Case of the Month: August

A Defining Variant in a Rare Metabolic Disorder: Familial Congenital Erythropoietic Porphyria

Clinical History:

A couple with a 9-year-old affected male child diagnosed with Congenital Erythropoietic Porphyria (CEP) presented for prenatal genetic evaluation. The child had photosensitive skin rashes, dental dysplasia, and reddish urine. The couple opted for targeted prenatal testing in subsequent pregnancies due to the known familial condition.

CEP is a rare autosomal recessive inherited metabolic disorder of heme biosynthesis caused by deficiency of uroporphyrinogen III synthase due to pathogenic variants in the UROS gene. Porphyrin accumulation results in severe photosensitivity, skin blistering and scarring, erythrodontia, hemolytic anemia, and reddish or dark urine. Early diagnosis is important for appropriate clinical management, avoidance of triggers, and appropriate genetic counseling. Although CEP is not uniformly life-threatening, its potentially significant lifelong manifestations warrant early recognition and variable severity necessitates individualized management.

Genetic Investigation:

Whole exome sequencing in the affected child identified a likely pathogenic UROS variant, c.185C>T (p.Thr62Ile), establishing the familial molecular diagnosis. As CEP is autosomal recessive, when both parents are carriers, each pregnancy has a 25% risk of being affected.

In the second pregnancy, CVS with targeted Sanger sequencing identified the fetus as homozygous for the familial UROS variant, indicating likely affected status. In the third pregnancy, amniocentesis followed by targeted Sanger sequencing identified the fetus as heterozygous for the familial variant, indicating an unaffected carrier. QF-PCR showed no common aneuploidies.

Conclusion:

This case demonstrates how early molecular diagnosis of an inherited metabolic disorder can directly influence reproductive management. In CEP, clinical manifestations may vary in severity, and early recognition of the underlying genetic cause allows appropriate clinical evaluation and counseling. Identification of the familial variant also makes targeted prenatal diagnosis possible, allowing distinction between an affected fetus, an unaffected carrier, and a fetus who has not inherited the familial variant. Thus, genetic testing provides important clinical and reproductive information for families affected by rare metabolic disorders.