Clinical characteristics.

Variegate porphyria (VP) is both 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 person with recurrent attacks; not all manifestations are present in a single episode; and acute symptoms may become chronic. Symptoms are more common in women than men. The most common manifestations 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.

Diagnosis/testing.

The biochemical diagnosis of VP is established in an individual with elevated urine porphobilinogen (PBG) or porphyrins and a fluorescence peak at ~626 nm on plasma fluorescence scanning; fecal porphyrins are also elevated, with a predominance of coproporphyrin III and protoporphyrin. The molecular diagnosis of VP is established by identification of a heterozygous pathogenic variant in PPOX on molecular genetic testing.

Management.

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 and in-patient observation for additional supportive management.

Cutaneous manifestations 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 gonadotropin-releasing hormone analogs; weekly or biweekly hemin infusions to prevent frequent noncyclical attacks may be effective, but experience is 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 drugs such as: 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 websites 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). While biochemical testing, especially plasma fluorescence scanning and fecal porphyrin analysis, is also useful, it is less sensitive than molecular genetic testing.

Pregnancy management: Exacerbations during pregnancy have been treated successfully with heme arginate or heme hydroxide (hematin); while neither preparation has been studied extensively during pregnancy, experience over many years suggests that treatment during pregnancy is unlikely to produce adverse fetal effects.

Genetic counseling.

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 manifestations, most do not. Prenatal testing 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.

Suggestive Findings

Variegate porphyria (VP) should be suspected in individuals with the following clinical findings and initial laboratory findings.

Clinical findings

• Cutaneous manifestations include chronic blistering photosensitivity, most commonly on the backs of the hands. Chronic features include blisters, milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. The skin lesions are identical to those of porphyria cutanea tarda (PCT) and other blistering cutaneous porphyrias [Meissner et al 2003] (see Differential Diagnosis).
• Neurovisceral symptoms most commonly include the following:
  • Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. Acute hepatic porphyrias should be suspected whenever abdominal pain remains unexplained after an initial workup for common causes.
  • Constipation
  • Pain in the back, chest, and extremities
  • Anxiety
  • Seizures
  • Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially, followed by hyporeflexia as motor neuropathy progresses.
  • Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion [Anderson et al 2005].

Initial biochemical laboratory findings. As VP may present with blistering cutaneous lesions on sun-exposed skin, neurovisceral symptoms or both, initial first-line testing aims to detect all porphyrias that can cause either skin or neurovisceral manifestations (see Differential Diagnosis).

• Blistering cutaneous porphyrias (including VP). When VP or any other blistering cutaneous porphyria is suspected, the recommended initial test is measurement of plasma or urine porphyrins. If elevated, further testing is needed to determine the type of porphyria or whether the porphyrin elevation – particularly in urine – represents nonspecific porphyrinuria rather than porphyria.
• Acute porphyrias (including VP). Measurement of urinary porphobilinogen (PBG)* and total porphyrins. Urine δ-aminolevulinic acid (ALA) is often measured at the same time as PBG but this is not necessary for initial screening.
  *Note: (1) If an acute porphyria is confirmed by substantial elevation of urinary PBG, treatment can be started, if appropriate, for symptoms of an acute attack (see Management, Treatment of Manifestations) while further biochemical testing is being performed to determine the type of acute porphyria (see Differential Diagnosis). (2) If PBG is normal, total porphyrins and ALA should be measured in the same urine sample, because total porphyrins often remain elevated longer than PBG. In ALA dehydratase-deficiency porphyria (ADP), the rarest type of porphyria, ALA and total porphyrins (but not PBG) are markedly elevated [Anderson et al 2005].
• Substantial elevation in erythrocyte porphyrins is not consistent with VP, and points to an erythropoietic porphyria as a cause of blistering skin manifestations and elevation of urine and plasma porphyrins. Alternatively, substantial erythrocyte protoporphyrin in an individual with VP may suggest a concurrent condition that elevates zinc protoporphyrin, such as iron deficiency, lead poisoning, or another erythrocyte disorder.

Establishing the Diagnosis

Clinical Description

Variegate porphyria (VP) is classified as both a cutaneous and an acute porphyria. It can present with chronic blistering cutaneous manifestations and/or acute attacks of neurovisceral manifestations that may become chronic.

Cutaneous manifestations. Chronic blistering photosensitivity, typically on the backs of the hands, is the most common manifestation of VP. The lesions result from sun exposure that activates porphyrins and makes the skin fragile and prone to blister formation. Lesions are located on sun-exposed areas, especially the dorsal aspects of the hands and less frequently the face, neck, ears, and lower extremities. Because sun-induced damage is not acute, the role of sunlight is often not recognized. Cutaneous manifestations may improve in winter and be less prevalent in northern regions and in dark-skinned individuals.

These and other manifestations of VP appear typically in adulthood and rarely before puberty.

The subepidermal vesicles, bullae, and erosions crust over and heal slowly. When blisters rupture they may become infected and painful.

Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur.

The skin manifestations are identical to those seen in porphyria cutanea tarda (PCT) and hereditary coproporphyria (HCP), and less severe than those seen in congenital erythropoietic porphyria (CEP) and hepatoerythropoietic porphyria (HEP). They contrast with the acute non-blistering photocutaneous manifestations of erythropoietic protoporphyria (EPP) (see Table 3).

Of note, the great majority of individuals who are heterozygous for a PPOX pathogenic variant are asymptomatic and are unlikely to be recognized unless they are screened for VP based on a family history of VP (see Genetic Counseling). In South Africa the frequency of acute attacks has decreased in recent decades. This may be due to less common use of harmful drugs such as barbiturates and sulfonamide antibiotics in clinical practice and perhaps better case recognition and better dissemination of information on how to avoid future attacks. VP now more commonly presents in South Africa with cutaneous rather than acute manifestations [Meissner et al 2003, Anderson et al 2005, Hift & Meissner 2005].

Neurovisceral symptoms can occur at any age after puberty as acute attacks, but may become chronic. Symptoms are more common in women than men, and occur less often in the elderly. The frequency and severity of attacks vary considerably and are determined, in part, by exacerbating factors such as certain drugs, hormones, and nutritional deficits [Anderson et al 2005]. The proportion of persons heterozygous for a PPOX pathogenic variant who experience acute attacks decreased from about 30%-40% in the 1980s to 5%-10% in 2005 [Hift & Meissner 2005].

The neurovisceral symptoms are identical to those in the other acute porphyrias (see Differential Diagnosis).

Acute manifestations vary. The most common symptoms are abdominal pain; nausea and vomiting; constipation; pain in the back, chest, and extremities; anxiety; seizures; and a predominantly motor peripheral neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis [Kauppinen & Mustajoki 1992, Meissner et al 2003, Anderson et al 2005, Hift & Meissner 2005]. Psychiatric disturbances and autonomic neuropathy can also be observed. Not all symptoms are present in a single episode and symptoms can vary from episode to episode; however, recurrent attacks are often similar. Acute attacks may be severe and are potentially fatal, but on average are less frequent and less severe than those observed in acute intermittent porphyria (AIP) [Hift & Meissner 2005].

Motor neuropathy usually manifests initially as proximal upper-extremity muscle weakness and can be difficult to detect. Hyperreflexia may be seen initially, followed by hyporeflexia as the motor neuropathy progresses. The motor neuropathy may be accompanied by sensory loss. Note: Motor neuropathy due to acute porphyrias is accompanied by little or no elevation of cerebrospinal fluid protein, which helps to differentiate it from the Landry Guillain-Barré syndrome [Anderson et al 2005].

Because abdominal pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present.

An acute attack can be fatal in the presence of severe manifestations including neuropathy, seizures, and respiratory compromise. If managed properly, the outcome of an acute attack is generally good. Even severe motor neuropathy is reversible with recovery over a variable period of months and sometimes over several years.

Factors that predispose to acute attacks that are often identified include exposure to a harmful drug, alcohol, reduced dietary intake, or stress from an infection or other illness. Most harmful drugs are known to be inducers of hepatic δ-aminolevulinic acid synthase (ALAS) and hepatic cytochrome P450 enzymes (see Agents/Circumstances to Avoid). Pregnancy is usually well tolerated but can precipitate acute attacks in some women.

Physical findings such as tachycardia, hypertension, restlessness, and agitation result from autonomic neuropathy and increased circulating catecholamines.

Chronic pain may be a manifestation of VP and other acute porphyrias. Depression may be more difficult to link to the disease. Chronic pain and depression may become important management issues.

Chronic liver abnormalities, particularly mild elevation of serum transaminases, are common. Risks for development of hepatocellular carcinoma and chronic renal disease are increased in VP (as well as in AIP and HCP). Hepatocellular carcinoma may develop, especially after age 50 years in persons with persistent elevations in porphobilinogen and porphyrins.

Note: The speculation that King George III (and perhaps others in the British royal family) had VP has been discounted [Peters 2011].

Genotype-Phenotype Correlations

PPOX pathogenic variants are generally severe and result in little or no enzyme activity; the residual approximately half-normal enzyme activity is a product of the normal allele. Therefore, different pathogenic variants are not associated with differences in disease severity [Whatley et al 1999, Whatley et al 2009].

Double heterozygosity for pathogenic variants in two different genes in the heme biosynthetic pathway. A patient with cutaneous manifestations initially diagnosed as HCP was found to be a double heterozygote for pathogenic variants in PPOX and CPOX after other family members were found to have clinical and biochemical features of VP [van Tuyll van Serooskerken et al 2011]. The phenotypes of such rare double heterozygotes are not necessarily more severe than the phenotype associated with heterozygosity for a pathogenic variant in one gene alone, suggesting that individuals who are doubly heterozygous for pathogenic variants in genes causing two different types of acute porphyria may be more common than has been assumed.

Note: Typically double heterozygosity is suspected because of unusual biochemical patterns, and thus is unlikely to be recognized without comprehensive biochemical testing [van Tuyll van Serooskerken et al 2011], which then identifies a need for additional molecular genetic testing.

Penetrance

PPOX pathogenic variants that result in VP produce little or no functional enzyme; the approximately 50% of normal residual enzyme activity results primarily from the normal allele. Penetrance is low, but may be increased by factors that increase the demand for hepatic heme synthesis. Penetrance is likely influenced by modifying genes that remain to be identified.

Nomenclature

Variegate porphyria (VP) and hereditary coproporphyria (HCP) were sometimes referred to as mixed porphyria, which is now an obsolete term.

VP has also been referred to as South African acute porphyria or protocoproporphyria.

In the past, familial porphyria cutanea tarda (PCT) may not have been clearly differentiated from VP in some instances.

Prevalence

It is estimated that in the South African population three individuals per 1,000 are heterozygous for the PPOX pathogenic variant p.Arg59Trp [Meissner et al 1996, Meissner et al 2003].

The prevalence of VP with present or past symptoms in Europe is about half that for acute intermittent porphyria (AIP), and has been estimated at 3.2:1,000,000 [Elder et al 2013].

Evaluations Following Initial Diagnosis

To establish the extent of disease and to plan the management of an individual diagnosed with variegate porphyria (VP), the following clinical and laboratory evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Degree of elevations on plasma and urine porphyrins and urine porphobilinogen (PBG), if not determined at the time of diagnosis
• Clinical evaluation of any current acute neurovisceral manifestations to determine the need for hospital admission and treatment with hemin.
• Nervous system. Assessment of the extent of neurologic involvement causing paresis, pain or sensory changes
• Psychiatric evaluation if depression or other psychiatric features are present
• Liver. Liver function tests to indicate chronic liver involvement and liver imaging in patients older than age 50 years
• Kidneys. Kidney function tests to assess for presence and progression of kidney damage
• Skin. Assessment of blistering cutaneous lesions to assess their relationship to VP
• Contributions of medications (see Agents/Circumstances to Avoid), diet, and concurrent conditions to severity of VP
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Prevention of Primary Manifestations

Acute attack

• Attacks are less likely to occur in the future if exacerbating factors are corrected or avoided (see Agents/Circumstances to Avoid).
• Recurrent premenstrual attacks of acute porphyrias, including VP, can be prevented with gonadotropin-releasing hormone analogs [Anderson et al 1990, Schulenburg-Brand et al 2017].
• Weekly or biweekly hemin infusions may prevent frequent noncyclical attacks; however, published experience is lacking [Marsden et al 2015].
• Givosiran, a small interfering RNA (siRNA) therapeutic, was recently approved by the FDA for treatment of acute porphyrias, including VP. In particular, monthly subcutaneous injections of givosiran can be effective for prevention of frequently recurring attacks [Sardh et al 2019].

Photocutaneous manifestations. Prevention of the skin manifestations of VP requires protection from sunlight. Avoidance of exacerbating factors may also be beneficial.

Surveillance

Hepatocellular carcinoma may develop especially after age 50 years in patients with acute porphyrias and persistent elevations in porphobilinogen or porphyrins; liver imaging at six-month intervals beginning at age 50 years may detect early lesions [Andant et al 2000, Schneider-Yin et al 2010].

Agents/Circumstances to Avoid

Precipitating factors that should be avoided include: barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins.

Updated lists are maintained at the websites of the American Porphyria Foundation and the European Porphyria Network.

Although birth control pills should generally be avoided, low-dose hormonal preparations may be tolerated.

Fasting and very low calorie diets should be avoided. Bariatric surgery should be avoided in patients who have had frequent exacerbations of VP and other acute porphyrias. Patients who wish to lose weight should do so gradually with moderate, long-term reductions in calorie intake under guidance of a dietician.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of a proband. This will identify individuals heterozygous for the familial PPOX pathogenic variant who may benefit from counseling regarding appropriate use of drugs and avoidance of known precipitating factors.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy is usually well tolerated in women with variegate porphyria (VP); however, some women with VP may experience exacerbations during pregnancy.

Badminton & Deybach [2006] published an anecdotal report of successful treatment of several pregnant women experiencing attacks of VP or other acute porphyrias during pregnancy with hemin (in the form of heme arginate) without adverse fetal effect. They emphasize that interruption of pregnancy is almost never indicated for management of acute porphyria.

Experience with heme hydroxide (hematin) is also limited but suggests no adverse effects during pregnancy [Isenschmid et al 1992]. As noted (see Treatment of Manifestations, Neurovisceral Symptoms), hemin is delivered to tissues as heme albumin when administered as either heme arginate or heme hydroxide, and these preparations are expected to have similar safety profiles.

A fetus heterozygous for a PPOX pathogenic variant has a good prognosis, because current postnatal management involves counseling the family regarding appropriate use of drugs and avoidance of known precipitating factors.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Variegate porphyria (VP) is inherited in an autosomal dominant manner with reduced penetrance.

Risk to Family Members

Parents of a proband

• Typically, one parent of an individual diagnosed with VP is heterozygous for the PPOX pathogenic identified in the proband and may or may not have had symptoms.
• Rarely, an individual diagnosed with VP may have the disorder as the result of a de novo pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported.
• The family history of some individuals diagnosed with VP may appear to be negative because of reduced penetrance or failure to recognize the disorder as the cause of nonspecific symptoms in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the PPOX pathogenic variant identified in the proband, each sib has a 50% chance of inheriting the variant. A sib who inherits the pathogenic variant may or may not develop symptoms of VP.
• If the proband has a known VP-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband

• Each child of an individual with VP has a 50% chance of inheriting the pathogenic variant.
• Offspring who inherit the pathogenic variant may or may not develop symptoms.

Other family members

• The risk to other family members depends on the status of the proband's parents: if a parent has the PPOX pathogenic variant, his or her family members may be at risk.
• A family member with the PPOX pathogenic variant may or may not develop symptoms of VP.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the PPOX pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for VP are possible. Note: The presence of a PPOX pathogenic variant detected by prenatal testing does not predict whether individuals will be symptomatic, or if they are, the age of onset or presentation of the disorder.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PPOX catalyzes the oxidation of protoporphyrinogen to protoporphyrin, with removal of six protons. The partial deficiency of PPOX in VP limits heme synthesis, particularly in the presence of factors that lead to increased hepatic heme synthesis and induction of δ-aminolevulinic acid synthase-1 (ALAS1) in the liver. ALAS1 is the ubiquitous form of ALAS, which is found in all tissues, in contrast to the erythroid-specific form known as ALAS2, which is produced only in the bone marrow.

Mechanism of disease causation. VP is caused by heterozygous loss-of-function PPOX variants, resulting in reduction of the enzyme in all tissues to approximately 50% of normal.

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Acknowledgments

This work is supported by the Porphyrias Consortium funded by the NIH/NIDDK and part of the Rare Diseases Clinical Research Network, and the American Porphyria Foundation.

Revision History

• 12 December 2019 (bp) Comprehensive update posted live
• 14 February 2013 (me) Review posted live
• 12 June 2012 (kea) Original submission