Hereditary Hemorrhagic Telengiectasia (HHT), an autosomal dominant (AD) disease, causes vascular malformations (telengiectasias), mainly on the skin, mucous membranes, lungs, liver and the brain. This leads to recurrent hemorrhages causing varying degrees of morbidity. The two main subtypes characterized by different genetic abnormalities are HHT-1 and HHT-2, defects of which are found on chromosome 9 (9q33–34) in the gene encoding Endoglin, and chromosome 12 (12q13) in the gene encoding Activin Receptor Like Kinase-1 (ACVRLI) respectively. Both gene products are members of the Transforming Growth Factor-Beta (TGF-×) receptor family, and are involved in regulation of angiogenesis. There is variable degree of penetrance leading to variations in disease phenotype.
A 33 years old man who presented with recurrent epistaxis and joint pains involving the wrist, fingers and ankles was diagnosed initially with Rheumatoid Arthritis (RA) and started on therapy with Prednisone and Hydroxychloroquine. His symptoms quickly resolved except for the epistaxis. A year later, while still on Prednisone, he developed worsening shortness of breath with a declining functional status over a few months. Computed tomography (CT) of the chest revealed extensive areas of abnormality predominantly located in the posterior segments of the lower lobes bilaterally, described as interstitial thickening, honeycombing with traction bronchiectasis suggestive of alveolar fibrosis. A right lower lobe AVM was also seen which was coiled successfully. 6 years later during a workup for an acute decline in respiratory status another AVM was found and coiled in the left upper lobe, while his parenchymal disease remained unchanged. He was continued on Prednisone throughout this time. Genetic testing revealed an Endoglin gene abnormality (HHT-1). Parental testing did not show any genetic abnormality. Attempts at reducing the dose of Prednisone was unsuccessful, resulting in worsening respiratory status, new areas of ground glass opacities on CT imaging and increased oxygen requirement at rest. Spirometry over an 8 year period showed a steady decline with severe restrictive defect although lung parenchyma on CT scan remains stable. During this time, while maintained on Prednisone patient has not had any other organ involvement. He does not have any skin or mucus membrane abnormalities. Based on his current clinical condition requiring 4 liters/ minute nasal canula oxygen flow at rest and progressive decline in lung function patient has been referred for lung transplantation.
There are several interesting aspects of this case. First, the coexistence of HHT and RA has never been reported in the literature. Unfortunately an open lung biopsy was never performed and the abnormalities seen on CT scan are not clearly defined. The initial insult could have resulted from either rheumatoid lung disease or bleeding from AVM’s. Worsening infiltrates while attempting a steroid taper favors the former. Second is the occurrence of HHT in our patient with genetically normal parents. Third is the presence of severe and progressive parenchymal lung disease as the only active manifestation of RA while on systemic therapy.
HHT is an aggressive AD disease, which in spite of its mode of inheritance could lead to a skip generation, mainly due to reduced penetrance. The gene product of this mutation may be linked with other disease processes including connective tissue diseases and cancers.
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