Dyskeratosis congenita (DC), also known as Zinsser–Engman–Cole syndrome, is a rare cause of hereditary aplastic anemia. Here, we report a case of a 31-year-old male who presented with complaints of shortness of breath and recurrent episodes of fever for 4 months. Other features on examination include pallor, nail dystrophy, thinning and loss of nails, hypopigmentation of skin on the back, and leukoplakia on the tongue. On evaluation, peripheral smear revealed pancytopenia with reduced precursors. Bone marrow studies revealed hypocellular bone marrow with no fibrosis. Diagnosis of DC was made based on the clinical triad of nail changes, skin changes, and leukoplakia along with bone marrow findings. The patient was given supportive management and prophylaxis for febrile neutropenia and was advised allogeneic hematopoietic stem-cell transplant in the further course. It is important to diagnose early because there is a high predisposition to solid tumors and hematologic malignancies.
Keywords: Aplastic anemia, dyskeratosis congenita, hereditary, leukoplakia, malignancies, nail dystrophy, pancytopenia
|How to cite this URL:|
Harshika C H, Kumar L S. A rare case report of zinsser–engman–cole syndrome: A hereditary cause of aplastic anemia. APIK J Int Med [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.ajim.in/preprintarticle.asp?id=361012
| Introduction|| |
Aplastic anemia is a rare condition characterized by pancytopenia and hypocellular bone marrow and results from inherited causes such as Fanconi anemia, Shwachman–Diamond syndrome, Diamond–Blackfan anemia, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita (DC), or acquired causes such as drugs, ionizing radiation, toxins, viral infections, or acquired clonal abnormalities such as paroxysmal nocturnal hemoglobinuria. The associated neutropenia and thrombocytopenia might cause serious life-threatening infections and bleeding.
| Case Report|| |
A 31-year-old male with no comorbidities and no addictions presented with shortness of breath and recurrent episodes of fever. Breathlessness was present for 1 month, which increased on exertion. There was no history of cough, orthopnea, paroxysmal nocturnal dyspnea, chest pain, palpitations, and hemoptysis. The patient complained of recurrent episodes of fever on and off for 4 months low grade, intermittent, not associated with chills and rigors, not associated with rash or bleeding manifestations, and was relieved with antipyretics. With the above-said complaints, the patient was admitted to our hospital.
On examination, pallor was present, no signs of icterus, cyanosis, clubbing, pedal edema, or lymphadenopathy.
Dental hygiene was poor and a white patch was noted on the dorsum of the tongue, resembling leukoplakia on examining the oral cavity [Figure 1].
Hypopigmentation was noted around the neck [Figure 2].
Nails showed cracking and the absence of some nails [Figure 3] and [Figure 4].
|Figure 4: Dystrophy of the hand nails with longitudinal ridges and some missing nails|
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Vital data were normal and there was no abnormality noted on systemic examination.
His investigations complete blood picture revealed (CBP): hemoglobin – 6.9 g/dl, red blood cell count – 2.1 million/mm3, white blood cell count – 2800 cells/mm3, and platelets – 1.0 lakh/mm3.
Mean corpuscular volume (MCV) – 110 fl, Mean corpuscular hemoglobin concentration (MCHC) – 34 g/dl, and absolute neutrophil count – 1000 cells.
Peripheral smear examination revealed pancytopenia with a megaloblastic erythropoiesis and a reduction in the number of megakaryocytes. Reticulocyte count was 1.5%, viral markers including Epstein–Barr virus, cytomegalovirus were negative, serum B12 levels were 220 pg/ml, and folate was 4.8 ng/ml, with normal iron profile and lactate dehydrogenase levels. Ultrasonography of the abdomen showed splenomegaly of size 14 cm.
Bone marrow aspirate showed 15% cellularity, hypocellular marrow suggestive of aplastic anemia [Figure 5].
Bone marrow trephine biopsy revealed bony trabeculae with a markedly hypocellular marrow space in with normal marrow elements including megakaryocytes were not observed suggestive of marrow hypoplasia. Reticulin stain was negative.
Flourescence in situ hybridization (FISH) analysis revealed no abnormality.
Histopathological examination (HPE) of tongue lesion revealed hyperkeratosis with flattened rete ridges suggestive of leukoplakia. Connective tissue showed fibrocollagenous tissue with proliferating capillaries and areas of hyalinization and atrophy.
Chest X-ray showed no evidence of pulmonary fibrosis.
The patient was given supportive care and vitamin supplements and was advised allogenic hematopoietic stem-cell transplantation.
| Discussion|| |
DC also known as Zinsser–Engman–Cole syndrome is an inherited disorder characterized by bone marrow failure, cancer predisposition, and somatic features and is caused by mutations that interfere with the normal maintenance of telomeres. Mutations are known to cause DC to encode proteins involved in telomerase activity and trafficking and telomerase stability such as adrenocortical dysplasia gene (ACD), CST Telomere replication Complex component 1 (CTC1), and Regulator of Telomere Elongation helicase 1 (RTEL1) genes.
The prevalence of DC is around 1 in 1 million people in the general population. Around 2% to 5% of patients with bone marrow failure are identified to have DC.
It is usually diagnosed clinically by the triad of mucocutaneous findings:
- Abnormal Lacy reticular skin hyperpigmentation involving upper chest and neck
- Nail dystrophy – Small and thin nail plates with longitudinal ridges
- Oral leukoplakia involves the oral mucosa and tongue.
Other somatic features include epiphora, developmental delay, pulmonary fibrosis, dental caries or severe periodontal disease, cirrhosis of the liver, esophageal strictures, recurrent infections due to immunodeficiency, enteropathy/enterocolitis, hypogonadism, urethral strictures, exudative retinopathy, increased risk of pulmonary fibrosis, liver disease including cirrhosis and hepatopulmonary syndrome, osteoporosis and premature graying of hair, abnormal eyelashes, hearing loss, Arterio-venous malformations (AV) malformations, and vascular ectasias, and neuropsychiatric manifestations including schizophrenia and bipolar disorder. These clinical features help in the early identification of the disease.
Unlike Fanconi's anemia, patients with DC do not have impaired fertility.
Bone marrow failure develops by 40 years of age in nearly half of the cases. Anemia and thrombocytopenia are often the first signs of marrow failure.
There is an increased predisposition to malignancies such as head-and-neck squamous cell carcinomas (most common, seen in around 40% of patients), gastrointestinal tract malignancies, skin malignancies, and hematological malignancies such as myelodysplastic syndromes and acute leukemias (myeloid more common than lymphoid). Other reported malignancies include Hodgkin's lymphoma, lung, pancreas, colon, and cervical cancers.
It is especially important to identify DC because patients may benefit from surveillance for additional manifestations such as malignancies and organ dysfunction, family members with a shared mutation but with less penetrant disease features may also be identified, and siblings who could serve as potential donors for hematopoietic cell transplantation (HCT) must be screened for DC.
Management includes regular screening for various complications and malignancies, screening family members and first-degree relatives, transfusions for cytopenias, pulmonary function tests, hepatic function, eye screening, and mental health.
Anabolic-androgenic steroids (e.g., fluoxymesterone and danazol) may improve blood counts, although this improvement is not permanent and is lost with drug cessation; danazol can be used to improve blood counts if a delay in starting HCT is anticipated for a patient with DC, or if a patient were ineligible to receive HCT.
Allogenic hematopoietic stem-cell transplantation remains the only curative treatment for bone marrow failure. However, HCT does not treat the extrahematopoietic complications of DC and related syndromes. HCT may actually increase the risk of nonhematologic malignancies. Importantly, potential sibling (or other related) donors must be evaluated for DC and demonstrated not to have the familial mutation.
| Conclusion|| |
DC is a rare cause of inherited aplastic anemia.
Early identification of clinical features helps to screen for bone marrow failure and malignancies. Immunosuppressive therapy is not indicated in the inherited causes of aplastic anemia unlike acquired causes.
The overall survival of individuals has been reported at 49 years with significant improvement attributed to better management of organ system involvement and improved outcomes with HCT. The primary cause of mortality in individuals is bone marrow failure and its consequences (e.g., bleeding and infection), or morbidity associated with its treatment using HCT. Solid tumors, pulmonary fibrosis, and hepatic disease account for significant mortality as well.
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.
The authors would like to thank the Department of General Medicine at Gandhi Medical College, Secunderabad, for their constant support and constructive criticism with their diverse knowledge and experience. Without their help, this project would not have been possible.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]