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Slipped capital femoral epiphysis in identical twins: is there an HLA predisposition? Report of a case and review of the literature.

Both endocrine and genetic factors have been suggested as the cause of slipping of the capital femoral epiphysis. In 1950, Harris postulated that decreased sex hormones and increased growth hormones predispose to a slip occurring. However, Brenkel and colleagues (1) could not demonstrate any hormonal imbalance in patients with a slipped upper femoral epiphysis. Rennie (2) suggested an autosomal dominant inheritance with variable penetrance. He showed a materially increased chance of a second case in a family of a girl suffering from slipped upper femoral epiphysis. In his review of 214 cases, 14.5% had a close relative with similar pathology (compared to 0.05% in the general population). The number of close relatives with slipped epiphysis or osteoarthritis was 25% (Hagglund and associates (3) in 1988 had shown that osteoarthritis of the hip can be secondary to a minor slip).

Four reports have been made to date of slipped capital femoral epiphysis in identical twins (Gorin, (4) Gajraj, (5) Allen and Calvert, (6) and Bednarz and Satnitski (7)). Only the last three had HLA analysis. This article reports a fifth set of identical twins with slipped capital femoral epiphysis, and the fourth with HLA analysis.

Case Report

An 11-year-old identical twin female presented with a two-week history of right hip pain and a limp. She had painful limitation of abduction and internal rotation. X-ray showed a Grade 1 slip of the upper capital femoral epiphysis (Fig. 1). She had an in-situ fixation of the slip with a single AO screw.

[FIGURE 1 OMITTED]

Three weeks later, her twin developed similar pain in her right hip. She was admitted by the same on-call team as her sister and was found to have a similar Grade 1 slip of the upper capital femoral epiphysis (Fig. 2). She too underwent a fixation in situ of the slip with a single screw.

[FIGURE 2 OMITTED]

Both sisters made an uneventful recovery and were pain free and achieved full weightbearing at follow-up. HLA analysis of DNA was carried out after they had recovered from surgery.

Discussion

The Human Leukocyte Antigens (HLA) are polymorphic cell surface glycoprotein products of a series of genes located on the short arm of chromosome 6. There are two distinct classes of HLA molecule: HLA class I (comprising A, B, and C) and HLA class II (comprising DR, DQ, and DP). HLA genes are inherited en bloc in Mendelian fashion as a "haplotype," one from each parent. Identical twins will therefore be HLA identical while siblings have a 1:4 chance of being HLA identical.

The association between HLA and certain rheumatic diseases is well established. One of the strongest associations is between the HLA class I antigen B27 and ankylosing spondylitis (AS). In a study of patients with AS, 94% were B27 positive compared with 9.4% of controls. (8) Several DRB1 alleles are associated with susceptibility to and severity of rheumatoid arthritis. (9) Each of these alleles share a common series of amino acids located in the critical peptide binding groove of the HLA molecule. (10) There are several possible explanations for these associations. The HLA genotype may serve as a genetic marker by virtue of a close association with a disease causing gene or genes. Alternatively, the HLA molecule itself is involved in disease susceptibility through various mechanisms. The quest to find similar markers has fuelled the suggestion that slipped upper femoral epiphysis (SUFE) may be linked to the presence of a specific HLA antigen.

Unsal and coworkers (11) found that there was an association of HLA DR4 with juvenile chronic arthritis (JCA) and SUFE. Of 16 children with JCA, 6 had SUFE (an incidence of 37.5%) and 5 had HLA DR4 (an incidence of 31.25%). In controls of 25 children, only 2 had HLA DR4 (an incidence of 8%). These investigators therefore predicted that the risk of a patient with JCA and HLA DR4 having a SUFE was 57.5%, while the risk was barely 1% in JCA patients without the HLA DR4 phenotype. It was suggested that the patients with JCA and HLA DR4 should be examined for SUFE.

Only three earlier reports of identical twins with slipped upper femoral epiphysis have included HLA analysis (5-7) The HLA-B12 phenotypes, which have been found in two of the three published reports, are also seen in our case report. While this finding may be significant, it should be noted that the HLA-A2 and HLA B-44 (12) specificity is common in Caucasoid populations with an average antigen frequency of 45.8% and 20.9% respectively (12).

Gunal and Ates, (13) in a study performed in Turkey, described a common HLA-DR4 phenotype in all their 6 unrelated patients with SUFE, while the B12 antigen was absent in all their patients except one. Wong-chung and colleagues (14) performed HLA analysis on 7 patients with SUFE. None of the patients were twins, although there were two brothers. They did not find the HLA-B12 antigen in any of their patients. HLA-B35 was seen in five patients, HLA-DR52 in four patients, and HLA-DR4 in three patients.

There are expected variations between diseases and HLA phenotype in different population groups with SUFE. While the HLA-B12 antigen was seen in identical twins from Britain and New Zealand, the HLA-A2 antigen was seen in British, Polish, and New Zealand twins, and the HLA-DR4 antigen were seen in Turkish patients with SUFE. Patients with juvenile chronic arthritis with the HLA-DR4 antigen have a 57.5% risk of having a slipped upper femoral epiphysis. There is, however, little evidence in the published literature that there is a clear relationship between SUFE and a specific class I or class II antigen. A large HLA study on different population groups with SUFE will need to be done before any closer link can be identified.

References

(1.) Brenkel IJ, Dias JJ, Davies TG, Iqbal SJ, Gregg PJ: Hormone status in patients with slipped capital femoral epiphysis. J Bone Joint Surg Br. 1989;71:33-8.

(2.) Rennie AM: The inheritance of slipped upper femoral epiphysis. J Bone Joint Surg Br. 1982;64:180-4.

(3.) Haggulund G, Hansson LI, Ordeberg G, Sandstrom S: Bilaterality in slipped upper femoral epiphysis. J Bone Joint Surg Br. 1988;70:179-81.

(4.) Gorin RL: Slipped capital femoral epiphyses in identical twins: report of a case. J Am Osteopath Assoc. 1977;77(2):124-8.

(5.) Gajraj HAR: Slipped capital femoral epiphyses in identical twins. J Bone Joint Surg Br. 1986;68(4):653-4.

(6.) Allen CPF, Calvert PT: Simultaneous slipped upper femoral epiphysis in identical twins. J Bone Joint Surg Br, 1990;72(5):928-9.

(7.) Bednarz PA, Stanitski CL: Slipped capital femoral epiphysis in identical twins: HLA predisposition. Orthopedics. 1998;21(12):1291-3.

(8.) Brown MA, Pile KD, Kennedy LG, et al: HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum. 1996;55:268-70.

(9.) Nepom GT, Byers P, Seyfried C, et al: HLA genes associated with rheumatoid arthritis. Arthritis Rheum. 1989;32:15-21.

(10.) Gregerson PK, Silver J, Winchester RJ: The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30(11):1205-13.

(11.) Unsal E, Gulay Z, Gunal I: The association of HLA-DR4 antigen with juvenile chronic arthritis and slipped capital femoral epiphysis. Arch Orthop Trauma Surg. 2001;12:571-3.

(12.) The Central Data Analysis Committee: Allele frequencies, section 6.3 splits combined (five loci). The Data Book of the 11th International Histocompatibility Workshop: Yokohma 2:807-814, 1991.

(13.) Gunal I, Ates E: The HLA phenotype in slipped capital femoral epiphysis. J Pediatr Orthop. 1997;17:655-6.

(14.) Wong-chung J, Al-Aali Y, Al-Aradi: A common HLA phenotype in slipped capital femoral epiphysis? Int Orthop. 2000;24(3):158-9.

Michael Flores, M.Ch.(Orth), and Sandesh G. Satish, M.R.C.S., are in the Department of Trauma and Orthopaedics, James Paget Healthcare NHS Trust, Great Yarmouth, United Kingdom. Tim Key, M.R.C.S.H.C., is the Deputy Head of the Tissue Typing Laboratory, Addenbrooks Hospital, Cambridge, United Kingdom.

Correspondence: Michael Flores, M.Ch.(Orth), Association Specialist in Orthopaedics, James Page Healthcare NHS Trust, Great Yarmouth, United Kingdom NR31 6LA.
Table 1 HLA Analysis on Twins with Slipped Capital Femoral Epiphysis

The Source Tissue Typing

Gajraj (1986) A11 B44(12)
British twins A11 B44(12)
Allen and Calvert (1990) A2 B12
New Zealand twins A2 B12
Bednarz and Stanitski (1998) A2,26(10) B51(5),60(40)Bw4,6
Polish twins A2,24(9) B51(5),60(40)Bw4,6
Flores et al (2004) A2,23(9) B44(12),38(16)Bw4 Cw4,12
 DR103, DQ5(1)
British twins A2,23(9) B44(12),38(16)Bw4
 Cw4,12 DR7, DQ2
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Title Annotation:human leukocyte antigens
Author:Flores, Michael; Satish, Sandesh G.; Key, Tim
Publication:Bulletin of the NYU Hospital for Joint Diseases
Geographic Code:1USA
Date:Jan 1, 2006
Words:1456
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