Congenital Erythropoietic Porphyria with Undescended Testis.

Hereditary porphyrias are a group of metabolic disorders of heme biosynthesis pathway that are characterized by acute neurovisceral symptoms, skin lesions, or both. Congenital erythropoietic porphyria (CEP) is an extremely rare disease with a mutation in the gene that codes for uroporphyrinogen III synthase leading to accumulation of porphyrin in different tissues and marked cutaneous photosensitivity. We report a case of CEP with infancy onset blistering, photosensitivity, red colored urine, and teeth along with scarring. Examination revealed an undescended testis of the left side. Mutation analysis revealed mutation in the uroporphyrinogen III synthase gene (UROS) resulting in c. 56 A > G (Tyr19Cys). The presence of undescended testis with a rare mutation in a case of CEP which itself is an extremely rare condition make the case interesting.

What was known?

Porphyrias are hereditary disorders of heme biosynthesis pathway

Congenital erythropoietic porphyria also known as Gunther's disease is an autosomal recessive disorder occurs as a defect of gene encoding for uroporphyrinogen III synthase enzyme

Hallmarks of presentation include photosensitivity, skin fragility with blistering, red staining of teeth, and red colored urine due to presence of porphyrins

Definitive management is bone marrow transplantation.

Introduction

Porphyrias are a group of autosomal recessive disorders of heme biosynthesis resulting from reduced activity of one of the enzymes in the heme synthesis pathway. Congenital erythropoietic porphyria (CEP) also known as Gunther's disease is an autosomal recessive disorder arising out of defect in the gene encoding for uroporphyrinogen III synthase (UROS) enzyme,[12] resulting in the accumulation of porphyrin in the erythrocytes, plasma and tissues including the skin and teeth. CEP was the first human porphyria to be described and first to be described with different mutations of the gene that code for the UROS.[3] Clinically, these cases present with photosensitivity, skin fragility with blistering, red staining of teeth, and red colored urine. Here, we report a case of a young male child of CEP who was diagnosed on the basis of his clinical, biochemical and genetic profile. He was also detected to have undescended testis an association not yet reported in the literature.

The CF3R mutation is most frequent, accounting for 20% of the reported mutations, which cause a deficiency of UROS, resulting in CEP.[456]

Case Report

A 13-year-old male child born off a consanguineous marriage [Figure 1] presented with complaints of red colored urine since birth, reddish brown-pigmented teeth, and excessive facial hair since 6 months of age. He also had a burning sensation and recurrent blistering over the sun-exposed areas, which healed with scarring and disfigurement of nails since 1-year of age. His birth and mental developmental history were normal. He had an asymptomatic female sibling 8 years of age, and there was no family history of similar complaints.

Figure 1

Pedigree chart

Examination revealed a short statured male child of height 133 cm (< −3 standard deviations).[7] Abdominal examination revealed a protuberant abdomen with hepatosplenomegaly [Figure 2] and undescended testis on the left side.

Figure 2

Above left: Hypertrichosis over face; above right: Bullae, postinflammatory hyperpigmentation and scars over the dorsum and hands; below right: Protuberant abdomen with hepatosplenomegaly; below left: Ultrasound scans of scrotum revealing absence of testis on the left side

He had obvious hypertrichosis over face involving the cheek and forehead, the forearms and multiple bullae over the dorsum of hands, fingers, forearms, and feet with postinflammatory hyperpigmentation and scars over affected skin [Figure 3]. Teeth showed brownish-red pigmentation, fluorescent under Wood's lamp [Figure 3]. Nails were discolored.

Figure 3

Left: Representative negative Watson–Schwartz test in left tube and negative Watson–Schwartz test revealed by no gain in color in test sample in the tube on right, with port wine fluorescent urine sample (inset); above right: Erythrodontia revealed by discolored reddish-brown teeth; below right: Teeth fluorescence under Woods lamp

Investigations revealed anemia an Hb of 8.3 g/dl, with peripheral blood smear revealing microcytic hypochromic anemia with anisopoikilocytosis. Urine was port wine color, which fluoresced in Wood's lamp. Porphobilinogen was not detected on Watson–Schwartz test in the urine [Figure 3]. Ultrasonography of abdomen confirmed the hepatomegaly, splenomegaly, and the undescended testes with hydrocele on the right side [Figure 2].

Mutation analysis was carried out for the affected child and his parents. The affected child exhibited a missense mutation in the UROS gene identified as a transversion of A to G at nucleotide 56, resulting in a substitution of tyrosine by cysteine. The patient showed a homozygous mutant profile, and the parents were heterozygous carriers for the mutation.

Based on the clinical presentation with onset in early childhood of a photosensitive disorder with erythrodontia, hypertrichosis, fluorescent red urine, absence of porphobilinogen in urine, and a demonstrated mutation of the UROS gene the child was diagnosed as a case of CEP.

He was managed with sun avoidance and liberal use of sunscreen administration. He was referred to the surgical center for definitive management of undescended testis. He has now been taken up for bone marrow transplantation with his sister serving as human leukocyte antigens (HLA) matched donor.

Discussion

CEP is an extremely rare disorder of heme biosynthesis of which less than 100 cases are reported worldwide.[8] This autosomal recessive disorder's genetic defect lies in a mutation most commonly in the gene encoding for the UROS enzyme and rarely the GATA1 gene,[91011] which results in accumulation of fluorescent porphyrins in the plasma, and their subsequent deposition in teeth and excretion in urine resulting in their pink fluorescence under Wood's lamp which is characteristic of CEP.[12] A childhood onset photosensitivity, recurrent blistering, erosions, scarring, and subsequent mutilation of the photo-exposed sites along with hypertrichosis of the face and extremities and the fluorescence described above characterize it. Rare instances of multiple cases in one family have been reported[13] and some cases have been reported without hemolysis.[14] Urine examination reveals port wine color which fluoresces under Woods lamp serving as an easy bedside test. Further tests to confirm CEP include showing the absence of porphobilinogen on Watson–Schwartz test [Figure 4] as the affected UROS enzyme is deficient. Skin biopsy in those with blistering reveals a sub epidermal split, festooning of papillary dermis into the blister and thickened blood vessel walls. Direct immunofluorescence reveals C3 and IgG along the dermo-epidermal junction and superficial blood vessels.

Figure 4

Heme biosynthesis pathway highlighting the defect in congenital erythropoietic porphyria

Management stresses on general measures such as sun avoidance, broad-spectrum sunscreens, prevention of minor trauma, and prompt treatment of secondary infections. Other interventions may include splenectomy for hemolytic anemia and hypersplenism, hypertransfusion, intravenous hematin, cord and bone marrow transplantation.[1516] Bone marrow transplantation aims at repopulating the bone marrow with hemopoietic cells having a normal copy of UROS enzyme, thereby preventing the accumulation of the uroporphobilinogen I and coproporphyrinogen I which are responsible of photosensitivity and erythrodontia. Furthermore, normal heme increases the chances of improvement of anemia. Intracellular rescue of the UROS enzyme has also been attempted.[17]

A 13-year-old male presented with a childhood onset photosensitivity, hypertrichosis, and erythrodontia as well as fluorescent teeth and urine under Wood's lamp. He was also detected to have undescended testis on clinical examination by an empty scrotal sac on the left side and confirmed by ultrasonography of the scrotum [Figure 2]. The diagnosis of CEP was made based on the clinical profile, florescence of teeth and urine and corroborated by mutation analysis, which revealed a homozygous defect in the UROS gene. Parents of the child were detected to be carriers for the above mutation. Skin biopsy was not done in our case as the diagnosis was already confirmed and would not have contributed additionally toward the final diagnosis. The detected mutation has been reported once earlier.[18] The patient has been planned for the surgical management of his undescended testes and bone marrow transplantation. His unaffected younger sister is the HLA-matched donor.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

What is new?

Association of undescended testis with Congenital Erythropoietic Porphyria

Mutation in the uroporphyrinogen III synthase gene resulting in c. 56 A > G (Tyr19Cys).