Novel mutation of PPOX gene in a patient with abdominal pain and syndrome of inappropriate antidiuresis.

Acute porphyrias are metabolic disorders of heme biosynthesis characterized by acute life-threatening attacks. The diagnosis is often missed since clinical presentation is aspecific mimicking other medical and surgical conditions. Variegate porphyria (VP) is an autosomal dominant inherited disease with incomplete penetrance due to decreased activity of the Protoporphyrinogen Oxydase (PPOX) gene; most VP mutations are family specific. We report the case of a 40 year-old woman who presented many times to the emergency department complaining of unexplained abdominal pain and laboratory investigations showed repeatedly hyponatremia. Syndrome of inappropriate antidiuresis (SIAD) was confirmed and measurement of urine porphobilinogen and delta-aminolevulinic acid disclosed the diagnosis of acute porphyria. The genetic analysis of PPOX gene was performed.

The entire coding sequence and exon/intron boundaries of PPOX gene were amplified in 5 different Polymerase Chain Reaction (PCR) fragments. In silico prediction of the pathogenicity of the mutation was determined by using different tools, Polyphen2, SNPs&GO, SNPs3D.

The genetic analysis of PPOX gene revealed a novel missense variant c.1376 G > A (p.Cys459Tyr) in heterozygous state. The same variant was later found in one of her cousins with skin lesions and other three younger asymptomatic relatives. We provided evidence that this novel mutation is likely to be pathogenetic.

Our case highlights the importance of considering VP in the differential diagnosis of SIAD and underlines the role of genetic screening in the management of such patients. The finding of a novel mutation of PPOX gene in our index case has allowed to recognize an affected family.