Cerebral X-Linked Adrenoleukodystrophy Associated with Hemophilia A: A Case Report

The co-occurrence of hemophilia A and X-linked adrenoleukodystrophy (ALD) represents an exceptionally rare clinical scenario. Both the F8 and ABCD1 genes are situated at the Xq28 locus, a gene-dense region where independent pathogenic variants may co-segregate due to low recombination rates and the presence of mutational hotspots. We report a rare co-occurrence of distinct pathogenic variants in both genes in the same patient.

A 12-year-old male with FVIII deficiency (hemophilia A), caused by a heterozygous c.3652delG variant in the F8 gene, presented with cutaneous hyperpigmentation, progressive cognitive decline, and behavioral issues including irritability and impulsivity. A first brain MRI revealed a leukodystrophic pattern over the posterior regions. Electroencephalogram revealed brief and sudden episodes of impaired consciousness associated with generalized epileptiform discharges consistent with absence seizures treated with lamotrigine. Given the presence of hyperpigmentation, adrenal function was tested revealing primary adrenal insufficiency. Adrenal autoantibodies were negative. Very-long-chain fatty acids were elevated, and molecular analysis revealed a pathogenic variant c.1978C>T in the ABCD1 gene, thus leading to a definitive diagnosis of cerebral ALD. Due to the severity and extent of MRI lesions at diagnosis (Loes score = 14), the patient was not eligible for hematopoietic stem cell transplantation; he received hydrocortisone and fludrocortisone replacement and supportive nutritional therapy. At last follow-up visit at 15 years of age, he presented with severe cognitive impairment, psychiatric issues, insomnia, neurological pyramidal signs, drug-resistant generalized epilepsy, and a Loes score of 23 at brain MRI.

This case highlights the genetic vulnerability of the Xq28 locus and the possible co-occurrence of hemophilia A and ALD. Physicians should maintain a high index of clinical suspicion for ALD in males with known FVIII deficiency and cognitive signs or concomitant hyperpigmentation as early diagnosis is vital for life-saving therapeutic interventions.