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X-linked reticulate pigmentary disorder
Other Resources UpToDate PubMed

X-linked reticulate pigmentary disorder

Contributors: Gabriel E. Molina, Susan Burgin MD
Other Resources UpToDate PubMed


X-linked reticulate pigmentary disorder (XLRPD), previously known as familial or X-linked cutaneous amyloidosis, is an exceedingly rare genetic disorder with distinct skin and systemic manifestations. Both X-linked recessive and dominant modes of inheritance have been suggested. Intronic mutation of POLA1, which encodes the catalytic subunit of DNA polymerase-α, is responsible for this condition. This mutation results in aberrant splicing and diminished expression of the gene, which ultimately leads to enhanced activity of type I interferon and reduced levels of interferon-γ and interleukin-17A. These changes are thought to account for the autoinflammatory and immunodeficient sequelae of XLRPD.

Affected males present during early childhood with diffuse reticulate (netlike) hyperpigmentation, interspersed with hypopigmented macules. These pigmentary changes are usually not present at birth, but rather initially develop as hypopigmented macules affecting the flexures. These asymptomatic spots may then spread to involve the face, trunk, and extremities, after which hyperpigmented macules arise within the hypopigmented areas. Extracutaneous manifestations in male patients include unique facial features of upswept frontal hairline and arched eyebrows, photophobia due to corneal opacification, hypohidrosis, recurrent respiratory infection with resultant pulmonary fibrosis, gastrointestinal inflammation, urethral strictures, nephrolithiasis, seizures, and developmental delay.

In contrast, female carriers of XLRPD exhibit only cutaneous involvement with the development of patchy hyperpigmentation along the lines of Blaschko during early childhood. There are no known systemic manifestations.


L81.8 – Other specified disorders of pigmentation

717224002 – X-linked reticulate pigmentary disorder with systemic manifestation syndrome

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Differential Diagnosis & Pitfalls

Other genetic reticulate pigmentary disorders:
  • Dyschromatosis universalis hereditaria – Skin lesions may be clinically indistinguishable from XLRPD, but there is usually no systemic involvement and inheritance is autosomal.
  • Dyschromatosis symmetrica hereditaria (acropigmentation of Dohi) – Acral and facial hypo- and hyperpigmented macules develop in infancy or early childhood leading to a mottled appearance of affected skin.
  • Dermatopathia pigmentosa reticularis – Reticulate pigmentation tends to be localized and is associated with nonscarring alopecia, onychodystrophy, palmoplantar keratoderma, and adermatoglyphia.
  • Naegeli-Franceschetti-Jadassohn syndrome – Autosomal dominant ectodermal dysplasia characterized by reticulate hyperpigmentation, hypohidrosis, keratoderma, and absence of dermatoglyphics. Allelic to dermatopathia pigmentosa reticularis.
  • Reticulate pigmented anomaly of the flexures (Dowling-Degos disease) – Brown-black hyperpigmentation classically affects the flexures with onset in adolescence or early adulthood.
  • Dyskeratosis congenita – Classic triad of reticulate pigmentation of upper chest and neck, dysplastic nails, and oral leucoplakia. Predisposition for hematologic malignancies.
  • Reticulate acropigmentation of Kitamura – Reticulate pigmentation of the dorsal hands and feet with palmoplantar pitting. 
Acquired pigmentary disorders:
  • Amyloidosis cutis dyschromia – Similar cutaneous and histopathologic findings without facial features or systemic involvement.
  • Idiopathic guttate hypomelanosis – Diffuse hypopigmented macules that typically present in older individuals in chronically sun-exposed skin.
In female carriers:
  • Incontinentia pigmenti – Stage 3 (after 6 months of age), which manifests as streaky pigmentary changes along the lines of Blaschko, is typically preceded by vesicular and verrucous stages.
  • Hypomelanosis of Ito – Lesions are hypopigmented and may be associated with birth defects.
  • Linear and whorled nevoid hypermelanosis – These hyperpigmented patches that follow the lines of Blaschko are usually present at birth and may be associated with neurologic complications.
  • Progressive cribriform and zosteriform hyperpigmentation – Pigmentary lesions are localized to specific dermatomes typically of the lower torso and legs.

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Last Reviewed:02/08/2018
Last Updated:01/18/2022
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X-linked reticulate pigmentary disorder
X-linked reticulate pigmentary disorder (Male Presentation) : Photophobia, Failure to thrive, Flexural distribution, Hypohidrosis, Hyperpigmented macules, Hypopigmented macules
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