Boys with unexplained adrenal insufficiency should be screened for adrenoleukodystrophy (ALD), and repeated blood testing for very-long chain fatty acids (VLCFAs) may be key to its diagnosis, a case report suggests.
The report also highlighted the importance of early ALD diagnosis so that patients can be monitored for progression to its cerebral form (CALD) and to allow for timely treatment.
The case study, “Adrenoleukodystrophy in the Differential Diagnosis of Boys Presenting with Primary Adrenal Insufficiency without Adrenal Antibodies,” was published in the Journal of Clinical Research in Pediatric Endocrinology.
ALD, a rare inherited metabolic disorder, is characterized by the toxic buildup of VLCFAs in several tissues and organs, mainly affecting the adrenal glands (small hormone-producing glands located above the kidneys) and the brain.
An estimated 35%–40% of boys with ALD develop CALD, typically between the ages of 3 and 12. CALD is marked by an inflammatory process that destroys myelin — the protective layer around nerve cells that allows fast communication between them — leading to the progressive loss of cognitive and neurological functions.
Hematopoietic stem cell transplant (HSCT) is seen as the only way to halt disease progression in CALD patients. The procedure is based on the transplant of healthy hematopoietic stem cells — cells that can form all types of blood cells in the body — from a genetically identical donor (allogeneic) to replace the patient’s diseased cells.
It is therefore crucial to diagnose ALD and start treatment as early as possible. However, “early identification of ALD remains challenging due to nonspecific initial symptoms that overlap with other medical and developmental issues,” the researchers wrote.
One of the symptoms is adrenal insufficiency, which can be caused by a number of conditions, the most common being autoimmune disease. An estimated 70%–80% of boys with ALD have impaired adrenal function before the onset of neurologic symptoms, and VLCFA testing has been recommended for boys with adrenal insufficiency unrelated to autoimmunity.
However, “a recent study highlights the continued need for education that [primary adrenal insufficiency] in the absence of adrenal antibodies should be a red flag for a potential ALD diagnosis,” the researchers wrote.
In the study, a team of researchers, in London, U.K., reported the case of a boy diagnosed with ALD after repeated testing for VLCFA levels and whose first symptoms were recurrent episodes of low blood sugar — which can be caused by adrenal insufficiency.
Before the age of 6, the boy had three episodes of low blood sugar that required hospitalization when he was 2, 2.5, and 5.2 years. While the two first episodes were associated with febrile seizures (those caused by high fever), the last one was not.
Because of his unexplained recurrent low blood sugar episodes, the boy underwent a synacthen test to assess adrenal function, which confirmed that he had adrenal insufficiency (at age 5.5).
Further testing found no autoantibodies against the adrenal glands, excluding the possibility that an autoimmune disease was the cause of the boy’s adrenal insufficiency, and he started on standard replacement therapy.
A first analysis (which had been delayed for several months due to family reasons) of the boy’s VLCFAs levels at 6.5 years old revealed no abnormalities. The continued clinical suspicion and absence of adrenal autoantibodies prompted subsequent VLCFA testing using a different laboratory when the boy was 7 and 7.5, which showed higher-than-normal VLCFAs levels, suggestive of ALD.
ALD diagnosis was confirmed by genetic testing, and the boy initiated Lorenzo’s oil treatment and a low-fat diet.
The boy underwent brain imaging at 7.5 years old, which showed cerebral involvement. Signs of CALD progression were detected three months later. At 8 years old, the boy underwent allogeneic HSCT, which effectively halted disease progression. At his last assessment when he was 11.5, the boy was performing as expected for his age.
“This case highlights the importance of pursuing a diagnosis when clinical suspicion remains, and the significance of VLCFA analysis for patients with adrenal insufficiency without adrenal antibodies in prompting an ALD diagnosis,” the researchers wrote.
According to the team, this case report also showed that continued monitoring and repeated VLCFA testing may be crucial for ALD diagnosis, as some ALD-causing mutations may not only result in normal initial VLCFA levels but also varying levels of adrenal insufficiency.
“The need for early diagnosis in order to initiate current and future treatments mandates pursuit of a clear diagnosis and awareness of the need to screen boys with unexplained [primary adrenal insufficiency] for ALD,” the team concluded.
