Endocrine Abstracts

JOINT3422

Objective: Triple A syndrome (Allgrove syndrome), is a rare autosomal recessive disorder, characterized by achalasia, alacrima, and adrenal insufficiency due to adrenocorticotropic hormone (ACTH) resistance. This study aims to evaluate the phenotypic and genotypic characteristics of patients with Triple A syndrome.

Methods: This retrospective study included data from 10 patients from 7 families who were followed in the pediatric endocrinology clinic between 1996 and 2024. Demographic information, clinical findings, biochemical and genetic results of the patients were collected from their medical records.

Results: Ten patients (M/F=7/3) with a median age of 11 (range: 6–35) years were included. Consanguinity rate was 71% among 7 families. Alacrima was detected in all cases, while adrenal insufficiency and achalasia were observed in 9 patients (90%). Adrenal insufficiency and achalasia presented between 2–8 and 1.5–17 years of age, respectively. Additional clinical findings included mineralocorticoid deficiency (40%), epilepsy (40%), short stature (40%), osteoporosis (10%), osteopenia (10%), hypogonadotropic hypogonadism (10%), cryptorchidism (10%), anal atresia (10%), and congenital hip dysplasia (10%). Ectodermal and autonomic features included dry skin (60%), dry mouth (30%), hyperhidrosis (50%), and multiple dental caries (90%). Neurological findings included hyperreflexia (50%), quadriplegia (10%), speech delay (50%), mild intellectual disability (40%), and severe intellectual disability (10%). Dysmorphic features such as deep-set eyes, down-slanting palpebral fissures, prominent and large ears, pectus excavatum, arachnodactyly, and joint hyperextensibility were observed, along with thenar and hypothenar atrophy (40%). Genetic analysis identified the previously reported homozygous frameshift mutation c.1066_1067del (p.Leu356fs*) in the AAAS gene in 6 cases from 3 families. Despite having same mutation, two siblings from the same family exhibited phenotypic variability, with one not developing adrenal insufficiency. In another family, adrenal insufficiency and achalasia onset varied among affected siblings. One case had a 46,XY, inv(9)(p11q13) karyotype. Additionally, a novel pathogenic variant, c.145C>T (p.Gln49), was identified in the AAAS gene, leading to premature termination of the ALADIN protein. Notably, the coexistence of anal atresia, congenital hip dislocation, osteoporosis, hypogonadotropic hypogonadism, cryptorchidism, and dysmorphic features associated with this mutation has not been previously reported in the literature, suggesting a potentially unique phenotypic spectrum.

Conclusion: Phenotypic variability and genetic diversity in Triple A syndrome are noteworthy. The novel AAAS gene mutation is believed to cause a loss of ALADIN protein function, expanding the genetic spectrum of Triple A syndrome. This study highlights the critical importance of genetic analysis, particularly in patients presenting with core symptoms such as alacrima and adrenal insufficiency.