Monitoring the estimated glomerular filtration rate (eGFR) in patients with small-cell lung cancer during chemotherapy: equations based on serum creatinine or cystatin C?
TO THE EDITOR: Braverman and colleagues (1) hypothesize 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 identified the genetic defects in most reported cases of POR deficiency (2–4), I find this unlikely. First described in 1975, ABS is a rare skeletal dysplasia syndrome characterized by craniosynostosis, radioulnar or radiohumeral synostosis, brachycephaly, femoral bowing, femoral fractures, midface hypoplasia, proptosis, a “pear-shaped” nose, choanal atresia, and other bony findings (5, 6). The ABS phenotype can result from either of 2 distinct genetic disorders: autosomal dominant gain-of-function mutations of FGFR2 or autosomal recessive loss-of-function mutations of POR (3). The multigenerational history of brachycephaly in Akhenaten’s family could be consistent with an autosomal dominant disorder, possibly in FGFR2. However, nothing in Akhenaten’s kindred suggests the femoral bowing or decreased range of motion that would accompany the elbow synostosis typical of ABS. Although the skeletal findings in ABS secondary to FGFR2 or POR mutations are indistinguishable, the 2 genetic disorders are readily distinguished not by the absence of a steroidogenic disorder in patients with FGFR2 mutations but by the presence of disordered steroidogenesis, often associated with genital ambiguity in patients with POR mutations (2). The clinical spectrum of steroid POR deficiency is broad: Minimal POR activity causes severe ABS and a severe disorder of steroidogenesis, resulting in ambiguous genitalia in both sexes, whereas persons with mild POR defects have infertility associated with normal external genitalia and a normal skeleton. However, even in very mild cases without a skeletal phenotype, infertility is typical (2, 3). Thus, if Akhenaten truly fathered 6 children, his POR function must have been sufficiently robust to preclude the skeletal disorder. Therefore, it seems unlikely that Akhenaten had either ABS or POR deficiency.