Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients.

[aromatase deficiency]

Cytochrome P 450 oxidoreductase (POR ) deficiency is a rare autosomal recessive disorder characterized by skeletal dysplasia , adrenal dysfunction , disorders of sex development (DSD ), and maternal virilization during pregnancy . Although multiple studies have been performed for this condition , several matters remain to be clarified , including the presence of manifesting heterozygosity and the underlying factors for clinical variability .The objective of the study was to examine such unresolved matters by detailed molecular studies and genotype-phenotype correlations .Thirty -five Japanese patients with POR deficiency participated in the study .Mutation analysis revealed homozygosity for R 457 H in cases 1 -14 (group A ), compound heterozygosity for R 457 H and one apparently null mutation in cases 15 -28 (group B ), and other combinations of mutations in cases 29 -35 (group C ). In particular , FISH and RT-PCR sequencing analyses revealed an intragenic microdeletion in one apparent R 457 H homozygote , transcription failure of apparently normal alleles in three R 457 H heterozygotes , and nonsense mediated mRNA decay in two frameshift mutation -positive cases examined . Genotype-phenotype correlations indicated that skeletal features were definitely more severe , and adrenal dysfunction , 46 ,XY DSD , and pubertal failure were somewhat more severe in group B than group A , whereas 46 ,XX DSD and maternal virilization during pregnancy were similar between two groups . Notable findings also included the contrast between infrequent occurrence of 46 ,XY DSD and invariable occurrence of 46 ,XX DSD and pubertal growth pattern in group A mimicking that of aromatase deficiency .The results argue against the heterozygote manifestation and suggest that the residual POR activity reflected by the R 457 H dosage constitutes the underlying factor for clinical variability in some features but not other features , probably due to the simplicity and complexity of POR -dependent metabolic pathways relevant to each phenotype .

Diseases
Validation

Diseases presenting "skeletal dysplasia" symptom

achondroplasia

aromatase deficiency

cohen syndrome

dentinogenesis imperfecta

gm1 gangliosidosis

oligodontia

This symptom has already been validated