Severe Variant of X‐linked Dyskeratosis Congenita (Hoyeraal‐Hreidarsson Syndrome) Causes Significant Enterocolitis in Early Infancy

Abstract

Hoyeraal-Hreidarsson syndrome (HHS, OMIM 300240) is a severe clinical variant of X-linked dyskeratosis congenita (DC) (1,2). In the majority of patients, the disease is caused by mutations in the X-linked dyskeratosis congenita gene DKC1(3). Mutations within the same regions in the DKC1 gene can cause either the clinical phenotype of HHS or DC. DKC1 encodes for the nucleoprotein dyskerin, which is a cofactor of human telomerase responsible for maintaining telomere length after DNA replication (4). In contrast to dyskeratosis congenita HHS manifests within the first years of life (5). The disease is characterized by progressive bone marrow failure with pancytopenia and concomitant immunodeficiency with several phenotypes (most commonly B- and natural killer [NK]–cell deficiency) (6). Neurological features are ataxia, microcephaly, and developmental delay (7). Patients usually have a history of intrauterine growth retardation. The typical skin and hair lesions with alopecia and nail dystrophy giving dyskeratosis congenita its name appear later during the course of the disease. Chronic bloody diarrhoea may be present in the early course of the disease. Attempts of bone marrow transplantation with different results have been made and death usually occurs at the end of the first decade (8). PATIENT REPORTS Patient 1 The boy was a child of unrelated parents born at term with weight, length, and head circumference being 2 SD below the mean. He presented with watery diarrhoea and pancytopenia from the eighth month of life. On admission at the age of 14 months abdominal distension, microcephaly, ataxia, and developmental delay were evident. Colonoscopy showed nonspecific pancolitis and ileitis with pieces of dissected mucosal tissue floating in the lumen. Histopatholgical evaluation demonstrated signs of chronic nonspecific inflammation with reduction of colon crypts and fibrosis of the lamina propria in parallel with apoptotic cell death (Fig. 1A). The patient acquired Pneumocystis jiroveci pneumonia and absence of B and NK cells and low levels of immunoglobulins in the blood were detected (Table 1). Molecular genetic analysis of the DKC1 gene revealed a previously published mutation in exon 10 (c.1058C>T; Ala353Val). Bloody diarrhoea with 15 to 20 stools per day was unresponsive to prednisolone, azathioprine, mesalazine, and cyclosporine. Severe abdominal pain requiring continuous analgesia was partially released by high doses of prednisolone, but finally an ileostomy was performed leading to relevant relief of pain. Recurrent bleeding episodes occurred from a nonhealing enterostoma with increased vascularization (Fig. 1C and D). A distal and an esophageal stenosis were successfully treated with endoscopic dilatation and systemic steroids. At the age of 6 years the patient died of septicemia.FIG. 1: (A) Low magnification of colonic biopsy specimen of patient 1 shows atrophy and architectural distortion with pronounced rarefication of crypts and mild fibrosis of the lamina propria without evidence of lymphatic tissue. High magnification of the cryptal epithelium shows apoptotic cell death as well as some mitotic figures; in some crypts Paneth cells are present. In the lamina propria chronic inflammatory cells are mildly increased (eosinophils, macrophages, and few plasma cells). (B) Colonoscopy of patient 2 revealing non-specific pancolitis and ileitis with pieces of dissected mucosal tissue floating in the lumen. (C) Photograph of nonhealing enterostoma (patient 1). (D) Contrast enhanced transverse magnetic resonance imaging sections of the abdomen showing massive neovascularization around the stoma (arrow) leading to difficult wound healing and recurrent bleeding (patient no. 1).TABLE 1: Distribution of lymphocytes and qualitative testing of T cell function of peripheral bloodPatient 2 The boy was born at 34 weeks of gestational age after fetal distress. Birth weight, length, and head circumference were between 1 and 2 SD of the mean and regression of gain of weight, length, and head circumference was visible since the second year of life (all 2 SD below the mean). In addition, developmental delay with ataxia was present. At the age of 36 months bloody diarrhea occurred and subsequently pancytopenia was detected. Immunological workup showed reduction of B and NK cells and the boy acquired P jiroveci infection. Colonoscopy revealed similar findings as in the first patient (Fig. 1B). Histology showed signs of increased basal apoptosis and sparse mononuclear infiltrates in the lamina propria. Genetic analysis revealed a previously unpublished mutation in exon 11 of the DKC1 gene (c.1133G>A; Arg378Gln). A trial of azathioprine was unsuccessful and cyclosporine A had to be discontinued because of hypertension. Finally, ileostomy was performed as in patient 1. Further palliative care permitted a painless time at home with his family. At the age of 5 years 4 months the patient died of septicemia. DISCUSSION We report 2 patients with Hoyeraal-Hreidarsson syndrome who presented with intractable diarrhea because of severe enterocolitis. Gastrointestinal complications dominated the further course of the disease with painful recurrent episodes of bowel obstruction, which were partially relieved by high-dose corticosteroids, but finally required surgical resections, dilatations, and ileostomy in both patients. To gain knowledge about the occurrence of gastrointestinal finding in HHS, we performed a PubMed search and found 23 reported cases of HHS. Table 1 gives the clinical manifestations extracted from these reports including our patients (no. 24 and no. 25). Involvement of the gastrointestinal system in HHS includes oral ulcerations, esophageal dysmotility with stenosis, and severe diarrhea resulting from enterocolitis. Diarrhea was reported in 52% (13 of 25) of all described patients in the literature (Table 2). The mean age of onset of diarrhea was 12 months (±10, range 1–36). In 7 patients (28%) diarrhea was the initial complaint of the disease, suggesting that inflammation of the gut is a consistent and early finding in HHS. Specimens of colonic mucosa were obtained in 5 patients including ours. All of the specimens showed mononuclear infiltrate and reduction of crypts. Ulcerations of the oral cavity were observed in 16 of the 25 patients and represent the most common gastrointestinal findings in HHS (64%). Esophageal dysmotility was also a common complaint reported in 9 of the 25 patients (36%). Despite awareness of gastrointestinal involvement in HHS patients, it has not been appreciated as a main feature and reason for hospitalization. In our experience, the enteropathy does not respond to mesalazine or immunosuppressive drugs. However, painful obstructive episodes because of swelling of the intestinal mucosa can be improved by high-dose corticosteroids unless fibrotic stenosis has been occurred. Ileostomy gave some relief, but further resections because of obstructions were required during the course of the disease. Macroscopic findings of shedding of the mucosal layer and the histopathological findings of only mild mononuclear infiltrates seem to be typical for the enterocolitis in HHS.TABLE 2: Clinical and biochemical features of all patients published and the present 2 patientsThere are few patients with HHS and DC in whom stem cell transplantation was performed showing no relevant improvement of the course (9). In our patients, we decided against stem cell transplantation for several reasons: an immunoablative therapy would have been necessary because T cell function was normal in both patients, thus exacerbation of the gastrointestinal situation was likely to occur; lymphocytes and fibroblasts of patients with HHS have an increased sensitivity to alkylating agents commonly used for conduction therapy leading to major telomere shortening (10); patients with HHS in whom transplantation was performed showed no benefit; and transplantation may only lead to an improvement of the hematological and immunological situations and does not correct for the defect of the gastrointestinal mucosa. Attempts at liver–small bowel transplantation have been performed in cases of multiple intestinal atresia with immunodeficiency (11). Although this approach may relieve some of the gastrointestinal problems, there is no influence on pancytopenia and immunodeficiency, suggesting a lack of feasibility in patients with HHS. Conclusions The clinical course of patients with HHS can be dominated by involvement of the oral, esophageal, and gastrointestinal mucosa and may precede the hematological and immunological problems. Hoyeraal-Hreidarsson syndrome has to be considered in infants and young children with intractable diarrhea and intestinal failure.