Variegate porphyria

Gene: PPOX

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: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
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 Variegate porphyria.

Created: 13 Oct 2025, 2:42 p.m. | Last Modified: 14 Oct 2025, 3:22 p.m.

Panel Version: 1.3

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: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyria attack), plasma porphyrin fluorescence emission (cutaneous symptoms)
PMID: 35584894 Schulenburg-Brand reports that patients with variegate porphyria (VP) may develop acute attacks often characterised by abdominal pain, nausea, vomiting and other neurological symptoms. They may also present with photosensitive skin lesions. Affected skin is excessively fragile, leading to blisters, milia, and scarring.
PMID: 10486317 Whatley found that skin lesions were the only manifestation of VP in 59% of patients whereas 21% of patients had acute attacks and skin lesions. The remainder having only acute attacks.
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 biochemical tests (urine porphobilinogen during an acute attack followed by plasma porphyrin fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence emission) as the penetrance of variegate porphyria is so low. Genetic testing of the PPOX gene should only be used for family testing so that the genetically predisposed individuals can be advised against precipitating factors such as alcohol and certain drugs.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 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, 10:01 a.m. | Last Modified: 8 Sep 2025, 10:46 a.m.

Panel Version: 1.1

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

Phenotypes
176200; 620483

Publications

• 35584894
• 10486317
• 38940544
• 37879139

Green List (high evidence)

PPOX has been added to the panel for R170 Variegate porphyria with a green rating as agreed with the NHS Genomic Medicine Service.

Created: 30 Jun 2023, 5:03 p.m. | Last Modified: 30 Jun 2023, 5:03 p.m.

Panel Version: 0.1

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal