The G_M2-gangliosidoses are a subgroup of sphingolipidoses in which there is an accumulation of the ganglioside G_M2, as a result of a defect in some aspect of the hexosaminidase system.^{68. and 74.} The most common clinical variant is Tay–Sachs disease (OMIM 272800) in which there is progressive psychomotor deterioration and blindness. It is due to a mutation in the gene encoding the alpha subunit of the hexosaminidase A enzyme (HEXA) on chromosome 15q23–q24. In Sandhoff’s disease (OMIM 268800), which is phenotypically similar, the gangliosides are deposited in nearly all cells of the body, in contrast to Tay–Sachs disease in which deposits do not occur outside the nervous system.^{69. and 75.} In Sandhoff’s disease the mutation involves the beta subunit of hexosaminidase (HEXB), on chromosome 5q13. ⁷⁶

G_M1-gangliosidosis (OMIM 230500) is an autosomal recessive lysosomal storage disease caused by a mutation in the gene encoding β-galactosidase-1 (GLB1). There are two major clinical variants of G_M1-gangliosidosis, of which Norman–Landing disease (pseudo-Hurler’s syndrome) is the more severe. ⁷⁴ This infantile form (type I) is characterized clinically by a gargoyle-like appearance, psychomotor regression, blindness, hirsutism, hepatosplenomegaly, and deformities of the hands and feet.^{69. and 79.} As in G_M2 gangliosidosis, a ‘cherry-red spot’ is often present. Extensive dermal melanocytosis has been reported in several patients with G_M1-gangliosidosis. ⁸⁰

Gaucher’s disease is the most prevalent sphingolipidosis with a frequency of 1 in 50 000–100 000 live births in white populations, and 1 in 850 in Ashkenazi Jews. ⁸² Gaucher’s disease is categorized phenotypically into three main subtypes. All forms are caused by mutations in the gene encoding glucocerebrosidase (GBA) on chromosome 1q21; more than 200 mutations are known.^{83.84.85. and 86.} Type I Gaucher’s disease (OMIM 230800) is the most common form of the disease; it lacks central nervous system involvement, as occurs in the other types. ⁸⁷

In Gaucher’s disease, glucocerebroside accumulates in the cells of the mononuclear macrophage system (reticuloendothelial system).^{88.89. and 90.} This condition will not be discussed further as skin biopsies have consistently been negative, with no evidence of stored lipid in sweat ducts, fibroblasts, or cutaneous nerves.^{69. and 81.}

Fabry’s disease (OMIM 301500) is an uncommon X-linked recessive disorder of glycosphingolipid metabolism in which there is a deficiency of the lysosomal hydrolase, α-galactosidase A (formerly called ceramide trihexosidase).^{91.92. and 93.} The gene maps to Xq22. This leads to the accumulation of ceramide trihexoside in various tissues of the body, particularly the vascular and supporting elements.

The disease usually presents in late adolescence with recurrent fevers associated with pain in the fingers and toes and intermittent edema.^{91.94.95. and 96.} Characteristic whorled opacities are usually present in the cornea (cornea verticillata).^{91. and 92.} Cerebrovascular and cardiovascular disturbances are common, and progressive renal damage leading to renal failure in the fourth and fifth decades of life is almost invariable.^{94. and 97.} Atopic eczema is not increased. ⁹⁸ Heterozygous females are often asymptomatic, but they may show evidence of the disease to different degrees.^{99.100.101. and 102.} Therefore, they are more than ‘carriers’ of the gene.

The diagnosis of Fabry’s disease can be made on the urine lipid profile, and by the reduced α-galactosidase A activity in peripheral blood leukocytes. ¹⁰²

The cutaneous lesions (angiokeratoma corporis diffusum) are multiple, deep red telangiectases clustered on the lower part of the trunk, buttocks, thighs, scrotum, and the shaft of the penis (see p. 896). ⁹¹ Angiokeratomas were present in 66% of males and 36% of females registered on the Fabry Outcome Survey, a multicenter European database of 714 patients (at time of the review). ¹⁰³ Most sites can be involved, although the face and scalp are usually spared. Petechial lesions are rarely present. ¹⁰⁴ Cutaneous lesions are occasionally absent. ⁹² Multiple leg ulcers have also been described. ¹⁰⁵ There may be anhidrosis.^{92. and 103.}

It should be noted that angiokeratomas are not confined to Fabry’s disease. They may also occur in sialidosis, fucosidosis, adult-onset G_M1-gangliosidosis, aspartylglycosaminuria, β-mannosidosis, α-N-acetylgalactosaminidase deficiency, galactosialidosis, and in an idiopathic form.

The effect of enzyme replacement therapy on the vasculopathy in Fabry’s disease appears to be minimal. ¹⁰⁶ As this therapy is expensive, ¹⁰⁷ it is important that a correct diagnosis, with biochemical confirmation, is made prior to therapy.^{108. and 109.}

Metachromatic leukodystrophy (OMIM 250100) results from a deficiency in the activity of arylsulfatase A and the accumulation of metachromatic sulfatides in the nervous system and certain other organs.^{68. and 74.} Clinically, there is progressive psychomotor retardation. The gene maps to chromosome 22q13.31–qter.

Krabbe’s disease (globoid cell leukodystrophy – OMIM 245200) is an autosomal recessive disease that results from a mutation in the galactosylceramidase gene on chromosome 14q31. As a consequence, there is a deficiency of the lysosomal enzyme galactocerebrosidase.^{68. and 117.} There are progressive neurological symptoms, beginning usually in childhood, as a consequence of the apoptotic death of oligodendrocytes and Schwann cells resulting from the accumulation of psychosine. ¹¹⁷ Its incidence in the United States is 1 in 100 000 live births. ¹¹⁷

Disseminated lipogranulomatosis (Farber’s disease – OMIM 228000) is a rare, autosomal recessive disorder of lipid metabolism in which there is a deficiency of acid ceramidase leading to an accumulation of ceramide and its degradation products.^{119. and 120.} The defect maps to chromosome 8p22–p21.3. Several mutations have been described. The main clinical features usually appear at the age of 2–4 months and comprise progressive arthropathy, the development of subcutaneous, often periarticular nodules, hoarseness, irritability, and pulmonary failure. ¹²¹ The disease is progressive, death usually occurring in early childhood. ¹²¹

The diagnosis can be made by demonstrating a deficiency in ceramidase in cultured fibroblasts or in white blood cells. ¹²²

Niemann–Pick disease is a rare autosomal recessive disorder in which sphingomyelin accumulates in many organs due to a deficiency of sphingomyelinase. ¹²⁵ It is characterized by progressive neurodegeneration. It is a heterogeneous entity with more than one enzyme defect involved.^{126.127.128. and 129.} Several types have been described: type A (OMIM 257200), the predominant type, is due to a mutation in the sphingomyelin phosphodiesterase-1 gene (SMPD1) on chromosome 11p15.4–p15.1; type B (OMIM 607616), which is allelic to type A, has visceral involvement, but no neurological disease (types E and F are included here); type C1 (OMIM 257220) and type D are caused by mutations in the NPC1 gene on chromosome 18q11–q12; and type C2 (OMIM 607625) is due to a mutation in the NPC2 gene at 14q24.3. ¹³⁰ The NPC genes appear to regulate intracellular trafficking of cholesterol and other lipids. The course is unremitting and death usually occurs in early childhood.

Cutaneous lesions have been reported in a small number of cases and include diffuse tan brown hyperpigmentation, indurated brown plaques, ¹³¹ facial papules, ¹³² xanthomas, ¹²⁵ and juvenile xanthogranulomas.^{133. and 134.} A nodular panniculitis has been described in a patient with type C disease. ¹³⁵ A small number of cases have abnormalities in skin barrier function as a consequence of a marked reduction in sphingomyelin-derived ceramide. ¹³⁶

Sialidosis (mucolipidosis I, neuraminidase deficiency – OMIM 256550) results from a deficiency of neuraminidase (sialidase), ¹³⁷ caused by mutations in the NEU1 gene on chromosome 6p21.3. Clinical features include coarse facies, ataxia, myoclonus, and a cherry-red spot in the macula. ¹³⁷

Galactosialidosis (OMIM 256540) is a slowly progressive neurodegenerative disease, with similar phenotypic features, which results from the combined deficiency of neuraminidase (sialidase) and β-galactosidase.^{138. and 139.} Several different mutations have been described in the PPGB gene that maps to 20q13.1. There is the lack of a 32 kDa ‘protective protein’ that is crucial for the biological activity of these two enzymes. Angiokeratomas have been reported in patients with this combined deficiency state.^{139. and 140.}

Fucosidosis (OMIM 230000) is a rare autosomal recessive disorder in which a deficiency of the lysosomal enzyme α-L-fucosidase leads to the accumulation of fucose-containing glycolipids and other substances in various tissues.^{142. and 143.} The gene FUCA1, on chromosome 1p34, encodes this enzyme; more than 20 different mutations have been described. ¹⁴⁴ About 100 cases have been reported worldwide. ¹⁴⁴ There is early onset of psychomotor retardation and other neurological signs. Three clinical variants have been reported, but only type 3 is associated with cutaneous lesions. ¹⁴⁵ These lesions are indistinguishable from the angiokeratomas seen in Fabry’s disease (see p. 485).^{144.146. and 147.} Hypohidrosis, increased palmoplantar vascularity, and widespread telangiectasia may also be present. ¹⁴⁸

Bone marrow transplantation is reported to be an effective treatment. ¹⁴⁴ Enzyme replacement therapy or gene therapy is unlikely to become available in the near future. ¹⁴⁴

Two types of mannosidosis have been identified: α-mannosidosis (OMIM 248500), caused by a mutation in the gene MAN2B1, found at 19cen–q12, encoding the lysosomal enzyme α-mannosidase; and β-mannosidosis (OMIM 248510), an extremely rare condition, due to a mutation in the MANBA gene, encoding β-mannosidase, on chromosome 4q22–q25.^{151. and 152.}

In α-mannosidosis, the deficiency of the lysosomal enzyme α-mannosidase leads to an accumulation of mannose-containing oligosaccharides in various tissues of the body, including the nervous system. ¹⁵³ Patients have a gargoyle-like facies and mental retardation. The condition runs a relatively benign clinical course.

In β-mannosidosis, there is facial dysmorphism, skeletal deformities, respiratory and skin infections, angiokeratomas, hepatosplenomegaly, and neurological abnormalities.^{151. and 152.}

I-cell disease (mucolipidosis II) is caused by a mutation in the GNPTAB gene. ¹⁵⁵ I-cell disease (OMIM 252500) is an autosomal recessive neurodegenerative disorder, characterized by a marked intracellular deficiency of a number of lysosomal hydrolases and by a significant elevation of these enzymes in plasma. ¹⁵⁶ It is caused by a deficiency of uridine-diphosphate-N-acetylglucosamine 1-phosphotransferase, the enzyme that phosphorylates mannose residues of glycoproteins to allow their delivery to lysosomes.^{157. and 158.} The gene maps to chromosome 12q23.3, although there has been conflicting assignment to 4q21–q23.

Clinically, there is short stature, facial dysmorphism, progressive mental and motor retardation, and bony deformities.^{159. and 160.} The skin is generally pale and smooth. ¹⁵⁹

Glycogenosis (type II), also known as glycogen storage disease II (OMIM 232300), is an autosomal recessive disease, caused by mutations in the gene (GAA) encoding acid alpha-1, 4-glucosidase (acid maltase), which maps to chromosome 17q25.2–q25.3. ⁶⁸ In the classic infantile form (Pompe’s disease) children are hypotonic with enlarged hearts.

The neuronal ceroid-lipofuscinoses are a heterogeneous group of progressive neurodegenerative disorders characterized by the accumulation of autofluorescent ceroid or lipofuscin-like substances in various organs, especially the nervous system.^{162.163. and 164.} Types 1 to 10 have been identified, all with different genetic abnormalities and gene localizations. They were originally identified by the age of onset, but this has been discontinued since the genetic abnormalities have been identified. Type 1 (OMIM 256730) was the original infantile form. Abnormal peroxidation of fatty acids may be the metabolic basis. ¹⁶²

Cystinosis (OMIM 219800) is a lysosomal storage disease resulting from an error in the transmembrane transport of the amino acid cystine. It results from a mutation in the gene encoding cystinosin on chromosome 17p13. There is storage of cystine in multiple organs of the body, particularly the kidney, pancreas, cornea, central nervous system, and muscle. Skin and hair pigmentation is reduced, possibly resulting from impaired pigment formation in melanosomes. Cystine deposits in macrophages in the skin (Fig. 18.4).

Diabetic microangiopathy refers to the abnormal small vessels found in many organs and tissues in diabetes mellitus. The kidneys, eyes, skin, and muscles are particularly affected by this disease process, which is the principal factor determining the prognosis of individuals with diabetes mellitus. ⁴¹⁰

Microangiopathy may be involved in the pathogenesis of the pigmented pretibial patches, the erysipelas-like erythema, and the necrobiosis lipoidica that may occur in diabetes mellitus. It may contribute to the neuropathy that sometimes occurs. Small vessel disease may be as important as atherosclerosis of large vessels in producing gangrene of the feet and lower limbs in diabetics. In many instances the microangiopathy is clinically silent.

Pigmented pretibial patches (diabetic dermopathy, skin spots) are the most common cutaneous finding in diabetes mellitus, although they are not specific to it.^{415. and 431.} They are found in up to 50% of diabetics, but as they are asymptomatic, they are usually overlooked. ⁴³² The patches are seen more frequently in older patients, and in those who have had diabetes mellitus for a longer period of time. ⁴³³ They begin as flat-topped, dull-red papules that are round or oval, discrete or grouped, and situated mainly on the pretibial areas. ⁴¹⁰ Involvement of the forearms and thighs has been recorded. ⁴³⁴ As the lesions evolve they develop a thin scale and finally become variably atrophic and hyperpigmented.^{411. and 426.} They vary from 0.5 cm in diameter up to large patches covering much of the pretibial skin.

It has been suggested that the lesions represent an exaggerated response to trauma in skin overlying bony prominences⁴¹⁵ and that there may be an underlying diabetic angiopathy.^{435. and 436.} Blood flow levels are considerably higher at the dermopathy sites than at contiguous uninvolved skin sites, refuting the theory that they are ischemic in origin. ⁴³⁷ The presence of pigmented pretibial patches has an unfavorable association with the three most common microangiopathic complications of diabetes mellitus: neuropathy, nephropathy, and retinopathy. ⁴³³ A relationship between these patches and coronary artery disease has also been demonstrated. ⁴³³

Bullae, usually multiple and confined to the lower extremities, are a rare complication of long-standing diabetes mellitus. ⁴³⁹ They were originally reported in 1963 as ‘phlyctenar lesions’ because they become dark as they dry up, in the manner of a burn blister. ⁴⁴⁰ The bullae, which arise on a non-inflamed base, are tense and vary in diameter from 0.5 to 17 cm.^{426. and 441.} They heal in several weeks, usually without scarring.

It seems likely that cases reported under this title do not represent a homogeneous entity, some possibly representing the bullous dermopathy of chronic renal failure.^{415. and 442.} Wang and Ackerman concluded their review on bullosis diabeticorum by supporting this view that it is not a discrete entity. ⁴⁴³ Furthermore, there is an increased frequency of diabetes in patients with bullous pemphigoid. ⁴⁴⁴

Acute intermittent porphyria (OMIM 176000) is an autosomal dominant disorder resulting from a defect in porphobilinogen deaminase (uroporphyrinogen I synthase) which catalyzes the formation of uroporphyrinogen from four molecules of porphobilinogen. ⁴⁷⁴ The gene encoding this enzyme is at 11q23.3. The disorder is usually latent, but acute episodes consisting of neurological, psychiatric, and abdominal symptoms may be precipitated by various factors, particularly drugs. ⁴⁷⁵ Barbiturates, sulfonamides, and griseofulvin are most often incriminated. ⁴⁶⁸ There are no cutaneous manifestations.

Laboratory findings include greatly increased levels of porphobilinogen and ALA in the urine during, and usually between, attacks.

This very rare, autosomal recessive disorder (OMIM 125270) results, as its name indicates, from a deficiency of ALA-dehydratase which was formerly known as porphobilinogen synthase (PBG-synthase). The gene encoding this enzyme is at 9q34. There are intermittent, acute episodes resembling those in acute intermittent porphyria; there are no cutaneous manifestations. ⁴⁷⁵

The pattern of overproduction of heme precursors closely resembles that seen in severe lead poisoning. There is overproduction of ALA and of coproporphyrinogen III.

Hereditary coproporphyria (OMIM 121300) is an autosomal dominant variant of acute porphyria which results from a deficiency of coproporphyrinogen oxidase. ⁴⁷⁰ The gene encoding this enzyme is at 3q12. Latent disease is more usual than the symptomatic form, which is characterized by episodic attacks of abdominal pain and neurological and psychiatric disturbances. These acute episodes are less severe than in acute intermittent porphyria. Cutaneous photosensitivity occurs in approximately 30% of cases and becomes manifest chiefly in association with the acute attacks.470. ^{and 476.} The lesions resemble those seen in porphyria cutanea tarda (see below). There has been one report of a patient with porphyria-like photosensitivity following liver transplant. The coproporphyrin levels were only mildly elevated. ⁴⁷⁷ Acute coproporphyria has also been induced by the anabolic steroid methandrostenolone (methandienone). ⁴⁷⁸

Laboratory findings include greatly elevated levels of urinary and fecal coproporphyrins. Porphobilinogen and ALA are increased, as in variegate porphyria (see below), during acute episodes. ⁴⁷⁶

Variegate porphyria (OMIM 176200), like hereditary coproporphyria, may be associated with acute episodes (as seen in acute intermittent porphyria) and with photocutaneous manifestations (as seen in porphyria cutanea tarda).^{479. and 480.} It is an autosomal dominant disorder in which the activity of the enzyme protoporphyrinogen oxidase (the penultimate enzyme in the pathway of heme biosynthesis) is reduced by approximately 50%. This disorder is quite common in white Afrikaaners and much less so in other white people and in people of other races. ⁴⁷⁹ The (PPOX) gene, which controls the formation of the responsible enzyme, maps to chromosome 1q22–q23. ⁴⁸¹ Homozygous cases of variegate porphyria are rare; they present with severe photosensitivity in childhood. ⁴⁸² Numerous mutations in this gene have been described in European patients, but in South Africa most patients have inherited the same mutation.^{483.484.485.486. and 487.} A founder mutation has also been reported from Chile. ⁴⁸² The simultaneous occurrence of symptoms of variegate porphyria has been reported in monozygotic twins. ⁴⁸⁸

Only a minority of people with the enzyme defect develop clinical manifestations, and only after puberty. The clinical penetrance of variegate porphyria in one large South African family with the R59W mutation was 40%. ⁴⁸⁹ Acute episodes are precipitated by exogenous factors such as the ingestion of various drugs.^{468. and 490.} Cutaneous changes include skin fragility, blistering and milia formation in sun-exposed areas, as in porphyria cutanea tarda, although very occasionally an acute phototoxic reaction (as seen in erythropoietic protoporphyria) may develop. ⁴⁷⁰ Variegate porphyria is not usually associated with liver dysfunction, although it has been reported in association with a hepatocellular carcinoma.^{491. and 492.} Dapsone, used in the treatment of dermatitis herpetiformis, has precipitated an acute attack of variegate porphyria. ⁴⁹³

Laboratory findings are somewhat variable, depending on the activity of the disease. ⁴⁷⁰ There is usually an elevated plasma porphyrin level with plasma fluorescence that is maximal at a wavelength of 626 ± 1 nm. ⁴⁹⁴ In practice, the diagnosis is most often suggested by finding elevated levels of fecal protoporphyrin and coproporphyrin. ⁴⁹⁰ Urinary ALA and porphobilinogen are usually increased during acute episodes. Porphobilinogen deaminase activity is sometimes decreased as a secondary phenomenon. ⁴⁹⁵

It has been reported in one homozygote that the erythrocyte protoporphyrin was raised and that this was predominantly zinc chelated. ⁴⁹⁶

Congenital erythropoietic porphyria (OMIM 263700) is a rare, autosomal recessive disorder of heme synthesis resulting from a deficiency of uroporphyrinogen III cosynthase (URO-synthase) which leads to an accumulation of porphyrins, particularly uroporphyrinogen I and III, in the bone marrow, blood, and other organs.497.^{498.499. and 500.} The URO-synthase gene has been localized to the narrow chromosomal region 10q25.3–q26.3. ⁴⁹⁸ Several different mutations have been described; ⁵⁰¹ some specific mutations appear to correlate with a milder disease. ⁵⁰² The defect leads to a chronic photobullous dermatosis, intermittent hemolysis, and massive porphyrinuria. ⁴⁹⁷ Presentation is usually in infancy with red urine which stains diapers a pink color. ⁴⁷⁰ Late onset of the disease has been recorded.^{503. and 504.}

The severe photosensitivity leads to the formation of bullae within a day or two of exposure to the sun. Recurrent eruptions may lead to mutilating deformities of the hands and face and sclerodermoid thickening of affected parts. ⁵⁰⁵ Squamous cell carcinoma of the skin is a rare complication. ⁵⁰⁶ Sunlight avoidance is the best therapy. ⁵⁰⁰ Other clinical features include the pathognomonic characteristic of erythrodontia (discoloration of the teeth under normal light and red fluorescence with ultraviolet light), hypertrichosis, patchy scarring alopecia, and nail changes.^{497.507.508. and 509.}

There are large amounts of uroporphyrins in the urine and coproporphyrins in the stool; these are predominantly type I isomers. ⁵⁰⁵ The plasma and erythrocytes contain increased levels of uroporphyrinogen and, to a lesser extent, coproporphyrinogen. ⁵¹⁰ Heterozygotes have blood levels of URO-synthase activity intermediate between affected individuals and controls. ⁵⁰⁵

In the more severely affected individuals, bone marrow transplantation is potentially curative, but is not without risks.^{511.512. and 513.}

Erythropoietic protoporphyria (OMIM 177000), more recently termed simply ‘protoporphyria’,^{470. and 514.} results from a defect in the terminal step of heme synthesis at which protoporphyrin IX and iron combine to form heme.^{515.516.517.518. and 519.} It is associated with a partial deficiency of ferrochelatase (heme synthase) leading to an accumulation of protoporphyrin IX in erythrocytes, plasma, liver, and skin. ⁵²⁰ Although originally regarded as autosomal dominant in inheritance, it is now known that autosomal recessive inheritance occurs in a few cases.^{518.521. and 522.} The gene for ferrochelatase has been cloned and mapped to the long arm of chromosome 18 (18q21.3). Over 110 different mutations have now been described.^{522.523.524.525. and 526.} The presence of liver disease appears to correlate with specific mutations. ⁵²⁵

It generally becomes manifest in early childhood with episodes of acute photosensitivity accompanied by a painful, burning sensation. ⁵¹⁶ Often there is edema and erythema and rarely there may be urticaria and petechiae.^{470. and 527.} The changes develop within a few hours of exposure to the sun. In the chronic stages there is waxy scarring of the nose, radial scars around the lips, and pits or scars on the forehead, nose and cheeks.^{470. and 528.} The skin on the dorsum of the hands has a leathery texture and it may also show ‘cobblestone’ thickening. ⁴⁷⁰ It has a marked impact on quality of life. ⁵²⁰ Deaths from cirrhosis accompanying heavy accumulation of protoporphyrin in the liver have been reported.^{529.530.531. and 532.} Cirrhosis and liver failure occur in less than 5% of patients, but up to 20% may have abnormalities in liver function. ⁵²²

Rare clinical presentations have included late onset,^{528.533. and 534.} the presence of scarring bullae and milia, ⁵³⁵ coexistence with lupus erythematosus, ⁵³⁶ a clinical picture resembling hydroa estivale⁵³⁷ (see p. 536), and the presence of a fibrous band involving a digit (pseudoainhum). ⁵³⁸ Late-onset disease often occurs in association with myelodysplastic syndrome, ⁵³⁹ often the sideroblastic anemia subtype. ⁵⁴⁰ Acquired erythropoietic protoporphyria has been reported in two patients as a result of myelodysplasia causing loss of chromosome 18, the locus of the ferrochelatase gene.^{540. and 541.} In one group of patients with protoporphyria the disease appears to be exacerbated by the ingestion of iron; ⁵¹⁵ in rare patients there is symptomatic response to iron supplementation. ⁵⁴² Exacerbation has also followed blood transfusion. ⁵⁴³ Clinical improvement, with lower erythrocyte porphyrin levels, occurs during pregnancy.^{544. and 545.}

Protoporphyria is the only disorder of porphyrin metabolism with normal urinary porphyrins. ⁴⁷⁰ There are markedly increased levels of protoporphyrin in the feces and blood. The erythrocytes show a red fluorescence which decays more rapidly than that in congenital erythropoietic porphyria (see above). ⁴⁷⁰

Advice about sun avoidance and sun-protective measures should always be given. These patients are at risk for the subsequent development of vitamin D deficiency. ⁵⁴⁶ Narrowband UVB desensitization phototherapy has been given to patients prior to their holidays, so that they might be asymptomatic during such a period. ⁵³⁴ Bone marrow transplantation may also be used for long-term control. ⁵⁴⁷

Porphyria cutanea tarda (PCT – OMIM 176100) is the commonest form of porphyria in Europe and North America.^{470. and 548.} Its prevalence ranges from 1 : 5000 to 1 : 25 000 people. ⁵⁴⁹ It is not a single disorder but an etiologically diverse group that share in common reduced activity of uroporphyrinogen decarboxylase (UROD), the enzyme which catalyzes the sequential decarboxylation of uroporphyrinogen to coproporphyrinogen in a two-stage process.^{470.550. and 551.} In most forms there is a reduction in hepatic UROD, leading to overproduction of porphyrins in the liver. ⁵⁵² In the uncommon familial form there is usually a deficiency of this enzyme in erythrocytes as well as in other tissues.

There are three major forms of PCT: familial, sporadic, and toxic. In addition, the porphyria resulting from porphyrin-producing tumors of the liver^{550. and 553.} and that associated with chronic renal failure and UROD deficiency are sometimes categorized as two further clinical variants of PCT.^{552.554.555.556.557. and 558.} Hepatoerythropoietic porphyria (see below) is regarded as the homozygous deficiency of UROD. ⁵⁵²

The familial form (type II) is inherited as an autosomal dominant trait. ⁵⁵² Numerous different mutations have been described.^{559. and 560.} The enzyme (UROD) is located on chromosome 1p34. ⁵⁶¹ The familial form was previously thought to be associated, invariably, with a deficiency of UROD in erythrocytes as well as in the liver, but cases with a normal level of erythrocyte UROD have been documented. ⁵⁶² Sometimes, overt disease is precipitated by some exogenous factor such as childbirth, exposure to ultraviolet radiation in tanning parlors, iron overload, or excessive alcohol intake.^{548. and 563.} Its onset is usually earlier than that of the sporadic form. ⁵⁶⁴ Type III PCT is characterized by a family history of the disease, although it is biochemically indistinguishable from the sporadic form. ⁵⁵⁹

The sporadic form (type I) usually has its onset in mid-life. More than 70% of cases in the past were associated with alcohol abuse and liver damage.^{552.565. and 566.} Now, there is a virtual ‘epidemic’ of cases associated with hepatitis C virus, some of whom also develop hepatocellular carcinoma.^{567.568.569.570.571.572.573. and 574.} The prevalence of hepatitis C infection in one Argentinean study was 35.2%. ⁵⁴⁹ It has been suggested that the porphyria subtype should be called ‘chronic hepatic porphyria’. ⁵⁷⁵ Estrogen therapy for carcinoma of the prostate^{576. and 577.} or for menopausal symptoms is sometimes the precipitating event. The menopause itself has also been incriminated; menstruation may act as a natural phlebotomy. ⁵⁷⁸ Oral contraceptives have also been incriminated. ⁵⁷⁹ Improvement in the disease has resulted from the use of anastrazole to treat a patient with concurrent carcinoma of the breast. ⁵⁸⁰ Anastrazole, an aromatase inhibitor, suppresses estrogen. Rare associations have included diabetes mellitus, ⁵⁶⁵ solar urticaria, ⁵⁸¹ Wilson’s disease, ⁵⁸² hepatocellular carcinoma,^{550. and 583.} lymphoma, ⁵⁸⁴ HIV infection,^{585.586.587. and 588.} agnogenic myeloid metaplasia, ⁵⁸⁹ idiopathic myelofibrosis, ⁵⁹⁰ and lupus erythematosus.^{591.592. and 593.} The sporadic form appears to result from inactivation of UROD in the liver⁵⁵¹ although this appears to be independent of, rather than the consequence of, liver injury. ⁵⁵² Mutations in the HFE gene associated with hereditary hemochromatosis have been associated with sporadic and familial PCT.561. ^{and 594.} There is a high prevalence of HFE gene mutations in patients with PCT in the Czech Republic. ⁵⁹⁵ The C282Y mutation in the HFE gene appears to predispose patients to PCT. ⁵⁹⁶ Co-inheritance of the genes for these two conditions appears to accelerate the onset of the porphyria.^{597. and 598.} Phlebotomy should be first-line therapy in these patients as HFE C282Y homozygotes do not respond to chloroquine; response is limited to those patients with PCT and HFE wild type. ⁵⁹⁹

The toxic form results from exposure to polychlorinated aromatic hydrocarbons.^{561. and 600.} Other hepatotoxins have rarely been incriminated.

The cutaneous changes occur predominantly on light-exposed areas such as the face, arms, and dorsum of the hands. ⁶⁰¹ Their severity is highly variable. They include increased vulnerability to mechanical trauma and the formation of subepidermal vesicles or bullae measuring 0.5–3 cm in diameter. ⁵⁶⁵ Erosions, milia, scars, and areas of hyperpigmentation are common. ⁵⁶⁵ Hypertrichosis, patchy alopecia, darkening of gray hair, ⁶⁰² infections, ⁶⁰³ dystrophic calcification, and sclerodermoid changes may occur but do so less frequently than the other cutaneous manifestations. ⁵⁶⁵ The sclerodermoid changes, which may be present in up to 20% of cases, do not always occur in light-exposed areas. They may involve the scalp.^{604. and 605.} They are not associated with sclerodactyly and they are not invariably permanent. It has been suggested that they are related to high levels of uroporphyrinogen. ⁶⁰⁶

Hepatic changes are common in PCT. There is an increased risk of developing hepatocellular carcinoma. ⁵⁵⁰

Laboratory findings include increased amounts of uroporphyrins in the urine and plasma and of coproporphyrins in the feces. The urine contains a predominance of 8-carboxyl and 7-carboxyl porphyrins, while the feces contain isocoproporphyrin, which is not found in significant amounts in other porphyrias. ⁵⁵¹

Hepatoerythropoietic porphyria (OMIM 176100, as for PCT) is a rare, severe variant that is manifested clinically by photosensitivity commencing in early childhood.^{607.608.609. and 610.} Fewer than 50 patients have been reported. ⁶¹¹ As in porphyria cutanea tarda (PCT), there is a deficiency of uroporphyrinogen decarboxylase (UROD), but the activity of this enzyme is much less than in PCT, reflecting a homozygous state.^{612. and 613.} Several different point mutations and/or a deletion in the UROD gene on chromosome 1p34 have been reported. ⁶¹⁴ Hepatic involvement is common. The cutaneous features resemble those of PCT. ⁶¹⁵

Laboratory findings are similar to those in PCT, but an additional feature is the presence of elevated levels of protoporphyrins in erythrocytes. ⁶⁰⁷

The term ‘pseudoporphyria’ is used for a phototoxic bullous dermatosis which resembles porphyria cutanea tarda (PCT).^{616. and 617.} However, there are normal levels of porphyrins in the serum, urine, and feces. ⁶¹⁸ The term ‘therapy-induced bullous photosensitivity’ has been suggested as more appropriate⁶¹⁹ as this condition has been reported following the use of a number of drugs including tetracyclines,^{620. and 621.} β-lactams (ampicillin-sulbactam and cefepime) ⁶²² sulfonamides, isotretinoin, ⁶²³ ketoprofen, ⁶²⁴ pravastatin, ⁶²⁵ bumetanide, furosemide (frusemide),^{626. and 627.} torsemide, ⁶²⁸ nalidixic acid, ⁶²⁹ ciprofloxacin, ⁶³⁰ voriconazole,^{624. and 631.} naproxen,^{632.633.634. and 635.} celecoxib, ⁶²⁴ rofecoxib, ⁶³⁶ amiodarone, ⁶³¹ oxaprozin, ⁶³⁷ mefenamic acid, ⁶³⁸ aspirin, ⁶³¹ nabumetone,^{639.640.641.642. and 643.} pyridoxine, ⁶⁴⁴ chlorthalidone, ⁶⁴⁵ the oral contraceptive pill, ⁶⁴⁶ flutamide⁶⁴⁷ cyclosporine (ciclosporin), 5-fluorouracil, excessive cola consumption, ⁶³¹ acitretin, ⁶⁴⁸ and etretinate. ⁶⁴⁹ A few cases have followed the prolonged use of tanning beds.^{650.651. and 652.} Blistering has also been reported in patients with chronic renal failure undergoing hemodialysis.^{653. and 654.} In one case it followed the use of narrowband UVB phototherapy, used in the treatment of psoriasis. ⁶⁵⁵ In some patients pseudoporphyria has been associated with a deficiency of uroporphyrinogen decarboxylase with increased levels of porphyrins; in others, many of whom were also receiving furosemide (frusemide), the porphyrin levels have been normal.^{653.656. and 657.} The various causes are listed in Table 18.2.