Rothmund-Thomson syndrome with herpes encephalitis

ARTICLE

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder, characterized by the infantile onset of a reticulate erythematous eruption and progression of hyperpigmentation. Out of 107 reviewed cases, 33% of patients were photosensitive and 100% developed poikiloderma [1]. Other features include a short stature, absence or sparcity of scalp hairs, eyelash, and eyebrows, cataracts, bone defects, small hands, hypogonadism, defective dentition, nail dystrophy and keratotic lesions [1]. Recent reports have suggested the presence of immunological abnormalities in patients with RTS. We describe a case of RTS who had herpes encephalitis at 5 months of age. It was suggested that this severe infection with herpes simplex virus was caused by immunological abnormalities.

Case report

A 4-year-old Japanese boy was born at 42 weeks' gestation with a weight of 3,600 g by normal delivery. He had no icterus. At one month of age, the patient developed erythema on the face, ears and dorsum of his hands, which was gradually replaced by hyperpigmentation, in particular, on the cheeks. Family history was unremarkable.

In December, 1992, when he was 5 months old, the patient had a severe cough, mild fever, and vomiting. Five days later, he had a convulsive fit with high fever, which continued for 1 hr with no therapeutic effectiveness from the administration of diazepam (10 mg). He was admitted to a general hospital for further treatment. On admission, laboratory tests of peripheral blood revealed: a leukocyte count, 19,000/mm³; serum glutamate oxaloacetate transaminase, 339 U/l (normal, 8-34 U/l); serum glutamate pyruvate transaminase, 51 U/l (normal, 5-30 U/l); lactate dehydrogenase, 3,280 U/l (normal, 235-440 U/l); creatine phosphokinase, 4,400 U/l (normal, 25-180 U/l), and a normal value of C-reactive protein. Serum anti-herpes simplex virus IgG and IgM antibodies were negative, but the IgM antibody became positive 6 weeks after the attack. Cerebrospinal fluid examination showed: a cell count, 5/mm³ (normal, less than 5/mm³); protein, 62 mg/dl (normal, 15-45 mg/dl); and sugar, 107 mg/dl (50-75 mg/dl). Herpes simplex virus DNA was detected by polymerase chain reaction in the cerebrospinal fluid. By computer tomography, his brain was remarkably edematous, and it became atrophic 4 days later. The patient was diagnosed as having herpes encephalitis. Whereas the clinical symptoms were relieved by acyclovir, severe neurological sequelae including mental retardation and motor disturbance remained with him.

At the age of 4 years, the patient was 110 cm in height and 25 kg in weight. There was diffuse erythema and a reticular pattern of hyperpigmented spots with telangiectasia on the cheeks (Fig. 1) and dorsum of the hands. The scalp hair was lost and the eye lashes were sparse. The nails were not dystrophic. Electroencephalogram showed a low voltage of brain waves even at waking, and only low-active, small spikes at sleeping.

A biopsy specimen obtained from a poikilodermatous lesion on the face showed atrophic epidermis with melanin incontinence. In the upper dermis, there were melanophages and a perivascular infiltrate of mononuclear cells.

Phototesting and ultraviolet light (UV) effects on patient's fibroblasts

Phototesting was performed on the patient's abdominal skin sites at the age of 4 years. The minimal erythemal dose (MED) for UVB was 30 mJ/cm² at 305 nm (normal, 80-150 mJ/cm²), and no erythema was induced by exposure to 3.3 J/cm² of UVA at 365 nm.

Primary fibroblast culture was established from the patient's skin biopsy specimen. DNA repair studies, including post-UV cell survival, UV-induced unscheduled DNA synthesis (UDS), and post-UV inhibition of RNA synthesis, were performed with a germicidal lamp as described previously [2]. The cultured cells showed the same sensitivity to killing by UVC as normal cells. Treatment with caffeine after UV irradiation did not result in any sensitizing effect on the UV-survival of the patient's cells. The level of UDS after UV irradiation was 82% of normal cells. The cells had normal recovery of RNA synthesis after UV treatment. These results suggested that the patient had a normal level of DNA repair activity after UV exposure, negating the diagnosis of photosensitive genodermatoses.

Immunological studies

At the age of 4 years, serum levels were, IgG, 550 mg/dl (normal, 680-1,620 mg/dl) and IgA, 32 mg/dl (normal, 84-438 mg/dl) and IgM, 76 mg/dl (normal, 57-288 mg/dl). IgE value was less than 5 units/ml (normal, less than 250 units/ml). The fractions of IgG were: IgG₁, 3.14; IgG₂, 0.88; IgG₃, 0.04; and IgG₄, less than 0.14 mg/ml.

By flow cytometry, the patient's peripheral blood mononuclear cells (PBMC) contained CD3 positive cells, 57.4%; CD4 positive cells, 47.9%; CD8 positive cells, 9.0%; and CD56 positive cells, 18.4%, indicating normal percentages of T cell subsets and natural killer cells. PBMC obtained by standard Ficoll-Hypaque centrifugion were cultured in triplicate with mitogens including streptococcal enterotoxin B (SEB), toxic shock syndrome toxin-1 (TSST-1), streptococcal pyrogenic exotoxin A (SPEA), and concanavalin A (Con A), at varying concentrations, as described previously [3]. After 3-day culture, the proliferative responses to these mitogens were assessed by ³H-thymidine (TdR) incorporation. The absolute count per minutes (cpm) of the patient's PBMC to the three superantigens, SEB, TSST-1 and SPEA at a concentration of 100 ng/ml and to Con A at 5 mg/ml were comparable to those of the normal subjects (n = 6). As shown in Figure 2, however, the responses of the patient's PBMC to SEB, TSST-1, and SPEA were lower than those of the normal controls at concentrations of 0.1, 1 and 10 ng/ml. Since each of the superantigens activates different populations of T cells in a T cell receptor Vß-dependent manner [4] and the patient PBMC exhibited comparable low responsiveness in the three superantigens, it seemed that there was no specific T cell population hyporesponsive to mitogens, and rather, all T cells were functionally perturbed.

Discussion

In our patient, RTS was diagnosed based on the clinical features, including erythema and the reticular pattern of hyperpigmented spots with telangiectasia, loss of scalp hairs, and sparseness of eyelashes. There has been no solid indication of the involvement of DNA repair deficiency in RTS. One patient with RTS had a normal level of repair activity measured by UV-induced RNA synthesis [5]. Cells from a sunlight-sensitive RTS patient have been reported to be slightly hypersensitive to 313-nm UVB light [6]. On the other hand, Shinya et al. reported that RTS cells show normal sensitivity to UVB and slight hypersensitivity to UVC by the colony-formation assay with reduced UDS, suggesting that the reduced cell survival and UDS may reflect the reduced DNA repair capacity [7]. In our patient, the level of UDS was 82% of normal cells, and the cells had normal recovery of RNA synthesis after UV treatment, indicating a normal level of DNA repair activity after UV exposure.

Recent reports have suggested the presence of immunological abnormalities in patients with RTS, including IgG₄ [7] and C1q deficiency [8] and defects in cellular immunity [9]. Patients with IgG₄ deficiency frequently suffer from sinus and pulmonary infections and are treated successfully with infusions of immunoglobulins [7, 10]. Our patient also had a low level of IgG, especially IgG₄. In addition, the patient's PBMC responded poorly to superantigens, each of which stimulate T cell populations with different T cell receptor Vß [4]. These results suggest that not only humoral immunity but also cellular immunity was perturbed in our patient, which might lead to severe herpes encephalitis.

REFERENCES

1. Berg E, Chuang TY, Cripps D. Rothmund Thomson syndrome: a case report, phototesting, and literature review. J Am Acad Dermatol 1987; 17: 332-8.

2. Itoh T, Ono T, Yamaizumi M. A new UV-sensitive syndrome not belonging to any complementation group of xeroderma pigmentosum or Cockayne syndrome: siblings showing biochemical characteristics of Cockayne syndrome without typical manifestations. Mutation Res 1994; 314: 233-48.

3. Tokura Y, Furukawa F, Wakita H, Yagi H, et al. T cell proliferation to superantigen-releasing Staphylococcus aureus by MHC class II-bearing keratinocytes under protection from bacterial cytolysin. J Invest Dermatol 1997; 108: 488-94.

4. Uchiyama T, Yan XJ, Imanishi K, Yagi J. Bacterial superantigens-mechanism of T cell activation by the superantigens and their role in the pathogenesis of infectious disease. Microbial Immunol 1994; 38: 245-56.

5. Cleaver JE, Thomas GH. Measurement of unscheduled synthesis by autoradiography. In: Friedberg EC, Hanawalt PC, eds. DNA Repair. New York, NY: Marcel Dekker Inc, 1981: 277-88.

6. Fujiwara Y. Rothmund-Thomson syndrome. Pediatr Int 1989; 21: 126-8.

7. Shinya A, Nishigori C, Moriwaki S, et al. A case of Rothmund-Thomson syndrome with reduced DNA repair capacity. Arch Dermatol 1993; 129: 332-6.

8. Leyva-Cobian F, Moneo I, Mampaso F, et al. Familial C1q deficiency associated with renal and cutaneous disease. Clin Exp Immunol 1980; 44: 173-80.

9. Veller Fornasa C, Cipriani R, Tomazzoli L, et al. Poichilodermia congenita con leucoplasia orale e deficit dell' immunita cellulo-mediata. Giorn Ital Derm Venereol 1981; 116: 329-31.

10. Kubota M, Yasunaga M, Hashimoto H, et al. IgG₄ deficiency with Rothmund-Thomson syndrome: a case report. Eur J Pediatr 1993; 152: 406-8.