Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 56, Num. 4, 2010, pp. 293-296

Journal of Postgraduate Medicine, Vol. 56, No. 4, October-December, 2010, pp. 293-296

Clinico-Pathological Correlation

Fatal hemoptysis in a child with ataxia-telangiectasia: Zeroing down on the rare cause

Y Gabhale¹, P Vaideeswar², SB Bavdekar¹

¹ Department of Pediatrics, Cardiovascular & Thoracic Division, Seth GS Medical College, Mumbai, India
² Department of Pathology, Cardiovascular & Thoracic Division, Seth GS Medical College, Mumbai, India

Correspondence Address: P Vaideeswar, Department of Pathology, Cardiovascular & Thoracic Division, Seth GS Medical College, Mumbai, India, shreeprajai@yahoo.co.in

Date of Submission: 25-Jun-2010
Date of Decision: 14-Aug-2010
Date of Acceptance: 25-Aug-2010

Code Number: jp10086

PMID: 20935403

DOI: 10.4103/0022-3859.70946

An 11-year-old girl born of non-consanguineous marriage was brought with a 4-day history of fever, cough, and progressive shortness of breath. The fever was high-grade and continuous, not responding to medications. The cough was associated with scanty whitish expectoration without any hemoptysis. The child had a significant past history of repeated monthly episodes of cold and fever since the age of 5 years, associated with progressive difficulty in walking due to swaying. Her handwriting had also deteriorated over the past 2 years. Her elder sister had similar complaints from the age of 8 years and she was bed-ridden at the age of 14 years. Pulmonary cavitatory lesions and consolidation had been noted on high-resolution computed tomographic scan (HRCT) 6 months back. Considering these lesions and her history of repeated episodes of respiratory infection, she was started on four-drug anti-tuberculosis therapy (ATT) at another institution, which was continued till her present illness. The child, however, had not shown any improvement in her symptomatology, despite the ATT.

On examination, the child had stable vitals (normal sensorium, pulse rate of 108/min, blood pressure of 108/58 mm Hg and respiratory rate of 30/min). She was stunted [height 110 cm, below fifth percentile as per National Center for Health Statistics (NCHS) height-for-age charts], weighing only 13 kg (below fifth percentile as per NCHS weight-for-age charts). She was pale, and telangiectatic vessels were seen in the sclerae. Respiratory examination revealed bilateral basal crepitations. Examination of the central nervous system was remarkable for hypotonia and abnormal cerebellar signs in the form of scanning speech, past pointing, dysdiadochokinesia and swaying while walking. She had a firm, non-tender liver and spleen, palpable 5 cm below the right costal margin and 3 cm below the left costal margin, respectively. The provisional clinical diagnosis was bronchopneumonia and anemia in a patient diagnosed to have pulmonary tuberculosis and a hereditary chronic progressive ataxia with bilateral telangiectasia, most probably ataxia-telangiectasia (A-T).

Initial investigations revealed the presence of anemia (Hb concentration: 6 g%) and leukocytosis (WBC count: 15,100/mm ³ with 78% neutrophils). Routine biochemical investigations performed included random blood glucose, blood urea nitrogen, bilirubin, transaminases, electrolytes and calcium and were found within the normal range. Ultrasonography of the abdomen showed multiple portal and para-aortic lymph nodes, the largest being 18 mm in diameter. The sputum was negative for acid fast bacilli (AFB) and blood culture did not grow any organisms. The chest radiograph showed right lower zone consolidation.

The patient was admitted and initial therapy was given with oxygen, complete bed rest, intravenous fluids and intravenous ceftriaxone. The child′s ATT was continued. Over the next 4 days, the child′s respiratory distress decreased but she continued to have fever and persistent crepitations. Hence, the anti-microbial therapy was stepped up by adding vancomycin and then piperacillin-tazobactam. She also received packed cell transfusion for her anemia. Investigations revealed normal prothrombin time (patient: 13 seconds, control: 11.5 seconds), absence of AFB in a repeat sputum sample and normal urinalysis.

Considering the suboptimal response to therapy and presence of para-aortic lymphadenopathy, investigations such as immunoglobulin levels, alpha-fetoprotein and carcinoembryonic antigen, HIV test, HRCT chest, sputum fungal culture, CT-guided lymph node biopsy and bone marrow aspiration were planned to rule out immunodeficiency with concurrent malignancy. The latter was specifically considered in view of higher propensity for patients with A-T to develop lymphoreticular malignancy. However, the parents refused additional investigations as they were aware of the progressive nature of the disease; the diagnosis of A-T was based on the clinical evaluation. On 14th day of hospitalization, she had a sudden bout of massive hemoptysis and could not be revived.

Discussion-Clinical

If we look back, this 11-year-old female child had clinical features of A-T and presented with episodes of fever, cough, and breathlessness. There was no response to ATT which was started on the initial presumptive diagnosis of tuberculosis. She had cavitatory lesions and mediastinal lymphadenopathy on CT, with hepatosplenomegaly. She died suddenly of severe bout of hemoptysis as the terminal event. The common causes of hemoptysis in children are depicted in [Table - 1]. [Table - 2] and [Table - 3] enlist the common causes of cavitatory lesions and prolonged fever, the two important features in the patient. If we consider common causes listed in the aforementioned tables, the pros and cons for the differential diagnoses summarized in [Table - 4] emerge. It may be worth mentioning that in patients with A-T, telangiectasia may also involve pulmonary vessels and this can lead to hemoptysis. ^[1]

Autopsy Findings

Complete autopsy was performed on averagely built and poorly nourished child. There was pallor and absence of superficial lymphadenopathy. Significant findings were seen in the central nervous, hemolymphatic, cardiovascular, and respiratory systems. The brain weighed 1060 g with small-sized cerebellum. There were degenerative and ischemic changes in Purkinje cells as well as molecular layer neurons. There were enlarged and matted mediastinal, perihilar, para-aortic, periportal and mesenteric lymph nodes, the largest being 3 Χ 2.5 Χ 1.5 cm and the smallest being 1 Χ 1 Χ 0.8 cm. The cut surfaces were grayish white, homogeneous with small foci of necroses. All showed similar histomorphology. The nodal capsules were mildly to moderately fibrotic. The nodal architecture [Figure - 1] was totally effaced and replaced by reticulin-rich fibrous tissue, in which lymphocytes and markedly atypical lymphoid cells were embedded [Figure - 2]. Many of the atypical cells had multiple nuclei with prominent nucleoli; few had the appearance of Reed-Sternberg cells. In many lymph nodes, the cells had infiltrated the capsule with extension into the surrounding soft tissue. A diagnosis of Hodgkin′s lymphoma (lymphocyte depletion type) was made. There was diffuse infiltration of the both layers of the pericardium; heart was normal.

The cavitatory lesion [Figure - 3], seen on radiological investigations, was entirely extrapulmonary in location and measured 5 cm in diameter. The walls were formed by the viable portion of the necrotic tumorous subcarinal lymph nodes and roof of the left atrium. Interestingly, the neoplastic proliferation had completely eroded the carina and the proximal portions of both main bronchi. Thus, there was a tracheomediastinal fistula, the air being confined by the tumor and tumor-induced fibrosis. In addition, the tumor had formed gray-white cuffs around both extrapulmonary and intrapulmonary airways and vessels, with formation of intrapulmonary and pleural nodules [Figure - 4] and [Figure - 5]. The massive and fatal hemoptysis could have resulted from bronchoarterial fistulization at the right hilum since there was extensive destruction of the right pulmonary artery [Figure - 6].

Discussion - Autopsy

This case highlights the varied manifestations and sequelae of A-T, which is a prototype of heredoataxias. The heredoataxias represent a group of genetic disorders that have predominant cerebellar involvement and may be autosomal dominant, autosomal recessive, X-linked, and maternally inherited. ^[2] A-T, inherited as an autosomal recessive disorder with full penetrance, is caused by a defect in the ataxia-telangiectasia-mutated (ATM) gene in chromosome 11q22-23, which is responsible for loss or inactivation of ATM kinase, an enzyme participating in the cellular response to DNA damage and cell cycle control. ^[3] Predictably, the disorder commences with neurological symptomatology, characterized by ataxic gait and truncal movements. ^[4] This is then generally followed by telangiectasia or dilatation of blood vessels, mainly of the ocular sclerae. ^[4] Additionally, the A-T patients are prone to repeated infections, especially involving the upper and lower respiratory tract due to variable degree of primary immunodeficiency, affecting cellular and humoral immunity. ^[5] This classical sequence of clinical progression was well documented in our patient. It is worth mentioning that neurological deterioration results not only from cerebellar involvement but also from changes that occur in the cerebrum, basal ganglia, brain stem, spinal cord and spinal ganglia in due course of time, ^[6] leaving the individual wheel-chair bound or bedridden as seen in the elder sister of the reported case.

Approximately one-third of A-T patients develop cancer during their lifetime, which after respiratory infections, forms the second most common cause of death. ^[7] These patients most commonly develop lymphoreticular neoplasia, though some also develop non-hematological cancers involving breast, lung, head and neck, gonads and stomach. ^[8] To add further insult to injury, the cancers often pursue an aggressive course, and these patients are unduly sensitive to ionizing radiation and radiomimetic chemicals. ^[9] Our patient developed Hodgkin′s lymphoma, which affected lymph nodes on either side of the diaphragm. Hodgkin′s lymphoma forms about 10% of cancers in A-T patients, and its aggressive course in such patients ^[10] was evident in its endobronchial spread and formation of intrapulmonary and pleural nodules with arteriovenous involvement. Even rarer was the total destruction of the carinal wall with formation of tracheomediastinal fistula. ^[11] Rarest of all was the terminal massive hemoptysis due to tumor-induced bronchoarterial fistulization, a phenomenon, which to the best of our knowledge, was not reported before.

This case of AT had typical manifestations of recurrent sino-pulmonary infections and progressive cerebellar dysfunction. The lymphadenopathy, hepatospelnomegaly and prolonged fever are attributed to tuberculosis, which is a common infection in India. However, non-response to ATT should have prompted search for an alternative diagnosis. As is well-known, Hodgkin′s lymphoma can have a prolonged course and is one of the malignancies commonly associated with AT. Had autopsy not been done, terminal hemoptysis could have been wrongly ascribed to tuberculosis.

References

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