Quiz Page November 2008: A Family History of Kidney Failure and Hearing Loss

What disorder is shown in the native kidney specimen obtained at autopsy? 

Congo Red staining of the native kidney shows amyloid in glomeruli, vessels, and interstitium (Fig 2A), and birefringence under polarized light (Fig 2B) confirms renal amyloidosis. Autopsy also showed an acute myocardial infarction, no cerebrovascular bleeding, no gastrointestinal abnormalities, and generalized AA amyloidosis, especially in vessels and native kidneys. The kidney allograft was normal.

In retrospect, our patient appears to have had amyloidosis for a long time. Gastrointestinal manifestations of amyloidosis include bleeding caused by vascular fragility and loss of vasomotor responses to injury. In addition, gastroparesis, constipation, bacterial overgrowth, malabsorption, and pseudo-obstruction resulting from dysmotility occur. Amyloid deposition in the vessels explains the progressive kidney function impairment without nephrotic syndrome, coronary artery disease resulting in myocardial infarction, and likely cerebrovascular disease.

The kidney biopsy specimen of the younger brother also showed amyloidosis. The occurrence of massive bleeding after the biopsy could have been related to amyloidosis.

What is the most probable diagnosis? 

The observations are consistent with Muckle Wells syndrome (MWS), a rare autosomal dominant autoinflammatory disorder characterized by intermittent episodes of fever, urticarial rash, joint pain, progressive sensorineural deafness, and frequent development of AA-type amyloidosis of the kidneys and other organs.1, 2 Most patients present to rheumatologists, immunologists, or pediatricians, with renal manifestations occurring later.1, 2

MWS arises from a missense mutation in the gene NLRP3 (also referred to as CIAS1, NALP3, and PYPAF1) on chromosome 1, encoding a protein called cryopyrin. Cryopyrin is involved in apoptotic and inflammatory pathways through its upregulation of interleukin 1β (IL-1β).3 IL-1 increases the synthesis of serum amyloid A protein by hepatocytes during the acute-phase response. A persistently high serum amyloid A concentration is a prerequisite for the development of AA amyloidosis.4 Mutations in the NLRP3 gene are associated not only with MWS, but also with a spectrum of other autoinflammatory diseases. The clinical features of the various syndromes associated with mutations in this gene overlap to a great extent within and between families.3, 5

How can we confirm the diagnosis? 

DNA analysis of the NLRP3 gene from material from both our patient and her older brother showed a c.1241G→T mutation in exon 3 (numbering based on the A of the ATG translation initiation codon being position +1 [corresponding to nucleotide 753 of NM_004895.3]), causing an amino acid change from tryptophan to leucine at codon 414. This confirmed the diagnosis of MWS.

Is treatment possible and indicated? 

Anakinra is a recombinant nonglycosylated homolog of human IL-1 receptor. It competitively inhibits binding of IL-1α and IL-1β to IL-1 receptor type 1. Successful responses to anakinra in patients with MWS have included recovery of hearing; decrease in CRP levels; disappearance of urticaria, arthralgias, and fever; and amelioration of nephrotic syndrome.6, 7, 8