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Variegate porphyria (VP) is a cutaneous porphyria (with chronic blistering skin lesions) and an acute porphyria (with severe episodic neurovisceral symptoms). The most common manifestation of VP is adult-onset cutaneous blistering lesions (subepidermal vesicles, bullae, and erosions that crust over and heal slowly) of sun-exposed skin, especially the hands and face. Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. Cutaneous manifestations may improve in winter, and be less prevalent in northern regions and in dark-skinned individuals. Acute neurovisceral symptoms can occur any time after puberty, but less often in the elderly. Acute manifestations are highly variable, but may be similar from episode to episode in a patient with recurrent attacks; not all symptoms are present in a single episode; and acute symptoms may become chronic. Symptoms are more common in women than men. The most common symptoms are abdominal pain; constipation; pain in the back, chest, and extremities; anxiety; seizures; and a primarily motor neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis. Psychiatric disturbances and autonomic neuropathy can also be observed. Acute attacks may be severe and are potentially fatal.
No clinical features are specific for VP. It is important for all physicians, including primary physicians, to be aware of porphyrias and their variable features. The diagnosis is established by biochemical testing and confirmed by identification of a heterozygous pathogenic variant in PPOX, encoding the mitochondrial enzyme protoporphyrinogen oxidase (PPOX).
Treatment of manifestations: The first step in treating either acute neurovisceral attacks or cutaneous manifestations is to identify and remove exacerbating factors (see Agents/circumstances to avoid). Most acute neurovisceral attacks require hospital admission; the presence of seizures, motor neuropathy, and hyponatremia suggest severe disease that ideally should be managed in an ICU. Narcotic analgesics are usually required for pain. Ondansetron or a related drug can be used for nausea and vomiting; phenothiazines can be effective for nausea, agitation, and hallucinations. Although mild attacks (without seizures, weakness or hyponatremia and not requiring narcotics) can sometimes be treated in an outpatient setting with glucose loading, most attacks require treatment with intravenous hemin. Cutaneous symptoms are best managed by wearing protective clothing and avoiding exposure to sunlight. Symptoms may decrease when exacerbating factors are removed. No treatment is known to be effective in lowering porphyrin levels and reducing cutaneous symptoms. Analgesics may be needed for painful lesions and antibiotics for superimposed infection. Prevention of primary manifestations: Acute neurovisceral attacks are less likely to occur if exacerbating factors are corrected or avoided. Recurrent premenstrual acute attacks can be prevented with GnRH analogues; weekly or biweekly hemin infusions to prevent frequent noncyclical attacks may be effective, but data are lacking. Prevention of the skin manifestations requires protection from sunlight. Surveillance: Liver imaging at six-month intervals beginning at age 50 years in those who have experienced persistent elevations in porphobilinogen or porphyrins may detect early hepatocellular carcinoma. Agents/circumstances to avoid: Exacerbating factors that should be avoided include: barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Although birth control pills should generally be avoided, low-dose hormonal preparations may be tolerated. Concomitant illnesses should be treated effectively using drugs that are considered safe whenever possible. Updated lists of safe and unsafe drugs are maintained at the Web sites of the American Porphyria Foundation and the European Porphyria Network. Evaluation of relatives at risk: At-risk family members can be offered molecular genetic testing for the family-specific PPOX pathogenic variant to identify those who are heterozygous (for the purpose of counseling regarding appropriate use of drugs and avoidance of known exacerbating factors). Pregnancy management: Exacerbations during pregnancy have been treated successfully with heme arginate and heme hydroxide (hematin); while neither preparation has been studied extensively during pregnancy, limited data suggest that treatment during pregnancy is unlikely to produce adverse fetal effects.
VP is inherited in an autosomal dominant manner with reduced penetrance. De novo pathogenic variants are rare. Each child of an individual with VP has a 50% chance of inheriting the pathogenic variant; while offspring who inherit the variant may or may not develop symptoms, most do not. Prenatal diagnosis for pregnancies at increased risk for VP is possible if the pathogenic variant in an affected family member has been identified. Of note, the presence of a PPOX pathogenic variant does not predict whether – or at what age – an individual will become symptomatic.