American Journal of Medical Genetics 50102-103 (1994)

Book Review CONNECTIVE TISSUE AND ITS HERITABLE DISORDERS: MOLECULAR, GENETIC, AND

MEDICAL ASPECTS. Peter M. Royce and Beat Steinmann, eds. New

York: Wiley-Liss, 1993, 709 pp.

Where would medical genetics be without Victor McKusick? Among his contributions are attention to the inbred, making the Amish a lasting symbol of genetic treasure; insights into heterogeneity, forged by the im- ages of Douglas and Lincoln; and the Herculean cata- logue, linking gene anatomy to human function through his new discipline of “genomics.”The soil for these ideas, enriched like a delta by the flow of cardiology clinic, was connective tissue. As emphasized by “Heritable Disor- ders of Connective Tissue” 119561 and its three subse- quent editions 11960, 1966, 19721, genetics can illumi- nate common disease by study of extremes. Some 20 years after the fourth edition, two offspring have ap- peared: the subject of review and a volume edited by Peter Beighton [1992] that retains McKusick’s eponym (correct possessive in this case). In preview, the Royce/ Steinmann offering provides more basic biology while Beighton’s 5th edition retains a clinical advantage.

Both single volumes are of standard size (8.5 x 11 inches) and modest thickness (1.5 inches), with silky pages and larger type distinguishing the Beighton en- try. Each has an introduction by McKusick. Paradox- ically, the namesake volume has an old preface to the fourth edition and a brief comment on future prospects; RoyceiSteinmann enticed a more current chapter that retraces the trail from Peutz-Jeghers [Jeghers et al., 19491 through Marfan [McKusick, 19551 to the classic four editions. As pointed out in McKusick‘s contempor- ary introduction, these volumes are triumphs of a ge- netic medicine that now extends to common arthritis. There is also the tragedy of complex k n o w l e d g d 4 contributors were needed by FbyceiSteinmann to cover territory once grasped by a single author, and the 15 contributors to Beighton attest more directly to our cur- rent information explosion.

After a 44 page introductory chapter on medical ge- netics by Bryan Sykes, the RoyceiSteinmann book pro- vides a 9 part, 266 page discussion of extracellular ma- trix biology. Review of Mendelism, cytogenetics, and molecular technology is followed by extensive informa- tion on skinitendon (Holbrook, Smith), cartilage (Hor- ton), bone (Schenk, Felix, Hofstetter, Dickson-two en- tries), collagen proteins (Kielty, Hopkinson, Grant), collagen genes (Chu, Prockop), elastin (Rosenbloom),

Address correspondence to Golder N. Wilson, M.D., Ph.D., De- partment of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9063.

0 1994 Wiley-Liss, Inc.

glycosylated matrix proteins (Heinegard, Oldberg), ad- hesive glycoproteins (von der Mark, Goodman), keratins (Lane), and matrix degradation (Murphy, Reynolds). The results are a fascinating review of evolutionary ingenuity, epitomized by the shuMing of epidermal growth factor, fibronectin, calmodulin, and von Will- ebrand factor-like exons to produce structurally similar but functionally different adhesive proteins (laminin, thrombospondin, tenascin, and nidogen). By contrast, the Beighton book features a shorter but comparable genetic primer by Judith Hall and a 17 page chapter on the biology of normal connective tissue by Peter Byers.

Over half (382 pp) of the RoyceiSteinmann volume concerns heritable disorders, with chapters on osteo- genesis imperfecta (Byers), Ehlers-Danlos (editors plus Superti-F’urga), cutis laxa (Mitto, Fazio, Christiano), pseudoxanthoma elasticum (Neldner), Marfan (Pyeritz), homocystinurias (Skovby), Menkes (Danks), epidermolysis bullosa (Bruckner-Tuderman), prolidase deficiency (editors), alpha-l-antitrypsin deficiency (Cox), osteopetrosis (Whyte), alcaptonuria (Hazleman, Adebajo), fibrodysplasia ossificans progressiva (Con- nor), lysosomal disorders (Leroy, Weismann), chondro- dysplasias (Horton, Hecht), and keratin disorders (Baden, Kvedar). The corresponding chapters in Be- ighton occupy 523 pages and have not deviated signifi- cantly from McKusick’s original format. Chapters on Marfan (Godfrey), homocystinuria (Pyeritz), Weill- Marchesani (Maumenee), Ehlers-Danlos (Beighton), cutis laxa (Pope), osteogenesis imperfecta (Tsipouras), alkaptonuria (Beighton, Berman, Srsen), pseudox- anthoma elasticum (Viljoen), mucopolysaccharidoses (Whitley), fibrodysplasia ossificans progressiva (Be- ighton), miscellaneous disorders (Beighton), and skele- tal dysplasias (Rimoin, Lachman) are included. Each has a substantial index. Beighton provides several ap- pendices including a glossary, repository of known mu- tations, and a summary of the International Nomencla- ture of Constitutional Disorders of Bone (not indexed or easily found in RoyceiSteinmann).

I tested the books with some questions arising from recent consultations. Acrodysostosis, indexed in both, receives a short paragraph in RoyceiSteinmann and an X-ray photographitabular description in Beighton. How reliable is urine screening for the mucopolysac- charidoses? I quickly located urine screening under mu- copolysaccharidosis in the Beighton index and was re- ferred to a 2-3 page extensive discussion comparing various tests. Neither index entry nor discussion was present in Royce/Steinmann. What management is rec- ommended for Marfan syndrome and achondroplasia? The expected attention to beta-blockers was found in the contribution of Pyeritz (Fbyce/Steinmann)-the de- tailed physiologic and experimental justification was instructive. Equally judicious but less extensive infor- mation was provided by Godfrey (Beighton). Both books

Book Review 103

attended well to the management of achondroplasia. Specific investigations were more thoroughly discussed by Rimoin and Lachman (Beighton), with anticipatory management of delivery and leg-lengthening options receiving more attention from Horton and Hecht (Royce/ Steinmann). What is the differential for blue schlerae? Three entries are found for this sign in Beighton (Mar- fan syndrome, fragilitis oculi, and osteogenesis). It is not indexed in RoyceiSteinmann.

Clinically, a slight edge goes to the Beighton book, with generally more photographs, references, and read- ability. However, clinical information is also substantial in the RoyceiSteinmann books, and the more extensive coverage includes skin diseases. Neither attempts an overall sign or symptom guide to the various disease categories, so that “user-friendly” books such as Jones 119881 still find application. As summarized above, the biology in RoyceiSteinmann is much more detailed and comprehensive; this is the book for researchers.

In his introduction to the Royce/Steinmann volume, McKusick recounts his earlier faith that three main principles of clinical genetics-pleiotropy, genetic het- erogeneity, and variability-would find molecular ex- planations. Molecular variation has certainly been de- tailed, exemplified most elegantly by the osteogenesis imperfectas. Unfortunately, the pathways by which these mutations effect organismal pathology are not yet understood, although concepts such as “protein suicide” have provided elegant models. In 1990, McKusick opined our dilemmas regarding phenogenesis: “It is a

matter of both surprise and deep regret to me that the Marfan syndrome is not now understood at the molecu- lar level; pseudoxanthoma elasticum is no better off.” [McKusick, 19931. Characterization of fibrillin gene mutations has now provided the etiology €or Marfan syndrome, but variable expressivity is far from under- stood in this or other autosomal dominant disorders. And so the cycle begins anew-the astute observer, the decisive patient, the right idea.

REFERENCES Beighton P, ed. (1992): “McKusick’s Hereditable Disorders ofconnective

Tissue,” 5th ED. St. Louis: Mosby. Jeghers H, McKusick VA, Katz KH (1949): Generalized intestinal

polyposis and melanin spots of the oral mucosa, lips and digits: A syndrome of diagnostic significance. N Engl J Med 241:993-1005.

Jones KL (1988): “Smith‘s Recognizable Patterns ofHuman Malforma- tion,” 4th ED. Philadelphia: W.B. Saunders.

McKusick VA (1955): The cardiovascular aspects of Marfan’s syn- drome: A hereditable disorder of connective tissue. Circulation 11:321-342.

McKusick VA (1993): Heritable disorders of connective tissue: A per- sonal account of the origins, evolution, validation, and expansion of a concept. In Royce PM, Steinmann B (eds.): “Connectiue Tissue and its Heritable Disorders: Molecular, Genetic, and Medical Aspects.” New York Wiley-Liss, p 3.

Golder N. Wilson Department of Pediatrics University of Texas Southwestern Medical Center Dallas, Texas