“Antley-Bixler Syndrome”—A Reply to Cragun and Hopkin

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To the Editor: Cragun and Hopkin (2005 [in this issue]) raise a series of points concerning use of the term “Antley-Bixler syndrome” (ABS), both in our recent paper in this journal (Huang et al. 2005) and elsewhere. We agree that it is useful to minimize confusion: the best way to do this may be to discard the term “ABS” and other eponymic terms once the molecular genetics and cell biology of a disease have been worked out. However, until such eponyms are discarded, as stated in our paper, “we propose that the term ‘ABS’ be reserved for those patients with the skeletal dysmorphologic findings initially reported by Antley and Bixler (1975) but who have normal genitalia and normal steroidogenesis” (Huang et al. 2005, p. 745). Cragun and Hopkin suggest that “patients with FGFR mutations should be grouped with those with other autosomal dominant FGFR-related craniosynostosis syndromes.” We agree. Describing dysmorphologic disorders by eponyms was appropriate when the responsible genes were not known, but little purpose is served in preserving these terms once the molecular genetics and cell biology are delineated. Although one may wish to honor investigators with eponyms, such nosology inhibits understanding of mechanisms: “post-streptococcal glomerulonephritis” may be less euphonious than “Bright's disease” but is more specific and informative. Cragun and Hopkin raise questions about the patient initially described by Antley and Bixler and about several other reported cases. Clearly, it is difficult (if not impossible) to make or exclude a diagnosis retrospectively. Lacking the individual’s DNA, we cannot know the molecular lesion in the patient described by Antley and Bixler (but we’d be happy to study it!). Whereas Cragun and Hopkin lament the paucity of published photographs and clinical detail in many case reports, we lament the poor descriptions of the external genitalia and the incomplete hormonal evaluations in most patients with “ABS.” Careful steroidal evaluation is crucial: mass spectrometric analysis of urinary steroids is highly reliable but not widely available; appropriate evaluation of pre- and poststimulation plasma steroids is equally reliable. The data available to Reardon et al. (2000) were insufficient to establish or exclude a steroidogenic disorder for several of their patients; hence, their report does not provide evidence for the suggestion that POR (P450 oxidoreductase) mutations might cause a skeletal disorder associated with normal genitalia. Thus, we believe that our conclusion that “aside from the genital anomalies attributable to disordered steroidogenesis, no dysmorphological feature distinguished patients with POR mutations from those with FGFR mutations” (Huang et al. 2005, p. 736) is well supported by the data in table 1 of Huang et al. (2005, p. 731). For convenience, we have compiled the clinical data from table 1 and the genetic data from table 4 (p. 737) in the table shown here. More-refined observations may identify other anatomic features distinguishing POR from FGFR mutations in infants with craniosynostosis; however, our data clearly show that dysmorphologists must pay very close attention to the external genitalia in these children and consider evaluation of steroid secretion before and after tropic stimulation with adrenocorticotropic hormone. Table 1 Genotype/Phenotype Correlations Collated from the Data in Tables 1 and 4 of Huang et al. (2005)[Note] Deficient POR activity can cause a broad spectrum of human disease (Fluck et al. 2004; Miller 2004; Huang et al. 2005), and clearly the patients described by us and others who have POR lesions without skeletal defects do not have ABS. Thus, we do not think it is reasonable to follow the suggestion of Cragun and Hopkin to use the term “ABS” for patients with the more severe form of POR deficiency associated with skeletal anomalies. If, as they propose (and we agree), all FGFR-based craniosynostosis disorders should be grouped together, then it is logical to group all POR disorders together. Regardless of whether the clinical genetics community agrees to discard eponyms in favor of a term such as “FGFR hyperactivity,” we believe that “POR deficiency,” which is a newly described monogenic disease, should be dissociated from the term “Antley-Bixler Syndrome.”