Hyperimmunoglobulinemia D Syndrome

Background

This disease, also known as HIDS, is a rare disroder associated with periodic fever of 3-7 days duration. There may be associated abdominal pain, arthralgia, and lymphadenopathy. There may be a skin rash characterized by small erythematous macules, papules, urticaria, and nodules occurring on the extremities.

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS HIDS

GEOGRAPHY
Dutch, French, or other European

DISEASE ASSOCIATIONS CHARACTERIZATION

Sweet's like or cellulitis-like rash

Henoch-Schonlein purpura

Erythema elevatum diutinum

PATHOGENESIS CHARACTERIZATION

Autosomal recessive

MVK gene (12q24) Nat Genet 1999;22:178-181
Codes for mevalonate kinase

LABORATORY/RADIOLOGIC/OTHER TESTS CHARACTERIZATION

Elevated serum IgD Elevated in 95% of cases

CLINICAL VARIANTS CHARACTERIZATION

GENERAL

Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group.

Drenth JP, Haagsma CJ, van der Meer JW.

Department of Medicine, University Hospital St Radboud, Nijmegen, The Netherlands.

Medicine (Baltimore) 1994 May;73(3):133-44 Abstract quote
We studied 50 patients (28 male and 22 female) with the hyper-IgD and periodic fever syndrome. Most patients originated from Europe, namely The Netherlands (28 cases; 56%), France (10 cases, 20%), and Italy (3 cases, 6%), but 1 patient was from Japan. A hereditary component is suggested by 18 patients coming from 8 families.

The syndrome is typified by a very early age at onset (median, 0.5 years) and life-long persistence of periodic fever. Characteristically, attacks occur every 4-8 weeks and continue for 3-7 days, but the individual variation is large. Attacks feature high spiking fever, preceded by chills in 76% of patients. Lymphadenopathy is commonly present (94% of patients). During attacks, 72% of patients complained of abdominal pains, 56% of vomiting, 82% of diarrhea, and 52% of headache. Joint involvement is common in the hyper-IgD syndrome with poly-arthralgia in 80% and a non-destructive arthritis, mainly of the large joints (knee and ankle), in 68% of patients.

Eighty-two percent of patients reported skin lesions with some attacks; these demonstrated vasculitis histologically. Serositis has been seen in only 3 patients (6%), while amyloidosis has not been recorded in any of the patients with this syndrome. Immunizations precipitated attacks in 54% of patients.

All patients had a persistently elevated serum IgD level (> 100 U/mL), and in 82% of cases the serum IgA was likewise elevated. During attacks there is an acute-phase response adjudged by leukocytosis, neutrophilia, and increased ESR.

The etiology remains to be elucidated, and treatment is supportive. The hyper-IgD syndrome is distinct from other periodic fever syndromes like systemic-onset juvenile rheumatoid arthritis, adult-onset Still disease, and familial Mediterranean fever.

ATYPICAL

Atypical hypergammaglobulinaemia D syndrome with amyloidosis: an overlap with familial Mediterranean fever?

Ostuni P, Vertolli U, Marson P.

Division of Rheumatology, University of Padova, Italy.
Clin Rheumatol 1996 Nov;15(6):610-2 Abstract quote
A case of hypergammaglobulinaemia D and periodic fever syndrome, developing an amyloidosis-related nephrotic syndrome, is reported.

Since such a complication represents a typical feature of another disease characterized by recurrent febrile attacks, i.e., familial Mediterranean fever, an overlap syndrome between these two rare clinical disorders can be suggested.

RETINA

Hyperimmunoglobulinemia D in idiopathic retinal vasculitis.

Kumano Y, Nagato T, Kurihara K, Kikukawa H, Goto M, Kawano Y, Ohnishi Y, Inomata H.

Department of Ophthalmology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Graefes Arch Clin Exp Ophthalmol 1997 Jun;235(6):372-8 Abstract quote
BACKGROUND: We examined four patients who exhibited both idiopathic retinal vasculitis and elevated serum IgD levels. Uveitis caused by Behcet's disease is also associated with high levels of serum IgD. Therefore, the clinical features of these patients were investigated and the possible relationship between retinal vasculitis and elevated serum IgD was examined after undertaking a study of increased IgD levels in patients diagnosed with uveitis.

METHODS: The study population was composed of 110 patients: 49 with Behcet's disease, 15 with sarcoidosis, 10 with Vogt-Koyanagi-Harada disease, and 36 with other forms of uveitis. IgD measurements were performed using modifications of the latex photometric immunoassay. Surface IgD (sIgD) expression in peripheral lymphocytes was determined by immunofluorescence, and the correlation between serum IgD levels and the percentage of sIgD-positive cells was examined.

RESULTS: Twelve of the 110 patients had an elevated serum IgD. Eight of the 12 had Behcet's disease, and 4 were diagnosed with idiopathic retinal vasculitis. These 4 patients were HLA-A24+ females whose ages ranged from 8 to 25 years. A linear correlation between the serum IgD levels and the percentage of sIgD-positive cells was found.

CONCLUSION: Hyperimmunoglobulinemia D state was found in Behcet's disease and idiopathic retinal vasculitis. These diseases may represent a new clinical entity characterized by signs of retinal vasculitis and hyperimmunoglobulinemia D that results from abnormal B cell activation and immune complex-mediated responses.

SKIN

Cutaneous manifestations and histologic findings in the hyperimmunoglobulinemia D syndrome. International Hyper IgD Study Group.

Drenth JP, Boom BW, Toonstra J, Van der Meer JW.

Department of Medicine, University Hospital St Radboud, Nijmegen, The Netherlands.

Arch Dermatol 1994 Jan;130(1):59-65 Abstract quote
BACKGROUND AND DESIGN: The hyperimmunoglobulinemia D (hyper-IgD) syndrome is characterized by recurrent febrile attacks with abdominal distress, headache, and arthralgias. Physical examination reveals cervical lymphadenopathy in most cases and, sometimes, splenomegaly. Skin lesions have been observed in isolated cases during attacks. We summarize the features of skin lesions and the histopathologic findings in biopsy specimens in the hyper-IgD syndrome.

RESULTS: A total of 44 patients with the hyper-IgD syndrome were studied. Thirty-five (79%) of them, 19 males and 16 females, had skin lesions during febrile attacks. Erythematous macules were the most common cutaneous manifestation (15 cases), followed by erythematous papules (12 cases); urticarial lesions (nine cases) and erythematous nodules (seven cases). Skin biopsy specimens of 10 patients with the hyper-IgD syndrome were available for review. The findings varied considerably. Most biopsy specimens showed mild features of vasculitis. Nonspecific findings were noted in five biopsy specimens; Sweet-like features in two, cellulitis-like findings in one, and deep vasculitis characteristics in one.

CONCLUSIONS: Skin lesions are common in the hyper-IgD syndrome suggesting that they are a true manifestation of the disease.

HISTOLOGICAL TYPES CHARACTERIZATION

General Diffuse neutrophilic dermatosis

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

FAMILIAL MEDITERRANEAN FEVER

Familial Mediterranean fever and hyperimmunoglobulinemia D syndrome: two diseases with distinct clinical, serologic, and genetic features.

Livneh A, Drenth JP, Klasen IS, Langevitz P, George J, Shelton DA, Gumucio DL, Pras E, Kastner DL, Pras M, van der Meer JW.

Heller Institute of Medical Research, Sheba Medical Center, Tel-Hashomer, Israel.
J Rheumatol 1997 Aug;24(8):1558-63 Abstract quote
OBJECTIVE: To determine whether the 2 periodic febrile syndromes familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS) are distinct diseases.

METHODS: Clinical manifestations of the diseases were analyzed by physicians experienced with FMF and HIDS. Serum immunoglobulin (Ig) levels were studied in 70 patients with FMF using nephelometry or ELISA and compared with Ig levels in 50 patients with HIDS. Genetic linkage of HIDS with the chromosome 16 polymorphic locus RT70, currently used for refined localization of the FMF susceptibility gene (MEFV), was studied in 9 HIDS families (18 patients) using polymerase chain reaction amplification and gel electrophoresis.

RESULTS: The main clinical features distinguishing FMF from HIDS were lymphadenectomy, skin eruption, and symmetrical oligoarthritis in HIDS, and monoarthritis, peritonitis, and pleuritis in FMF. Increased IgG levels were found in 12 patients with FMF (17%), IgA in 16 (23%), IgM in 9 (13%), and IgD in 9 (13%), significantly lower than the prevalence reported for HIDS. We found no evidence for genetic linkage between HIDS and the chromosome 16 marker RT70.

CONCLUSION: HIDS and FMF are different entities, clinically, immunologically, and genetically.

PROGNOSIS AND TREATMENT CHARACTERIZATION

Treatment NSAIDs or corticosteroids

Ped Infect Dis J 1996;15:72-77.
Ann Rheum Dis 1993;52:81

Commonly Used Terms

Skin

Last Updated 11/18/2002

CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Drenth JP, Haagsma CJ, van der Meer JW. Department of Medicine, University Hospital St Radboud, Nijmegen, The Netherlands.	Medicine (Baltimore) 1994 May;73(3):133-44 Abstract quote We studied 50 patients (28 male and 22 female) with the hyper-IgD and periodic fever syndrome. Most patients originated from Europe, namely The Netherlands (28 cases; 56%), France (10 cases, 20%), and Italy (3 cases, 6%), but 1 patient was from Japan. A hereditary component is suggested by 18 patients coming from 8 families. The syndrome is typified by a very early age at onset (median, 0.5 years) and life-long persistence of periodic fever. Characteristically, attacks occur every 4-8 weeks and continue for 3-7 days, but the individual variation is large. Attacks feature high spiking fever, preceded by chills in 76% of patients. Lymphadenopathy is commonly present (94% of patients). During attacks, 72% of patients complained of abdominal pains, 56% of vomiting, 82% of diarrhea, and 52% of headache. Joint involvement is common in the hyper-IgD syndrome with poly-arthralgia in 80% and a non-destructive arthritis, mainly of the large joints (knee and ankle), in 68% of patients. Eighty-two percent of patients reported skin lesions with some attacks; these demonstrated vasculitis histologically. Serositis has been seen in only 3 patients (6%), while amyloidosis has not been recorded in any of the patients with this syndrome. Immunizations precipitated attacks in 54% of patients. All patients had a persistently elevated serum IgD level (> 100 U/mL), and in 82% of cases the serum IgA was likewise elevated. During attacks there is an acute-phase response adjudged by leukocytosis, neutrophilia, and increased ESR. The etiology remains to be elucidated, and treatment is supportive. The hyper-IgD syndrome is distinct from other periodic fever syndromes like systemic-onset juvenile rheumatoid arthritis, adult-onset Still disease, and familial Mediterranean fever.
ATYPICAL
Atypical hypergammaglobulinaemia D syndrome with amyloidosis: an overlap with familial Mediterranean fever? Ostuni P, Vertolli U, Marson P. Division of Rheumatology, University of Padova, Italy.	Clin Rheumatol 1996 Nov;15(6):610-2 Abstract quote A case of hypergammaglobulinaemia D and periodic fever syndrome, developing an amyloidosis-related nephrotic syndrome, is reported. Since such a complication represents a typical feature of another disease characterized by recurrent febrile attacks, i.e., familial Mediterranean fever, an overlap syndrome between these two rare clinical disorders can be suggested.
RETINA
Hyperimmunoglobulinemia D in idiopathic retinal vasculitis. Kumano Y, Nagato T, Kurihara K, Kikukawa H, Goto M, Kawano Y, Ohnishi Y, Inomata H. Department of Ophthalmology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.	Graefes Arch Clin Exp Ophthalmol 1997 Jun;235(6):372-8 Abstract quote BACKGROUND: We examined four patients who exhibited both idiopathic retinal vasculitis and elevated serum IgD levels. Uveitis caused by Behcet's disease is also associated with high levels of serum IgD. Therefore, the clinical features of these patients were investigated and the possible relationship between retinal vasculitis and elevated serum IgD was examined after undertaking a study of increased IgD levels in patients diagnosed with uveitis. METHODS: The study population was composed of 110 patients: 49 with Behcet's disease, 15 with sarcoidosis, 10 with Vogt-Koyanagi-Harada disease, and 36 with other forms of uveitis. IgD measurements were performed using modifications of the latex photometric immunoassay. Surface IgD (sIgD) expression in peripheral lymphocytes was determined by immunofluorescence, and the correlation between serum IgD levels and the percentage of sIgD-positive cells was examined. RESULTS: Twelve of the 110 patients had an elevated serum IgD. Eight of the 12 had Behcet's disease, and 4 were diagnosed with idiopathic retinal vasculitis. These 4 patients were HLA-A24+ females whose ages ranged from 8 to 25 years. A linear correlation between the serum IgD levels and the percentage of sIgD-positive cells was found. CONCLUSION: Hyperimmunoglobulinemia D state was found in Behcet's disease and idiopathic retinal vasculitis. These diseases may represent a new clinical entity characterized by signs of retinal vasculitis and hyperimmunoglobulinemia D that results from abnormal B cell activation and immune complex-mediated responses.
SKIN
Cutaneous manifestations and histologic findings in the hyperimmunoglobulinemia D syndrome. International Hyper IgD Study Group. Drenth JP, Boom BW, Toonstra J, Van der Meer JW. Department of Medicine, University Hospital St Radboud, Nijmegen, The Netherlands.	Arch Dermatol 1994 Jan;130(1):59-65 Abstract quote BACKGROUND AND DESIGN: The hyperimmunoglobulinemia D (hyper-IgD) syndrome is characterized by recurrent febrile attacks with abdominal distress, headache, and arthralgias. Physical examination reveals cervical lymphadenopathy in most cases and, sometimes, splenomegaly. Skin lesions have been observed in isolated cases during attacks. We summarize the features of skin lesions and the histopathologic findings in biopsy specimens in the hyper-IgD syndrome. RESULTS: A total of 44 patients with the hyper-IgD syndrome were studied. Thirty-five (79%) of them, 19 males and 16 females, had skin lesions during febrile attacks. Erythematous macules were the most common cutaneous manifestation (15 cases), followed by erythematous papules (12 cases); urticarial lesions (nine cases) and erythematous nodules (seven cases). Skin biopsy specimens of 10 patients with the hyper-IgD syndrome were available for review. The findings varied considerably. Most biopsy specimens showed mild features of vasculitis. Nonspecific findings were noted in five biopsy specimens; Sweet-like features in two, cellulitis-like findings in one, and deep vasculitis characteristics in one. CONCLUSIONS: Skin lesions are common in the hyper-IgD syndrome suggesting that they are a true manifestation of the disease.

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	HIDS
GEOGRAPHY	Dutch, French, or other European

DISEASE ASSOCIATIONS	CHARACTERIZATION
Sweet's like or cellulitis-like rash
Henoch-Schonlein purpura
Erythema elevatum diutinum

PATHOGENESIS	CHARACTERIZATION
Autosomal recessive
MVK gene (12q24)	Nat Genet 1999;22:178-181 Codes for mevalonate kinase

LABORATORY/RADIOLOGIC/OTHER TESTS	CHARACTERIZATION
Elevated serum IgD	Elevated in 95% of cases

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Diffuse neutrophilic dermatosis

PROGNOSIS AND TREATMENT	CHARACTERIZATION
Treatment	NSAIDs or corticosteroids