title: Abnormal steroidogenesis in three patients with Antley-Bixler syndrome: apparent decreased activity of 17alpha-hydroxylase, 17,20-lyase and 21-hydroxylase.
abstract: BACKGROUND
  Antley-Bixler syndrome (ABS) is characterized mainly by abnormal skeletal morphogenesis such as craniosynostosis and radiohumeral synostosis, and by ambiguous genitalia in some cases. The mechanisms resulting in these deformities have not been determined.
  
  
  METHODS
  The adrenal and gonadal function of three Japanese ABS patients were evaluated. Patient 1 (17-year-old-male) had bilateral cryptoorchidism, delayed puberty and symptoms of glucocorticoid deficiency. Patient 2 (14-year-old male) and patient 3 (4-year-old female) presented with emaciation. Additionally, patient 3 had partial labial fusion and common urogenital sinus. In each patient, blood sampling for steroid analysis before and after rapid adrenocorticotropic hormone (ACTH) stimulation was carried out. Additionally, urinary steroids were quantified. Molecular analysis of CYP17 and CYP21A2 were also performed.
  
  
  RESULTS
  All patients showed elevated basal 17alpha-deoxysteroid levels. Although the 17alpha-deoxysteroid levels further increased after rapid ACTH stimulation, 17alpha-hydroxysteroids including cortisol did not respond, suggesting impaired 17alpha-hydroxylation. Patient 1 and patient 2 showed low adrenal androgen blood levels both before and after rapid ACTH stimulation. Patient 3 showed lower than normal excretions of urinary androgens. Additionally, a prolonged ACTH stimulation in patient 3 failed to elicit significant increase of adrenal androgens. These findings suggested impaired 17,20-lyase activity. In contrast to attenuated 17alpha-hydroxycorticosteroids, notably cortisol, elevated 17alpha-hydroxyprogesterone (17OHP) levels were observed, not only in pubertal patients (1 and 2) but also in prepubertal patient 3, indicating impaired 21-hydroxylation. This assumption was supported by increased urinary 21-deoxycortisol metabolite excretion in patients 2 and 3. With the exception of a heterozygous mutation of CYP17 in one of the patients, other mutations of this gene or CYP21A2 were identified in any of the patients.
  
  
  CONCLUSIONS
  Combined decreased 17alpha-hydroxylation, 17,20-lyase activity and 21-hydroxylation was detected in three ABS patients. Considering that the enzymes responsible are all cytochrome P450 enzymes and that another cytochrome P450 enzyme, lanosterol 14alpha-demethylase, has recently been shown to be impaired in an ABS patient, we speculate that dysfunction of a system which commonly regulates cytochrome P 450 activity may be responsible for the ABS phenotype.
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan. madachi@mars.sannet.ne.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Asakura
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tachibana
authors.forename: Cedric
authors.initials: C
authors.lastname: Shackleton
mesh_terms: D000015:Abnormalities, Multiple / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis / Q000378:metabolism; D002675:Child, Preschool; D005221:Fatigue / Q000473:pathology; D005260:Female; D005938:Glucocorticoids / Q000172:deficiency; D012739:Gonadal Steroid Hormones / Q000172:deficiency; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D006889:Hydroxycorticosteroids / Q000096:biosynthesis / Q000378:metabolism*; D007564:Japan; D008297:Male; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism*; D013255:Steroid 21-Hydroxylase / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis / Q000378:metabolism; D013577:Syndrome; D013580:Synostosis / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids; D012739:Gonadal Steroid Hormones; D006889:Hydroxycorticosteroids; D013256:Steroids; D000324:Adrenocorticotropic Hormone; D013255:Steroid 21-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase; D006854:Hydrocortisone