Rare anaemia

Gene: CPOX

Green List (high evidence)

Comment on list classification: There at least 5 unrelated families affected by Coproporphyria (AR) / Harderoporphyria (AR), with affected individuals harbouring biallelic variants in CPOX. Importantly, autosomal dominant Coproporphyria has low clinical penetrance and it does not usually present with anaemia. Based on the available evidence, CPOX should be rated Green for Rare anaemia, with Mode of Inheritance set to BIALLELIC, autosomal or pseudoautosomal.

Created: 14 Oct 2025, 11:14 a.m. | Last Modified: 14 Oct 2025, 1:01 p.m.

Panel Version: 3.10

Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Schmitt et al., 2005). The presentation does not usually include anaemia.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G p.(Asp233Gly) & c.1207_1218del12, p.(Thr403_Gly406del).

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).

Created: 14 Oct 2025, 11:05 a.m. | Last Modified: 16 Oct 2025, 1:23 p.m.

Panel Version: 3.13

Review added on behalf of Sharon Whatley (International Porphyria Network):

Relevant metabolic investigation: Plasma porphyrin fluorescence emission and faecal coproporphyrin isomer (III:I) ratio (for hereditary coproporphyria) and faecal harderoporphyrin (for harderoporphyria)

PMID: 38940544 Aarsand reports that porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes. Defects in the CPOX gene cause hereditary coproporphyria.

PMID: 16159891 Schmitt reports that there are two very rare, homozygous forms of HCP one of which is characterised by the faecal excretion of harderoporphyrin. Harderoporphyria has predominantly haematological manifestations such as neonatal jaundice, haemolytic anaemia and hepatosplenomegaly.

PMID: 30828546 Moghe, 9454777 Lamoril, 7757079 Lamoril, 40296768 Kelestemur, 21103937 Hasanoglu report eight patients (from five families) with biallelic pathogenic CPOX variants. They presented with neonatal jaundice, haemolytic anaemia and hepatosplenomegaly.

PMID: 16159891 Schmitt reports that during childhood and adulthood, a mild residual anaemia is chronically observed in harderoporphyria patients.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Sources: Other

Created: 14 Oct 2025, 9:50 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892

Publications

• 7757079
• 9454777
• 11309681
• 16159891
• 21103937
• 30828546
• 38940544
• 40296768