Hyper-Igd Syndrome

A number sign (#) is used with this entry because of evidence that the hyper-IgD syndrome is caused by homozygous or compound heterozygous mutation in the gene encoding mevalonate kinase (MVK; 251170) on chromosome 12q24.

Mevalonic aciduria (MEVA; 610377), in which some patients exhibit hyper-IgD and periodic fever in addition to other dysmorphic and neurologic features, is also caused by mutation in the MVK gene.

Clinical Features

Van der Meer et al. (1984) described a possibly distinct syndrome on the basis of 6 patients of Dutch ancestry with a long history of recurrent attacks of fever of unknown origin. They found a high serum IgD level and in the bone marrow a large number of plasma cells with cytoplasmic IgD. The serum of only 1 of 8 patients with familial Mediterranean fever (FMF; 249100) showed a raised IgD. Tuberculosis, brucellosis, recurrent cytomegalovirus infection, and persistent Epstein-Barr virus infection were ruled out. No precipitating event was identified; some patients had premonitory headache. High fever was usually preceded by chills and accompanied by headache and swollen glands. The white count was commonly increased to 10,000-20,000 cu mm. Abdominal complaints, except for diarrhea, were minimal and serositis was not identified in any patient. The attacks had no fixed periodicity. In the female patients the attacks bore no relationship to the menstrual cycle. No Jewish, Armenian, Arab, or Mediterranean ancestry was identified for any. Three patients had a positive family history. Cases 1 and 2 were in brother and sister. In case 5 the mother had the same disorder and died of amyloidosis, and 2 of her brothers had periodic fever, 1 of them with amyloidosis for which renal transplantation was performed. Colchicine prevented attacks. The level of IgD was as high as 5300 IU/l in 1 patient and 1383 in a second, normal being less than 150. One patient developed an erysipelas skin lesion, like that of FMF, below the knee. Differences from FMF include the swollen lymph nodes, the lack of serositis, and diarrhea rather than constipation which is more usual during attacks of FMF. The mode of inheritance was obscure. The family with 2 affected generations may have been an example of pseudodominance; were the parents of the proband related? Cases of presumed FMF in persons of seemingly pure Dutch ancestry have been explained by an infusion of genes during the era of Spanish domination of the Netherlands.

Drenth et al. (1994) collected clinical and laboratory data on 50 patients, mainly from Europe. The recurrent febrile attacks usually had an early onset, under 1 year of age. An even male-female distribution was found. Typical attacks occurred every 4 to 8 weeks and lasted 3 to 7 days, with large individual variation. High spiking fever was sometimes preceded by chills. Abdominal pains, vomiting, and diarrhea were associated with the episodes. Headache and arthralgias occurred frequently with attacks. On physical examination during the attacks, swollen, tender lymph nodes, most often in the cervical region, could be palpated. Especially in younger patients, splenomegaly was found. Many patients had nondestructive recurrent arthritis, mainly in larger joints. Laboratory testing during attacks demonstrated an acute-phase response (leukocytosis, neutrophilia, and elevated ESR). Diagnosis was based on the clinical picture and a persistently elevated serum IgD level (more than 100 U/mL). Most patients also had an elevated serum IgA. The occurrence of febrile attacks elicited by various immunizations was a clue to early diagnosis. The attacks tended to diminish with age, although symptoms usually continued throughout life. Amyloidosis was recorded in none of the patients. Twenty patients had a positive family history for periodic fever. Eighteen patients, all sets of sibs, came from 8 families. There were 3 sets of brother-sister sibs. Two patients were sisters. Ten patients were brothers, with 4 brothers in 1 family. Drenth et al. (1994) were not aware of individuals with symptoms suggesting the hyperimmunoglobulinemia D and periodic fever syndrome in the ancestry of their patients. The serum IgD levels in the parents and other relatives of the patients was without exception normal.

Drenth and van der Meer (2001) reviewed the hyper-IgD syndrome and 2 other forms of hereditary periodic fever. They pointed out that hyper-IgD syndrome almost always develops in infancy. If a patient presents with symptoms suggestive of the syndrome, IgD and IgA should be measured. If both are elevated, the diagnosis can be made. For confirmation, they recommended screening for the V377I mutation (251170.0002) in the MVK gene.

D'Osualdo et al. (2005) detected MVK mutations in 15 unrelated Italian patients affected with recurrent fever of unknown origin. There was neither parental consanguinity nor additional affected members in any of the families of the 15 patients. In 11 of the 15 patients, the disorder appeared before the age of 1 year. Cervical lymph node enlargement was a constant feature and was in 3 cases sufficiently striking to change the shape of the patient's face. Severe enlargement of the mesenteric lymph nodes and thickening of the ileal were found in some patients who underwent echo-scan examination during an acute attack. D'Osualdo et al. (2005) reported 2 patients with life-threatening meningococcal sepsis infections. One patient in the series had been previously reported by Obici et al. (2004) with the complication of systemic amyloidosis leading to nephrotic syndrome, which D'Osualdo et al. (2005) noted as representing an overlap with FMF. Amyloidosis in HIDS was also reported by Ostuni et al. (1996).

Balgobind et al. (2005) reported a 5-year-old boy who presented with episodic fever beginning at 9 months of age, usually without an infectious focus and associated with profound apathy, painful cervical lymphadenopathy, and a macular rash on the extremities. Urinary excretion of MVA was extremely high, and mevalonic kinase deficiency (MKD) was confirmed by enzyme activity assay showing activity less than 1% of the control mean. At 3.5 years of age, his parents reported night blindness, and funduscopy revealed attenuated arterioles and retinal pigment epithelium atrophy in the midperiphery, suggestive of retinitis pigmentosa (RP; see 268000). On full-field electroretinography (ERG), rod and cone responses were undetectable, confirming severe and early RP. There was no family history of RP. Balgobind et al. (2005) noted that retinal dystrophy had been reported in other patients with MKD (see MEVA, 610377 and Prietsch et al., 2003), suggesting vulnerability of the retinal photoreceptors.

Siemiatkowska et al. (2013) studied a Dutch brother and sister, originally ascertained for retinitis pigmentosa, who were compound heterozygous for mutations in the MVK gene (see MOLECULAR GENETICS). Clinical reexamination elicited the history in both patients of recurrent childhood fever episodes that ceased to occur in adulthood; both had elevated levels of IgD, and MVK activity was significantly decreased compared to control. The 32-year-old woman also had a history of scoliosis, eczema, and infertility; in her 35-year-old brother, neurologic examination revealed mild but evident ataxia, and he also had long-standing daily diarrhea, profuse sweating without fever, morning stiffness without arthritis or arthralgia, and a history of recurrent pneumonia in the past. The presenting ocular symptom in both sibs was visual field loss, although in retrospect the sister had had night blindness since childhood and the brother from 25 years of age. Visual acuity was well preserved in both, and funduscopy showed optic disc pallor, attenuated vessels, and peripheral degeneration; ERG displayed a rod-cone pattern, and Goldmann visual fields revealed midperipheral loss in the sister and tunnel vision with peripheral islands in the brother. There was trace evidence for a posterior subcapsular cataract in the brother.

Population Genetics

Drenth and van der Meer (2001) stated that the hyper-IgD syndrome registry in Nijmegen, the Netherlands, had clinical data on more than 170 published and unpublished cases of hyper-IgD syndrome worldwide. Most were white and from western European countries; approximately 60% were Dutch or French.

Mapping

Drenth et al. (1999) performed a genomewide search to map the HIDS locus. Haplotype analysis placed the gene at 12q24 between D12S330 and D12S79.

Exclusion Studies

Drenth et al. (1994) did linkage studies in 10 families with 19 members affected by hyper-IgD syndrome and 28 unaffected members. They used highly polymorphic markers surrounding the familial Mediterranean fever locus on 16p to test for a possible allelic relationship. Only negative lod scores were obtained and haplotype analysis excluded the FMF locus as the cause of the hyper-IgD syndrome. Other candidate gene regions on 17q and 14q were also excluded.

Molecular Genetics

Houten et al. (1999) and Drenth et al. (1999) demonstrated mutations in the gene encoding mevalonate kinase in families with hyper-IgD syndrome; see, for example, V377I (251170.0002) and I268T (251170.0004).

Cuisset et al. (2001) studied 25 unrelated patients with HIDS and identified mutations in the MVK gene. The most common mutation was V377I, detected in 20 patients, followed by I268T, detected in 7 patients. Three of the patients illustrated genotypic and phenotypic overlap with mevalonic aciduria, suggesting that factors in addition to specific mutations are important for the resultant phenotype.

Houten et al. (2002) studied the effect of temperature on the activity of wildtype and several mutant MVK proteins in fibroblasts. All fibroblast cell lines from HIDS patients, which harbored the common V377I MVK allele, displayed substantially higher MVK activities at 30 degrees C as compared to 37 degrees C. When HIDS cell lines were cultured at 39 degrees C, MVK activity decreased further. This triggered a compensatory increase in 3-hydroxy-3-methylglutaryl-CoA reductase activity, suggesting that MVK becomes progressively rate-limiting. A similar phenomenon occurred in vivo; MVK activity in peripheral blood mononuclear cells dropped 2- to 8-fold when HIDS patients experienced febrile attacks. The authors hypothesized that minor elevations in temperature can set off a chain of events with MVK becoming progressively rate-limiting, leading to a temporary deficiency of isoprenoid end-products, which induces inflammation and fever.

In a 5-year-old boy with HIDS who also exhibited retinitis pigmentosa, Balgobind et al. (2005) identified compound heterozygosity for a missense mutation (A334T; 251170.0006) and a 1-bp insertion (251170.0017) in the MVK gene.

In a 32-year-old Dutch woman with retinitis pigmentosa and a history of episodic fever in childhood, who was known to be negative for mutation in 111 RP-associated genes, Siemiatkowska et al. (2013) performed exome sequencing and identified compound heterozygosity for the A334T and I268T missense mutations in the MVK gene, which segregated with disease in the family and were not found in 174 Dutch controls. The proband and her affected brother both had elevated IgD levels and severely reduced MVK activity. Analysis of the MVK gene in 769 additional RP patients without a genetic diagnosis revealed a 61-year-old Dutch man who was homozygous for the A334T mutation. He had presented at 56 years of age with loss of visual fields and was diagnosed with late-onset RP; the classic triad of RP features, including bone spicules, attenuated arterioles, and pale optic discs, was seen bilaterally, but with significant asymmetry due to much more prominent retinal degeneration in the left eye. There was also trace evidence of posterior subcapsular cataract, but visual acuity was well preserved. In addition, the patient had ischemic heart disease and renal failure; his IgD level was normal, but MVK activity was only 0.22% of control. Siemiatkowska et al. (2013) noted that all 3 patients had mild systemic symptoms despite markedly reduced activity of MVK, and suggested that differences in genetic background or environmental factors might play a role in disease manifestations.