scholarly journals A novel mutation of the StAR gene with congenital adrenal hyperplasia and its association with heterochromia iridis: a case report

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Vera Splittstösser ◽  
Felix Schreiner ◽  
Bettina Gohlke ◽  
Maik Welzel ◽  
Paul-Martin Holterhus ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Novel Mutation ◽  
Regulatory Protein ◽  
Homozygous Mutation ◽  
Elevated Concentration ◽  
Adrenal Hyperplasia ◽  
Heterochromia Iridis ◽  
Phenotypical Feature ◽  
Steroidogenic Acute Regulatory ◽  
Star Gene

Abstract Background We report a novel mutation within the StAR gene, causing congenital adrenal hyperplasia, with the so far unreported association with heterochromia iridis. Case presentation In a now 15-year-old girl (born at 41 + 6 weeks of gestation) adrenal failure was diagnosed in the neonatal period based on the clinical picture with spontaneous hypoglycaemia, hyponatremia and an extremely elevated concentration of ACTH (3381 pmol/l; ref. level 1,1–10,1 pmol/l), elevated renin (836 ng/l; ref. level 5–308 ng/l), and a decreased concentration of aldosterone (410 pmol/l; ref. level 886–3540 pmol/l). In addition to hyperpigmented skin the patient exhibited sectorial heterochromia iridis. Sequence analysis of the steroidogenic acute regulatory protein (StAR) gene showed a novel homozygous mutation (c.652G > A (p.Ala218Thr), which was predicted in-silico to be possibly damaging. Under daily steroid substitution her electrolyte levels are balanced while she became obese. Puberty occurred spontaneously. Conclusion A novel mutation in the StAR gene was identified in a patient with severe adrenal hypoplasia and sectorial heterochromia iridis. We discuss a causal relationship between these two rare phenotypes, i.e. whether very high levels of ACTH and alpha-MSH during early development might have disturbed early differentiation and distribution of uveal melanocytes. If confirmed in additional cases, discolorization of the iris might be considered as an additional phenotypical feature in the differential diagnosis of congenital adrenal insufficiency.

scholarly journals Characterization of Two Novel Variants of the Steroidogenic Acute Regulatory Protein Identified in a Girl with Classic Lipoid Congenital Adrenal Hyperplasia

2020 ◽  
Vol 21 (17) ◽  
pp. 6185
Author(s):  
Efstathios Katharopoulos ◽  
Natascia Di Iorgi ◽  
Paula Fernandez-Alvarez ◽  
Amit V. Pandey ◽  
Michael Groessl ◽  
...  
Keyword(s):  
Protein Expression ◽  
Congenital Adrenal Hyperplasia ◽  
Regulatory Protein ◽  
Cell System ◽  
Adrenal Hyperplasia ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Steroidogenic Acute Regulatory ◽  
The Impact

Congenital adrenal hyperplasia (CAH) consists of several autosomal recessive disorders that inhibit steroid biosynthesis. We describe a case report diagnosed with adrenal insufficiency due to low adrenal steroids and adrenocorticotropic hormone excess due to lack of cortisol negative feedback signaling to the pituary gland. Genetic work up revealed two missense variants, p.Thr204Arg and p.Leu260Arg in the STAR gene, inherited by both parents (non-consanguineous). The StAR protein supports CYP11A1 enzyme to cleave the side chain of cholesterol and synthesize pregnenolone which is metabolized to all steroid hormones. We used bioinformatics to predict the impact of the variants on StAR activity and then we performed functional tests to characterize the two novel variants. In a cell system we tested the ability of variants to support cholesterol conversion to pregnenolone and measured their mRNA and protein expression. For both variants, we observed loss of StAR function, reduced protein expression and categorized them as pathogenic variants according to guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. These results fit the phenotype of the girl during diagnosis. This study characterizes two novel variants and expands the list of missense variants that cause CAH.

scholarly journals Mechanism for the development of ovarian cysts in patients with congenital lipoid adrenal hyperplasia

2000 ◽  
pp. 274-279 ◽  
Author(s):  
M Shima ◽  
A Tanae ◽  
K Miki ◽  
N Katsumata ◽  
S Matsumoto ◽  
...  
Keyword(s):  
Body Temperature ◽  
Basal Body ◽  
Regulatory Protein ◽  
Ovarian Cysts ◽  
Adrenal Hyperplasia ◽  
Basal Body Temperature ◽  
Congenital Lipoid Adrenal Hyperplasia ◽  
Steroidogenic Acute Regulatory ◽  
Lh Releasing Hormone ◽  
Star Gene

OBJECTIVE: Although ovarian cysts commonly occur in patients with congenital lipoid adrenal hyperplasia (CLAH), the mechanism of development remains to be determined. To clarify the pathogenesis of the ovarian cysts, endocrinological examinations were performed in patients with CLAH. METHODS: The subjects were three Japanese CLAH patients. Basal body temperature, serum and urinary gonadotropin levels, serum and/or urinary ovarian hormones and mutations of the steroidogenic acute regulatory protein (StAR) gene were examined. RESULTS: The basal body temperature was not biphasic in any patient. Basal LH levels were high in all CLAH patients and markedly responded to LH-releasing hormone in two patients. Urinary gonadotropin analysis revealed repetitive LH surges in the menstrual cycles of the CLAH patients. No increase in the urinary pregnanediol suggested anovulation in all patients, and bilateral ovarian cysts were found in two of the subjects. Examination of the StAR gene revealed a frameshift mutation 840delA at codon 238, a nonsense mutation Q258X at codon 258, a homozygotic mutation at Q258X, and a compound heterozygotic mutation with 251insG and Q258X. CONCLUSIONS: We concluded that the development of ovarian cysts may be derived from continued anovulation in CLAH patients. Elevated LH levels may be explained by increased sensitivity of the anterior pituitary to circulating estrogen.

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