Cutaneous photosensitivity with a likely genetic cause

Gene: PPOX

Comment on phenotypes: OMIM phenotypes accessed on 13 October 2025.

Created: 13 Oct 2025, 7:42 p.m. | Last Modified: 13 Oct 2025, 7:42 p.m.

Panel Version: 3.11

Green List (high evidence)

Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Cutaneous photosensitivity with a likely genetic cause.

Created: 13 Oct 2025, 2:56 p.m. | Last Modified: 13 Oct 2025, 3:01 p.m.

Panel Version: 3.9

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577

Publications

• 10486317
• 33159949
• 35584894
• 37879139
• 38940544
• 40114189

Green List (high evidence)

Relevant metabolic investigation: plasma porphyrin fluorescence emission
PMID: 10486317 Whatley reports that variegate porphyria (VP) is usually classified as an acute porphyria but in 59% of cases skin lesions may be the only manifestation.
PMID: 8290408 Hift reports that the cutaneous disease presents with photosensitivity which may result in blistering, erosions, a fragile skin with chronic scarring and pigmentary changes.
PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using a biochemical test for plasma porphyrin fluorescence emission as the penetrance is so low.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (21 families) reported with homozygous VP (PMID: 40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.

Created: 8 Sep 2025, 10:06 a.m. | Last Modified: 8 Sep 2025, 10:06 a.m.

Panel Version: 3.9

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
176200; 620483

Publications

• 10486317
• 8290408
• 38940544
• 37879139
• 40114189
• 33159949

Green List (high evidence)

Following discussion with the Genomics England clinical team it was agreed that genes associated with porphyrias should be included on this panel. Therefore added to panel as a Green gene.

Created: 2 Dec 2019, 3:48 p.m. | Last Modified: 2 Dec 2019, 3:48 p.m.

Panel Version: 0.10