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Blood, 1 February 2003, Vol. 101, No. 3, pp. 1205-1205
CORRESPONDENCE
To the editor:
Should patients with FMF undergo BMT?
Recently, Milledge et al1 reported a patient
suffering from both CDA (congenital dyserythropoietic anemia) and
presumptive FMF (familial Mediterranean fever). They observed that the
patient's symptoms of "FMF" rapidly abated after BMT (bone marrow
transplantation) that was required to treat her CDA. This prompted the
authors to conclude that through BMT the missing factor in FMF was provided. I feel that this assertion should be tempered. The fact that the
symptoms have stopped after BMT does not necessary mean that the
allogenic healthy bone marrow complemented the defect responsible for
the clinical expression of the disease. Spontaneous remissions are not
rare in FMF, and it is well known that some environmental factors
(cold, stress, fatigue, infections, etc) precipitate FMF attacks. The gain in quality of life promoted by the curation of the
concomitant CDA could simply account for the improvement of FMF
symptoms. The authors, by suggesting that BMT should be considered as a
last resort in patients extremely unresponsive to other therapies,
could lead clinicians to expeditiously deduce from this single case
that BMT is an alternative cure for FMF. Moreover, from the genetic and clinical data described in this report,
this little girl might suffer from an hereditary inflammatory disorder
other than FMF, for example hyper-IgD syndrome (HIDS) or chronic
infantile neurologic cutaneous and articular syndrome (CINCA), and be
simply a carrier for Met680Ile, the most frequent FMF mutation
in the Egyptian population. Finally, I would like to mention that the
MEFV-encoded protein contains 781 amino acids (not 791, as written in
the introduction) and that the "Asp692Ile" mutation does not exist
and was probably meant as the rare "Ile692del" deletion (mutation analysis).
Isabelle Touitou
Correspondence: Laboratoire de
génétique moléculaire et chromosomique, Hôpital
A de Villeneuve, 34295 Montpellier Cedex 5, France; e-mail:
Isabelle.touitou{at}igh.cnrs.fr
References
1.
Milledge J, Shaw PJ, Mansour A.
Allogeneic bone marrow transplantation: cure for familial Mediterranean fever.
Blood.
2002;100:774-777[Abstract/Free Full Text].
Response:
Bone marrow transplantation for FMF
Dr Touitou raises questions about the diagnosis of FMF in our
patient and the temporal relationship between disappearance of symptoms
and the transplantation. The diagnosis of familial Mediterranean fever (FMF) in our patient was
initially a clinical one, although perhaps her disease might better be
described as familial paroxysmal polyserositis rather
than FMF, as it was the characteristic recurrent serositis rather than
the fever that led to the clinical diagnosis at 14 months of age. Her
clinical presentation was given in brief in the case report, but we are
happy to expand on this here. She presented with recurrent joint
swellings of the elbows and knees, which were asymmetrical.
She showed exquisite sensitivity to colchicine, with rapid response in
her symptoms after 1-2 doses of colchicine and clinically her grunting
respiration and tachypnea (taken as evidence of pleuritic involvement)
also responded rapidly to this therapy. Although she responded to
colchicine, she suffered frequent attacks, and this was not the prime
reason for her undergoing bone marrow transplantation (BMT). She did
have some symptoms and signs that were not typical of FMF. Her diarrhea
was felt to be related to exacerbation of her lactose intolerance with the use of colchicine, and her hepatomegaly was related more to her CDA
than FMF. Dr Touitou raises other possible diagnoses. The
patient being Egyptian rather than northern European without an elevated IgA makes a diagnosis of hyperimmunoglobulinaemia D with
periodic fever syndrome unlikely. Unfortunately we do not have a
pre-BMT specimen on which to check her IgD level, but her urinary
mevalonic acid was not elevated. With regards to the possible diagnosis of chronic infantile neurologic
cutaneous and articular syndrome (CINCA), our patient was lacking 2 of
the cardinal features of the triad, namely a cutaneous rash and chronic
meningitis,1 and so we believe this diagnosis to be
extremely unlikely. There was a close temporal relationship between the start of the BMT
countdown and the disappearance of her elbow swelling, despite her
stopping colchicine. None of her symptoms have recurred and the patient
failed to show any signs of recurrence when she was stressed by
bacterial sepsis at 14 months after BMT, when she was off all
immunosuppressive drugs. We feel confident in our diagnosis of FMF in
this patient and find it implausible that she had a spontaneous
remission of 3 years that coincided with the onset of conditioning for
her BMT. We agree that it is possible that this patient was merely a carrier for
the Met680Ile mutation. There are many examples in human genetics of
clinically or biochemically well-characterized disorders where a
disease-causing mutation is not found in the coding sequence of the
gene associated with that disorder, for instance, in ornithine
transcarbamylase deficiency2 and Rett syndrome.3 The author does point out 2 typographical errors, which should have
been corrected in the galley proofs. The symbol " " was used for
"del." This was lost in a font change and was to converted to
"D," which was then expanded to the 3 amino acid code of "Asp". The MEFV-encoded protein does contain 781 amino acids and not 791.
Peter J. Shaw, John Christodoulou, and Albert Mansour
Correspondence: Peter J. Shaw, Discipline of
Paediatrics and Child Health, University of Sydney
References
1.
Prieur AM.
A recently recognised chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy.
Clinic Experiment Rheumatol.
2001;19:103-106.
2.
Tuchman M, Jaleel N, Morizono H, Sheehy L, Lynch MG.
Mutations and polymorphisms in the human ornithine transcarbamylase gene.
Hum Mutat.
2002;19:93-107[CrossRef][Medline]
[Order article via Infotrieve].
3.
Hoffbuhr K, Devaney JM, LaFleur B, et al.
MeCP2 mutations in children with and without the phenotype of Rett syndrome.
Neurol.
2001;56:1486-1495[Abstract/Free Full Text].
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Related Article in Blood Online:
-
Allogeneic bone marrow transplantation: cure for familial Mediterranean fever
- John Milledge, Peter J. Shaw, Albert Mansour, Sarah Williamson, Bruce Bennetts, Tony Roscioli, Julie Curtin, and John Christodoulou
Blood 2002 100: 774-777.
[Abstract]
[Full Text]
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