Clinical characteristics of cytochrome P450 oxidoreductase deficiency: a nationwide survey in Japan

Abstract

Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis that causes various symptoms such as skeletal malformations, disorders of sex development, and adrenal insufficiency. The aim of this study was to elucidate the clinical characteristics, especially age at diagnosis and treatment, of PORD from the perinatal period to adulthood in Japan. The first questionnaire was sent to 183 council members of the Japanese Society for Pediatric Endocrinology on 1 September 2018. The response rate was 65%, and a total of 39 patients with PORD were examined at 20 hospitals. The second questionnaire was sent in November 2018 to the council members examining these 39 patients with PORD. The response rate was 77%, and we received clinical information on 30 of the 39 patients. The two novel clinical findings were the age at diagnosis and the treatment of Japanese patients with PORD. In many cases, PORD can be diagnosed at <3 months of age. Hydrocortisone as the primary treatment during infancy can be used daily or in stressful situations; however, because patients with PORD generally have mild to moderate adrenal insufficiency, some might be able to avoid hydrocortisone treatment. Patients with PORD should be carefully followed up, and treatment should be optimized as for patients with other types of adrenal insufficiency. Other characteristics in the present study were similar to those described in previous reports.

Disorders of Sex Development: Classification, Review, and Impact on Fertility

“…(2) Cytochrome P450-oxidoreductase deficiency (PORD). PORD is a disorder of steroidogenesis that causes DSDs, adrenal insufficiency, and skeletal malformations [147]. It is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities.…”

“…It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1, and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis [148]. In a study by Yatsuga et al [147] on the clinical characteristics of PORD in Japan, it is shown that in many cases, PORD can be diagnosed at <3 months of age. Hydrocortisone, as the primary treatment during infancy, can be used daily or just in stressful situations; however, because patients generally have mild-to-moderate adrenal insufficiency, some might be able to avoid the treatment.…”

Two cases of cytochrome P450 oxidoreductase deficiency with severe scoliosis and surgery requirement

“…1 A decreased POR function causes various symptoms, such as skeletal malformations, disorders of sex development, and adrenal insufficiency. 2,3 Skeletal malformations, such as joint contracture, radiohumeral synostosis, midface hypoplasia, and craniosynostosis, are distinctive clinical features of PORD, also known as Antley-Bixer syndrome, when associated with facial and cranial malformations and limb deformities. 1,3 The predicted cause of the malformations is impairment of cholesterol production and retinoic acid metabolism.…”

“…The frequency of skeletal malformations ranges from 80% to 95%, 2,3,5 with joint contraction and radiohumeral synostosis being the most common. 2 Although recent studies have reported that 15% to 20% of PORD patients have scoliosis, 2,3,5 there were no reports of its severity or surgical cases.…”

“…A287P reportedly have relatively mild skeletal malformations. 2,5 These clinical features have been ascribed to impaired activities of the POR-dependent microsomal enzymes, CYP51A1 and squalene monooxygenase, which are involved in cholesterol production, CYP26A1, CYP26B1, and CYP26C1, which are involved in retinoic acid metabolism. 4 Krone et al found that patients with an absent or mild to moderate skeletal malformation phenotype were either homozygous or compound heterozygous for missense mutations.…”