Homozygous V377I mutation causing mevalonate kinase
- 1 Pediatrics Department, Hospital de São Bernardo, Centro Hospitalar de Setúbal, EPE, Setubal, Portugal
- 2 Primary Immunodeficiencies Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, EPE, Setubal, Portugal
- Correspondence to Denise Banganho; denise_banganho@hotmail.com
Abstract
Hyperimmunoglobulinaemia D syndrome (HIDS) is a rare autosomal recessive disorder caused by mutations in the mevalonate kinase (MVK) gene, located on chromosome 12. The most common mutation identified in MVK gene so far is V377I. Compound heterozygotes that include this variant may exhibit a more severe phenotype of the disease and homozygotes are rarely found in clinical practice probably they express a milder phenotype. HIDS is a chronic autoinflammatory disease characterised by recurrent febrile episodes, associated with lymphadenopathies, abdominal pain, rash and arthritis. These flares can be triggered by vaccination, minor trauma, surgery and stress.
We report a case of a 2-year-old girl who had recurrent attacks of fever associated with cervical lymphadenopathy, macular erythematous skin rash, abdominal pain and aphthous ulcers in the mouth. The patient was found to excrete elevated amounts of urinary mevalonic acid and a homozygous V337I mutation in the MVK gene was identified.
Background
Fever is a common symptom in paediatrics and it can be associated with a wide variety of causes, most frequently infectious diseases.1 The presence of fever in an otherwise well-appearing child should raise the suspicion of occult bacteriemia.1 Its frequency in an incompletely immunised child with fever is about 3–11%.1
While most patients who are admitted with the clinical diagnosis of occult bacteriemia have no underlying disease, some patients present features that should raise the suspicion of a previously unidentified diagnosis.1 Recurrent fever, lymphadenopathies and the presence of consanguinity are some of those characteristics.1 2
Autoinflammatory syndromes are a group of disorders that share the common effect of causing the inability to finely regulate the inflammation and include both the classic hereditary recurrent fever syndromes (familial Mediterranean fever (FMF), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and criopirinopathies associated periodic syndrome (CAPS), and also a various number of diseases that interfere with the normal function of the innate immune system.2
Early diagnosis of these conditions is essential for the adequate handling of the affected patients.2
Case presentation
A 2-year-old girl was admitted with high fever (40°C every 4 hours) and bilateral cervical lymphadenopathy. She is the first child of healthy consanguineous parents. She had a normal psychomotor development but her weight was on the fifth percentile. Since the age of 12 months, she had 10 episodes (every 4–8 weeks) of high fever and cervical lymphadenopathy (3×4 cm, elastic lymph nodes in the submandibular region), accompanied in three of these by a macular erythematous skin rash, abdominal pain and oral aphthous ulcers. She did not present splenomegaly, arthralgia/arthritis or other signs or symptoms. These flares usually lasted for 4–7 days, and, despite an extended workup, no aetiology was identified. She was hospitalised eight times with a presumptive diagnosis of occult bacteremia and treated with ceftriaxone. The patient was perfectly asymptomatic and well between the episodes.
Investigations
Episodes were accompanied by marked leukocytosis, neutrophilia and very elevated c-reactive protein and serum amyloid A (table 1). Urine analyses and chest X-ray did not show alterations. Cultural examinations were always negative. No infectious agents were identified.
Workup results during and between flares
| Reference range | During flares | Between flares | |
| Leukocytes | 5–15×109 /L | 25.34 | 14.37 |
| Neutrophils | 1.5 to 8×109 /L | 22.7 | 8.63 |
| C-reactive protein (mg/dL) | <0.3 | 25 | 0.2 |
| Serum amyloid A (mg/L) | <6.4 | 600 | 11.6 |
| Immunoglobulin D (mg/L) | <152 | – | 39.2 |
| Mevalonic acid (umol/mmol crn) | 0.06–0.21 | 15.8 | 0.18 |
All the inflammatory markers normalised between the flares. The immunologic evaluation was normal. Immunoglobulin D was normal, as was mevalonic acid in a spot urine sample outside the crisis. Nevertheless, mevalonic aciduria (MA) during a flare was very high. A next-generation sequencing (NGS) panel for autoinflammatory diseases was performed and identified a homozygous V377l mutation in the mevalonate kinase (MVK) gene, inherited in trans from her heterozygous parents. It has previously been described as causing MKD.3–5
Differential diagnosis
The differential diagnosis is vast, including much more frequent viral infections, which complicates the definitive diagnosis and its correct approach.2
Other autoinflammatory syndromes, such as PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenitis), FMF and TNF TRAPS should be considered.2 4 6
In PFAPA, febrile episodes occur more often and more regularly (every three to 4 weeks) than in hyperimmunoglobulinaemia D syndrome (HIDS) and are frequently accompanied by cervical lymphadenopathy, while in HIDS all lymph nodes may be involved.4 6
FMF is characterised by recurrent attacks of severe pain (especially abdominal pain) and fever lasting from 1 to 3 days, with spontaneous resolution.4 6 Contrary to what is observed in HIDS, colchicine prevents flares in most patients.6
In TRAPS, fever attacks usually last longer than in HIDS, sometimes up to 2 weeks.6 Besides, flares can be associated with conjunctivitis, periorbital oedema and myalgias.6
Treatment
After the clinical suspicion of an autoinflammatory syndrome, she received 1 mg/kg of prednisolone in the two subsequent episodes with immediate resolution of the episode.
Outcome and follow-up
She is now 3.5 years old and her flares have been less frequent (every 10–12 weeks) and respond to a single dose of prednisolone, so she has not required IL-1 blockade.
Discussion
Autoinflammatory diseases arise through inappropriate antigen-independent hyperactivation of the immune system that plays a central role in a wide variety of diseases in which inflammation contributes to tissue injury.2
Therefore, they represent primary diseases of innate immunity, even though lymphocytes, cells typically associated with adaptive immunity, may also contribute to autoinflammation.2
The vast majority of these diseases are rare and unlikely to be encountered in routine clinical practice, so they should be suspected when a patient presents unexplained repeated episodes of inflammation.2
Inflammasomes play an important role in autoinflammatory diseases.2 They are large intracellular protein complexes responsible for cleaving inactive pro-interleukin (IL) 1-beta into its highly inflammatory mature form.2 Abnormal triggering of inflammasomes leads to hyperactivation of IL-1-beta, a strong endogeneous pyrogen, resulting in inflammation with fever.2
HIDS is also known as MKD, a rare autosomal recessive condition caused by mutations in the MVK gene on chromosome 12, leading to a deficient activity of the MVK enzyme.3–5 The spectrum of severity of the disease is wide, depending on the MVK enzyme activity.3 4 7 When its activity is below detection levels, it usually leads to the extremely rare and most severe phenotype, known as MA, a multisystemic disease characterised by psychomotor retardation, microcephaly, hypotonia, dysmorphic features, failure to thrive, hepatosplenomegaly, anaemia and recurrent febrile episodes.3–5 7 On the other hand, in HIDS, a residual MVK activity varying between 1% and 7% can be quantified, expressing a more benign disorder. In these cases, patients suffer from repeated fever episodes that can be accompanied by other symptoms such as lymphadenopathy, arthralgia, abdominal pain or skin rash.3–5 Some triggers have been identified, that is, vaccination, minor trauma, surgery and stress.4 Complications include macrophage activation syndrome and AA-amyloidosis.4 7
Most patients with HIDS present the V377I mutation and another missense mutation in the MVK gene.3–5 On the other hand, MA patients do not carry this mutation, strongly suggesting that the V377I mutation does not abolish the MVK activity.3 In fact, homozygous V377I patients have higher residual MVK activity than patients who are compound heterozygotes and might exhibit a milder phenotype of MVK deficiency or no disease-phenotype at all, depending on their ethnicity and genetic background.3 5 Interestingly, V377I has also been related to early-onset inflammatory bowel disease.8
Elevated serum levels of immunoglobulin D and immunoglobulin A are frequently noted and they usually remain so in asymptomatic periods, but they are not observed in all of the patients with HIDS, specially in younger children, and are not necessary for the diagnosis.4 Moreover, urine mevalonic acid levels are elevated during febrile episodes.6 However, the definitive diagnosis is established by identification of MVK mutation in a patient with clinical suspicion of HIDS.3–5 The inability to identify gene mutations does not exclude the diagnosis, since it cannot be found in 25% of the patients with HIDS.6
The generalisation of NGS techniques has led to a broadening of the knowledge of congenital defects in immunity, with dozens of new autoinflammatory diseases being described in the last 5 years.2 These diseases can have enormous clinical heterogeneity, but many present recurrent fever.2 The vast majority of these diseases are caused by heterozygous mutations that lead to the gain of function of components of the inflammasome, so clinical suspicion is fundamental for the diagnosis.2
Timely diagnosis allows proper therapeutic interventions. The most effective option for HIDS treatment is focused on IL-1 blocking with canakinumab, mainly used in patients with frequent disease flares.7 Ultimately, allogeneic haematopoietic stem cell transplantation is reserved for MA and severe HIDS resistant to IL-blockade.7
Undoubtedly, HIDS can have a negative effect on patient’s quality of life. It is essential to suspect of this disease for patients with history of recurrent fever of unknown origin. In this case, previous knowledge of parent’s consanguinity facilitated the presumptive diagnosis of an autosomal recessive disease, allowing for a correct follow-up and appropriate family counselling.
Learning points
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Hyperimmunoglobulinaemia D syndrome (HIDS) should be considered in the differential diagnosis of children presenting recurrent episodes of fever of unknown origin.
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HIDS has a wide spectrum of manifestations depending on mevalonate kinase enzyme activity.
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Homozygotes for V377I mutation may not express the gold standard phenotype of HIDS and be lost for correct and early diagnosis.
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Timely diagnosis is essential for the early establishment of therapeutics, a better prognosis, as well as for improving the patient’s quality of life.
Ethics statements
Patient consent for publication
Footnotes
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Contributors TB and DB: data acquisition and interpretation; writing and approval of the manuscript; CP and JFN: revision and approval of the manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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