Tissue Antigens (1975), 5, 205-212 Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permission from the author(s)

Ankylosing Spondylitis in a Large Kindred: Clinical and Genetic Studies JAMES

M. S T R O S B E RFRED G ~ ~ ~H. , ALLEN,JR.3, JOHN J. CALABRO* EDWARD D. HARRIS, JR.V

AND

1Department

of Medicine, Dartmouth/Hitchcock Medical Center, Hanover, New Hampshire; 2 Veterans Administration Hospital, White River Junction, Vermont; 3 The New York Blood Center, New York; and 4 Department of Medicine, Worcester City Hospital, Worcester, Massachusetts, U.S.A.

In a kindred of 66 members spanning four generations, seven cases of ankylosing spondylitis ( A S ) have been found. Four of these were in a single sibship of 13. AS was associated with HL-A27 in three of the four involved siblings, but close linkage was shown to be unlikely. Knowledge of HL-A genotype has made possible informed counseling for younger members of the sibship of 13, some of whom, as teenagers, already have back pain.

Received for publication 12 November 1974, accepted I5 January 1975

Early studies of the genetics of ankylosing spndylitis (AS) have been limited to population surveys. Most authors agree that the susceptibility to the disease is inherited as an autosomal dominant with incomplete penetrance (Hersh et al. 1950, Blecourt et al. 1961, OConnell 1959). Emery & Lawrence (1967) have criticized the autosomal dominant theory of inheritance, citing the rarity of reported families in which the disease was clearly transmitted in this manner through several generations. They favored a theory of polygenic inheritance.

A recent development has been the demonstration (Schlosstein et al. 1973) that the leukocyte antigen W27 is found in 88 'j% of 40 spondylitics and only 8 % of 906 normal controls. This has been confirmed (Brewerton et al. 1973a) by the detection of the W27 antigen in 72 out of 75 patients with AS and in 31 of 60 first degree relatives. The W27 antigen has also been reported in eight out of nine patients with Reiter's disease (Zachariae et al. 1973) and in a high percentage of patients with uveitis (Brewerton 1973b, Ehlers et al. 1974).

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Reported here are clinical and genetic studies of a kindred of 66 members in which seven cases of definite AS were present in three generations including four in a. single sibship. Materials and Methods Case Report The proband, a 34-year-old white father of three, came to the Arthritis Clinic of the Dartmouth/Hitchcock Medical Center in 1971 because of back pain, stiffness and fatigue of 10 years' duration. There was no history of iritis, colitis, psoriasis, urethritis or peripheral joint involvement. Two of his uncles had received radiation therapy for AS 25 years previously, and several of his 12 brothers and sisters had back pain. General physical examination was unremarkable. His chest expansion was 2.0 cm (normal, greater than 4.3 cm) and his spine flexion by the modified Schober technique was 4.5 cm (normal, greater than 6.5 cm) (Moll & Wright 1971). T h e remaining joints were normal. His complete blood count was normal. Both the anti-nuclear antibodies by immunofluorescence and latex fixation tests were negative. Routine blood chemistry tests were also normal. Roentgenograms of the pelvis revealed bilateral sclerosis, erosions and narrowing of the sacroiliac joints, as well as early syndesmophyte formation and lumbar squaring. Because of the remarkable prevalence of AS in the family, a clinical and genetic study was undertaken. Methods Clinical information was elicited about 66 members in four generations of the family. Roentgenograms of pelvis and lumbar spine were observed in 24, including the proband's parents, siblings, maternal aunts

and uncles, oldest nephew and oldest cousin in each sibling group. Special views of the sacroiliac joints were obtained when indicated. The films were read by two of us (EDH, JJC) not aware of the clinical data. Physical examinations, including spine and chest expansion measurements (Moll & Wright 1972) were done on the entire large sibship of 13 as well as the parents. In seven cases (including the proband), a diagnosis of definite AS was made according to the New York Criteria (Bennett & Wood 1968). Blood was drawn from the proband, the parents, and nine siblings for determination of complete bIood counts, anti-nuclear antibodies by immunofluorescence, latex fixation titer (Singer & Plotz 1956) and serum protein electrophoresis." Routine blood chemical values were determined by the Technicon 660 Autoanalyzer. HL-A typing of blood cells from all 13 members of the large sibship and their parents was performed at the New York Blood Center with modified two stage lymphocytotoxicity techniques and standard antisera provided by the serum bank of the National Institutes of Health. Red blood cells and serum were analyzed for other genetic markers, also at the New York Blood Center by standard methods (Giblett 1969). Linkage analysis was carried out for 23 autosomal genetic markers by a computerized method (FaIk & Edwards 1970). Results Affected Family Members Seven members of the kindred (Fig. 1) including the proband (111.2) and four of

* Complete blood counts, chemical tests, and serum protein electrophoresis were done by the clinical laboratory of the Mary Hitchcock Memorial Hospital. The anti-nuclear antibody and latex fixation tests were done at the Worcester City Hospital.

ANKYLOSING SPONDYLITIS IN A LARGE KINDRED

207

M FAMILY 1973

I

71

m

Figuse 1 . Pedigree of M Family in 1973. 0 = male; 0 = female; Q = four children, some-male and some female; or = definite ankylosing = back pain without positive radiographic signs of spondyspondylitis; litis; 0 or JZf= deceased. The proband (designated by arrow) is identified by the Roman numeral I11 (third generation and Arabic number 2

(111.2).

his sibship had definite AS when first examined in December, 1971. No one in the pedigree had a history of iritis, colitis, psoriasis or urethritis. Only one (111.7) had peripheral joint involvement. ( 1 ) S.M. (111.3), brother of the proband, was 33 years old and had back pain for 10 years. Chest expansion was 1.5 cm and lumbar spine flexion by the modified Schober technique was 4.5 cm. Spine films showed Grade 111 sacroiliitis and lumbar squaring. ( 2 ) The only affected female in the kindred, J. H. (111.4), aged 31, had had intermittent mild back pain for three years. Chest expansion was 1.5 cm and spine flexion 6.0 cm. Roentgenograms showed Grade 111 bilateral sacroiliitis. ( 3 ) N.M. (111.7), aged 25, had a two year history of moderate back pain. Chest expansion was 3.0 cm and spine flexion 6.0 cm. Roentgenograms showed sclerosis and slight irregularities of both sacroiliac joints

(Grade 11). When seen two years later (March, 1974), he complained of fatigue, back pain, increasing stiffness, and limitation in both wrists and pleuritic chest pain. O n physical examination there was minima1 soft tissue swelling and tenderness of both wrists. The right was limited to 15' of dorsiflexion and 30' of palmar flexion. There was also tenderness of the costochondral articulations. Chest expansion had decreased to 2.0 cm and spine flexion to 3.5 cm. Furthermore, roentgenograms showed mild sclerosis without erosions or irregularity of the sacroiliac joints and normal wrists films. ( 4 ) G.C. (11.7), aged 56, maternal uncle of the proband, had a 35 year history of back pain. Roentgenograms disclosed complete fusion of the sacroiliac joints as well as syndesmophyte formation (Grade I V sacroiliitis) . (5) F.C. (11.8), another maternal uncle, had a long history of back pain. His roent-

Name Age

ABO

I Rh

I MNSs

P,

K

Fy"

Fyb

I I I 1 I Jk" 1

Red cell antigens Xg"'

HL-A G m l Hp

Gc

Ag

I 1 1 C3

Serum proteins lOro

Bf

AcPa

All are Lutheran (a-), Inv (- l), transferrin C, pseudocholinesterase nl, phosphoglucomutase 1, hemoglobin A and adenosine deaminase 1. Those with AS are indicated by capital letters. Those with back pain but without radiographic evidence of AS are italic only. Red cell antigens: K is Kell, F y is Duffy, Jka is Kidd. Serum proteins: Gm and TnV are antigenic sites on IgG; G c is an OC, globulin of unknown function; Ag is an OC lipoprotein; C , is the third component of the complement system; Oro is orosomucoid, an OC, acid glycoprotein. a Phosphoglucomutase, adenosine deaminase and acid phosphatase (AcP) are intracellular enzymes, measured in erythrocytes. The family, incidentally, illustrates the very close linkage that has been demonstrated between H G A and Bf (GBG) (Allen 1974).

Pedigree no.

W

N 0

209

ANKYLOSING SPONDYLITIS I N A LARGE KINDRED

genograms showed Grade I11 bilateral sacroiliitis and irregularities ( “whiskering” ) of the symphysis pubis. At age 55 he died of metastatic renal adenocarcinoma.

(6) E.B. ( I . l l ) , aged 59, maternal great-uncle of the proband, had back pain for 35 years. His roentgenograms showed Grade I11 sacroiliitis and syndesmophyte formation. Genetic Studies Table 1 lists the results of all typing for red cell, HL-A and protein antigens in the large sibship and their parents. Linkage analysis for nine markers for which the mother was segregating are tabulated in Table 2. Analysis was carried out for only the four sibs with definite AS because penetrance of AS is not 100 ”/o and one could not know which of the apparently normal sibs carried the abnormal genetic material. When Nelson (111.7) (the sib with moderate back pain and marked limi-

tation of chest expansion and spine flexion but with relatively normal roentgenograms) was included (Table 2), linkage was neither confirmed nor ruled out between AS and the markers tested. I n general, a LOD score (i.e.“log odds” [log probability ratio]) of less than - 2.0 is an indication that two loci are not linked at the recombination fraction considered. A score of more than 4-3.0 indicates that they are likely to be linked at or near the recombination fraction (theta-1) considered. I n this analysis only acid phosphatase (AcP) had a positive LOD score. Similar analyses for linkage were performed with the exclusion of Nelson. A POsitive LOD score ($0.602 at the recombination fraction of 0.1) was obtained for the comparison ASIHL-A, but this is not significant. Similarly, an insignificant LOD score was obtained for AcP. Three of the four siblings initially diagnosed as having definite AS had the W27 antigen. This was passed to them through

Table 2 LODa, scores of linkage analysis Markerb ABO Rh

P Kell

MN Gm

HGA HP AcP

0.000

0.01

0.05

0.10

0.30

-1.126 - 1.126 - 0.047 -1.126 -1.126 -1.126 -1.126 -1.126 0.873

-0.833 -0.833 -0.047 -0.833 -0.953 -0.833 -0.833 -1.117 0.856

-0.405 -0.405 -0.045 - 0.405 - 0.601 -0.405 - 0.405 -0.965 0.785

-0.206 -0.206 -0.040 -0.206 -0.389 -0.206 -0.206 -0.710 0.693

-0.010 - 0.01 3 - 0.010 - 0.069 -0.010 -0.010 -0.138 0.281

-0.010

a LOD = “log odds” or “log probability ratio”. See Table 1 for abbreviations. 0 is the frequency of recombination that is assumed for purposes of computation. If the assumption is correct, or nearly so, LOD scores will be positive. The chance of recombination between two linked loci is greater (Le. 0 greater) the further apart they are (e.g. if 5% offspring were crosses over then e would be 0.05). 0 is considered a direct index of distance between genes ( e = 0.05 = 5 centimorgans). 0 larger than 0.15 need correction for double crossover and other factors before they can be directly related to map distance (Race & Sanger 1968).

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hypothesis that genetic control of the immune resFonse to certain antigens determines the clinical manifestations of specific infections. In our M family, there is support both for the autosomal dominant theory of inheritance and for an association with HLA W27. Such an association, however, is not the same as linkage. Indeed, in this particular family the negative LOD scores suggest the absence of close linkage of AS and HL-A loci. Of course, the incomplete penetrance of spondylitis and the strong possibility that some of the young memDiscussion bers of the sibship will develop spondylitis In recent years, it has become known that as they reach their middle 20’s adds to the several genes located on different chromo- complexity of linkage studies. Failure of our study to demonstrate linksomes code for cell surface transplantation antigens (Hildemann 1970). I n man, sys- age of AS with genetic markers has been tematic genetic studies have revealed asso- shared by others. Riecker et al. (1950) reciations between the presence of certain ported a family with five cases of AS in two generations. Thirty-nine members of diseases and cross-reacting HL-A types. The risk that a person with HL-A type the kindred were tested for blood group W27 antigen will develop AS appears to antigens in saliva and the ability to taste be 81 times greater than for persons lack- phenylthiocarbamide. No linkage was ing this antigen (Schlosstein et al. 1973). found in this study or in another (KornThis association is strong enough to war- stad & Kornstad 1960) in which blood rant extensive study for the possibility that groups only were analyzed. N.M. (111.7) presented a problem in an immune response gene ( I r gene)) which could be the principal determinant of AS, diagnosis. He had evidence of systemic disis linked closely to the W27 antigen (Bene- ease (fatigue, pain and stiffness), progrescerraf & McDevitt 1972). Of great interest sive limitation of chest expansion and spine in this regard is that at least two other syn- flexion, and had developed peripheral joint dromes often associated with spondylitis, involvement. Yet, he did not have sufi.e. Reiter’s syndrome (Zachariae et al. ficient skeletal abnormalities on recent 1973) and acute anterior uveitis (Brewer- roentgenograms to fulfil standard diagnoston et al. 1973b, Ehlers et al. 1974), also tic criteria for definite AS and was negashare a strong association with the HL-A tive for HL-A W27. I t would be of inW27 antigen. In addition, it has been re- terest to review a large series of spondyported (Ah0 et al. 1973) that the W27 litics to learn if patients without HL-A antigen was present in 20 of 22 patients W27 have fewer sacroiliac changes than do with Yersinia arthritis (an acute, non- those with the antigen. The converse of purulent arthritis sometimes following me- this has been tested; data have been presenteric lymphadenitis and/or enteritis) sented to suggest that persons possessing caused by Y.pseudo-tuberculosis and Y.en- HL-A27 antigen will be much more likely terocolitica. These data lend support to the to develop sacroiliitis if they contract either

their mother whose two brothers and uncle had AS. Two of 13 siblings (111.1 and 111.10) have juvenile diabetes mellitus. They share an identical HL-A genotype: 2,W10,9,W 15. Another brother (111.8),who also had 9,W15, has a son who has had diabetes since 19 months of age. These findings are consistent with the recent report of an association between diabetes mellitus and HL-A W15 (Nerup et al. 1974).

ANKYLOSING SPONDYLITIS IN A I.ARGE KINDRED

ulcerative colitis or psoriasis (Brewerton et al. 1974). Retrospective reading of Nelson’s first roentgenogram, read originally as Grade I1 sacroiliitis, showed definite changes. On examination two years later the films were normal. Minor erosions and sclerotic areas had either healed, or this was an example of the difficulty in the interpretation of sacroiliac roentgenograms (Gofton et al.

1972). From the standpoint of preventive medicine, it was important to identify the two sibs (111.11 and 111.13) with back pain and W27, but with normal physical and roentgenographic examinations. Today, with regular physical therapy and anti-inflammatory drugs, the majority of patients with AS can maintain satisfactory functional status and continue the usual routine of their lives (Calabro 1968). Finally, we believe that the unmarried siblings in the M family with W27 should select their sFouses without regard to HL-A genotype.

Acknowledgements This work was supported by the New Hampshire Chapter of the Arthritis Foundation, the Hitchcock Foundation, and USPHS grant AM 14780. Dr. Harris is recipient of Research Career Development Award AM 35506 from the USPHS. The authors are grateful to Ceci Tseng and Paula Parker for help in preparing the manuscript. Dr. Thomas P. Almy provided thoughtful criticism of our work.

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21 1

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Schlosstein, L., Terasaki, P. I., Bluestone, R. & Pearson, C. M. (1973) High association of an HL-A antigen, W27, with ankylosing spondylitis. New Engl. J. Med. 288, 704-706. Singer, J. M. & Plotz, C. M. (1956) The latex fixation test: Application to the serological diagnosis of rheumatoid arthritis. Amer. /. Med. 21, 888-892. Zachariae, H., Hjortsherj, A. & Kissmeyer-Nielsen, F. (1973) Reiter’s disease and HL-A27. Lancet ii, 565-566. Address: James M . Strosberg Connective Tissue Disease Section Dartmouth/Hitchcock Medical Center Hanover New Hampshire 03755, U.S.A.