Clinical Guidance

The genotype-phenotype correlations that have been established in CEP are largely determined by the amount of residual enzyme activity encoded by the specific pathogenic variants. UROS. The most common UROS pathogenic variant,, is observed in about one third of individuals with CEP.

• Homozygosity for the c.217TC (p.Cys73Arg) variant results in less than 1% of normal URO-synthase activity and a severe phenotype that may manifest as nonimmune hydrops fetalis .

• Compound heterozygosity for the c.217TC (p.Cys73Arg) variant and a pathogenic variant that expresses a very low level of residual activity results in a severe or moderately severe phenotype.

Source: GeneReviews — "Congenital Erythropoietic Porphyria"

Diagnostic Criteria

No consensus clinical diagnostic criteria for congenital erythropoietic porphyria (CEP) have been published. Suggestive Findings Congenital erythropoietic porphyria (CEP) should be suspected in individuals with the following clinical and laboratory findings and family history. Clinical findings • Nonimmune hydrops fetalis • Signs of congenital erythropoietic porphyria • Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants) • Hemolytic anemia • Severe cutaneous photosensitivity with onset usually in infancy or early childhood • Blisters and vesicles in light-exposed areas, which are prone to rupture and infection • Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption • In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation • Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia • Corneal ulcers and scarring • Hypertrichosis of the face and extremities Laboratory findings include markedly increased levels of uroporphyrin I and coproporphyrin I isomers in erythrocytes, urine, or amniotic fluid as well as coproporphyrin I in stool . Table 1. Biochemical Characteristics of Congenital Erythropoietic Porphyria

Source: GeneReviews — "Congenital Erythropoietic Porphyria"

Differential Diagnosis

See for other disorders that present with a congenital erythropoietic porphyria (CEP)-like phenotype.

Table 3.

Disorders to Consider in the Differential Diagnosis of Congenital Erythropoietic Porphyria

Disease Name | Gene(s) | MOI | Clinical Features

Overlapping | Distinguishing

Porphyria cutanea tarda (PCT) type I (OMIM 176090) | See footnote 1. | • Cutaneous photosensitivity w/blistering friability of skin in sun-exposed areas

• Facial hypertrichosis

• Discolored urine

| • Usually manifests in adulthood

• Distinct biochemical porphyrin profile

Porphyria cutanea tarda (PCT) type II

| UROD | AD

Hepato-erythropoietic porphyria

| UROD | AR | • Phenotype similar to PCT

• Manifests in early childhood

• Discolored urine

• Photosensitivity

Management Guidelines

A management algorithm for congenital erythropoietic porphyria (CEP) has been published .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with congenital erythropoietic porphyria (CEP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Hematologic indices including reticulocytes and bilirubin (to assess hemolysis) and iron profile (to assess iron storage)

• Serum calcium and vitamin D concentrations; bone densitometry

• Hepatic function tests, especially in transfusion-dependent individuals given the risk for liver disease due to iron storage

• Dermatologic evaluation to assess photosensitivity, photomutilation, and secondary skin changes (thickening, hyper- or hypopigmentation, hypertrichosis)

• Ophthalmologic evaluation for corneal ulcers and scarring and other ocular manifestations

• Dental assessment for erythrodontia (reddish-brown color from porphyrin deposition)

• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CEP in order to facilitate medical and personal decision making

Clinical Guidance

The following are appropriate:

• Avoidance of sunlight and UV light

• In individuals with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens)

• In individuals undergoing surgeries, use of protective filters for artificial lights in the operating room to prevent phototoxic damage

Source: GeneReviews — "Congenital Erythropoietic Porphyria"

Therapies Under Investigation

Although there are no clinical trials at the present time, therapeutic approaches under investigation include phlebotomy or iron chelation strategies to reduce the hemolysis and decrease the accumulated porphyrins and, thus, photosensitivity [, , , ]. A murine CEP model is being used to investigate pharmacologic chaperone therapy (i.e., administration of small-molecule drugs to enhance the residual activity of mutated enzymes that have low activities or are unstable). Specifically, use of the antimicrobial agent ciclopirox as a chaperone-stabilized UROIII-synthase and reversed CEP-related findings such as abnormal URO I levels in the blood, splenomegaly, and liver porphyrins . Studies involving use of this medication in humans have not yet been performed. Search ClinicalTrials.

Source: GeneReviews — "Congenital Erythropoietic Porphyria"

Surveillance Guidelines

Monitor the following:

• Hematologic indices including iron profile, reticulocyte count, and bilirubin to assess hemolysis every six months

Note: Individuals receiving transfusion therapy need closer monitoring.

• Iron profile on a regular basis to assess for iron overload for those who are transfusion dependent

• Hepatic function every six to twelve months

• Vitamin D 25-OH levels in all individuals whether or not they are receiving vitamin D supplements

Source: GeneReviews — "Congenital Erythropoietic Porphyria"