Clues Hidden in the Skin

The patient had multifocal neurological illness with optic nerve, spinocerebellar, extrapyramidal, and neuromuscular involvement. Brain MRI showed cortical atrophy. Cervical spine MRI was normal. EMG revealed axonal polyneuropathy. Electroretinogram was normal. Skin biopsy showed lymphocyte intracellular inclusions and amyloid deposition. Lymphocyte panel revealed low natural killer cell activity. Light microscopy of hair shaft showed pigmentary clumping. Normal labs included CK, cryoglobulins, HTLV-1 and 2, SCA 1-3 and 6, OPA-1. VEP was extinguished (age 43). Genetic testing diagnosed Chediak-Higashi Syndrome (CHS). SNP array showed no loss of heterozygosity, suggesting no close parental relationship. Sequencing of the entire coding region of LYST identified homozygosity for a novel six base pair in-frame deletion in exon 43, predicting the loss of asparagine and threonine residues from the LYST protein product. The proband was also heterozygous for an intronic sequence variant distal to the deletion. Homozygosity was confirmed in both affected brothers and both parents. Unaffected brothers were confirmed heterozygotes. Mutations in LYST, a ubiquitously expressed gene concerned with lysosomal trafficking, cause CHS. It is an autosomal recessive disorder characterized by childhood-onset immune dysfunction and hemophagocytic syndrome, partial oculocutaneous albinism and other pigmentary abnormalities, and neurologic dysfunction. Amyloidosis, as in this case, is reported in CHS and may contribute to the neurodegenerative process. Rare CHS patients, such as ours, present with absent or subclinical immunological abnormalities, but develop progressive neurodegenerative disease in early adulthood. Oculocutaneous albinism is characteristic, but was absent in our patient and in other reported cases. There is one case of visual dysfunction in CHS with an extinguished ERG. To our knowledge, optic nerve involvement has not been reported in CHS. Vision loss progressed over two years, with acuity at age 43 of 20/80 OD and 20/100 OS with complete loss of color vision. Both homozygous brothers had bilateral optic nerve involvement.