Diffuse fractures in a neonate with homozygous UROS C73R congenital erythropoietic porphyria: An unreported phenotype

Abstract Introduction: Congenital erythropoietic porphyria (CEP) is an ultra-rare autosomal recessive disorder, usually caused by mutations in uroporphyrinogen III synthase (UROS) gene (Erwin et al, 2019; PMID: 30685241). Biallelic mutations result in impairment of the heme biosynthesis pathway, and accumulation of the non-physiological porphyrins [uroporphyrin I (URO I) and coproporphyrin I (COPRO I)] in erythroid precursors in the bone marrow (BM) and red blood cells (causing chronic hemolytic anemia) and in the plasma with toxic effects on tissues including skin (causing cutaneous phototoxicity), bones, teeth, spleen and liver. Phenotypic severity correlates with residual enzyme activity related to the specific pathogenic UROS variant involved. The C73R variant is the most common (~50 cases reported) and severe (Katugampola et al, 2012; 22816431). C73R/C73R patients have <1% UROS activity in BM cells and massive amounts of urinary URO and COPRO I isomers (de Verneuil et al,1995;7550841). Although skeletal abnormalities such as osteopenia, acro-osteolysis and rare fractures have been described in older patients with CEP (Levesque et al, 1988; 3340434), diffuse bony abnormalities or fractures in the neonatal period have not been reported. We report here what we believe is the first case of CEP with diffuse neonatal fractures resulting from homozygosity for the UROS C73R variant. Results: A Hispanic male neonate was born at 37 weeks to a gravida 2, para 1 mother. At birth, he exhibited dysmorphic features including microcephaly, low-set ears, short neck, wide-spaced nipples, rocker bottom feet, and nail dysplasia. Clinical findings included icterus, cola-colored urine, hepatosplenomegaly and generalized edema. Laboratory evaluation revealed hemolytic anemia, thrombocytopenia, hyperbilirubinemia (bilirubin: 10mg/dl, upper limit of normal (ULN) 1.2 mg/dl) and ABO incompatibility. Within minutes of birth, he developed respiratory distress requiring non-invasive pressure ventilation. Progressive skin blistering was noted with phototherapy, which was discontinued on day 5, as CEP was suspected. A skin biopsy raised suspicion for epidermolysis bullosa; however, immunofluorescence studies were negative. Urinary and plasma porphyrins were markedly elevated (e.g., urinary: URO I >71,000 mcg/g creat, ULN 21 mcg/g creat; Copro I >71,000 mcg/g creat, ULN 33; and total porphyrins >184,000 mcg/g creat, ULN 183), all consistent with CEP. Initial treatment included removal from light, blood transfusions and pain control. Strikingly, the infant at 4.7 weeks of life developed lower extremity deformities with pain, prompting imaging that revealed multiple pathological fractures involving all long bones, ribs, and metacarpals, at different stages of healing. Vitamin D levels were normal, 34.3 ng/ml, LLN 20 ng/ml. Radiographs demonstrated diffuse osteodystrophy, concerning for osteogenesis imperfecta.Whole exome sequencing confirmed homozygosity for the common pathogenic UROS variant (c.217T>C, p.C73R), with one allele inherited from the mother and the other, possibly inherited from the partner (did not submit DNA for sequencing); no other pathogenic gene mutations were observed. The parents denied consanguinity and had no features of CEP. The neonate was also initiated on bisphosphonate therapy and referred for allogeneic stem cell transplant. Conclusion: Homozygosity of UROS C73R, previously linked to severe CEP and Hydrops fetalis, here also presented with severe osteodystrophy and multiple fractures in the early neonatal phase. Consanguinity was denied, despite C73R homozygosity, and prior instances of homoallelic cases without consanguinity have been reported (Katugampola et al, 2012; 22816431). With improvements in perinatal care and awareness of the presentation, more extreme phenotypes of ultra-rare disorders like CEP may become increasingly recognized. Possible contributing mechanisms for skeletal manifestations in CEP include chronic hemolysis, driving BM expansion, direct porphyrin-mediated toxicity to bone, and vitamin D deficiency related to sunlight avoidance. In this case, in utero hemolysis likely contributed to early-onset skeletal demineralization, leading to diffuse fractures with minimal handling. This case expands the clinical spectrum of CEP and highlights the need to consider it in neonates with unexplained fractures and cutaneous phototoxicity.