Hyperimmunoglobulinemia D with recurrent fever
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2] Synonyms and keywords: HIDS
Overview
Hyperimmunoglobulinemia D with recurrent fever (commonly abbreviated as HIDS) is a periodic fever syndrome originally described in 1984 by the internist Prof. Jos van der Meer, then at Leiden University Medical Centre. No more than 300 cases have been described worldwide.
Historical perspective
- Hyperimmunoglobulinemia D with recurrent fever was first discovered by Prof. Jos van der Meer, a Dutch internist, in 1984 during the workup of 6 patients with recurrent attacks of fever of unknown origin.[1]
- In 1999, MVK gene mutations were first implicated in the pathogenesis of hyperimmunoglobulinemia D with recurrent fever.[2][3]
Classification
- There is no established system for the classification of hyperimmunoglobulinemia D with recurrent fever.
Pathophysiology
- Hyperimmunoglobulinemia D with recurrent fever is a autosomal recessive disorder that occurs due to mutation in MVK gene, encoding for mevalonate kinase enzyme.[2][3]
- Mutation in this gene is associated with reduced activity of mevalonate kinase enzyme engaged in cholesterol and isoprene biosynthesis.[4]
- Isoprenes are used in a variety of cellular functions, and the pathogenic mechanism leading to recurrent inflammatory attacks remains poorly understood.[5]
- Previously it was thought that elevated levels of mevalonate is the cause of presenting symptoms. However, attemps to reduce its level via statin usage led to the exacerbation of attacks.
- Currently, it is hypothesized that lack of other metabolites produced by the absent enzyme mediates inflammation and leads to a caspase-mediated increase in IL‑1β production.
Causes
- Hyperimmunoglobulinemia D with recurrent fever may be caused by mutation in MVK gene.[2][3]
- Mutation in this gene result in reduced activities of mevalonate kinase (MK), a key enzyme of isoprenoid biosynthesis.
Virtually all patients with the syndrome have mutations in the gene for mevalonate kinase, which is part of the HMG-CoA reductase pathway, an important cellular metabolic pathway (Drenth et al 1999, Houten et al 1999). Indeed, similar fever attacks (but normal IgD) have been described in patients with mevalonic aciduria - an inborn error of metabolism now seen as a severe form of HIDS.
Differentiating Hyperimmunoglobulinemia D with recurrent fever from other Diseases
The differential diagnosis includes fever of unknown origin, familial Mediterranean fever (FMF) and familial Hibernian fever (or TNFα reception associated periodic syndrome/TRAPS).
Epidemiology and Demographics
- The exact prevalence of hyperimmunoglobulinemia D with recurrent fever is not known. However, no more than 300 cases have been described worldwide.[4]
- Hyperimmunoglobulinemia D with recurrent fever commonly affects individuals younger than 1 year of age. All the cases will develop this disorder before 5 years of age.[6]
- The majority of hyperimmunoglobulinemia D with recurrent fever cases are reported in western European countries.[7]
- Approximaatley, 60% of the reported cases are Dutch or French.[8]
- This disorder affects men and women equally.
- White ethnicity is affected at a greater extent.
Risk Factors
- There are no established risk factors for hyperimmunoglobulinemia D with recurrent fever. However, attacks may be provoked by factors such as:[9]
- Emotional stress
- Trauma
- Infection
- Vaccinations
Natural History, Complications, and Prognosis
If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3]. Common complications of [disease name] include [complication 1], [complication 2], and [complication 3]. Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.
Diagnosis
Diagnostic Study of Choice
- The diagnosis of hyperimmunoglobulinemia D with recurrent fever is based on clinical features. In 2014, the international registry of autoinflammatory diseases (Eurofever) developed validated, evidence-based criteria for the diagnosis of this disorder. The following table is the suggested criteria:[10]
| Presence | Score |
| Age at onset <2 years | 10 |
| Aphthous stomatitis | 11 |
| Generalised enlargement of lymph nodes or splenomegaly | 8 |
| Painful lymph nodes | 13 |
| Diarrhoea (sometimes/often) | 20 |
| Diarrhoea (always) | 37 |
| Absence | Score |
| Chest pain | 11 |
- The cut-off value for the diagnosis of hyperimmunoglobulinemia D with recurrent fever is score equal or higher than 42 scores.
- The overall sensitivity and specificity of this set of criteria for the diagnosis of hyperimmunoglobulinemia D with recurrent fever is 53% and 89%, respectively.
History and Symptoms
- The hallmark of hyperimmunoglobulinemia D with recurrent fever is a high fever. A positive history of diarrhea, lymph node enlargement, and arthralgia is suggestive of hyperimmunoglobulinemia D with recurrent fever.[11]
- Episodes of fever may take 3 to 7 days and is accompanied by shaking chills.
- The episodes may recur at irregular intervals of 2 to 8 weeks.
Physical Examination
- Patients with hyperimmunoglobulinemia D with recurrent fever usually appear normal. Physical examination of patients with hyperimmunoglobulinemia D with recurrent fever is usually remarkable for high fever (regularly exceeds 40 °C), .[11]
- Other possible findings are:
- Maculopapular rash
- Urticaria
- arthritis
Laboratory Findings
Laboratory features include an acute phase response (elevated CRP and ESR) and markedly elevated IgD (and often IgA), although cases with normal IgD have been described.
Electrocardiogram
There are no ECG findings associated with hyperimmunoglobulinemia D with recurrent fever.
X-ray
There are no x-ray findings associated with hyperimmunoglobulinemia D with recurrent fever.
Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with hyperimmunoglobulinemia D with recurrent fever.
CT scan
There are no CT scan findings associated with hyperimmunoglobulinemia D with recurrent fever.
MRI
There are no MRI findings associated with hyperimmunoglobulinemia D with recurrent fever.
Other Imaging Findings
There are no other imaging findings associated with hyperimmunoglobulinemia D with recurrent fever.
Other Diagnostic Studies
There are no other diagnostic studies associated with hyperimmunoglobulinemia D with recurrent fever.
Treatment
Medical Therapy
There is no treatment for hyperimmunoglobulinemia D with recurrent fever; the mainstay of therapy is supportive care. The recurring fevers are highly unpleasant for patients, but so far only the immunosuppressant drugs etanercept (Enbrel) and anakinra have been shown to be effective. Statin drugs might decrease the level of mevalonate and are presently being investigated.
Surgery
Surgical intervention is not recommended for the management of hyperimmunoglobulinemia D with recurrent fever.
Primary Prevention
There are no established measures for the primary prevention of hyperimmunoglobulinemia D with recurrent fever.
Secondary Prevention
There are no established measures for the secondary prevention of hyperimmunoglobulinemia D with recurrent fever.
References
- ↑ Van Der Meer, JosW.M.; Radl, Jiri; Meyer, ChrisJ.L.M.; Vossen, JaakM.; Van Nieuwkoop, JannyA.; Lobatto, Sacha; Van Furth, Ralph (1984). "HYPERIMMUNOGLOBULINAEMIA D AND PERIODIC FEVER: A NEW SYNDROME". The Lancet. 323 (8386): 1087–1090. doi:10.1016/S0140-6736(84)92505-4. ISSN 0140-6736.
- ↑ 2.0 2.1 2.2 Houten SM, Kuis W, Duran M, de Koning TJ, van Royen-Kerkhof A, Romeijn GJ, Frenkel J, Dorland L, de Barse MM, Huijbers WA, Rijkers GT, Waterham HR, Wanders RJ, Poll-The BT (June 1999). "Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome". Nat. Genet. 22 (2): 175–7. doi:10.1038/9691. PMID 10369261.
- ↑ 3.0 3.1 3.2 Drenth JP, Cuisset L, Grateau G, Vasseur C, van de Velde-Visser SD, de Jong JG, Beckmann JS, van der Meer JW, Delpech M (June 1999). "Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group". Nat. Genet. 22 (2): 178–81. doi:10.1038/9696. PMID 10369262.
- ↑ 4.0 4.1 van der Burgh, Robert; ter Haar, Nienke M.; Boes, Marianne L.; Frenkel, Joost (2013). "Mevalonate kinase deficiency, a metabolic autoinflammatory disease". Clinical Immunology. 147 (3): 197–206. doi:10.1016/j.clim.2012.09.011. ISSN 1521-6616.
- ↑ Mandey, Saskia H. L.; Kuijk, Loes M.; Frenkel, Joost; Waterham, Hans R. (2006). "A role for geranylgeranylation in interleukin-1β secretion". Arthritis & Rheumatism. 54 (11): 3690–3695. doi:10.1002/art.22194. ISSN 0004-3591.
- ↑ Frenkel J, Houten SM, Waterham HR, Wanders RJ, Rijkers GT, Duran M, Kuijpers TW, van Luijk W, Poll-The BT, Kuis W (May 2001). "Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D". Rheumatology (Oxford). 40 (5): 579–84. doi:10.1093/rheumatology/40.5.579. PMID 11371670.
- ↑ Simon A, Mariman EC, van der Meer JW, Drenth JP (February 2003). "A founder effect in the hyperimmunoglobulinemia D and periodic fever syndrome". Am. J. Med. 114 (2): 148–52. PMID 12586237.
- ↑ Drenth, Joost P.H.; van der Meer, Jos W.M. (2001). "Hereditary Periodic Fever". New England Journal of Medicine. 345 (24): 1748–1757. doi:10.1056/NEJMra010200. ISSN 0028-4793.
- ↑ van der Hilst, Jeroen C. H.; Bodar, Evelien J.; Barron, Karyl S.; Frenkel, Joost; Drenth, Joost P. H.; van der Meer, Jos W. M.; Simon, Anna (2008). "Long-Term Follow-Up, Clinical Features, and Quality of Life in a Series of 103 Patients With Hyperimmunoglobulinemia D Syndrome". Medicine. 87 (6): 301–310. doi:10.1097/MD.0b013e318190cfb7. ISSN 0025-7974.
- ↑ Federici, Silvia; Sormani, Maria Pia; Ozen, Seza; Lachmann, Helen J; Amaryan, Gayane; Woo, Patricia; Koné-Paut, Isabelle; Dewarrat, Natacha; Cantarini, Luca; Insalaco, Antonella; Uziel, Yosef; Rigante, Donato; Quartier, Pierre; Demirkaya, Erkan; Herlin, Troels; Meini, Antonella; Fabio, Giovanna; Kallinich, Tilmann; Martino, Silvana; Butbul, Aviel Yonatan; Olivieri, Alma; Kuemmerle-Deschner, Jasmin; Neven, Benedicte; Simon, Anna; Ozdogan, Huri; Touitou, Isabelle; Frenkel, Joost; Hofer, Michael; Martini, Alberto; Ruperto, Nicolino; Gattorno, Marco (2015). "Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers". Annals of the Rheumatic Diseases. 74 (5): 799–805. doi:10.1136/annrheumdis-2014-206580. ISSN 0003-4967.
- ↑ 11.0 11.1 Bader-Meunier, B.; Florkin, B.; Sibilia, J.; Acquaviva, C.; Hachulla, E.; Grateau, G.; Richer, O.; Farber, C. M.; Fischbach, M.; Hentgen, V.; Jego, P.; Laroche, C.; Neven, B.; Lequerre, T.; Mathian, A.; Pellier, I.; Touitou, I.; Rabier, D.; Prieur, A.-M.; Cuisset, L.; Quartier, P. (2011). "Mevalonate Kinase Deficiency: A Survey of 50 Patients". PEDIATRICS. 128 (1): e152–e159. doi:10.1542/peds.2010-3639. ISSN 0031-4005.