Endocrine Abstracts

Background: Mutations in the ACTH receptor (MC2R) gene or in its melanocortin accessory protein (MRAP) gene disrupt receptor expression, signaling, and constitutive activity of the MC2R, leading to familial glucocorticoid deficiency (FGD) type 1 and type 2 respectively. FGD is a life-threatening, rare autosomal recessive disorder characterized by impaired cortisol synthesis and classically preserved mineralocorticoid production. There have also been described other mutations that disrupt the signaling pathways of ACTH. The clinical picture of FGD varies depending on the age of onset, the underlying genetic cause, and the severity of the deficiency and may include: recurrent hypoglycemia, seizures, hyperpigmentation, severe, recurrent infections and other symptoms linked to cortisol deficiency.

Case report: Our patient is a slightly hyperpigmented girl with no significant natal or family history and a normal psychomotor development in the first year of life. At the age of two she presented epileptic crisis, ataxia, neuropsychological delay and an autism spectrum disorder, attributed at first to a mutation in the MTOR gene, corresponding to Smith-Kingsmore phenotype. At 3 y 10 mo evaluation, she displayed a tall stature and primary hypothyroidism, therefore levothyroxine substitution was initiated. It was on the age of 6 when a second genetic study identified a homozygous mutation in the MRAP gene c.106+2dup consistent with FGD type 2. Laboratory tests showed undetectable cortisol, very high ACTH level, normal renin and aldosterone levels. Consequently, glucocorticoid substitution was initiated, then she was referred to our clinic for further follow up. It is noteworthy that she has a history of a viral meningo-encephalitis and cerebral parasitosis aspect on the MRI.

Discussions: MRAP defects have been associated with a more severe clinical picture and an early onset of the disease. Our patient’s diagnosis at the age of 6 is remarkable, considering that the median age at diagnosis is typically less than 1 year. Interestingly the thyroid function substitution did not precipitate an adrenal crisis. Literature data report several cases of patients with FGD and primary hypothyroidism, but we haven’t found any strong association. Another interesting fact is that tall stature associated with FGD is attributed to MC2R gene defects, and not to MRAP mutations, probably due to the early diagnosis of the latter and the lack of the prolonged effect of ACTH excess on the growth plate. We consider that early diagnosis would have improved our patient’s outcome in terms of infections and seizures that could have been precipitated by cortisol deficiency.