Monogenic autoinflammatory syndromes

Author: Dr Delwyn Dyall-Smith FACD, Australia, 2011.

What are monogenic autoinflammatory syndromes?

Monogenic autoinflammatory syndromes are inherited conditions caused by mutations in one or both copies of a single gene that result in over-activation of the innate immune system causing inappropriate inflammation. Importantly infection, allergies, immune deficiencies and autoimmune diseases must be excluded.

When the concept of autoinflammatory syndromes was first proposed in 1999, it was synonymous with hereditary periodic fever syndromes. However subsequent studies have uncovered the genetic cause of other conditions previously thought to be unrelated.

A monogenic condition means it is due to mutation(s) in a single gene.

The inheritance pattern can be used as an initial classification of the monogenic autoinflammatory syndromes. Some examples of these syndromes with dermatological manifestions are listed.

Autosomal recessive autoinflammatory syndromes
Familial Mediterranean fever (FMF): MIM 249100
Hyperimmunoglobulinaemia D syndrome (hyperIgD syndrome, HIDS): MIM 260920
Majeed syndrome (chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia, and inflammatory dermatosis): MIM 609628
Deficiency of the IL-1 receptor antagonist (DIRA): MIM 612852
Autosomal dominant autoinflammatory syndromes
Tumour necrosis factor receptor-associated periodic fever (TRAPS): MIM 142680
Cryopyrin-associated periodic syndromes (CAPS):
Pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome (PAPA syndrome, PAPGA): MIM 604416
Juvenile systemic granulomatosis (paediatric granulomatous arthritis) Blau syndrome (familial juvenile granulomatosis; systemic arthrocutaneouveal granulomatosis (ACUG); Jabs syndrome; granulomatous inflammatory arthritis, dermatitis, and uveitis; familial granulomatosis Blau type): MIM 186580; Early onset sarcoidosis: MIM 609464

How do monogenic autoinflammatory syndromes present clinically?

Clinical clues that may suggest a monogenic autoinflammatory syndrome have been proposed by Gattorno et al:

Most, but not all, present as recurrent attacks of fever with associated symptoms of inflammation often of joints, eyes and skin. Each syndrome has additional distinctive clinical features (see specific syndrome).

Many monogenic autoinflammatory syndromes have a major effect on quality of life including significant disability and potentially life-threatening complications.

How are monogenic autoinflammatory syndromes diagnosed?

Diagnosis is primarily based on clinical features. Although these are genetic disorders, a family history of similar symptoms and signs is not always present, especially in those forms inherited as autosomal recessive.

Infections, allergy, malignancy, immunodeficiency and autoimmune disorders must be excluded on testing.

Some syndromes can be diagnosed on biochemical testing eg high level of mevalonic acid in urine during an attack of HIDS. Others show such a dramatic response to treatment that a trial of specific therapy confirms the clinical impression, e.g., colchicine for familial Mediterranean fever.

Genetic testing is possible for most of these syndromes, although not always readily available or affordable. Mutations in the identified gene are not currently detectable in all sufferers. The test is therefore only helpful if a mutation is definitely identified.

Where a gene mutation has been identified in the presenting patient (proband), genetic testing of family members may identify asymptomatic carriers who would benefit from treatment, e.g., colchicine for familial Mediteranean fever to prevent the development of potentially fatal amyloidosis. Prenatal diagnosis may also be considered for severe forms of monogenic autoinflammatory syndromes.

Treatment of monogenic autoinflammatory syndromes

As these are genetic conditions they cannot be cured. However many can be successfully controlled with specific therapy.

Familial Mediteranean fever shows a dramatic response to colchicine in the majority of sufferers, although the mechanism of effect is not yet known.

A number of these syndromes share the feature of interleukin-1-induced amplification of the innate immune system and therefore respond to blockade of this pathway using biologic agents such as anakinra. Anakinra is registered in several countries to treat rheumatoid arthritis.

DIRA is due to a specific deficiency of IL-1 receptor antagonist, which can be replaced by anakinra.

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