A number sign (#) is used with this entry because of evidence that childhood-onset variegate porphyria (VPCO) is caused by homozygous or compound heterozygous mutation in the protoporphyrinogen oxidase gene (PPOX; 600923) on chromosome 1q23.

Heterozygous mutation in the PPOX gene causes an autosomal dominant form of variegate porphyria (VP; 176200).

Childhood-onset variegate porphyria (VPCO), also called 'homozygous' variegate porphyria, is a rare disorder of heme biosynthesis characterized by severe PPOX deficiency, onset of photosensitization by porphyrins in early childhood, skeletal abnormalities of the hand, and, less consistently, short stature, impaired intellectual development, and seizures. The term 'homozygous' refers to the presence of mutations on both alleles of the PPOX gene, resulting in earlier onset and more severe manifestations than those seen in variegate porphyria (VP), a low-penetrance disorder inherited as an autosomal dominant trait (summary by Roberts et al., 1998). Heterozygous family members of VPCO patients are usually clinically silent, but symptomatic heterozygotes have been reported (Mustajoki et al., 1987; Palmer et al., 2001; Kauppinen et al., 2001).

Nomenclature

'Homozygous' variegate porphyria was so designated before the molecular defect in PPOX was elucidated, on the basis of severe reduction in PPOX activity (between 5 and 20% of control values) compared to that seen in variegate porphyria (approximately 50% reduction), in which autosomal dominant transmission had been observed. It is probable that most cases of 'homozygous' variegate porphyria actually result from compound heterozygosity for PPOX mutations (Frank et al., 1998; Palmer et al., 2001).

Homozygous variegate porphyria was reported in 2 Czech sibs by Korda et al. (1984) and Korda et al. (1985) and in 2 unrelated English patients by Murphy et al. (1986). In the family of Korda et al. (1984) and the first case of Murphy et al. (1986), both parents were, by the biochemical evidence, heterozygotes. Photosensitivity dating from the first year or so of life, growth retardation, and raised red cell protoporphyrin concentration with 60 to 70% zinc chelation were the seemingly characteristic features. The Czech sibs also had mental retardation and nystagmus.

Mustajoki et al. (1987) described a 2.5-year-old Finnish boy with variegate porphyria, who was later found to have biallelic mutations in the PPOX gene (Kauppinen et al., 2001). The proband developed a severe bullous skin disease a few days after birth, followed by increased fragility and keloid scarring of exposed skin in spring and summer. The patient had high concentration of protoporphyrin in red cells, and lymphocyte protoporphyrinogen oxidase was very low in the patient and half-normal in his first-cousin parents, suggesting that the patient had homozygous variegate porphyria. Both grandmothers, who were sisters, had high fecal porphyrin content; and 1 grandmother was mildly affected, experiencing vesicular dermatitis in the summer followed by minor scarring on the exposed areas. Kauppinen et al. (2001) provided follow-up on the proband, noting that from 5 years of age, the proband had no severe acute photo reactions, but blistering and fragility with deep erosions complicated by bacterial infections had occurred. His fingers were markedly shortened with flexion impairment, and early closure of the phalangeal epiphyses was detected on radiography. Electroneuromyography (ENMG) and sensory evoked potentials revealed sensory polyneuropathy, primarily in the upper extremities. Fine motor coordination disturbances were accompanied by minor verbal and visuospatial deficiencies, and he also had elevated intraocular pressure and myopia. IgA nephropathy (see 161950) was confirmed by renal biopsy.

Coakley et al. (1990) described an unusual form of variegate porphyria in a young girl with epilepsy, mental retardation, and premature adrenarche. Symptoms of porphyria commenced about the age of 12 years and death occurred about 18 months later. The patient had a very low level of protoporphyrinogen oxidase activity in her cultured fibroblasts, whereas both parents had half-normal activity of the enzyme in lymphocytes. Coakley et al. (1990) suggested the patient was homozygous. Two of the subjects with homozygous VP described by Korda et al. (1984) were similar to this patient in that they had severe neurologic symptoms which included convulsions and mental retardation. The ratio of 5-beta to 5-alpha steroids in urine suggested a defect in hepatic 5-alpha-reductase activity in the patient of Coakley et al. (1990). This presumed defect as well as anticonvulsant therapy may have contributed to the severity of the patient's condition. Noting that the proband described by Coakley et al. (1990) had no photosensitivity and had a normal stool protoporphyrin with markedly elevated coproporphyrin, Hift et al. (1993) stated that this was incompatible with VP and suggested that the diagnosis might be incorrect.

Norris et al. (1990) reported a 14-year-old girl with variegate porphyria, who was later found to have biallelic mutations in the PPOX gene (Frank et al., 1998). From the age of 18 months, the proband experienced recurrent blisters and erosions associated with sun exposure, and increased skin fragility was noted from age 5 years, with mild flexural atopic eczema from age 6. In addition, she experienced 2 seizures in the first year of life and had impaired intellectual development. Examination revealed crusts, erosions, milia, and superficial scars on the skin of the face, hands, and knees, with perioral radial linear scarring. She also exhibited fifth-finger clinodactyly and brachydactyly, and flexion deformities of the other fingers. Stool porphyrin concentrations were elevated, with protoporphyrin higher than coproporphyrin, and the urinary porphyrin profile was also compatible with variegate porphyria. Fluorescence-emission spectroscopy of patient plasma showed a large porphyrin peak at 624 nm; her mother showed a very small peak at 625 nm and her father showed no abnormality. Norris et al. (1990) noted that both parents were asymptomatic, with normal fecal porphyrin concentrations, despite half-normal protoporphyrinogen oxidase (PO) activity.

Homozygous variegate porphyria was also described by D'Alessandro Gandolfo et al. (1991).

Hift et al. (1993) described the first South African case of autosomal homozygous VP, a 6-year-old Afrikaner girl with severe symptoms who was later found to have biallelic mutations in the PPOX gene (Meissner et al., 1996). She developed severe blistering of the face and hands within days of birth. Examination showed markedly foreshortened stubby fingers and toes, resulting in such severe functional impairment that she could not hold a pencil or use scissors. X-rays showed brachydactyly with broad short metacarpals and phalanges, and a delayed bone age. She had severe skin disease, manifested by blistering, erosions, crusting, hyperpigmentation, and milia. Skin in nonexposed areas was also abnormally thickened and infiltrated. Histology showed perivascular PAS-positive hyalin deposits in papillary and upper reticular dermis of exposed skin; similar but less marked changes were present in unexposed skin. Acute and chronic photodamage was evident, with basket-weave hyperkeratosis, epidermal atrophy with necrotic keratinocytes, and marked dermal solar elastosis. She also had severe myopia, pendular nystagmus, and developmental delay. From the age of 3 years, she had infrequent complex partial seizures; electroencephalogram was normal. At age 4, she developed sensory neuropathy of the hands and feet, confirmed by electrophysiologic studies showing a reduced amplitude of conduction in the right and left median sensory nerves; sural nerve biopsy showed features of early segmental demyelination. No motor abnormalities were detected. PPO activity assays in patient lymphoblasts showed no detectable activity; lymphoblasts from her mother and father showed 50% and 70% of normal activity, respectively. Hift et al. (1993) also reported a male infant, born to consanguineous parents, who developed seizures at 5 months of age and had developmental delay, nystagmus, and clinodactyly. He exhibited skin manifestations at 6 months of age. Examination at age 6 years showed blistering and fragility of skin of hands, face, and ears, with hypertrichosis, hyperpigmentation, scarring, and milia in those areas. His PPO activity was approximately 5% of normal levels; his parents were unavailable for testing. He had no neuropathy, and nerve conduction studies were normal.

Corrigall et al. (2000) reported 2 severely affected probands from 2 unrelated South African families with variegate porphyria. In family 1, of Afrikaner origin, the proband was a 7-year-old girl who first presented at age 10 months with severe skin disease and the typical urine and stool porphyrin excretion profile of VP. Examination showed fragile skin with blisters, scars, and milia most marked in sun-exposed areas, although even her unexposed skin was abnormal. She had brachydactyly, photo-onycholysis, nystagmus, myopia, sensory neuropathy, and problems with concentration. She had never experienced an acute attack. In family 2, the proband was a 26-year-old South African woman of mixed-race origin who presented at age 19 years with symptoms suggestive of a porphyric acute crisis; biochemical analysis confirmed VP. She subsequently experienced 2 milder acute attacks, and also manifested an unusually severe form of skin disease with chronic blistering of the face and hands, hypertrichosis, and photomutilation of the hands with progressive shortening of the fingers and deformities of the joints of the fingers. Her affected 25-year-old sister exhibited typical skin disease of VP and a typical porphyrin excretion pattern.

Palmer et al. (2001) reported a 36-year-old British woman with variegate porphyria and mutation in the PPOX gene. Skin fragility, blisters, and scarring developed at 9 months of age on sun-exposed skin. At 4 years of age, she experienced a febrile seizure associated with an upper respiratory tract infection; an electroencephalogram was normal. At age 19, her bone age was estimated at 16 years, and she had short stature. Dysmorphic features included a small face with flattened nose, and accentuated skin creases with perioral radial linear furrowing. There was hyperpigmentation, milia, scarring, and crusted erosions in a photosensitive distribution. Her hands were small, with brachydactyly, clinodactyly, fixed flexion deformities, and variable nail dystrophy. X-rays revealed short misshapen terminal phalanges. The proband's mother experienced 3 acute neuroabdominal episodes, 2 related to drug ingestion, and she had no cutaneous manifestations. The proband's deceased father was reported to be asymptomatic.

Cho et al. (2021) reported a 33-year-old Chinese man, born of consanguineous parents, who at 3 months of age developed itchiness, rash, and blistering skin lesions, followed by atrophic scar formation, only on exposed skin of the face and forearms. Skin biopsy findings were consistent with porphyria, and biochemical testing of urinary and fecal porphyrins showed a pattern suggestive of variegate porphyria that was not observed in his unaffected parents and sibs.

The transmission pattern of childhood-onset variegate porphyria in the family studied by Frank et al. (1998), originally reported by Norris et al. (1990), was consistent with autosomal recessive inheritance.

In a girl of Afrikaner origin with photosensitivity, severe brachydactyly, seizures, developmental delay, sensory neuropathy, and an abnormal porphyrin excretion pattern, who was originally described by Hift et al. (1993), Meissner et al. (1996) identified compound heterozygosity for missense mutations in the PPOX gene: an R59W substitution (600923.0003) and an R168C substitution (600923.0004). Her mother, who met the criteria for VP, was heterozygous for the R59W mutation, and her father, who had normal porphyrin biochemistry and a 25% reduction in PPO activity, was heterozygous for the R168C variant. The authors also detected the R59W mutation in 43 of 45 patients with autosomal dominant VP (176200) from 26 of 27 South African families; genealogic analysis of 1 of the South African families demonstrated relatedness to the original South African VP family tree, suggesting a founder effect. Functional analysis of the R59W mutation demonstrated that the mutant enzyme had an almost undetectable catalytic rate but a relatively invariant K(m), consistent with the 50% reduction in PPO activity seen in the proband's mother.

In a 20-year-old woman with variegate porphyria, impaired intellectual development, and hand deformities, who was originally described by Norris et al. (1990), Frank et al. (1998) sequenced the PPOX gene and identified compound heterozygosity for missense mutations: a G169E substitution (600923.0014) and a G358R substitution (600923.0015). Her asymptomatic parents, who both exhibited approximately half-normal levels of PPO activity, were each heterozygous for 1 of the mutations, neither of which was found in 50 unrelated controls.

Roberts et al. (1998) confirmed the molecular characterization of the rare homozygous variant of variegate porphyria. They identified biallelic PPOX mutations in 5 of the 11 unrelated patients with apparent autosomal recessive VP reported to that time. Two patients were homozygous for missense mutations (D349A, 600923.0007 and A433P), whereas 2 were compound heterozygous for a G358R substitution and either a G169E substitution or a splice site mutation, respectively, and the remaining patient was compound heterozygous for a 12-bp insertion and another splice site mutation. Functional analysis by prokaryotic expression showed that the D349A and A433P mutations and 1 missense mutation in each of the 3 compound heterozygous patients (G538R in 2 patients and c.657ins12) preserved some PPOX activity (9.5-25% of wildtype). Mutations on the other allele of the compound heterozygous patients abolished or markedly decreased activity. There was no relation between genotype assessed by functional analysis and the presence or severity of noncutaneous manifestations. All the mutations found in the homozygous patients were absent from 104 unrelated patients with autosomal dominant VP. The authors concluded that mild PPOX mutations occur in the general population but have a very low or no clinical penetrance in heterozygotes.

In a 7-year-old girl of Afrikaner origin (family 1) with severe photosensitivity, brachydactyly, and sensory neuropathy, Corrigall et al. (2000) identified compound heterozygosity for the recurrent R59W mutation in the PPOX gene, and a Y348C mutation (600923.0016). Testing of 10 additional family members revealed heterozygosity for the R59W mutation in the proband's asymptomatic mother and 12-year-old sister; the mother showed a fecal porphyrin excretion pattern typical of VP, but the sister was biochemically negative. The proband's asymptomatic father, half brother, and half sister were heterozygous for the Y348C mutation; her father had a normal fecal porphyrin excretion profile but showed a small peak at 625 nm on plasma fluoroscanning, her half brother had a typical VP fecal porphyrin excretion pattern but normal plasma fluoroscan, and her half sister was biochemically negative. In 2 South African sisters of mixed-race origin (family 2), 1 of whom experienced acute porphyric attacks and severe cutaneous photosensitivity and the other of whom showed typical VP skin disease, Corrigall et al. (2000) identified compound heterozygosity for R59W in PPOX and a R138P mutation (600923.0017). None of the mutations was found in 50 ethnically matched controls.

In a 36-year-old British woman with severe cutaneous manifestations of variegate porphyria and brachydactyly, Palmer et al. (2001) sequenced the PPOX gene and identified compound heterozygosity for mutations in the PPOX gene: an in-frame 12-bp insertion (600923.0010) and a splice site mutation (600923.0011). The proband's mother, who was heterozygous for the splice site mutation, experienced 3 neuroabdominal episodes, 2 of which followed drug ingestion; she had no cutaneous manifestations. A maternal first cousin, who also carried the splice site mutation, was asymptomatic. DNA was unavailable from the proband's deceased father, who was reported to be asymptomatic.

In a follow-up study of the Finnish boy with apparent homozygous variegate porphyria reported by Mustajoki et al. (1987), Kauppinen et al. (2001) identified compound heterozygosity for 2 missense mutations in the PPOX gene: an I12T substitution (600923.0012) and a P256R substitution (600923.0013). Affected members of another Finnish family were compound heterozygous for the same mutations, suggesting a common ancestor. One heterozygous carrier in each family was mildly symptomatic.

In a 33-year-old Chinese man with childhood-onset variegate porphyria, Cho et al. (2021) sequenced the PPOX gene and identified homozygosity for a missense mutation (V270L; 600923.0018) at the first base of exon 8 of the PPOX gene. His unaffected consanguineous parents were heterozygous for the mutation. Functional analysis revealed that the mutation affected splicing, resulting in exon skipping that was predicted to result in a truncated protein.