Browsing by Author "Portugal, Jorge"
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- Molecular analysis of the NR0B1 in three Portuguese families with X-linked Adrenal Hypoplasia CongenitaPublication . Pereira-Caetano, Iris; Toste Rêgo, Ana; Pereira, Bernardo; Portugal, Jorge; Raimundo, Luísa; Gonçalves, JoãoX-linked Adrenal Hypoplasia Congenita (X-linked AHC) is a rare disorder associated with acute adrenal insufficiency in the newborn age that typically cause vomiting, feeding difficulty, dehydration, and shock due to a salt-wasting episode. Hypoglycemia, frequently presenting with seizures, may be the first symptom. If untreated, adrenal insufficiency is lethal. Affected males, despite hormonal treatment, typically have delayed puberty (onset after age 14) caused by hypogonadotropic hypogonadism, and most of them are infertile at adult age. Carrier females may occasionally have symptoms of adrenal insufficiency or hypogonadotropic hypogonadism, possibly caused by skewed X-chromosome inactivation. X-linked AHC is caused by mutations in NR0B1 gene, a critical gene involved in the development of adrenals and hypothalamic-pituitary-gonadal axis. Since the identification of the NR0B1 gene, numerous mutations have been discovered including deletions, alterations of splice-sites, missense, nonsense and frameshift mutations. Here we present the molecular results obtained in three Portuguese families with NR0B1 mutations. Mutation analysis was performed by PCR followed by SSCP analysis and sequencing of DNA fragments showing abnormal patterns on a second PCR product, or by direct DNA cycle sequencing of PCR products. Molecular analysis of the NR0B1 gene in proband A revealed a nonsense mutation, c.1084A>T, p.Lys362*, in exon 1, not previously described. His mother and sister were asymptomatic carriers; in family B a nonsense mutation, c.243C>G; p.Tyr81*, also in exon 1, was identified in two affected males and their mother and sister were also asymptomatic carriers; in family C a frameshift mutation, c.1292delG, p.Ser431Ilefs*6, in exon 2, was detected in a 7 years old affected male and his mother. The maternal origin of mutations was confirmed in the three families studied. The identification of a NR0B1 mutation in a family has important implications: a correct clinical diagnosis can be established, appropriate clinical management of affected members and suitable genetic counselling can be offered, female carriers can be identified and disease can be prevented.
- X-linked Adrenal Hypoplasia Congenita: report of two families and a new NR0B1 mutationPublication . Pereira, Bernardo D.; Nunes, Tiago S.; Luiz, Henrique V.; Veloza, Andreia; Matos, Catarina; Cordeiro, Maria C.; Gonçalves, João; Raimundo, Luísa; Portugal, JorgeBackground: X-linked Adrenal Hypoplasia Congenita (X-linked AHC) tipically manifests as adrenal insufficiency in a bimodal clinical presentation (5–60 days and 2–13 years) and, at pubertal age, hypogonadotropic hypogonadism (HH) in males. It is caused by mutations in NR0B1 (present in Xp21.2), a gene with a critical role in the development of adrenals and hypothalamic-pituitary-gonadal (HPG) axis. It represents ~1% of all causes of primary adrenal insufficiency under age 18. We present two kindreds with NR0B1 mutations, one with a previously unreported mutation. Clinical case - family A: The proband presented with adrenal crisis at day 18 of life. Family history was relevant for an uncle death as a newborn. Hormonal assays revealed elevated ACTH (34,5 pmol/L, reference: <11), normal cortisol (220.8 nmol/L, reference: 56-665) and androgens (17-OHP: 9.9 nmol/L, reference: 7.5-24.6; 11-deoxycortisol: 83.52 nmol/L, reference: 47.9-260.9;), which showed no response to ACTH stimulation test and progressed to undectetable levels on serial measurements. From 6,8 years-old (yo) to 14 yo his height curve crossed from -0,1SD to -1,86SD, and at 14,1 yo testicular volume was 3mL. His gonadotropins (FSH 0.95 UI/L; LH <0.1 UI/L), total testosterone (TT, <0.35 nmol/L; reference: 0.5-17.5) and GnRH test (LH - basal: <0.1 UI/L; peak: 0.8 UI/L; FSH - basal: 0.67 UI/L; peak: 1.9 UI/L) confirming HH. Molecular analysis of the NR0B1 gene revealed the mutation c.1084A>T, leading to a premature stop codon, p.Lys362*, in exon 1. His mother and sister were both asymptomatic carriers for this mutation. This mutation, not described previously, leads probably to a non-functional truncated protein. Clinical case - family B: Kindred B had two males who presented with adrenal crisis at the newborn age (proband: 14 days; brother: 16 days). At 6 months of age, the proband had elevated ACTH (193.2 pmol/L, reference: <11) and elevated levels of cortisol (634 nmol/L, reference: 107-405) and 17-OHP (15.2 nmol/L; reference: 1.55-5.03), with no increase at Synacthen test (peak cortisol: 635 nmol/L; peak 17-OHP: 11.5 nmol/L). His affected brother had also elevated 17-OHP at presentation (48.5 nmol/L, reference: 7.5-24.6), but beyond the 1st year poor compliance with replacement therapy revealed persistently elevated ACTH (249.3 pmol/L) and undectectable androgens (17-OHP: <0,3 nmol/L; androstenedione <1 nmol/L; DHEA-S <0,27 nmol/L). Both cases had delayed bone age at 9 months (proband: 6 months of chronologic age) and 2 years (brother: 2,6 years of chronologic age). At 14 yo they had pubertal Tanner stage 1. Basal gonadotropin and TT levels were also prebubertal (proband: FSH 2.61 UI/L; LH <0.1 UI/L; TT <0.35, reference: 0.5-17.5; brother: FSH 0.4 UI/L; LH <0.1 UI/L; TT <0.35 nmol/L). NR0B1 molecular analysis allowed the identification of the nonsense mutation, c.234C>G; p.Tyr81*, in exon 1, present in the two affected males. His mother and one sister were also asymptomatic carriers. Conclusion: Our kindreds highlights the clinical aspects of the rare X-linked AHC and its challenging differential diagnosis. The diagnosis was based on …. Completar … and an apparently X-linked mode of inheritance. Molecular analysis of the NR0B1 gene allowed the identification of the molecular defect in both families. Two different nonsense mutation in exon 1 were identified, giving rise most probably to truncated non-functional proteins, confirming the disease severity or the clinical phenotype of the affected boys. Mutation identification was relevant for genetic counseling of the parents, as well as for the patient’s sisters.