CYP21A2 AND CYP11B1: FIRST REPORT OF A DIGENIC INHERITANCE IN CAH.

Background Congenital adrenal hyperplasia is caused mostly by 21-hydroxylase deficiency (>90%) and 11 f-hydroxylase deficiency (5\u20138%). Both enzymes are required for cortisol synthesis and the non classical (NC) phenotype of both deficiencies is characterized by hyper-androgenic manifestations in childhood/adolescence. Objectives To complete the characterization of a NC case in which the identified CYP21A2 mutations do not mach completely the phenotype by analysis of the CYP11B1 gene. Population and/or methods Case: female that present: precocious puberty at 5,5 yrs; at 6,7 yrs advanced bone age (10 yrs), hypertrophic clitoris and the following hormonal data: 17-OHP 8200/14600 ng/dl, ACTH 66 pg/ml; T 0.98 ng/ml; Cortisol 190/170 ng/ml; D4-A 315/377 ng/dl. A therapy with hydrocortisone (5 mg x3/die) has been started. A first clinical diagnosis of NC-21OHD was made. Genetic analysis of CYP21A2 and CYP11B1 genes was performed as previously described. Results The sequencing analysis of CYP21A2 gene revealed the presence of 3 mutations: Q318X (null), A391T (mild) and *13 G>A 3\u2019UTR (very mild) all carried by the maternal allele. Complete sequencing of the paternal CYP21A2 gene do not show any alterations. The MLPA analysis of the family revealed a normal arrangement of the locus, therefore all the 3 maternal mutations lie on a unique gene. In order to identify other possible molecular causes, we performed the CYP11B1 gene analysis even without a complete hormonal profile, as the patient was in therapy. This analysis revealed the presence of 2 mutations: R43Q and A386V, both present on the paternal allele and individually reported as mild. Conclusions The patient, with the standard clinical NC-CAH manifestations, resulted to be heterozygous for both the deficiencies. We suggest therefore the possibility of a cumulative effect on the phenotype of the two mutants as previously reported in other conditions for enzymes catalyzing consecutive reactions on the same pathway. This is the first report of a di-genic inheritance in CAH

Three Novel AMHGene Mutations in a Patient with Persistent Mullerian Duct Syndrome and Normal AMH Serum Dosage.

Background:Persistentmullerian duct syndrome (PMDS) is characterized by the presence of uterus, fallopian tubes and the upper part of the vagina in 46,XY patients with perfectly virilized external genitalia. It is mostly caused by mutations of the AMH or AMH type 2 receptor (AMHR2) gene. The AMH serum level is very often low or undetectable in the AMH gene defect and normal in the AMHR2 gene defect. Aim: We investigate an Italian patient, genotypically and phenotypically male, observed at 1 month of age for a right inguinal hernia that at surgery showed the presence of both testes in the same hernial sac and uterus and fallopian tubes in the abdomen. Results: Genetic tests first showed the absence of the common 27-bp deletion in the AMHR2 gene, then the presence of three new sequence variations in the AMH geneleading to the following variants: the p.A405P carried by the paternal allele; the p.G326V plus the p.V508A carried by the maternal allele. Conclusions: The determination of serum AMH, performed after the genetic analysis, showed a normal level for age, suggesting that these mutations may affect the function and the bioactivity of the hormone and not the secretion rate

Mitochondrial Injury and Protection in Ischemic Pre- and Postconditioning

Mitochondrial damage is a determining factor in causing loss of cardiomyocyte function and viability, yet a mild degree of mitochondrial dysfunction appears to underlie cardioprotection against injury caused by postischemic reperfusion. This review is focused on two major mechanisms of mitochondrial dysfunction, namely, oxidative stress and opening of the mitochondrial permeability transition pore. The formation of reactive oxygen species in mitochondria will be analyzed with regard to factors controlling mitochondrial permeability transition pore opening. Finally, these mitochondrial processes are analyzed with respect to cardioprotection afforded by ischemic pre- and postconditioning

Two Moroccan Sisters Presenting with a Severe Salt-Wasting Form of Congenital Adrenal Hyperplasia but Normal Female Genitalia

We report the case of 2 sisters (46,XX) born from consanguineous Moroccan parents. Both sisters had normal female genitalia, but within 2 weeks after birth, they presented with a severe salt-wasting crisis. Hormonal investigations suggested the diagnosis of congenital adrenal hyperplasia, which was confirmed by subsequent molecular analysis to be caused by 3\u3b2-hydroxysteroid dehydrogenase type 2 deficiency. Here, we discuss the main features like onset, possible complications, genetics, and replacement therapy of this rare disease