hyperimmunoglobulinemia D with periodic fever

Summary

hyperimmunoglobulinemia D with periodic fever (MONDO:0009849) is a disease caused by MVK (GenCC Definitive), with 3 cohort genes and 3 clinical trials. Top therapeutic interventions include canakinumab and givinostat.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: MVK (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 666
• Phenotypes (HPO): 26
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0001954	Recurrent fever	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0002239	Gastrointestinal hemorrhage	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002716	Lymphadenopathy	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003261	Increased circulating IgA level	Very frequent (80-99%)
HP:0003326	Myalgia	Very frequent (80-99%)
HP:0003565	Elevated erythrocyte sedimentation rate	Very frequent (80-99%)
HP:0001025	Urticaria	Frequent (30-79%)
HP:0001369	Arthritis	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002076	Migraine	Frequent (30-79%)
HP:0002633	Vasculitis	Frequent (30-79%)
HP:0011107	Recurrent aphthous stomatitis	Frequent (30-79%)
HP:0200034	Papule	Frequent (30-79%)
HP:0000979	Purpura	Occasional (5-29%)
HP:0001063	Acrocyanosis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0002586	Peritonitis	Occasional (5-29%)
HP:0005214	Intestinal obstruction	Occasional (5-29%)
HP:0010783	Erythema	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperimmunoglobulinemia D with periodic fever
Mondo ID	MONDO:0009849
OMIM	260920
Orphanet	343
DOID	DOID:0081450
UMLS	C0398691
MedGen	140768
GARD	0002788
Is cancer (heuristic)	no

Also known as: HIDS · hyper IgD syndrome · hyper-IgD syndrome · hyperimmunoglobinemia D with recurrent fever · hyperimmunoglobulinemia D syndrome · partial mevalonate kinase deficiency · periodic fever Dutch type

Data availability: 666 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › hyperimmunoglobulinemia D with periodic fever

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, inborn error of immunity, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, TNF receptor 1-associated periodic fever syndrome, epidermodysplasia verruciformis, Vici syndrome, proteosome-associated autoinflammatory syndrome, transcobalamin II deficiency, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, granulomatosis with polyangiitis, autosomal recessive osteopetrosis 7, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, Roifman syndrome, cryopyrin-associated periodic syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

244 likely benign, 202 uncertain significance, 47 conflicting classifications of pathogenicity, 42 pathogenic, 27 likely pathogenic, 11 benign, 10 pathogenic/likely pathogenic, 9 not provided, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071478	NM_000431.4(MVK):c.605dup (p.Val203fs)	MVK	Pathogenic	criteria provided, single submitter
1075609	NC_000012.11:g.(?110032813)(110034402_?)del	MVK	Pathogenic	criteria provided, single submitter
11929	NM_000431.4(MVK):c.1129G>A (p.Val377Ile)	MVK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11930	NM_000431.4(MVK):c.1000G>A (p.Ala334Thr)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
11931	NM_000431.4(MVK):c.59A>C (p.His20Pro)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
11932	NM_000431.4(MVK):c.803T>C (p.Ile268Thr)	MVK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11934	NM_000431.4(MVK):c.928G>A (p.Val310Met)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
11935	NM_000431.4(MVK):c.16_34del (p.Leu6fs)	MVK	Pathogenic	no assertion criteria provided
1460450	NC_000012.11:g.(?110013783)(110013970_?)del	MVK	Pathogenic	criteria provided, single submitter
2024803	NM_000431.4(MVK):c.1090_1091del (p.Gly364fs)	MVK	Pathogenic	criteria provided, single submitter
2090149	NM_000431.4(MVK):c.671T>G (p.Leu224Ter)	MVK	Pathogenic	criteria provided, single submitter
2137420	NM_000431.4(MVK):c.481_482del (p.Cys161fs)	MVK	Pathogenic	criteria provided, single submitter
2142782	NM_000431.4(MVK):c.345dup (p.Tyr116fs)	MVK	Pathogenic	criteria provided, single submitter
2196384	NM_000431.4(MVK):c.790dup (p.Leu264fs)	MVK	Pathogenic	criteria provided, single submitter
234379	NM_000431.4(MVK):c.643C>T (p.Arg215Ter)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
2423080	NC_000012.11:g.(?110032813)(110034382_?)del	MVK	Pathogenic	criteria provided, single submitter
2635502	NM_000431.4(MVK):c.560_561del (p.Lys187fs)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
2921862	NM_000431.4(MVK):c.621_630del (p.Ser208fs)	MVK	Pathogenic	criteria provided, single submitter
2925505	NM_000431.4(MVK):c.1A>C (p.Met1Leu)	MVK	Pathogenic	criteria provided, single submitter
2925507	NM_000431.4(MVK):c.395del (p.Val132fs)	MVK	Pathogenic	criteria provided, single submitter
2931188	NM_000431.4(MVK):c.417del (p.Ala141fs)	MVK	Pathogenic	criteria provided, single submitter
2938110	NM_000431.4(MVK):c.207_208del (p.Leu70fs)	MVK	Pathogenic	criteria provided, single submitter
2943228	NM_000431.4(MVK):c.46_49del (p.Leu16fs)	MVK	Pathogenic	criteria provided, single submitter
2944926	NM_000431.4(MVK):c.661_668dup (p.Leu224fs)	MVK	Pathogenic	criteria provided, single submitter
2947497	NM_000431.4(MVK):c.976G>T (p.Gly326Ter)	MVK	Pathogenic	criteria provided, single submitter
2948422	NM_000431.4(MVK):c.664del (p.Ser222fs)	MVK	Pathogenic	criteria provided, single submitter
2949233	NM_000431.4(MVK):c.712A>T (p.Lys238Ter)	MVK	Pathogenic	criteria provided, single submitter
2952122	NM_000431.4(MVK):c.629G>A (p.Trp210Ter)	MVK	Pathogenic	criteria provided, single submitter
2953001	NM_000431.4(MVK):c.386_422del (p.Leu129fs)	MVK	Pathogenic	criteria provided, single submitter
2953508	NM_000431.4(MVK):c.1063del (p.Ala355fs)	MVK	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MVK	Definitive	Autosomal recessive	hyperimmunoglobulinemia D with periodic fever	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MVK	Orphanet:29	Mevalonic aciduria
MVK	Orphanet:343	Hyperimmunoglobulinemia D with periodic fever
MVK	Orphanet:735	Porokeratosis of Mibelli
MVK	Orphanet:79152	Disseminated superficial actinic porokeratosis
VPS41	Orphanet:95434	Autosomal recessive cerebellar ataxia-movement disorder syndrome
MMAB	Orphanet:79311	Vitamin B12-responsive methylmalonic acidemia type cblB

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MVK	HGNC:7530	ENSG00000110921	Q03426	Mevalonate kinase	gencc,clinvar
VPS41	HGNC:12713	ENSG00000006715	P49754	Vacuolar protein sorting-associated protein 41 homolog	clinvar
MMAB	HGNC:19331	ENSG00000139428	Q96EY8	Corrinoid adenosyltransferase MMAB	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MVK	Mevalonate kinase	Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis.
VPS41	Vacuolar protein sorting-associated protein 41 homolog	Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways.
MMAB	Corrinoid adenosyltransferase MMAB	Converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), a coenzyme for methylmalonyl-CoA mutase, therefore participates in the final step of the vitamin B12 conversion.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	9.2×	0.313
Enzyme (other)	1	4.0×	0.321
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MVK	Kinase	yes	2.7.1.36	GHMP_knse_ATP-bd_CS, GHMP_kinase_N_dom, Mev_gal_kin
VPS41	Transcription factor	no		Clathrin_H-chain/VPS_repeat, Znf_RING, TPR-like_helical_dom_sf
MMAB	Enzyme (other)	yes	2.5.1.17	CblAdoTrfase-like, PduO-typ, CblAdoTrfase-like_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
lower esophagus mucosa	1
metanephros cortex	1
adrenal tissue	1
calcaneal tendon	1
gall bladder	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MVK	271	ubiquitous	marker	lower esophagus mucosa, right lobe of liver, metanephros cortex
VPS41	275	ubiquitous	marker	calcaneal tendon, adrenal tissue, gall bladder
MMAB	235	ubiquitous	marker	right lobe of liver, right adrenal gland cortex, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MVK	3,424
MMAB	1,121
VPS41	1,068

Intra-cohort edges

A	B	Sources
MMAB	MVK	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMAB	Q96EY8	6
MVK	Q03426	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS41	P49754	86.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective MMAB causes MMA, cblB type	1	1903.3×	0.009	MMAB
Cobalamin (Cbl) metabolism	1	423.0×	0.011	MMAB
Cholesterol biosynthesis	1	380.7×	0.011	MVK
SARS-CoV-2 modulates autophagy	1	346.1×	0.011	VPS41
Defects in cobalamin (B12) metabolism	1	271.9×	0.011	MMAB
Lanosterol biosynthesis	1	253.8×	0.011	MVK
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	211.5×	0.011	MMAB
Defects in vitamin and cofactor metabolism	1	200.3×	0.011	MMAB
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	105.7×	0.018	MVK
Activation of gene expression by SREBF (SREBP)	1	86.5×	0.020	MVK
Metabolism of water-soluble vitamins and cofactors	1	60.4×	0.025	MMAB
Metabolism of steroids	1	45.9×	0.028	MVK
Metabolism	2	7.7×	0.028	MVK, MMAB
Metabolism of vitamins and cofactors	1	38.8×	0.031	MMAB
Diseases of metabolism	1	26.8×	0.042	MMAB
Metabolism of lipids	1	10.5×	0.098	MVK
Disease	1	4.4×	0.212	MMAB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
isopentenyl diphosphate biosynthetic process, mevalonate pathway	1	1872.4×	0.005	MVK
isoprenoid biosynthetic process	1	561.7×	0.005	MVK
cobalamin metabolic process	1	510.7×	0.005	MMAB
Golgi vesicle transport	1	510.7×	0.005	VPS41
protein targeting to vacuole	1	432.1×	0.005	VPS41
regulation of SNARE complex assembly	1	432.1×	0.005	VPS41
endosomal vesicle fusion	1	374.5×	0.005	VPS41
late endosome to lysosome transport	1	330.4×	0.005	VPS41
cholesterol biosynthetic process	1	140.4×	0.011	MVK
endosome to lysosome transport	1	112.3×	0.012	VPS41
macroautophagy	1	80.2×	0.016	VPS41
cellular response to starvation	1	64.6×	0.018	VPS41
negative regulation of inflammatory response	1	45.7×	0.023	MVK
vesicle-mediated transport	1	32.1×	0.031	VPS41

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MVK	0	0
VPS41	0	0
MMAB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MMAB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MVK	2.7.1.36	mevalonate kinase
MMAB	2.5.1.17	corrinoid adenosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	MVK, MMAB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	VPS41

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MVK	0	—
VPS41	0	—
MMAB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT06838143	Not specified	RECRUITING	Ilaris NIS in Korea
NCT01568736	Not specified	WITHDRAWN	B7 Coreceptor Molecules in Hyper IgD Syndrome Form of Mevalonate Kinase Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CANAKINUMAB	4	1
GIVINOSTAT	4	1