Pigmentary Disorder, Reticulate, With Systemic Manifestations, X-Linked

A number sign (#) is used with this entry because of evidence that X-linked reticulate pigmentary disorder (PDR) with systemic manifestations is caused by hemizygous or heterozygous mutation in the POLA1 gene (312040) on chromosome Xp22.

X-linked reticulate pigmentary disorder shows more severe manifestations in hemizygous males compared to heterozygous females. Affected males have early onset of recurrent respiratory infections and failure to thrive resulting from inflammatory gastroenteritis or colitis. Patients also show reticular pigmentation abnormalities of the skin and may develop corneal scarring. Carrier females may be unaffected or have only pigmentary abnormalities along the lines of Blaschko (summary by Starokadomskyy et al., 2016).

Partington et al. (1981) described a large Canadian family in which 2 males and 7 females had brown pigmentation of the skin. In the females, the type and distribution of the pigmentation mimicked incontinentia pigmenti; in the males, the pattern was generalized and reticulate. In both sexes, histologic studies showed amyloid deposits in the papillary dermis, melanin in the basal layer, and slight hyperkeratosis. The females were otherwise normal. Both males failed to thrive as infants. One had severe gastroenteritis with blood in the stools starting at the age of 3 weeks, followed by seizures, hemiplegia and developmental delay. The other had recurrent pneumonia, urethral stricture, inguinal hernias, and near-blindness from amyloid deposits in the cornea. Five other males in the family had had severe illnesses. Two died of pneumonia by age 3 months. One died at 3 months of colitis. Two had colitis as infants, failed to thrive, and developed recurrent pneumonia from which 1 died at age 3 years. Partington and Prentice (1989) provided follow-up. The early life of most of the affected boys was marked by ulcerative colitis (see 266600), failure to thrive, and pneumonia from which several had perished in the earlier generations. With improved management, affected males survived and some developed other manifestations such as corneal dystrophy with severe photophobia or chronic respiratory disease. Whereas amyloid deposits were originally found in the pigmented skin of adults of both sexes, later studies failed to show amyloid in the skin of the affected children, suggesting that its deposition may be an age-dependent secondary change.

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

Starokadomskyy et al. (2016) reported 12 families with X-linked PDR, 5 of whom had previously been reported, including the families of Partington et al. (1981) and Ades et al. (1993). The families were of various origins, including Canada, Italy, Malta, Spain, Israel, China, Serbia, and the United States. Starokadomskyy et al. (2016) summarized the clinical features of patients reported to that time. The disease typically manifests in the first few months of life, when male patients develop recurrent pneumonias, bronchiectasis, chronic diarrhea, and failure to thrive. Diffuse skin hyperpigmentation with a distinctive reticulate pattern becomes evident by early childhood, and may later be followed by hypohidrosis, corneal inflammation and scarring, enterocolitis that resembles inflammatory bowel disease, and recurrent urethral strictures. Males also have a characteristic facies with frontally upswept hair and flared eyebrows. Female carriers are known to have only restricted pigmentary changes along the lines of Blaschko. Starokadomskyy et al. (2016) did not report autoimmune manifestations, and the patients did not have elevated titers of autoantibodies. Laboratory studies showed basically normal immunologic parameters, but there was an increased plasma interferon I (see 147660) gene profile signature. Patients also had decreased plasma IL17A (603149), which may have predisposed to pyogenic infections, and decreased gamma-interferon (147570), which may have predisposed to mycobacterial infections.

Megarbane et al. (2005) reported a boy, born to healthy first-cousin parents, with diffuse hyperpigmentation of the skin and guttate hypomelanotic lesions, photophobia, abnormal hair, developmental delay, and recurrent bronchitis. Skin histology showed pigmentation incontinence with numerous melanophages; electron microscopy showed a very high number of melanosomes and some degenerating keratinocytes. Dermatologic examination of the mother was normal, and skewed X-inactivation patterns were detected in her lymphocytes. Megarbane et al. (2005) suggested that the involved gene may play a critical role in embryonic development. Starokadomskyy et al. (2016) did not identify the common pathogenic mutation in the POLA1 gene (312040.0001) in the patient reported by Megarbane et al. (2005).

Gedeon et al. (1994) performed linkage studies in the original family of Partington et al. (1981) and mapped the disorder to Xp22-p21. Peak lod scores of 3.21 at theta = 0.0 were obtained between PDR and DXS989 and between PDR and a marker at the 5-prime end of the dystrophin locus. Gedeon et al. (1994) noted that the brown pigmentation of the skin in this disorder follows the lines of Blaschko in females.

Santos et al. (2008) performed linkage analysis of the expanded Canadian pedigree originally described by Partington et al. (1981) as well as 3 additional PDR families previously reported by Ades et al. (1993), Anderson et al. (2005), and Megarbane et al. (2005), and narrowed the locus to an approximately 4.9-Mb interval on Xp22.11-p21.3 between markers DXS1052 and DXS1061. Santos et al. (2008) sequenced all annotated coding exons within a 4.9-Mb interval but found no causative mutation. Sequencing of other X-linked genes outside of the linked interval also failed to identify the cause of PDR.

In affected members of 12 unrelated families with X-linked PDR, including 5 families who had previously been reported, Starokadomskyy et al. (2016) identified a hemizygous (in males) or heterozygous (in females) intronic mutation in the POLA1 gene (312040.0001). All affected individuals carried the same mutation, which was initially identified by whole-genome sequencing of 4 probands. The mutation segregated with the disorder in 5 multiplex families tested. Haplotype analysis showed that 2 of the families shared a common founder, but others gained the mutation independently, including at least 1 de novo case. Cells derived from patients with the mutation showed increased expression of genes involved in type I interferon (IFNA1; 147660) signaling pathways and other proinflammatory genes. Patient cells showed enhanced activation of genes in the interferon regulatory factor (IRF; see 147575) and NFKB (see 164011) pathways in response to double-stranded DNA, cytosolic double-stranded RNA, and TNF (191160). Patient cells also showed almost undetectable cytosolic RNA:DNA, which was rescued by expression of wildtype POLA1. Transfection of endogenous and synthesized RNA:DNA into POLA1-deficient cells normalized the increased expression of IRF genes. The findings suggested that the splice site mutation caused POLA1 deficiency, which resulted in constitutive activation of IRF- and NFKB-dependent genes and an increased type I interferon profile, possibly by the reduction in the POLA1-mediated generation of cytosolic RNA:DNA. Starokadomskyy et al. (2016) noted that RNA:DNA hybrids may function to squelch an inflammatory response generated by stimulatory nucleic acids.