X-linked reticulate pigmentary disorder with systemic manifestations L99.0

X-linked reticular pigment disorder is a rare syndrome characterized by recurrent infections and sterile multi-organ inflammation. The syndrome is caused by an intronic mutation in the POLA1 gene(312040) on chromosome Xp22, the gene encoding the catalytic subunit of DNA polymerase-alpha (Pol-α) responsible for the synthesis of Okazaki fragments during DNA replication (Starokadomskyy Pet al. 2019). Histological examination series have demonstrated amyloid deposits in the papillary dermis (Partington et al. 1981).

The systemic disease shows more severe expression in hemizygous males than in heterozygous females. Cells from patients with the mutation show increased expression of genes involved in interferon type I (IFNA1; 147660) signaling pathways and other proinflammatory genes. Patient cells show increased activation of interferon regulatory factor (IRF) and NFKB pathway genes in response to double-stranded DNA, cytosolic double-stranded RNA, and TNF (191160). The results suggest that the splice site mutation causes POLA1 deficiency leading to constitutive activation of IRF- and NFKB-dependent genes and increased type I interferon profile, possibly by reducing POLA1-mediated generation of cytosolic RNA:DNA (Starokadomskyy et al. 2016). Starokadomskyy P et al (2019) reported that patients with X-linked reticular pigmentary disorder have decreased NK cell cytotoxic activity and reduced NK cell numbers.

Affected male individuals suffer early recurrent respiratory infections and failure to thrive as a result of inflammatory gastroenteritis or colitis. Patients also show reticular pigmentation abnormalities of the skin and may develop corneal scars. Female carriers may be unaffected or have only Blaschko-linear (systematized) pigmentation (Pezzani L et al 2013, Starokadomsky et al 2016).

Partington et al (1981) described a large Canadian family that included 2 males and 7 females with systematized pigmentation of the skin. In the females, the type and distribution of pigmentation were reminiscent of incontinentia pigmenti; in the males, the pattern was generalized and reticular. Histologic examination revealed amyloid deposits in the papillary dermis, melanin in the basal layer, and mild hyperkeratosis in both sexes.

Male infants suffered from failure to thrive with severe gastroenteritis, seizures, hemiplegia, severe even fatal recurrent pneumonias, hernias, amyloid deposits on the cornea. In adulthood, corneal dystrophies with severe photophobia or chronic respiratory disease developed. While amyloid deposits were originally found in the pigmented skin of adults of both sexes, later studies failed to detect amyloid in the skin of affected children, suggesting that the deposition may be an age-related secondary change.

Ades et al (1993) described another family of Maltese origin and renamed the disorder X-linked reticulate pigmentary disorder with systemic manifestations, abbreviated PDR.

Starokadomskyy et al (2016) reported 12 families with X-linked pigmentary disorder. The families were from different countries, including Canada, Italy, Malta, Spain, Israel, China, Serbia, and the United States. The disease typically manifests in the first months of life, when male patients develop recurrent pneumonia, bronchiectasis, chronic diarrhea, and failure to thrive. Diffuse hyperpigmentation of the skin with a distinct reticular pattern is evident in early childhood and may be followed later by hypohidrosis, corneal inflammation and scarring, enterocolitis resembling inflammatory bowel disease, and recurrent urethral strictures.

Female carriers are known to have limited Blaschco-linear pigmentary changes. Laboratory tests showed essentially normal immunologic parameters. Plasma IL17A and gamma interferon levels were decreased (cause of the tendency to infection?).

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2. Anderson RC et al (2005) X-linked reticulate pigmentary disorder with systemic manifestations: report of a third family and literature review. Pediat. Derm. 22: 122-126.

3. Légeret C et al. (2021) JAK inhibition in a patient with X-linked reticulate pigmentary disorder. J Clin Immunol 41:212-216.

4. Partington MW et al (1989) Familial cutaneous amyloidosis with systemic manifestations in males. Am J Med Genet 10: 65-75.
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6. Pezzani L et al (2013) X-linked reticulate pigmentary disorder with systemic manifestations: a new family and review of the literature. Am J Med Genet A 161A:1414-1420.

7. Starokadomskyy P et al (2016) DNA polymerase-alpha regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. Nature Immun 17: 495-504.
8. Starokadomskyy P et al (2019) NK cell defects in X-linked pigmentary reticulum disorder. JCI Insight 4:e125688.