American Journal of Medical Genetics 27:959-963 (1987)

Editorial Comment: Nager “Syndrome” Versus “Anomaly” and Its Nosology With the Postaxial Acrofacial Dysostosis Syndrome of Genee and Wiedemann

John M. Opitz

Department of Medical Genetics, Shodair Children’s Specialty Hospital, Helena, Montana; Departments of Pediatrics and Medicine (Medical Genetics), University of Washington, Seattle, Washington; Departments of Biology, History and Philosophy, Medicine (WAMI Program), and Veterinary Sciences, Montana State University, Bozeman, Montana; Departments of Medical Genetics and Pediatrics, University of Wisconsin, Madison. Wisconsin

INTRODUCTION

The preceding paper by Hecht and coworkers challenges our current understanding of the acrofacial dysostoses and begs the question whether the entity under discussion should be called a “syndrome” or an “anomaly” qua developmental field defect.

It makes a difference. In genetic parlance, a syndrome is a causally defined, specific entity in which the

component manifestations bear a pleiotropic relationship to each other. A developmental field defect (or anomaly) is a causally nonspecific entity in which the component manifestations bear a direct pathogenetic relationship to each other. The fetal alcohol syndrome (FAS) is causally defined on the basis of 1 ) a uniquely characteristic combination of functional and morphological manifestations, 2) history, 3) epidemiology, and 4) animal models. One manifestation-complex in the FAS may be the DiGeorge anomaly,” which is a causally highly heterogeneous polytopic developmental field defect,

which may occur per se, and in the Zellweger syndrome, del(22qll) syndrome and other forms of aneuploidy, the bisdiamine and 1 3-cis-retinoic acid disruption sequences, etc. [ Lammer and Opitz, 19861.

“

Received for publication January 7, 1987.

Address reprint requests to Dr. John M. Opitz, Shodair Children’s Specialty Hospital, P.O. Box 5539, Helena, MT 59604.

0 1987 Alan R. Liss, Inc.

960 Opitz

In a syndrome, none of the morphogenetic anomalies are obligatory in the sense that they are present in all cases and must be present before a diagnosis can be made; this is because of the rather indirect pathogenetic relationship between the component anomalies, especially in mosaic pleiotropy [Opitz et al, 19691. Because of the rather direct pathogenetic relationship between the parts of a developmental field (especially a monotopic field), impairment of one part is by definition almost always associated with (or leads to) visible defect in the other parts.

Syndromes are clinically studied in a process (syndrome delineation or phenotype analysis) that seeks to identify all actual and potential component manifestations, before and after birth, in both sexes and over the entire life-span of the affected individual by clinical and morphological methods. Because of the causally nonspecific and pathogeneti- cally limited nature of all of the component manifestations, the phenotypic spectrum of virtually every syndrome overlaps to some extent with that of others, identifying pathogenetic but not causal commonalities.

Syndromes are studied causally in a process (syndrome definition, genotype-r genetic-analysis) that seeks to identify the reason for the uniqueness of their overall phenotype through genealogical, segregational, cytogenetic, and biochemical methods that demonstrates etiologic homogeneity. The two methods are complementary and lead to the conclusion that cause of the phenotype is unique, but components of phenotype are not.

The study of developmental field defect works exactly in reverse to that of syndromes in the sense that one specific (primary or secondary) malformation, regardless of how complex, is studied with the aim to demonstrate its etiologic heterogeneity. Sometimes these studies are deliberate, occasionally the discovery of causal heterogeneity falls into one’s lap serendipitously. The prepared mind will seize hold of the observation joyfully and will pursue with grateful and humble disposition the developmental insights thus offered virtually gratis. The set mind with antipathy against the concept of fields, will, sometimes against better judgment, dismiss the data as irrelevant much as “primitive” peoples who seek separate explanations for lightning, thunder, and rain because they may be separated from each other by a moment of time (ie, may not be absolutely correlated).

NAGER SYNDROME VERSUS NAGER ANOMALY

How one wishes for the art of Verdi who went directly at the business of Rigoletto with only a few powerful chords to precede the first act, and his drive to create a major masterpiece of Western musical culture rather than a modest scholarly comment in only 40 days. But the matter brought up by Jacqueline Hecht and her coworkers is not easy, witness the entry of Dr. McKusick in the latest edition of his catalogs: “No. 15440: Mandibulofacial Dysostosis, Treacher Collins Type With Limb Anomalies (Nager Acrofacial Dysostosis, AFD, Nager Type).” It is not preceded by an asterisk, for the evidence for causal heterogeneity seems reasonably compelling. Hecht et al [ 19871 quote the recent paper by Reynolds et al [1986] who report on a previously apparently unreported autosomal dominant form of acrofacial dysostosis (AFD), which may repre- sent an iceberg (dominant) trait. The slightly modified Table I from the paper by Reynolds et al is reproduced here; the first entry in the Table is changed from “MFD with mild acral anomalies” to Reynolds-Webb syndrome, with appropriate reference citation. The word syndrome in the second entry has been put into quotation marks, for I think the time has come to change syndrome to “anomaly.”

Acrofacial Dysostosis Anomaly 961

TABLE I. Conditions of Mandibulofacial Dysostosis with Acral Anomalies (The Acrofacial Dysostoses Broadly Speaking)*

Syndrome or association Cause Reference

Reynolds- Webb syndrome Nager “syndrome” Postaxial acrofacial

dysostosis syndrome (Genie- Wiedemann syndrome)

Fontaine syndrome Kelly syndrome Weyers syndrome

Townes-Brocks syndrome

AD AR, AD

Reynolds et al [ 19861 Halal et al [ 19831

AR

AD AR’? X-linked‘?

AD Roubicek and Spranger

AD

Miller et al [ 19791 Lewin and Opitz [ 19861 Fontaine et a1 [ 19741 Kelly et al [ 19771

[I9841 Kurnit et al [ 19781

Chromosome anomalies: distal 2q duplication Trisomy 18 Bersu and Ramirez-Castro

Trisomy 7 mosaicism Hodesetal [I9811

*Reprinted with some modifications by permission of Alan R. Liss, lnc. from Reynolds et a1 [1986].

Wagner and Cole [ 19791

[ 19771

The reasons for that change were explained previously [Opitz, 19861 and refer to apparent causal heterogeneity of acrofacial dysostosis (Nager) [Halal et al, 19831 and its suspected occurrence in a t least one instance of the Down syndrome. Since it seems likely that mandibulofacial dysostosis (MFD) represents a disturbance of neural crest action and/or development [Johnston and Sulik, 1979; Johnston et al, 19811 and since AFD does appear to be a polytopic developmental field, it follows that neural crest may indeed have something to do with limb development as postulated by McCredie [qv, North and McCredie, 19871. Recently, Sulik et a1 [ 19871 have postulated that MFD represents primary interference with first and second arch ectodermal placodal cells at a time when the neural crest cells are being released from the fusing neural folds.

NAGER ANOMALY VERSUS THE GENEE-WIEDEMANN SYNDROME

Figure 2 in the paper by Hecht et al [1987] possibly suggests slightly short 5th fingers; however, Figure 3 clearly shows bilateral abnormality of the most ulnar ray as well. On the right, the proximal portions of metacarpals 4 and 5 are fused (or never separated), and on the left the 5th metacarpal is represented by such a minute distal remnant that on radiologic examination the fetus appears to have only 3 metacarpals; the bones of both 5th digits are hypoplastic.

Does this mean that the fetuses observed by Hecht et al have the “postaxial acrofacial dysostosis syndrome” [Miller et al, 19791 ? Possibly, since in this misnamed condition affected individuals may also have radioulnar synostosis, preaxial involvement with hypoplastic or duplicated thumb(s), in addition to postaxial oligodactyly. However, absence of fibular involvement with polydactyly of toes speaks against the diagnosis in the fetuses studied by Hecht et al. Lewin and Opitz [ 19861 have suggested that this condition be called the GenCe-Wiedemann syndrome instead of postaxial acrofacial dysostosis syndrome. The observations in the syndrome of GenCe and Wiedemann and Reynolds and Webb suggest that acrofacial dysostosis need not be confined to pre- or postaxial involvement, but can involve both sides, as it does in the W T syndrome [Gonzalez et al, 19771.

962 Opitz

All of the above notwithstanding, it is important to underscore one of the points made by Hecht et al-namely, given the birth of a fetus or child with AFD to a couple, a 25% recurrence risk must be considered and suggested in counseling unless examination of the parents documents in one of them evidence of AFD, which may be as mild as that reported by Reynolds et a1 [ 19861.

ACKNOWLEDGMENTS

This work was supported in part by a grant from the Montana State Department of Health and Environmental Sciences under HB430. I am most grateful to LaVelle M. Spano for expert secretarial collaboration.

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Edited by James F. Reynolds