American Journal of Medical Genetics 175363-865 (1984)

Letter to the Editor: Diagnosis and Penetrance of Dystopia Canthorum in Waardenburg Syndrome Type I (WSI)

To the Editor:

In a paper o n penetrance of major signs in WSl, the authors [Preus et al, 19831 conclude that only 83 9% of heterozygotes showed dystopia canthorum; they based themselves on 144 patients from the literature and 6 of their own (the latter number was not explichim without proof that index W is “. . . less discriminant than the simpler formula X + Y . . . .” Previously, we demonstrated [Arias and Mota, 19781 that many patients, both from the literature (Waardenburg’s family 7) [Waardenburg, 19511 and our own (111-6, III- 1 in pedigree 3) [Arias, 19711 when using X + Y 2 1.55 were at or below the threshold of abnormality (1.55, I .51, respectively), but far above the threshold of nonapparent dystopia (NAD) by using W index (NAD: 1.86 < W < 2.07), and wirhin the range of dystopia canthorum (W 3 2.07) with W = 2.12 and 2.19, respectively.

Apparently the authors missed part of our definition of nonapparent dystopia canthorum [Arias and Mota, 19781 which we gave as “. . . the phenotype with at least the first three of these four features: 1) clinically ambiguouslor unaffected, 2) offspring and/or parent of a typical WS1 case, 3) W index > 1.87 < 2.07, and 4) carrier of a typical sign (white forelock, unilateral deafness, pigmentary troubles, synophrys, etc)” It was also stated by us that 19% of the normal population have indeed 2.06 2 W 2 1.87, but izoizc in that group, who are not carriers of the WSf gene, shows concurrently conditions 1, 2, and 4, above.

Unfortunately, Preus and colleagues did not publish their raw measurements, to enable one to test how it was possible, as they claim, that X + Y, resulted i n a better discriminant than X + Y + a/b = W. That is in contradiction to what we found in 151 WS1 patients from the literature, plus our 40 new cases [Arias and Mota, 19781 and by the results from all measured patients with WS 1 that appeared in the literature before and after our 1978 paper, both with complete and incomplete measurements (the latter generally lacking the interpupillary distance) which show that W index is

Received for publication October 11, 1983.

Address reprint requests to Sergio Arias, Laboratory of Human Genetics, IVIC, Apartado 1827, Caracas 1010-A, Venezuela.

0 1984 Alan R. Liss, Inc.

864 Arias

far better than X + Y, as anyone can test (Case I , [Omenn and McKusick, 1979 (in Arias, 1980); Parry et al, 1978; Dausch et al, 19821).

It is trivial to estimate either variable in the obvious case, but in the “normal” or ambiguous relative, W index proves its value, as in the cases for which it was originally devised: 083046, 083053, 083543, etc [Arias and Mota, 19781 and many others for whom a WSI diagnosis was neither made nor typical dystopia canthorum present. In all these diagnostically doubtful cases the error always is lower using W rather than X + Y. If X + Y 3 1.55 and W 2 2.07 are set. respectively, as the lower expected thresholds with 99% and 100% certainty for WSI, then which of‘ these indices is closer to the true diagnosis in the suspected cases, measured by the observediexpected ratio? Without exception. it is the W index, as shown in Table 1 for a few examples, which can be extended at length to any case in the literature.

Evidently. the diagnostic efficiency for “difficult” cases is in no instance superior for X + Y. On the other hand, W index is on the average 6% better. Nothing would be gained, and a confusing stepdown will ensue if X + Y (our former suggestion) [Arias, 19711 is recommended, instead of W index. A careful reading of our 1978 paper will give the interested reader an insight into the nosographic advan-

TABLE I. Comparison of the Diagnostic Value for Dystopia Canthorum Between Indices W and X + Y in Doubtful Cases of WSl

(1) (2) W X + Y

Case obslexp obstexp Ratio (1)/(2) Reference

083046 1.000 0.920 1.076 [Arias and Mota, 19781 083053 0.986 0.923 1.068 [Arias and Mota, 19781 083543 1.000 0.935 1.070 [Arias and Mota, 19781 Case 1 0.957 0.890 1.075 [Omenn and McKusick,

1979; Arias, 19801 Index case 0.990 0.942 1.05 1 [Parry et al, 19781 Ped. 3 111- 1 1.024 0.974 1.051 [Arias, 19711 111-6 1.058 1.000 1.058 [Arias, 19711 Index case 1.000 0.948 1.054 [Dausch et al, 19821 Index case 1.014 0.948 1.070 [Branski et al, 1979; NR

Dennis, personal comm, 19801

Mother 1.024 0.961 1.066 [Branski et al, 1979; NR Dennis, personal comm, 19801

Mat. grand- 1.029 0.969 1.062 [Branski et al, 1979; NR mother Dennis, personal comm,

19801 Ped. 7 Mother” 0.899 0.845 1.063 [Waardenburg, 195 I ] Fatherb 0.845 0.800 1.057 [Waardenburg, 19511 x f SD (N = 11) 1.007 f 0.027 0.946 f 0.030 1.064 f 0.009 (Excluding Waardenburg’s

SD (N = 13) 0.987 f 0.057 0.920 f 0.058 1.063 f 0.009 (Including Waardenburg’s pedigree 7)

pedigree 7)

“Non dystopic carrier [Arias and Mota, 19781. ’Normal [Arias and Mota, 19781.

Waardenburg Syndrome Type 1 865

cage of our latest index, and the indispensability of measuring carefully all relevant relatives.

REFERENCES

Arias S (1971): Genetic heterogeneity in the Waardenburg syndrome. Birth Defects: Original Article Series 7(4):87- 101.

Arias S, Mota M (1978): Apparent non-penetrance for dystopia in Waardenburg syndrome type I , with mine hints on the diagnosis of dystopia canthorum. J Genet Hum 26: 101-131.

Arias S (1980): Letter to the Editor: Waardenburg syndrome. Two distinct types. Am J Med Genet 6:99-100.

Branski D, Dennis NR, Neale JM, Brooks LJ (1979): Hirschprung’s disease and Waardenburg’s syndrome. Pediatrics 63:803-805.

Dausch D , Wegner W, Franke KD, Flach M (1982): Sinnerverluste bei genetischen Pigmentmangelsyn- dromen. Deut Med Wochensch 107: 1029-1032.

Omenn GS, McKusick VA (1979): The ociation of Waardenburg syndrome and Hirschsprung mega- colon. Am J Med Genet 3:217-223.

Parry DM, Safyer AW, Mulvihill JJ (1978): Waardenburg-like features with cataracts, small hcad size, joint abnormalities, hypogonadism, and osteosarcoma. J Med Genet 15:66-69.

Preus M , Linstrom C , Poloineno RC, Milot J (1983): Wd~rdenbUrg syndrome. Penetrance of major signs. Am J Med Genet 15:383-388.

Waardenburg PJ (195 I ) : A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J Hum Genet 3: 195-253.

Sergio Arias Laboratory of Human

Genetics, IVIC Curacas 1010-A, Venezuela