Primary Adrenocortical Insufficiency Case Series: Genetic Etiologies More Common than Expected

Abstract

Background/Aims: Primary adrenal insufficiency (AI) is an important cause of morbidity in children. Our objectives were: (1) to describe the clinical presentation of children with new-onset primary AI, and (2) to identify monogenic causes of primary AI in children. Methods: Chart review and mutation detection in candidate genes were conducted for 11 patients with primary AI. Results: The likely cause of AI was determined in 9 patients. One had a homozygous MC2R mutation associated with familial glucocorticoid deficiency. Two had the same homozygous mutation in the AIRE gene which is associated with type 1 autoimmune polyglandular syndrome. One patient had a heterozygous change in this gene of undetermined significance. Five were homozygous for the previously reported p.R188C STAR mutation causing nonclassic lipoid congenital adrenal hyperplasia, representing the largest cohort of such patients from a single geographic area. In the remaining 2 patients, no clear etiology was identified. Conclusions: We recommend genetic testing for patients who have negative anti-adrenal antibodies or suggestive family history. Diagnosing a genetic etiology can provide information about prognosis and treatment, and is therefore beneficial for patients. Our high proportion of patients with nonclassic lipoid congenital adrenal hyperplasia likely represents a founder effect.

Familial Glucocorticoid Defificiency in a Newborn Caused by a Mutation in Melanocortin 2 Receptor: Case Report

“…9 Mutations in MCM4 and NNT genes, which are involved in DNA replication and antioxidant defense, have been recognized in patients with FGD. 5,6 Hypoglycemia in the neonatal period is usually seen in patients with FGD, in many cases clinical diagnosis can not be made at this time. 3,4 Similarly, hypoglycemia did not persist in our patient, she improved quickly with enteral feeding and IV glucose treatment.…”

“…However nicotinamide nucleotide transhydrogenase (NNT), and mini-chromosome maintenance-deficient 4 homologue (MCM4) gene are recently discovered FGD causal genes. 5,6 Herein we report a newborn diagnosed as PAI with generalized hyperpigmentation and hypoglycemia due to a mutation in MC2R gene (c.560delT).…”

Адреногенітальний Синдром: Молекулярні Механізми Розвитку

“…В обох випадках функція активного гена порушується. На частку великих делецій припадає близько 20 % мутацій, на частку точкових мутацій, що найчастіше є результатом генних конверсій, -75 % [1,24,33].…”

“…Tsai et al [33] вивчали в сироватці крові рі-вень андрогенів і 17-гідроксипрогестерону, а також HLA-генотип у 124 сімей пацієнтів із класичним де-фіцитом 21-гідроксилази. У 8 родоводах були знай-дені 16 особин пубертатного або постпубертатного віку різних статей, які мали біохімічні докази недо-статності 21-гідроксилази без клінічних симптомів надлишку андрогенів, тобто були відсутні вірилізм, аменорея або безплідність.…”

Lipoid congenital adrenal hyperplasia by steroidogenic acute regulatory protein (STAR) gene mutation in an Italian infant: an uncommon cause of adrenal insufficiency

“…A milder form of lipoid CAH, defined as “non-classic,” is related to mutations retaining 10–25% of normal STAR activity [7]. These patients typically experience adrenal insufficiency after infancy, mineralocorticoid secretion is minimally affected and the 46,XY individuals may masculinize normally [8–10]. …”