Progress Report A-1282: A Study of Heritable Disorders of Connective Tissue
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1959-02-09 (February 9, 1959)
McKusick, Victor A.
Original Repository: Alan Mason Chesney Medical Archives. Victor Almon McKusick Collection
Reproduced with permission of Anne B. McKusick.
Medical Subject Headings (MeSH):
Connective Tissue Diseases
From "Musical Murmurs" to Medical Genetics, 1945-1960
September 1, 1954-August 31, 1959
Summary: Clinical, genetic, and pathologic studies have been performed in relatively large series of six heritable disorders
of connective tissue. (Several other minor hereditary disorders of connective tissue have also been studied.) The total
number of families in which at least one affected individual has been identified is as follows for each syndrome:
What are reported here are our personal observations and findings since July, 1955, when my monograph Heritable Disorders
of Connective Tissue, describing our experiences up to that time, went to press.
Our tissue culture program for study of these syndromes was abandoned because of technical difficulties and greater interest
in other aspects and approaches. It is still planned to pursue collaborative studies with others engaged in tissue culture
studies of connective tissue.
The following relevant publications have appeared or have been prepared in the last two years:
1. McKusick, V. A.: Genetic factors in diseases of the cardiovascular system. Ann. Int. Med. 49: 556, 1958.
2. McKusick, V. A.: Hereditary diseases of connective tissue. Bull. New York Acad. Med., March, 1959.
3. McKusick, V. A.: Heritable Disorders of Connective Tissue. St. Louis: C. V. Mosby Co., 1959 (2nd and revised edition).
4. McKusick, V. A.: Genetic factors in diseases of connective tissue. A survey of the current state of knowledge. Am. J. Med.,
The Marfan Syndrome
1. Ventricular septal defect in unequivocal Marfan syndrome has been observed.
2. The upper segment-lower segment measurements of growing children with the Marfan syndrome have been recorded and compared
with measurements in normal sibs and other normals. Thirty-eight patients with the Marfan syndrome have been measured. In
seven measurements have been made over a span of years. In two, three measurements, the longest span being 10 years, have
been made. All measurements were made photographically with the patient in the nude against a measured grid.
3. Experience with cardiac surgery in one case suggests that, for the present, neither total replacement of the ascending
aorta by graft or prosthesis nor plication of the ascending aorta by the Bahnson technique can be expected to be successful,
mainly because of the intimate involvement of the sinuses of Valsalva and the aortic cusps themselves.
1. Acrocyanosis, a feature emphasized by European writers, has now been seen in two patients.
2. Experience with the cardiovascular aspects have been increased.
a. Two cases with major grade abnormalities (incompletely diagnosed) have been studied in detail.
b. Two more cases of rupture of the aorta or large juxta-aortic arteries have been identified.
3. The occurrence of multiple diverticula of the gastrointestinal tract has been documented.
4. Fragility of the gut, with repeated episodes of spontaneous colonic perforation, was found in two cases.
5. Epicanthus was a striking feature of affected persons in to families.
1. It has been possible to diagnose osteogenesis imperfecta in both of twin fetuses while still in utero.
2. The development and evolution of hydrocephalus in one case of OI congenita has been followed to death of the infant at
3. Clinical aspects of the teeth have been studied.
4. Important initial steps have been taken toward linkage analyses in this syndrome and in the Marfan syndrome.
a. Arrangements have been made with Dr. F. H. Allen, Jr., at the Blood Typing Center in Boston to do multiple blood groupings.
Haptoglobin typing by starch gel electrophoresis has been set up in our own laboratory and testing for secretor factor is
b. A program for electronic (digital) computer analysis of these and other linkage data have been initiated. Dr. James H.
Renwick, of the Galton Laboratory, London, here for five months Oct. 1, 1958, to March 1, 1959, has been responsible for setting
up this program in my department. IBM has given us free time to the liberal extent of 15 hours per month on the IBM 704 at
the Glenn L. Martin plant in Middle River. Mrs. Jane Schultz, an experienced programmer who formally worked on this same
machine, has been hired as a permanent member of our group. As a preliminary test of the method data on ABO and nail-patella
linkage have been analyzed with success.
1. Plastic surgery has been used for the skin changes of the neck in one patient.
2. The Leriche syndrome -- obliterative thrombosis of the bifurcation of the aorta -- has been observed in one patient with
PXE. Whether the association is merely coincidence is not clear. Vascular changes in the extremities in coronary arteries
are conspicuous and well recognized.
3. Further family studies support the view that inheritance is as an autosomal recessive.
1. Through the collaboration of Dr. Karl Meyer at Columbia it has been possible
a. To identify increased amounts of chondroitin sulfate B and heparitin sulfate in the urine of several of our patients.
b. To demonstrate no apparent qualitative or quantitative difference in the two genetic varieties of the disease -- the autosomal
recessive and the sex-linked recessive.
2. In collaboration with Dr. Richard Lindenberg, neuropathologist in the Medical Examiner's office of the city of Baltimore,
it has been possible to study the gross and microscopic morbid anatomy of this disease.
a. Hydrocephalus due apparently meningeal involvement as part of the mucopolysaccharide abnormality.
b. Coronary artery disease and mucopolysaccharide deposits in the intima of the aorta and pulmonary artery stimulating atherosclerosis
pathologically as well as clinically.
3. Studies of the Morquio syndrome, the condition most likely to be confused with the Hurler syndrome, were conducted in
two families. Absence of increased urinary mucopolysaccharide (see above) permitted definitive differentiation of borderline
cases and formed the basis of analysis of differentiating clinical features.
One case of fibrodysplasia ossificans progressiva was observed. Noteworthy features were 1) start of the disease in the gallea
aponeurotica, 2) normal serum transaminase levels in active wide-spread stages of the disease (ruling out "myositis"),
3) occurrence of short femoral necks as well as the classical microdactyly.
Plans for the future are outlined in the application for continued support.