1 Dr Sami Ulus Children's Hospital, Departments of Pediatric, Nephrology and Pathology, 2 Gazi University Department of Pathology, 3 Hacettepe University Department of Pediatric Immunology, Ankara, Turkey
Sir,
Hyperimmunoglobulin M syndrome (HIMS) is a rare genetic disorder characterized by recurrent infections in association with markedly decreased serum immunoglobulin (Ig) G, IgA and IgE, but normal or elevated serum IgM levels [1]. It is inherited by an X-linked recessive pattern in approximately 70% of patients, but autosomal recessive, autosomal dominant, and acquired forms of the disease have also been reported. Patients with HIMS have an increased risk of malignancy, IgM-mediated autoimmune disorders, and pyogenic and opportunistic infections [1]. However its association with systemic amyloidosis has not been reported before except our index case (case 1) [2]. We present here a family with HIMS and AA type systemic amyloidosis in order to discuss the pathogenesis of amyloidosis in this family.
Cases.
Our first case [2] was a 12-year-old boy who was admitted to the hospital in 1992 with the complaints of cough, fever, and orbital swelling. He had been suffering from recurrent pulmonary infections since infancy. His parents were healthy, first degree cousins. His five siblings (four females, one male) had died because of various infections between 6 months and 13 years of age. He had also three living siblings: a 1-year-old healthy brother, and two sisters (cases 2 and 3) who were diagnosed with HIMS during family screening (Fig. 1). He had growth retardation, oedema, hepatosplenomegaly, lymphadenopathy, left orbital cellulitis, and crepitant rales on physical examination. Laboratory examinations showed: heavy proteinuria (13.4 g/m2/day), with unremarkable urinary sediment, hypoalbuminaemia, and slightly deteriorated renal functions with creatinine clearance of 85 ml/min/1.73 m2 (Table 1
).
|
|
Case 2 was a 6-year-old girl when she was first screened for HIMS in 1992. She had a history of recurrent infections and growth retardation on physical examination. She had no other remarkable clinical finding with normal urinalysis and biochemical tests. Her immunological analysis showed IgG and IgA absent, IgM elevated. With the diagnosis of HIMS the patient was started on gammaglobulin therapy. However she had been lost to follow-up for the following 4 years and did not receive any therapy. In 1996 she was admitted again with the clinical findings of growth retardation, oedema, hepatosplenomegaly and lymphadenopathy. On laboratory examination she had anaemia, heavy proteinuria, hypoalbuminaemia, and deteriorated renal functions (Table 1). Renal biopsy showed amyloidosis AA. She was started on monthly gammaglobulin therapy and colchicine. Peritoneal dialysis was started. Antibiotics were given when necessary. She was incompliant to therapy again and 10 months later she died because of multiorgan failure. Her autopsy revealed massive amyloid deposition in various organs.
Case 3 was 3 years old in 1992 and she had also been suffering from recurrent infections since infancy. She had growth retardation, and lymphadenopathy on physical examination with normal urinalysis and biochemical tests. She had decreased IgG, and IgA, increased IgM levels. She was also lost to follow-up after initial diagnosis. In 1996 she presented with growth retardation, oedema, and lymphadenopathy. She had 1(+) proteinuria, normal albumin level, and normal renal functions. Percutaneous renal needle biopsy also revealed amyloidosis AA. She was started on monthly gammaglobulin and colchicine therapy. Being incompliant to therapy she developed nephrotic syndrome 10 months later with 4(+) proteinuria and hypoalbuminaemia, but normal BUN and creatinine levels. She died because of infection 9 months after the development of nephrotic syndrome.
After their death DNA samples from case 2 and case 3 were tested for: I-EXON 10: 11 FMF mutations: M6801 (two different mutations), T6811, 1692 del, M694 del, M 694 V, M 694 I, K 695 R, V 726 A, A 744 S, R 761 H; 2-EXON 2: 2 FMF mutations: E 148 Q, E 167 D; 3-EXON 3: P 369 S. All tests for these 14 known FMF mutations at the time of study were found negative.
Comment.
The pattern of inheritance of HIMS in this family seems to be an autosomal recessive form. The most interesting point in the affected members of this family is the early onset of systemic amyloidosis type AA which rapidly progressed to renal insufficiency after the first symptoms had occured. The cause of amyloidosis in this family seemed to be due to chronic infections that the patients had been suffering since their infancies because of their immunodefficiencies. However being the most common cause of childhood amyloidosis in our country, FMF phenotype II could not be excluded in these patients at the time of initial diagnosis [3]. Therefore besides gammaglobulin therapy, colchicine was also given to the patients. Negative tests for 14 known mutations for FMF gene reduced the possibility of this disease as the cause of amyloidogenesis, but a new mutation for FMF that had not been identified yet when the study was performed could not be excluded [4].
AA type amyloid fibrils are derived from the circulating acute phase reactant-serum amyloid A (SAA) by proteolytic cleavage [5]. SAA is synthesized by hepatocytes with the induction of inflammation-induced cytokines such as tumour necrosis factor-alpha, interleukin (IL)-6, and IL-1, and its over production lead to transformation of SAA into AA causing secondary amyloidosis [5]. Both infectious stimulus due to recurrent infections, or inflammatory stimulus due to FMF phenotype II might induce these cytokines leading to secondary amyloidosis in the members of this family.
Human SAA genes are located in chromosome 11-p and only SAA 2 is amyloidogenic [5]. Susceptibility to amyloidosis may be related to an as yet unidentified factor associated with SAA protein proteolysis, because of the extraordinarily low incidence of amyloidosis in individuals with prolonged severe inflammatory disorders in which SAA levels are known to be high for long periods [5]. A higher frequency of gamma-allele, a new alleic variant of human SAA, was shown in the AA amyloid patients than the control population by Baba et al. in 1995 and it was concluded that it might be an important risk factor for the development of AA amyloidosis [6]. Perhaps investigation of this alleic variant in our patients might have been of benefit in clarifying the mechanisms of amyloidogenesis if they had survived. Finally, the amyloidosis in this family might have been a part of an independent genetically determined syndrome.
In conclusion, HIMS associated infections must be the causative factor for amyloidosis in this family. However, a new mutation for FMF gene that has not been identified yet, or a genetically independent syndrome leading to amyloidosis, cannot be, excluded.
Acknowledgments
This report has been presented in the 33rd Annual Meeting of the European Society for Paediatric Nephrology, 25 September 1999, Prague as poster presentation, and in the XXXVI Congress of the European Renal Association European Dialysis and Transplant Association, September 58 1999 in Madrid as oral presentation. We would like to thank Ivona Aksentijevich at NIH, Bethesta, USA for her assistance in genetic studies.
References