X-linked reticulate pigmentary disorder with systemic manifestations L81.8

Rare syndrome characterized by hyperpigmentation of the skin, sterile multiorgan inflammation, recurrent infections, and marked facial features.

Mutation in the POLA1 gene. POLA1 encodes the catalytic unit of DNA polymerase α, which together with the primase complex initiates the DNA replication process. XLPDR has been shown to be associated with profound activation of type I interferon signaling, but unlike other interferonopathies, it is not associated with autoantibodies or classic autoimmunity. Rather, it is associated with marked natural killer (NK) cell dysfunction, which may explain the recurrent infections observed in this syndrome. To date, all XLPDR cases are caused by the same recurrent intronic mutation leading to gene missplicing.

Early childhood

Clinically, diffuse reticular patchy but also linear hyperpigmentation is found, appearing already in early childhood. Furthermore, hypohidrosis, hair shaft anomalies with a high frontal hairline, failure to thrive and chronic lung diseases are found in varying degrees. Rarer are: corneal dystrophies and photophobias.

POLA1 encodes the catalytic unit of DNA polymerase α, which together with the primase complex initiates the DNA replication process. Complete deficiency of this essential gene is probably lethal (Starokadomskyy P et al. 2021), at least two diseases due to partial POLA1 deficiency have been described:

• X-linked reticular pigmentary disorder (XLPDR).
• van Esch-O'Driscoll syndrome (VEODS, OMIM: 301030). This disorder results in growth retardation, microcephaly, hypogonadism and in some cases overlap with immunological features as seen in XLPDR.