Congenital lipoid adrenal hyperplasia due to STAR deficency (ORPHA:90790)
A severe form of congenital adrenal hyperplasia (CAH) characterized by severe adrenal insufficiency and sex reversal in males.
Epidemiology
The prevalence is unknown but it is extremely rare and is more common in people of Japanese, Korean (where the heterozygous carrier frequency is estimated to be about one in 300 leading to an estimated number of affected newborns of one in every 250,000 to 300,000) and Palestinian ancestry.
Clinical description
It involves both glucocorticoid and mineralocorticoid deficiencies in the adrenal and androgen deficiency in the testis. Age of onset typically occurs in the antenatal period but congenital anomalies are typically seen in the perinatal period. Boys are not virilized and demonstrate a complete girl phenotype with lack of Müllerian structures. The external genitalia of girls are normal. Hypoglycemic seizures, vomiting or symptoms of dehydration are common manifestations in the first few weeks of life and can be life threatening. Acute adrenal insufficiency is an emergency and can occur in some cases. Non-classic lipoid CAH patients typically have an insidious onset of symptoms of adrenal insufficiency beginning as early as two to four years of age. The 46,XY patients have normal-appearing external genitalia, indicating normal intrauterine Leydig cell function leading to normal male external genital development. However, such patients with non-classic lipoid CAH may also have azoospermia and hypergonadotropic hypogonadism.
Etiology
This disease is due to a mutation in the STAR gene, which encodes for a protein that regulates steroid hormone synthesis by mediating cholesterol transfer across the mitochondrial membrane.
Diagnostic methods
Absence of all glucocorticoids, mineralocorticoids and sex steroids is observed. Diagnosis is usually performed during the neonatal period due to glucocorticoid and mineralocorticoid deficiencies. 46,XY are phenotypically female due to impaired testicular steroidogenesis. Biologically, high basal concentrations of ACTH, elevated plasma renin activity, and hypergonadotropic hypergonadism are seen. Milder ''non-classical'' forms have been reported with intermediate phenotypes. Patients may have minimal disorders of mineralocorticoid secretion, with normal electrolytes and mildly elevated plasma renin activity.
Differential diagnosis
Differential diagnosis includes familial glucocorticoid deficiency.
Antenatal diagnosis
Prenatal diagnosis through chorionic villus sampling is possible in case of a familial form, when the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment includes physiological replacement with glucocorticoids, mineralocorticoids, and in the newborn period, salt. Genetic males have female external genitalia and typically undergo orchidectomy and are raised as females. They require estrogen replacement to induce puberty and long term sex steroid administration.
Prognosis
When affected 46,XX patients receive appropriate glucocorticoid and mineralocorticoid replacement therapy and reach the usual age of puberty, they undergo spontaneous breast development and experience cyclical vaginal bleeding. Successful pregnancy has been achieved. Affected 46,XY individuals are unfertile. Uncontrolled CAH may be associated with life-threatening acute adrenal insufficiency and a higher risk for metabolic and cardiovascular comorbidities.

                            Last update: 
                            February 2022


                            - Expert reviewer(s): 
                            Pr Juliane LEGER | Endo-ERN*


                                * European Reference Network