X-linked reticulate pigmentary disorder

X-linked reticulate pigmentary disorder is a rare X-linked genetic condition in which males manifest multiple systemic symptoms and a reticulated mottled brown pigmentation of the skin, which, on biopsy, demonstrated dermal deposits of amyloid. Females usually only have linear streaks of hyperpigmentation.^[1]

The syndrome can also be referred to by the acronym X-Linked-PDR or XLPRD.^[2] Its a very rare recessive disease, genetically determined, with a chronic course.

It was characterized in 1981.^[3] Mutation of the POLA1 gene lead to loss of expression of the catalytic subunit of DNA polymerase-α and is responsible for XLPDR.^[2] Loss of POLA1 expression resulted in reduced levels of RNA:DNA hybrids in the cytosol and unexpectedly triggered aberrant immune responses (e.g. type I interferon production) which in part can account for the symptoms associated with XLPDR.^[2] Another trigger of the immunodeficiency phenotype is a functional deficiency of Natural killer (NK) cells, which are major players in innate antiviral immune system.^[4]

Presentation

Affected males develop generalized

• Recurrent respiratory infections
• Dyskeratosis corneal
• Photophobia
• Hypohidrosis (lack of sweat glands)
• NK cell
  functional deficiency
• Growth retardation
• Gastrointestinal disorders
• Kidney disease
• Kidney stones
• Urinary infections
• Webbed feet or hands
• Electrolyte imbalance
• Retinitis pigmentosa
• Lymphedema
• Thyroid abnormalities

Not every patient shows all of the listed symptoms. However,

Most XLPDR patients stabilize with age and have a less complicated clinical course after

All XLPDR probands shared the same unique intronic variant mapping to intron 13 of POLA1, (NM_016937.3:c.1375-354A>G). XLPDR lacks allelic heterogeneity, meaning that the disorder is uniquely associated with the NM_016937.3:c.1375-354A>G intronic variant.^[2][5] The final diagnosis usually requires PCR or WGS confirmation.

Treatment

Management of other XLPDR symptoms is largely supportive. Conventional management of recurrent lung infections with

Recently, a number of reports suggest encouraging results with the use of JAK inhibitors baricitinib and ruxolitinib in several distinct type I interferonopathies. In fact, one XLPDR patient with refractory colitis was treated with tofacitinib with positive response of the colitis and no exacerbation of pulmonary infections.^[5]

Other options that may be worth considering in the future are

• Waardenburg syndrome
• List of cutaneous conditions

References