Adrenal Hypoplasia Congenita: A Rare Cause of Primary Adrenal Insufficiency and Hypogonadotropic Hypogonadism

Abstract

Primary adrenal insufficiency is defined by the impaired synthesis of adrenocortical hormones due to an intrinsic disease of the adrenal cortex. Determining its etiology is crucial to allow adequate long-term management and genetic counseling. We report the case of a male adolescent that presented in the neonatal period with adrenal crisis and received replacement therapy for primary adrenal insufficiency. During follow-up, adrenal hypoplasia congenita (AHC) was suspected given his persistently raised adrenocorticotropic hormone levels, with markedly low 17-OH progesterone and androstenedione levels. DNA sequence analysis revealed a mutation in NR0B1 gene (c.1292delG), confirming the diagnosis. Delayed puberty and persistent low levels of gonadotropins led to testosterone replacement therapy. X-linked AHC is a rare cause of primary adrenal insufficiency and hypogonadotropic hypogonadism, related to mutations in NR0B1 gene. Despite its rarity, AHC should be considered in patients who present with primary adrenal failure, low levels of 17-OH progesterone and hypogonadotropic hypogonadism.

Primary Adrenocortical Insufficiency Case Series in the Neonatal Period: Genetic Etiologies Are More Common Than Expected

“…It is important to use the lowest effective glucocorticoid dose because excessive dosing is associated with poor long-term health outcomes. Patients with CAH should also be monitored for signs of pubertal onset, patients with AHC be monitored for other coexisting endocrine disturbances such as delayed/precocious puberty and infertility ( 30 – 33 ). Because marginal gross motor developmental delay and gigantism may exist in FGD1, growth and development should also be monitored during follow-up in patients with FGD1 ( 28 , 31 ).…”

“…Until the patient is stable and feeding normally, oral glucocorticoid replacement can be chose, and wheather mineralocorticoid replacement is necessary depends on the cause of PAI. Mineralocorticoid replacement is necessary for classic forms of CAH and AHC, not necessary for FGD (29)(30)(31). The goal of therapy is to replace deficient steroids and minimize iatrogenic glucocorticoid excess.…”

Cholestasis and Hepatic Iron Deposition in an Infant With Complex Glycerol Kinase Deficiency

“…2 Each gene deletion contributes to the phenotype, with the deletion of the dystrophin gene causing weakness and muscle breakdown consistent with DMD, the deletion of the NR0B1 gene causing AHC due to a deficiency of the DAX-1 protein and finally, the deletion of the glycerol kinase gene causing elevated glycerol levels. 8 When all 3 genes are deleted, the presentation of this recessive X-linked condition is more severe and occurs in the infantile period. Due to the involvement of NR0B1 in gonadal development, cryptorchidism may be present, as in our patient, and there is potential for later hypogonadotropic hypogonadism during puberty.…”

“…Due to the involvement of NR0B1 in gonadal development, cryptorchidism may be present, as in our patient, and there is potential for later hypogonadotropic hypogonadism during puberty. 8 Most patients with complex GKD involving the AHC loci will present with an acute adrenal crisis in the first few weeks to months of life. Our patient's presumed septic crisis in the first week of life was likely his first manifestation of his AHC.…”

“…When an infant presents with symptoms of adrenal insufficiency, clinicians must rightly consider congenital adrenal hyperplasia, as it has a much higher incidence of 1:5000 to 1:15 000 compared with 1:140 000 to 1:1 200 000 for AHC. 8,9 Importantly, AHC usually presents with normal 17-hydroxyprogesterone levels, excluding the most common cause of congenital adrenal hyperplasia. 10 -12 In addition, given AHC's involvement of the entire adrenal gland, it has the potential for an Addisonian-like presentation of hyperpigmentation, which can help differentiate it from other forms of adrenal insufficiency.…”