Hyperpigmentation Should Be Considered in Diagnosing X-ALD, Case Report Says

Hyperpigmentation Should Be Considered in Diagnosing X-ALD, Case Report Says

Physicians should consider generalized hyperpigmentation, or skin darkening, in the differential diagnosis of patients with adrenoleukodystrophy, a case report suggests.

The case report study, “Generalized skin hyperpigmentation as the only manifestation of X‐linked adrenoleukodystrophy,” was published in the British Journal of Dermatology.

Adrenoleukodystrophy (ALD), also known as X-linked ALD (X-ALD), is a rare genetic, neurodegenerative disorder caused by mutations in the ABCD1 gene. This leads to the accumulation of fatty molecules, called very long‐chain fatty acids (VLCFA), in different regions of the body, such as the brain, spinal cord, and adrenal glands.

Although the most common symptom of X-ALD is adrenal insufficiency — a condition in which the adrenal glands are unable to produce normal amounts of certain hormones, such as cortisol — the disease may manifest itself in different ways. In some cases, this different manifestations may lead to delays in patients’ diagnoses.

In this case report study, researchers from the Seoul National University College of Medicine in Korea described the clinical case of a man whose first and only symptom of X-ALD was generalized hyperpigmentation.

The 19-year-old man started showing patches of darker skin in his gums, elbows, and knees when he was a teenager. Apart from that, he was healthy, and denied experiencing other symptoms, including fatigue, dizziness, vomiting, or headaches.

Lab tests showed the man most likely had adrenal insufficiency, due to his high levels of adrenocorticotropic hormone (ACTH; 6,315 pg/mL, normal range 0-60 pg/mL), and low cortisol levels (4.5 μg/dL, normal range 2-12 μg/dL).

Further tests excluded hyperthyroidism, or overactive thyroid, and congenital adrenal hyperplasia, a rare genetic disorder that affects the activity of the adrenal glands. At that point, clinicians started to suspect the patient might have X-ALD.

To confirm the diagnosis, the clinicians performed a VLCFA test to assess the levels of fatty molecules, and a genetic sequencing test to look for mutations in the ABCD1 gene in the patient and some of his family members.

The VLCFA test showed the levels of fatty molecules were abnormally high. In addition, genetic sequencing confirmed the man carried a “likely pathogenic” mutation in the ABCD1 gene (c.986T>A, p.Met329Lys) that had never been described in the literature.

Interestingly, clinicians found that his two sisters and his mother also carried the same mutation, despite showing no symptoms of the disorder.

The patient is currently being treated with hydrocortisone, a steroid to reduce inflammation, and Lorenzo’s Oil.

“Without suspecting X-ALD, the skin manifestation can lead to a misdiagnosis of idiopathic Addison’s disease, and the delay in the accurate diagnosis, and the progression to cerebral disease may cause irreversible damage to a patient,” the researchers said.

“Therefore, in addition to other medical conditions showing generalized hyperpigmentation … it is crucial for dermatologists to acknowledge the possibility of X-ALD,” the team concluded.

Joana holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. She is currently finishing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Joana holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. She is currently finishing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.

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