A 2yr, 10mo girl with recurrent fever (temp-106F) every 6-8 wks - started when she was 13 months old. Fever lasts few days and typically does not respond to tylenol/NSAIDs. No rashes, abd pain, diarrhea, or other signs of infx during acute illnesses. No recurrent sinopulm ds. No family history; not of European descent.

Labs taken at baseline: nml cbc with diff; ESR-3; CRP (<0.3); nml C3, C4, CH50; nml IgE,A,M,G (575mg/dl)
Labs during acute illness: wbc increased from 6.6 to 10.1 with 10% bandemia (neuts and lymphos slightly reduced from low normal range). ESR increased to 39 mm/hr and CRP increased to 54.1 mg. All other labs remained normal.

Please help with evaluation and how to proceed with work-up/dx/tx.

Thank you in advance.


Thank you for your inquiry.

Unfortunately, the differential diagnosis of recurrent fever of unknown origin in a toddler is extremely extensive, and it is therefore something we really cannot do justice to on our website. As you are well aware, there are textbook chapters devoted to this issue, and I think that they would be your most fruitful source of help in this regard.

In general, as I am sure you are well aware, the broad differential consists of generalized and localized infections, neoplasms, and auto-inflammatory diseases with periodic fevers. I suppose since you sent the question to our website, you perhaps are most concerned with the periodic fever syndromes (familial Mediterranean fever, TNF receptor-1 associated periodic syndrome, PFAPA syndrome, and hyper IgD syndrome (as well as cryopyrin-associated periodic syndromes, PAPA syndrome, and Blau syndrome). These perhaps would be the ones most commonly considered related to our area of expertise.

These syndromes would be considered after exclusion of infections, malignancy, et cetera.

As mentioned, an extensive review of these areas would not be possible in this venue. However, we do have a previous entry about this topic which includes a response from Dr. Marwan Shinawi. I have copied the full entry below for your convenience. It will give you the source of a laboratory which could help you with the workup of these syndromes. It also gives an excellent reference.

Thank you again for your inquiry and we hope this response is helpful to you.

Autoinflammatory syndromes of hyper-IgD (mevalonate kinase deficiency) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

Is there a standard for making the diagnosis of Hyper IgD (mevalonate kinase deficieny) syndrome)? It is my understanding that a MVK mutation is the gold standard but are a single IgD +IgA elevation >100IU or 2 IgD elevations 4 weeks apart considered diagnostic in the appropriate clinical context?

Also, is the diagnosis of TRAPS only made with a TNFRSF1A mutation or is there a laboratory that measures soluble type I TNF receptor levels? When I've tried to order the test through Labcorp I end up with a TNF-alpha level. I am assuming this is not the same thing? Thank you.

Thank you for your inquiry.

I am not an expert in this area, and therefore I can simply share with you my knowledge regarding these syndromes. However, I will also recruit help from Dr. Marwan Shinawi, who is a recognized expert in this field, and who has written reviews on the subject of hyperinflammatory syndromes.

First of all, the information I am sharing with you, as stated above, is gleaned from the literature, and I will of course accept any correction of this from Dr. Shinawi, but I wanted to get you at least some information to facilitate your approach to what I assume is a patient with whom you are dealing.

You are correct that a mutation analysis is the definitive test for mevalonate kinase deficiency. I am not aware of any "standard" based upon elevated IgD levels or elevated IgD in combination with IgA. However, I can speak more certainly of the IgD levels than the combination of the two because I am not aware of any other autoinflammatory disorder that exhibits elevation of both of these immunoglobulins. Other autoinflammatory conditions have elevated levels of IgD as you can see from the abstract copied below. Therefore an elevated IgD is not sufficient, in my opinion, to establish a diagnosis even when the clinical manifestations are consistent with this disorder. Also some patients with clinically identical manifestations and elevated levels of IgD do not have a mutation of MVK (1, 2).

Again, I am not sure how much specificity the combination of an elevated IgD and IgA adds, but I would think that you would still require either an elevated urine level of mevalonic acid during an episode and/or a mutation analysis to make a diagnosis of this condition.

The second question you asked was regarding TNF receptor levels.

TNF receptor levels in TRAPS are usually down between episodes as well as during episodes. Therefore they are a useful test to establish the diagnosis. You are correct in that a soluble serum TNF receptor level is not the same as analysis of the mutation. Nonetheless, as mentioned, such levels are useful (3).

Thank you again for your inquiry and we hope this response is helpful to you. And if we receive information from Dr Marwani I will send it to you.

1. European Journal of Human Genetics 2005; 13:314-320.
2. Annals of Internal Medicine 2001; 135:358-343.

Medicine 2002; 81:349-368
Rheumatology (Oxford). 2001 May;40(5):579-84.
Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D.
Frenkel J, Houten SM, Waterham HR, Wanders RJ, Rijkers GT, Duran M, Kuijpers TW, van Luijk W, Poll-The BT, Kuis W.
Departments of General Paediatrics, Wilhelmina Children's Hospital, University Medical Centre Utrecht, P.O. Box 85090, 3508AB Utrecht, The Netherlands.
Objectives: The hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was found recently to be caused by a deficiency of mevalonate kinase (MK). The aim of this study was to examine whether a relationship exists between the clinical expression of HIDS and the extent of MK deficiency.
Methods: The medical records of children diagnosed with HIDS were reviewed for clinical features and serum immunoglobulin values. The mevalonic acid excretion in urine and MK enzyme activity in patients' cells were measured and the cDNA of the MVK gene was sequenced.
Results: Fifteen patients with recurrent fever and raised serum immunoglobulin (Ig) D were included. Their clinical features varied. Eleven patients had a deficiency of MK, caused by mutations in the MVK gene. One mutation (V377I) was common to all 11 patients. Nine patients were compound heterozygotes for V377I and various other MVK mutations. There was no apparent relationship between the observed mutations and the clinical features. Surprisingly, four boys had normal MK activity and no MVK mutations.
Conclusions: Most HIDS patients have mutations in the MVK gene. The clinical variability observed cannot be explained by genotypic differences. Periodic fever and elevated IgD can result from other, still unknown, causes. Hence, testing for MK deficiency is necessary in patients with unexplained periodic fever.

Phil Lieberman, M.D.

We received the response from Dr. Shinawi. Thank you again for your inquiry and we hope this response is helpful to you.

Phil Lieberman, M.D.

Response from Dr. Marwan Shinawi:
There are 2 sets of diagnostic criteria of hyperIgD syndrome:

I) diagnostic criteria

• Constant: High IgD level (>100 U/mL) measured on 2 occasions at least 1 month apart

• During attacks
o Elevated erythrocyte sedimentation rate (ESR) and leukocytosis

o Abrupt onset of fever (temperature at least 38.5°C)

o Recurrent attacks

o Elevated immunoglobulin A (IgA) level

o Cervical lymphadenopathy

o Abdominal distress (vomiting, diarrhea, pain)

o Skin manifestations (erythematous macules and papules)

o Arthralgias and/or arthritis

o Splenomegaly

II) Drenth and van der Meer recommended (NEJM 2001) the following diagnostic strategy:

1. Review the clinical and family history.

2. Measure IgD and IgA. IgD should be measured on 2 occasions at least 1 month apart.

3. Measure urinary mevalonic acid. These tests help in detecting only a slight elevation and are generally ineffective.

4. Perform genetic testing to screen for the most common V377I mutation. Sequencing of the gene in highly suspicious cases with negative V377I mutation is a possibility, although the large size of the gene and the nonavailability of this testing in many countries are major obstacles.

5. In rare cases, measure MK activity.

As you can see, the elevation of IgD (with or without IgD) is not diagnostic by itself and other clinical and lab criteria are needed to make the diagnosis.

GenDx is the only lab in the US that offers the molecular testing for hyperIgD syndrome. The same Lab offers the testing for TRAPS. I attached the req. needed for the genetic testing.

If you are interested to read more about the hereditary periodic fever syndromes, please visit Medscape.

Marwan Shinawi, M.D., F.A.C.M.G.
Department of Pediatrics, Division of Genetics and Genomic Medicine
Washington University School of Medicine

Phil Lieberman, M.D.

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