Retinitis pigmentosa and hypogammaglobulinemia.

Abstract: This report describes a family demonstrating an unusual association of retinitis pigmentosa and hypogammaglobulinemia. The proband in this family suffered from another rare illness, ie, Sertoli cell only syndrome. The incidence of retinitis pigmentosa is 1 in 5,000 and that of common variable immunodeficiency state is 1 in 100,000, making a chance association of these illnesses very unlikely.

Key Words: retinitis pigmentosa, hypogammaglobulinemia, Sertoli cell only syndrome

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Retinitis pigmentosa is a genetically determined disease of the retina characterized by night blindness, peripheral visual field constriction, and pigmentary retinopathy. Retinitis pigmentosa has been associated with a number of systemic diseases, including common variable immunodeficiency state. (1) No family with both of these disorders has been described. We wish to report a family with members having one or both of these conditions. In addition, the proband in our report manifested Sertoli cell only syndrome.

Case Report

A 36-year-old former factory worker with mild cerebral palsy was admitted to the hospital with cough, purulent nasal discharge, malaise and bilateral lower lobe infiltrates. He had multiple previous admissions for pneumonia and sinusitis and had been diagnosed with bronchiectasis.

Physical examination revealed a well-developed man with slight spasticity of the limbs. Crackles were heard in both lung bases. There was no clubbing of the nails. Examination of the eyes showed a sluggish reaction of the pupils. Posterior subcapsular cataracts were seen and the optic nerves had a waxy pallor. The retinal vessels were small and atrophic. Marked bone spicule-like changes extended from the arcades to the mid periphery.

Total atrophy of the retinal pigment epithelium was noted on the right and cystoid macular edema was present on the left.

The patient's past medical history revealed a history of night blindness since age 5. Retinitis pigmentosa was diagnosed at age 12 at Rhode Island Hospital. Hypogammaglobulinemia was diagnosed at age 21. At age 36, bilateral testicular biopsies were done because of aspermia. Sertoli cell only syndrome was diagnosed. A nasal biopsy found no evidence of ciliary disease. A sister, age 52, was known to have a diagnosis of hypogammaglobulinemia. A scalene node biopsy from the sister (done at age 36) found normal lymph node architecture and abundant CD20 positive B-cells. Her son, age 33, had retinitis pigmentosa with the onset of visual symptoms at age 17 (see Fig.). At age 48, the proband in this report developed infraclavicular lymphadenopathy. A biopsy of this node found changes consistent with B-cell lymphoma.

Pertinent laboratory studies in the proband included the following: White blood cell count 7,700 with 71% neutrophils, 10% bands, 7% lymphocytes, 9% monocytes and 3% eosinophils. Total protein was 5.3 g/dL; IgG 164 mg/dL (normal 640-1,500); IgA 1.4 mg/dL (normal 80-350) and IgM 8.8 mg/dL (normal 50-350). An anergy panel revealed a positive reaction to Monilia at 1:1,000 and Trichophyton at 1:100 with a negative reaction to intermediate- strength purified protein derivative (PPD). Flow cytometry revealed 68% CD3 lymphocytes with 44% CD4 lymphocytes and 12% CD8 lymphocytes.

The helper/suppressor ratio was 3.6. Complement studies were C3 of 87 mg/dL (normal 80-177), C4 of 8 mg/dL (normal 13-45), C3 PA of 17 mg/dL (normal 10-40) and Clq of 69% normal human serum. Total hemolytic complement was 401 U (normal 427-480). Immunoglobulin and complement values from several family members are shown in the Table. Following stimulation of isolated lymphocytes, gamma interferon levels in the patient and his sister were normal at 113 and 293 U/mL respectively (done by Specialty Laboratories, Santa Monica, CA).

Discussion

While some cases of retinitis pigmentosa occur sporadically, (2,3) most are inherited. Familial cases occur in an autosomal dominant, autosomal recessive or X-linked fashion. Primary retinitis pigmentosa involves only the eye while secondary types have systemic symptoms as well as ocular manifestations. (3) Most secondary forms are inherited in an autosomal dominant or autosomal recessive manner. The family described here demonstrates a previously unreported familial association of retinitis pigmentosa and common variable immunodeficiency state. The incidence of retinitis pigmentosa is 1 in 5,000 and that of common variable immunodeficiency state is 1 in 100,000, making a chance association of these illnesses very unlikely. (4,5)

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Since Fessel's report of antibodies to gamma globulin in some patients with retinitis pigmentosa, there has been interest in the possibility of immunologic aberrations in this disease. (6) Newsome at al presented a detailed study of humoral immunity, cytokine production and T-lymphocyte subsets in these patients. (2) Heredia et al found circulating immune complexes in some patients with this condition. (7) In that series, an association was noted between low C3, C4 and CH50 levels and circulating immune complexes. Our patient demonstrated low levels of C4 and CH50 as well as a reduction of Clq consistent with the presence of immune complexes. In addition, a reduced level of C3 was noted in his nephew (see Table). To the best of our knowledge, immune complexes have not been definitively reported in common variable immunodeficiency, although these patients are subject to diseases of an autoimmune nature in which such complexes might be expected.

Some studies have reported deficient lymphocyte production of gamma interferon in retinitis pigmentosa, while other investigations have not confirmed this finding. (8) A more recent report would seem to indicate that gamma interferon production is normal in most patients with retinitis pigmentosa. (2) Interestingly, lymphocytes from some patients with common variable immunodeficiency are deficient in gamma interferon production. (9) Mononuclear cells from our patient and his sister both produced low normal levels of gamma interferon after appropriate stimulation.

Thus, it seems unlikely that defective interferon production is the immunologic link between retinitis pigmentosa and common variable immunodeficiency state.

Recurrent infections have been mentioned in association with retinitis pigmentosa and Sertoli cell only syndrome. (1,10) Rudge et al described three patients with retinitis pigmentosa and common variable immunodeficiency state. No familial cases were noted. More recently X-linked retinitis pigmentosa in association with recurrent otitis media, sinopulmonary infections and hearing loss has been reported. (11) Immunoglobulin levels were not given in these cases. An association of Sertoli cell only syndrome, bronchiectasis and recurrent sinusitis was described by Valero et al (10) Immunoglobulin levels were normal in his patient, and retinitis pigmentosa was not mentioned. The proband in our report had biopsy-proven Sertoli cell only syndrome. Of interest, sperm abnormalities and ciliary defects are reported in retinitis pigmentosa. (12,13) Ciliary studies were normal in our patient. One could speculate that there may be an association between retinitis pigmentosa, common variable immunodeficiency state, Sertoli cell only syndrome, recurrent sinusitis, bronchitis, and repeated pneumonia. Interestingly, inflammatory cytokines have been found to influence Sertoli cell growth in a rat model. (14) Repeated episodes of inflammation could conceivably damage Sertoli cells.

In conclusion, we report an immune deficiency state associated with retinitis pigmentosa and Sertoli cell only syndrome. Our study suggests that serum immunoglobulins should be measured in those patients with retinitis pigmentosa or Sertoli cell only syndrome who have recurrent infections.

References

1. Rudge P, We AD, Revesz T, et al. Encephalomylitis in primary hypogammaglobulinemia. Brain 1996;119:1-15.

2. Kalloniatis M, Fletcher EL. Retinitis pigmentosa: understanding the clinical presentation, mechanisms and treatment options. Clin Exp Optom 2004;87:65-80.

3. Heckenlively JR. Retinitis Pigmentosa. Philadelphia JB Lippncott, 1988.

4. Rivolta C, Sharon D, DeAngelis MM, et al. Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns. Hum Mol Genet 2003;12:583-4.

5. Fasth A. Primary immunodeficiency disorders in Sweden: ases among children, 19741979. J Clin Immunol 1982;2:86.

6. Fessel WJ. Serum protein disturbances in retinitis pigmentosa and the association of retinitis pigmentosa with psychosis. Am J Ophthalmol 1962;53:640-642.

7. Heredia CD, Huguet J, Cols N, et al. Immune complexes in retinitis pigmentosa. Br J Ophthalmol 1984;68:811-814.

8. Hendricks RL, Fishman GA. Interferon gamma production and HLA-DR expression in patients with retinitis pigmentosa. Exp Eye Res 1987;45:923-931.

9. Paganelli R, Capobianchi MR, Ensoli B, et al. Evidence that defective interferon production in patients with primary immunodeficiences is due to intrinsic incompetence of lymphocytes. Clin Exp Immunol 1988;72:124-129.

10. Carrion Valero FC, Ferrer Gomez C, Pascual Izuel JM Sinobronchial infections and male sterility. Presentation of a new varient. Arch Bronconeumol 1998;34:405-408.

11. Zito I, Downes SM, Patel RJ, et al. RPGR mutation associated with retinitis pigmentosa, in paired hearing, and sinorespiratory infections. J Med Genet 2003;40:609-615.

12. Ohga H, Suzuki T, Fujiwara H. et al. A case of immotile cilia accompanied by retinitis pigmentosa. Nippon Ganka Gakkai Zasshi 1991;95 795-801.

13. Van Dorp DB, Wright AF, Carothers AD, et al. A family with RP3 type of x-linked retinitis pigmentosa: an association with ciliary abnormalities. Hum Genet 1992;88:331-334.

14. Peterson C, Froysa B, Soder O. Endotoxin and promflammatory cytokines modulate Sertoli cell proliferation in vitro. J Reprod Immunol 2004;61:13-30.

Total absence of humor renders life impossible
--Sidonie Gabrielle Colette

John C. Starr, MD, George W. Brasher, MD, John Dominguez, MD, and Arundhati Rao, MD, PhD

From the Division of Allergy and Immunology and the Department of Pathology, Scott and White, Scott, Sherwood, and Brindley Foundation, The Texas A & M University Health Sciences Center College of Medicine, College Station and Weslaco, TX.

Reprint requests to John C. Starr, MD, 2401 South 31st Street, Temple, TX 76508. Email: [e-mail]

Accepted November 22, 2005.

RELATED ARTICLE: Key Points

* Some patients with retinitis pigmentosa have recurrent infections.

* On rare occasions, hypogammaglobulinemia can be associated with these infections.

* Retinitis pigmentosa, common variable immune deficiency and Sertoli cell only syndrome may be associated.

Table. Immunoglobulin and complement values from family members

         C-3 mg/dL  C-4 mg/dL  CH 50      C1q

Proband   84.6        7.95     401        69%
II-1     114         23.2
III-1     68.2       13.6
IV-1      91.9       15.0
IV-2      85.6       11.7

         IgG mg/dL  IgA mg/dL  IgM mg/dL

Proband  164          1.4       88
II-1      71         <1.11      <1.11
III-1    721        139        155
IV-1     986        230        124
IV-2     786        251         59