Cytomegalovirus Retinitis as a Presenting Feature of Multisystem Disorder: Dyskeratosis Congenita.

Cytomegalovirus (CMV) retinitis is an opportunistic infection commonly seen in disorders that affect the immune system of the body such as acquired immunodeficiency syndrome and hematological malignancies such as leukemia/lymphoma or organ transplantation. The occurrence of CMV retinitis in the absence of such condition should be thoroughly investigated, as it is a strong indicator of poor immune competence. We here report an interesting case of CMV retinitis as a presenting feature of rare multisystem disorder "Dyskeratosis congenita."

Introduction

Cytomegalovirus (CMV) retinitis is a potentially blinding disease often seen in patients infected with human immunodeficiency virus (HIV).[1] It has also been reported in patients with compromised immune system like in organ transplant, leukemias, lymphomas, and systemic lupus erythematosus.[2] Prompt diagnosis and treatment is not only important to save the vision but also in some instances can unveil the underlying fatal systemic disorder. We here present an interesting case of CMV retinitis leading to diagnosis of rare multisystem disorder “Dyskeratosis congenita (DC).”

Case Report

A 45-year-old male presented with decreased vision in the left eye (LE) for 3 months. He was diagnosed as a case of viral retinitis elsewhere and received a course of intravenous acyclovir with minimal response before referring to our tertiary care hospital. HIV was ruled out by referring ophthalmologist. Best-corrected visual acuity at presentation was 6/6 in the right eye (RE) and light perception in LE. RE examination was normal. On anterior segment examination, LE had cellular reaction 2+ with posterior subcapsular cataract. LE fundoscopy revealed vitritis, optic disc pallor, retinitis patches at posterior pole, and midperiphery along the retinal vessels associated with retinal hemorrhages and inflammatory vascular sheathing [Figure 1a], suggesting a clinical diagnosis of CMV retinitis. Considering the clinical diagnosis of CMV retinitis in non-HIV patient, he was subjected to detailed systemic evaluation. Simultaneously, vitreous biopsy was performed in LE that confirmed CMV on polymerase chain reaction.

Figure 1

(a) Fundoscopy of the left eye showing pale optic disc with retinitis lesions. (b) Nails of the right hand showing ridging (black arrow). (c and d) Picture showing hypopigmented macules with reticular hyperpigmentation on the trunk and upper limb

Retrospective history revealed significant weight loss in the last 6 months but was not investigated. General examination showed hypopigmented macules with reticular hyperpigmentation involving the trunk, upper, and lower limbs [Figure 1c and d]. Nails had ridging and pterygium, suggesting progressive nail dystrophy [Figure 1b]. Buccal mucosa had leukoplakia. He had premature graying of hair and alopecia. These features led to the clinical diagnosis of a rare disorder termed “Dyskeratosis congenita”.

Complete hemogram including blood counts, peripheral smear, liver, and renal function tests was within normal limits. Telomerase length in peripheral white blood cells by flow cytometry and fluorescence in situ hybridization was below the first percentile, confirming the diagnosis of DC. HIV, venereal disease research laboratory, hepatitis B surface antigen, hepatitis C virus, and toxoplasma serology were nonreactive. Mantoux test was negative. His CD4 and CD8 percentages were 7.01% and 83.19%, respectively, with CD4/CD8 ratio of 0.08 suggestive of isolated CD4 lymphocytopenia. Chest imaging and pulmonary function test revealed normal study. Nasopharyngeal and laryngeal carcinoma was ruled out. Contrast-enhanced computer tomography of the abdomen showed asymmetric wall thickening of the pylorus part of the stomach [Figure 2a]. Upper gastrointestinal endoscopy showed multiple polyps in the stomach with antropyloric wall thickening. Biopsy from the lesion proved to be superficially invasive well-differentiated adenocarcinoma [Figure 2b]. The patient subsequently underwent laparoscopic D2 subtotal gastrectomy. Simultaneously, we also treated CMV retinitis with oral valganciclovir 900 mg BD for 3 weeks followed by maintenance dose of 900 mg OD. Retinitis lesion subsequently healed with scarring in LE. During the course of treatment and follow-up, RE remained unremarkable. The patient is now under regular follow-up with gastroenterologist, hematologist, and ophthalmologist every 3 monthly and doing fine at 1-year follow-up.

Figure 2

(a) Contrast-enhanced computed tomography showing asymmetric wall thickening of the pylorus part of the stomach. (yellow arrow). (b) Histology slide showing the presence of malignant cells arranged in infiltrating glands with desmoplastic stroma. (H and E, ×200)

Discussion

CMV retinitis is an opportunistic infection commonly seen in patients infected with HIV and occasionally in patients with leukemia, lymphomas, or organ transplant.[12] The occurrence of CMV retinitis in the absence of such conditions as in our case should be thoroughly investigated since it is a strong indicator of the underlying poor immune status of the patient. In our case, the presence of reticular skin pigmentation, nail dystrophy, oral leukoplakia and telomerase length less than the first percentile on flow cytometry and fluorescence in situ hybridization led to diagnosis of rare multisystem genetic disorder, DC.

DC is a disorder involving defective telomere maintenance. They have excessively short telomeres that impede replicating cells from maintaining genetic integrity over time, leading to premature stem cell exhaustion and tissue failure.[3] Telomere maintenance plays an important role in aging and cancer predisposition. Hence, they are at increased risk for mainly hematological and immunological disturbances, malignancies, pulmonary fibrosis, and subsequently infections.[3] The clinical diagnosis of DC is based on the presence of the four major features of the disease, which include the mucocutaneous triad (abnormal skin pigmentation, nail dystrophy, and leukoplakia) and bone marrow failure. Multisystem features of the disease include epiphora, developmental delay or mental retardation, pulmonary disease, periodontal disease, esophageal stricture, premature hair graying or loss, hyperhidrosis, or development of malignant lesions. To make a correct clinical diagnosis of DC, at least two of four major features and at least two multisystem features must be present.[4]

Due to wide spectrum of disease, a series of differential diagnosis must be considered. Dermatologic manifestations seen in DC may resemble ectodermal dysplasia, Rothmund–Thomson syndrome, pachyonychia congenital, or keratosis follicularis. However, these syndromes can be differentiated from DC by its associated symptoms. The hematological alterations seen in DC must be differentiated from other disorders with aplasia of the bone marrow such as Shwachman–Diamond–Blackfan anemia, thrombocytopenia with radial aplasia, Kostmann's syndrome, Pearson's syndrome, and Fanconi's anemia. Fanconi's anemia closely resembles DC. The presence of high percentage of skeletal anomalies (radial aplasia and anomalies of the thumb), microcephaly, and renal and gonadal anomalies are some of the distinguishing features of Fanconi's anemia.[3]

DC can be inherited in one of the three forms, X-linked, autosomal dominant, and autosomal recessive. In addition to the different modes of inheritance, genetic anticipation has been reported in telomerase-specific reverse transcriptase and telomerase-interacting nuclear factor 2 pedigrees.[56] This phenomenon is marked by increasing severity in the clinical phenotype and shorter telomeres with each successive generation. The phenotype characteristics of DC are variable even between family members with the same mutation, and they can present differences in the penetrance, severity, and development of clinical features. According to the inheritance of the disease, the variability in healthy individuals depends more on telomere length of paternal chromosomes in the zygote than on the telomere length of maternal chromosomes. The importance of disease anticipation is reflected in the possible situation that a mutation-positive person with an unaffected phenotype can have affected sons. Correlations between clinical manifestations of DC and genetic mutations are complicated by the presence of disease heterogeneity, incomplete penetrance, and genetic anticipation.

Our patient had normal blood counts and peripheral blood smear, but strikingly, he had low CD4% with grossly impaired CD4/CD8 ratio, suggesting compromised lymphocyte response and hence had opportunistic infection mainly CMV retinitis. Contrarily, a single case report documents a patient with DC manifesting CMV retinitis but secondary to aplastic anemia 5 years after the diagnosis of DC.[7] The authors relate the occurrence of CMV retinitis in this case secondary to aplastic anemia. Second, being at risk for malignancies, our patient was thoroughly screened and upper gastrointestinal endoscopy did reveal multiple polyps in the stomach with antropyloric wall thickening, and biopsy from this suspicious lesion proved to be superficially invasive (early) well-differentiated adenocarcinoma. DC has poor prognosis, with the primary cause of death being infections (35%), malignancies (25%), and hemorrhage (15%). Almost 70% of patients with malignancy die before the age of 30 years.[3] Strikingly, our case remained undiagnosed till 45 years of age, and evaluation for CMV retinitis infection exposed the underlying fatal disorders. Hence, ophthalmologists can serve as an important link to the diagnosis in many such cases. Furthermore, proper workup and prompt management can improve prognosis in these cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.