Macroglossia – Not Always AL Amyloidosis

Amyloidosis is characterized by extracellular deposition of abnormal insoluble fibrillar proteins. The two most frequent systemic amyloidoses are the light-chain (AL amyloidosis) and familial transthyretin (ATTR) forms. Clinical presentations often vary between the two types. Macroglossia is viewed as pathognomic of AL amyloidosis, and has not previously been described in patients with hereditary TTR amyloidosis. Here, we describe two cases of systemic amyloidosis with macroglossia in which immuno-electron microscopy diagnosed ATTR in one and AL in the other.

A 61 year old woman presented initially to her general internist with weight loss, difficulty swallowing, and tongue numbness. Her clinical exam revealed macroglossia and peripheral neuropathy. Tongue and axillary lymph node biopsies demonstrated amyloid deposits by Congo red staining. There was no evidence of renal, cardiac or other vital organ involvement. She had no evidence of a plasma cell dyscrasia with negative serum and urine immunofixation electrophoresis, normal serum free light chain concentration and ratio as well as polytypic plasma cells in the bone marrow. Immuno-electron microscopy using gold-labeled antibodies was performed on the tongue biopsy. The fibrils were immunoreactive with anti-TTR but not anti-kappa, anti-lambda, or anti-AA antibodies. DNA sequencing identified a known amyloidogenic T60A TTR mutation in exon 3 of chromosome 18, confirming the diagnosis of ATTR with amyloidotic polyneuropathy and macroglossia. The second case involved a 59 year old man with renal insufficiency. He complained of fatigue, weight loss, and tongue swelling. Physical examination was significant for macroglossia and submandibular gland enlargement. Tongue biopsy demonstrated amyloid deposits by Congo red staining. As in the previous case, markers of plasma cell dyscrasia with clonal plasma cells in the bone marrow, blood, and urine were absent. Immuno-electron microscopy of the tongue biopsy documented antibody reactivity to lambda light chain and not TTR, kappa light chain or AA proteins, confirming the diagnosis of AL amyloidosis. He subsequently underwent treatment with high dose intravenous melphalan followed by stem cell transplantation achieving a good clinical response sustained for 2 years to date.

While macroglossia is thought to be pathognomonic of AL amyloidosis, we report a case of macroglossia with fibrillar ATTR amyloid deposits diagnosed by immuno-electron microscopy. This is contrasted with a clinical presentation consistent with AL in which routine laboratory testing failed to identify evidence of a plasma cell dyscrasia. In both cases, electron microscopy demonstrated immunoreactivity for the fibrils of a single pathogenic protein. The first case was confirmed by DNA sequencing, and the second had a typical response to anti-plasma cell chemotherapy, in spite of the lack of identifiable markers of disease.

No relevant conflicts of interest to declare.