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1/389. Normal female infants born of mothers with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

    women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, especially those patients with the salt-losing form, have decreased fertility rates. pregnancy experience in this population is limited. We report the pregnancy outcomes and serial measurements of maternal serum steroid levels in four women with classic 21-hydroxylase deficiency, three of whom were female pseudohermaphrodites with the salt-losing form. These glucocorticoid-treated women gave birth to four healthy female newborns with normal female external genitalia, none of whom were affected with 21-hydroxylase deficiency. In three women, circulating androgen levels increased during gestation, but remained within the normal range for pregnancy during glucocorticoid therapy. In the fourth patient, androgen levels were strikingly elevated during gestation despite increasing the dose of oral prednisone from 5 to 15 mg/day (two divided doses). Notwithstanding the high maternal serum concentration of androgens, however, placental aromatase activity was sufficient to prevent masculinization of the external genitalia of the female fetus and quite likely the fetal brain, consistent with the idea that placental aromatization of androgens to estrogens is the principal mechanism that protects the female fetus from the masculinizing effects of maternal hyperandrogenism. These four patients highlight key issues in the management of pregnancy in women with 21-hydroxylase deficiency, particularly the use of endocrine monitoring to assess adrenal androgen suppression in the mother, especially when the fetus is female. Recommendations for the management of pregnancy and delivery in these patients are discussed.
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2/389. Identification of CYP21 mutations, one novel, by single strand conformational polymorphism (SSCP) analysis. Mutations in brief no. 218. Online.

    Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a common autosomal recessive disorder (MIM# 201910) due to mutations in the 21-hydroxylase (CYP21) gene (GDB Accession # M12792). Using our protocol for single strand conformational polymorphism (SSCP) analysis, we have identified two mutations not known to exist in the 21-hydroxylase pseudogene (CYP21P). One mutation involving codon 169, TGC to AC appears to be novel. The 46,XX patient carried the codon 169 mutation on her paternal allele and a large gene deletion/conversion event on her maternal allele. This patient had been referred in the immediate neonatal period for the evaluation of genital ambiguity and had developed hyponatremia and hyperkalemia. The second patient presented with premature pubic hair. She carried R356Q on her maternal allele and V281L on her paternal allele.
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3/389. Failure of cortisone acetate treatment in congenital adrenal hyperplasia because of defective 11beta-hydroxysteroid dehydrogenase reductase activity.

    Congenital adrenal hyperplasia in children is often treated with cortisone acetate and fludrocortisone. It is known that certain patients with congenital adrenal hyperplasia require very high substitution doses of cortisone acetate, and a few patients do not respond to this treatment at all. A patient with 21-hydroxylase deficiency, for whom elevated pregnanetriol (P3) levels in urine were not suppressed during treatment with cortisone acetate (65 mg/m2 x day), was examined. The activation of cortisone to cortisol was assessed by measuring urinary metabolites of cortisone and cortisol. The patient's inability to respond to treatment with cortisone acetate was found to be caused by a low conversion of cortisone to cortisol, assumed to be secondary to low 11beta-hydroxysteroid dehydrogenase activity (11-oxoreductase deficiency). All exons and exon/intron junctions of the 11beta-hydroxysteroid dehydrogenase type1 gene (HSD11L) were sequenced without finding any mutations, but a genetic lesion in the promoter or other regulatory regions cannot be ruled out. The deficient 11-oxoreductase activity seems to have been congenital, in this case, but can possibly be attributable to a down-regulation of the enzyme activity. The results support the use of hydrocortisone, rather than cortisone acetate, for substitution therapy in adrenal insufficiency.
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4/389. aldosterone production despite absence or defectiveness of the CYP21 genes in two patients with salt-losing congenital adrenal hyperplasia caused by steroid 21-hydroxylase deficiency.

    aldosterone and cortisol were found in plasma samples from two patients with salt-losing congenital adrenal hyperplasia caused by steroid 21-hydroxylase deficiency. One patient had a CYP21 gene deletion on one chromosome and a mutation causing erroneous mRNA splicing on the other. The other patient had a CYP21 gene deletion on one chromosome and a large scale conversion of CYP21 to CYP21P on the other. All CYP21P-like genes in these patients were defective, since they carried a deleterious 8 bp deletion in the third exon. After HPLC purification of the patients' plasma samples, cortisol was no longer detectable in the radioimmunoassay, but aldosterone levels were still within or slightly above the normal reference range. aldosterone dropped to very low levels after steroid replacement therapy had taken effect. In at least one of these patients, the genetic defect rules out normal functioning of the adrenocortical steroid 21-hydroxylase, which implies involvement of an alternative enzyme system.
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5/389. A novel frameshift mutation 840delA and a novel polymorphism D203A in the steroidogenic acute regulatory protein gene in a Japanese patient with congenital lipoid adrenal hyperplasia. Mutations in brief no. 117. Online.

    Congenital lipoid adrenal hyperplasia (CLAH) is an autosomalrecessive disorder characterized by impaired production of all steroids including glucocorticoids, mineralocorticoids and sexsteriods. It has recently been reported that mutations in the steriodogenic acute regulatory protein (StAR) gene cause CLAH. We analyzed the StAR gene in a Japanese patient with CLAH. The patient was revealed to be a compound heterozygote bearing a nonsense mutation Q258X, changing codon 258 (CAG) encoding Gln to the stop codon TAG, and a novel framshift mutation 840delA resulting from deletion of one of the three adenosines normally present in codon 238 (AAA), thus leading to a frameshift after codon 237 (Thr) in the StAR gene. The patient was also revealed to be homozygous for a novel missense point mutation D203A, changing codon 203 (GAC) encoding Asp to GCC encoding Ala in the StAR gene. To elucidate the significance of the D203A mutation, we analyzed the StAR gene sequence in twenty normal subjects, and found that all of them were homozygous for the D203A mutation, indicating that the D203A mutation is an innocent polymorphism. In conclusion, we have identified a novel frameshift mutation 840delA which seems to cause 840delA and the first polymorphism D203A in the human StAR gene.
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6/389. Gonadal histology with testicular carcinoma in situ in a 15-year-old 46,XY female patient with a premature termination in the steroidogenic acute regulatory protein causing congenital lipoid adrenal hyperplasia.

    Mutations in the steroidogenic acute regulatory protein (StAR) gene cause congenital lipoid adrenal hyperplasia, characterized by diminished or absence of adrenal and gonadal steroids, resulting in severe adrenal insufficiency and ambiguous or complete female external genitalia in genetic males. We report on a 15-yr-old 46,XY phenotypic female, referred because of lack of pubertal development. ACTH and gonadotropin concentrations were elevated; and aldosterone, cortisol and its precursors, and sex steroids before and after stimulation were below the lower limit of detection. In the StAR gene, a homozygous nonsense mutation (TGG --> TAG) in exon 7 (W250X) was identified. Histologic examination after gonadectomy showed seminiferous tubules containing immature sertoli cells and a few single germ cells with positive placental-like alkaline phosphatase immunoreactivity, indicating carcinoma in situ. This is the first report on testicular morphology, at a pubertal age, in a female patient with 46,XY karyotype and a mutation in the StAR gene, in whom gonadal neoplasia had developed.
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7/389. Unilateral adrenal medullary hyperplasia: another form of curable hypertension?

    A case of unilateral adrenal medullary hyperplasia is presented in a 49-year-old caucasian female without multiple endocrine neoplasia association. The patient presented with episodic hypertension and paroxysms suggesting an underlying phaeochromocytoma. Biochemical supported this diagnosis but no discrete tumour was found on preoperative localising studies or at the time of surgery. The patient underwent a unilateral adrenalectomy with confirming adrenal medullary hyperplasia with complete resolution of her symptoms for six months.
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8/389. Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.

    McCune-Albright syndrome consists of fibrous dysplasia of bone, cafe-au-lait skin pigmentation, and endocrine dysfunction (usually precocious puberty). Other endocrine abnormalities occur in a minority of patients, and of these, Cushing's syndrome is the least often recognized. We present 5 children (4 girls) with features of McCune-Albright syndrome who had Cushing's syndrome in the infantile period (<6 months). In 2 children spontaneous resolution occurred, but the remaining 3 required bilateral adrenalectomy. In addition, all 4 girls have experienced precocious puberty, and 3 children demonstrated radiologic evidence of nephrocalcinosis. Understanding of the underlying defect causing McCune-Albright syndrome emphasizes the importance of searching for other endocrine dysfunction in these children.
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9/389. A microdeletion within DAX-1 in X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism.

    BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is a developmental disorder characterized by primary adrenal gland failure, which produces extreme and potentially fatal endocrine deficiencies. Hypogonadotrophic hypogonadism (HHG) also may be associated with AHC. AHC has been shown to result from a variety of mutations in the DAX-1 gene, which encodes a member of the nuclear hormone receptor superfamily. methods: The proband, one of the world's oldest living patients with AHC and HHG, was diagnosed in 1955. He was on corticosteroid replacement therapy since that time and androgen replacement therapy since puberty. We sequenced his DAX-1 gene. RESULTS: We found a 4 bp ACTC deletion between nucleotides 1464 and 1467 in the second exon of the normal DAX-1 sequence. This mutation caused a shift in the reading frame and predicted a premature stop codon at amino acid position 416. The mutation abolished a recognition site for DdeI, allowing for confirmation by restriction analysis. CONCLUSIONS: The position of the mutation confirms the functional importance of the COOH-terminal 10% of the DAX-1 sequence. The clinical history also reinforces the importance of early diagnosis in AHC, which can be associated with longevity and no obvious morbidity after more than 40 years of hormone replacement therapy.
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10/389. Fluorescent PCR and automated fragment analysis in preimplantation genetic diagnosis for 21-hydroxylase deficiency in congenital adrenal hyperplasia.

    Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease which is most often caused by a deficiency in steroid 21-hydroxylase. The disease is characterized by a range of impaired adrenal cortisol and aldosterone synthesis combined with an increased androgen synthesis. These metabolic abnormalities lead to an inability to conserve sodium and virilization of females. The most common mutation causing the severe form of CAH is a conversion of an A or C at nucleotide (nt) 656 to a G in the second intron of the steroid 21-hydroxylase gene (CYP21) causing aberrant splicing of mRNA. A couple was referred to our centre for preimplantation genetic diagnosis (PGD) for 21-hydroxylase deficiency in CAH. A PGD was set up to detect the nt656 A/C-->G mutation using fluorescent polymerase chain reaction (PCR) and subsequent restriction enzyme digestion and fragment analysis on an automated sequencer. Using dna or single cells from the father, the normal allele could not be amplified. Non-amplification of the normal allele has been previously described in asymptomatic carriers, therefore the PCR was further developed using heterozygous lymphoblasts from the mother. The PCR was shown to be highly efficient (96% amplification), accurate (0% contamination) and reliable (0% allelic drop-out). The couple started PGD treatment and the second PGD cycle resulted in a twin pregnancy. The genotype of the fetuses was determined in our laboratory using chorionic villus sampling material using the method described here. Both fetuses were shown to be heterozygous carriers of the mutation, and two healthy girls were born.
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