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Juvenile systemic granulomatosis

Author: Dr Delwyn Dyall-Smith, Dermatologist, 2011.


What is juvenile systemic granulomatosis?

Juvenile systemic granulomatosis is a new term proposed to include Blau syndrome (MIM186580, also called Jabs syndrome) and early onset sarcoidosis (MIM609464) as these two conditions have now been linked following the identification of mutations affecting the same gene and molecular basis. Paediatric granulomatous arthritis has also been proposed as a unifying name, but this focuses on only the commonest clinical feature, which does not occur in all patients.

Juvenile systemic granulomatosis is one of the monogenic autoinflammatory syndromes.

What is the cause of juvenile systemic granulomatosis and who gets it?

Juvenile systemic granulomatosis results from mutations in the NACHT domain of the CARD15 (caspase recruitment domain 15) gene also known as the NOD2 gene located on chromosome 16q12.1-13. So far this has always been one heterozygous single-nucleotide substitution. R224W and R334Q are the commonest mutations reported. The same CARD15 mutations have been identified in both Blau syndrome and early onset sarcoidosis, but not in adult sarcoidosis. To date, all patients found to have such a mutation have shown clinical signs of this syndrome (100% penetrance).

CARD15 encodes the NOD2 (Nod2) protein and is mainly expressed in the cytoplasm of monocytes. NOD2 recognises muramyl dipepetide in the cell wall of gram-negative and gram-positive bacteria. Binding results in activation of NK-κB and the mechanism of inflammation does not involve excess interleukin(IL)-1 activity. The CARD15 gene mutations result in a single amino acid change in the NOD2 protein.

Blau syndrome was defined as being an autosomal dominant condition, whereas early onset sarcoidosis was not familial. However it would now appear that early onset sarcoidosis is due to a sporadic mutation, compared to the inherited mutation in Blau syndrome. A female diagnosed with early onset sarcoidosis due to the lack of family history subsequently gave birth to an affected baby and the diagnosis was therefore Blau syndrome.

Juvenile systemic granulomatosis presents in early childhood, before the age of 4 years. It is rare, with an incidence rate of less than 1 per 1.5 million person-years. Early onset sarcoidosis more commonly affects white rather than black individuals, in contrast to adult-onset sarcoidosis.

Clinical features of juvenile systemic granulomatosis

There is sequential involvement of the skin, joints and eyes in juvenile systemic granulomatosis, usually beginning before the age of 3 years. Not all patients develop all of the classic triad over time. Approximately 40% develop all three features. Variability in clinical presentation occurs even within the one family.

Juvenile systemic granulomatosis
Skin lesions
  • Affect 80%
  • Usually the first sign
  • Commonest are yellowish to brown-red papules, slightly scaly, flat-topped (lichenoid), discrete, pinhead sized – described as ‘tapioca grain-like’
  • Perifollicular pattern may be noted
  • Often in clusters or linear arrays, can become confluent
  • Scaly plaques
  • Start on face and extremities, later spread to trunk
  • Asymptomatic
  • Intermittent episodes over years with spontaneous resolution
  • Poikiloderma (red, white and brown discolouration) and pitted scars due to follicular atrophoderma (skin thinning confined to hair follicles) may develop later at sites of previous inflammation.
  • Other skin changes with granulomatous histology reported have included:
  • Commonest of the three signs (90%)
  • Symmetrical polyarthritis
  • Boggy, nontender joint swelling
  • Wrists, knees and ankles most common joints affected
  • Large and small joints can be affected
  • Relatively normal range of movement
  • Minimal to moderate pain
  • In one series, age at onset was 4 months to 6 years
  • Affect 60%
  • Recurrent uveitis is the most common presentation
  • Eye pain, photophobia, blurred vision
  • 50% develop cataracts
  • 1 in 3 develops secondary glaucoma
  • Inflammation can involve the conjunctiva, lacrimal (tear) glands, retina and optic nerve
  • Rarely the presenting or only feature
  • Usually the last feature to develop – in one series, 2 to 16 years of age
Other manifestations
  • Intermittent or persistent fever
  • Flexion contractures of proximal interphalageal joints
  • Cranial neuropathies
  • Malignant hypertension
  • Enlargement of lymph nodes, liver and/or spleen
  • Internal organ involvement is rare and in particular lung or hilar lymph node enlargement do not occur, in contrast to adult-onset sarcoidosis.
  • If untreated, 80% develop severe visual disturbances and joint deformities.
  • Increased severity has been reported in subsequent generations (‘anticipation’).

How is juvenile systemic granulomatosis diagnosed?

Skin biopsy shows noncaseating granulomatous dermatitis. This dermatopathology term describes the particular pattern of mixed inflammatory infiltrate characteristic of sarcoidosis. The granulomas are found in the upper dermis and are often around hair follicles. Non-caseating granulomas are also seen in biopsies from the eye, synovium of affected joints and other involved sites.

X-rays of the affected joints are near normal and do not show the erosive changes of juvenile rheumatoid arthritis.

Slit lamp examination of the eyes should be performed regularly as early eye disease can be asymptomatic.

CARD15 (NOD2) gene mutation studies can be performed on a buccal mucosal scraping.

What is the treatment for juvenile systemic granulomatosis?

Genetic counselling is required and prenatal diagnosis can be considered if the mutation has been identified in the proband.

To prevent eye damage, long-term systemic immunosuppression is required. Options include:

Inflammation of the eye can be the most difficult manifestation to treat and the main cause of long-term complications.



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