In their “History of Medicine” article “Akhenaten and the strange physiques of Egypt’s 18th dynasty” (Ann Int Med 150:556, 2009), Braverman et al. present the intriguing hypothesis that Akhenaten (Amenophis IV) had gynecomastia and brachycephaly attributable to the form of the Antley- Bixler syndrome (ABS) caused by mutations in P450 oxidoreductase (POR). Having reviewed the clinical findings and/or identified the genetic defects in most reported cases of POR deficiency (1-3), I find this unlikely. ABS, first described in 1975, is a rare skeletal dysplasia syndrome characterized by craniosynostosis, radio-ulnar or radio-humeral synostosis, brachycephaly, femoral bowing, femoral fractures, midface hypoplasia, proptosis, a “pear-shaped” nose, choanal atresia and other bony findings (4, 5). The ABS phenotype can result from either of two distinct genetic disorders: autosomal dominant, gain-of-function mutations of FGFR2 and autosomal recessive, loss-of-function mutations of POR (2). The multi-generational history of brachycephaly described in Akhenaten’s family could be consistent with an autosomal dominant disorder, possibly in FGFR2. However, there is nothing in Akhenaten’s kindred to suggest the femoral bowing or decreased range-of-motion that would accompany the elbow synostosis typical of ABS.
While the skeletal findings in ABS secondary to FGFR2 or POR mutations are indistinguishable, these two genetic disorders are readily distinguished by the absence of a steroidogenic disorder in patients with FGFR2 mutations, but the presence of disordered steroidogenesis, often associated with genital ambiguity in patients with POR mutations (2). The clinical spectrum of steroid POR deficiency is quite broad: minimal POR activity causes severe ABS and a severe disorder of steroidogenesis resulting in ambiguous genitalia in both sexes, whereas individuals having mild POR defects have infertility associated with normal external genitalia and a normal skeleton. However, even in very mild cases devoid of a skeletal phenotype, infertility is typical (1, 2). Thus, if Akhenaten truly fathered six children, his POR function would have to have been sufficiently robust so as to have precluded the skeletal disorder. Thus it seems unlikely that Akhenaten had either ABS or POR deficiency.
1. Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, et al. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet. 2004;36:228-230.
2. Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, et al. Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet. 2005;76:729-749.
3. Scott RR, Miller WL. Genetic and clinical features of P450 oxidoreductase deficiency. Hormone Res. 2008;69:266-275.
4. Antley R, Bixler D. Trapezoidocephaly, midfacial hypoplasia and cartilege abnormalities with multiple synostoses and skeletal fractures. Birth Defects Orig Artic Ser. 1975;11:397-401.
5. Crisponi G, Porcu C, Piu ME. Antley-Bixler syndrome: case report and review of the literature. Clin Dysmorphol. 1997;6:61-68.