318). No mutation was found in the mother. The fetus, the mother, and the affected sib shared a haplotype, further suggesting heterozygosity. The unaffected status was confirmed postnatally.

17-alpha-Hydroxyprogesterone↗
PubMed1997

Magnetic resonance imaging in the congenital adrenal hyperplasia population: increased frequency of white-matter abnormalities and temporal lobe atrophy.

Congenital adrenal hyperplasia results from an adrenal enzyme deficiency, that causes an underproduction of glucocorticoids and sometimes mineralocorticoids and a resultant overproduction of androgens, until treatment with replacement glucocorticoids is instituted. The goal of this study was to determine the frequency and etiology of white-matter changes and temporal lobe atrophy demonstrable on magnetic resonance imaging (MRI) in a group of children and young adults with congenital adrenal hyperplasia. About one third of the patients evidenced white-matter abnormalities or temporal lobe atrophy. All patients, except one with a known stroke, had normal neurologic examinations. Exposure to excess exogenous glucocorticoids in the process of being treated for congenital adrenal hyperplasia is the most theoretically appealing explanation for these MRI findings. However, the relationship of MRI findings to treatment status (over-versus under-suppressed) does not run in clear parallel.

Adolescent↗
PubMed1997

Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism (GRA) is a rare form of inherited hypertension caused by a characteristic gene duplication. With the advent of definitive genetic testing for GRA, the performance of the traditional screening test for GRA, the dexamethasone suppression test (DST), can be evaluated. We compared the DST to direct genetic testing in 24 patients referred for genetic screening for GRA (12 GRA positive and 12 GRA negative) based on clinical and biochemical findings, DST, and family history. Plasma aldosterone was measured before and after oral dexamethasone administration to determine the extent to which aldosterone was suppressed by glucocorticoids in each patient group. The results of the DST in these subjects were also compared to those in 19 historical patients with primary aldosteronism [4 bilateral hyperplasia and 15 aldosterone-producing adenoma (APA)] reported previously. The DST differentiated GRA-positive from GRA-negative patients with 92% sensitivity and 100% specificity. Cutoffs based on the post-DST plasma aldosterone level (< 4 ng/dL) or percent suppression compared to baseline (> 80%) were equally effective in correctly diagnosing GRA (only one GRA-positive patient would have been incorrectly diagnosed). However, DST in 15 APA patients revealed that 33% had greater than 80% suppression of aldosterone, and 1 had aldosterone levels below 4 ng/dL. We conclued that a post-DST aldosterone level below 4 ng/dL will correctly diagnose GRA patients with high sensitivity and specificity. Suppression compared to baseline can be misleading, as evidenced by the results in APA patients and referred subjects who genetically screened negative.

Adrenocorticotropic Hormone↗