uveitis

Autoinflammation with Arthritis and Dyskeratosis

Clinical Characteristics
Ocular Features: 

Signs and symptoms of dry eyes are evident early in the first decade.  Punctate keratitis with photophobia are present by 5 or 6 years of age followed by corneal dyskeratosis and neovascularization.  One 16-year-old male was reported to have uveitis.

Systemic Features: 

Recurrent febrile episodes lasting 3-4 days with impaired sweating occur early in the first decade.  Small hyperkeratosis may be seen on the limbs, shoulders, and flanks.  Diffuse xerosis is evident throughout.  Keratotic lesions occur on the soles as well.   Arthritis in the lower limbs occurs by the beginning of the second decade or earlier.  Metaphyseal striations and irregular condensations may be seen in the distal femora and proximal tibial bones.

Hypereosinophilia with elevated IgE and IgA levels and reduced vitamins A and C have been reported.  Immune hemolytic anemia, thyroiditis, and abnormal B-cell profiles may be present.

Genetics

Heterozygous and homozygous mutations in the NLRP1 gene (17p13) have been associated with this condition in several families.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis)

Grandemange S, Sanchez E, Louis-Plence P, Tran Mau-Them F, Bessis D, Coubes C, Frouin E, Seyger M, Girard M, Puechberty J, Costes V, Rodiere M, Carbasse A, Jeziorski E, Portales P, Sarrabay G, Mondain M, Jorgensen C, Apparailly F, Hoppenreijs E, Touitou I, Genevieve D. A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis). Ann Rheum Dis. 2016 Dec 13. pii: annrheumdis-2016-210021. doi: 10.1136/annrheumdis-2016-210021.

PubMed ID: 
27965258

Behcet-Like Familial Autoinflammatory Syndrome

Clinical Characteristics
Ocular Features: 

A minority of reported patients (3 of 14) have had Behcet-like uveitis with retinal vasculitis and chorioretinal lesions.  In two of the 3 patients with uveitis the inflammation was anterior but the authors reported significant visual loss.

Systemic Features: 

Fourteen patients in 6 unrelated families have been reported.  Onset usually occurs during the first or second decades of life.  Patients usually developed oral and genital ulcers.  Other features variably present were polyarthritis, a skin rash and inflammatory disease or ulcerations in the GI tract.  Several patients had periodic fevers and hemolytic anemia was present in one.  The majority of individuals have been female.

Three patients in a single family had lupus anticoagulant and three others had antinuclear antibodies.

Genetics

This syndrome results from heterozygous mutations in the TNFAIP3 gene (6q23.3) with loss of function leading to A20 haploinsufficiency.  Changes in the TNFAIP3 gene have also been identified in rheumatoid arthritis, systemic lupus erythematosis, and idiopathic juvenile arthritis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Several patients have responded positively to treatment with tumor necrosis factor inhibitors or colchicine.

References
Article Title: 

Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Lyons JJ, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, P Hanson E, Yu Z, Mullikin JC, Hasni SA, Wertz IE, Ombrello AK, Stone DL, Hoffmann P, Jones A, Barham BK, Leavis HL, van Royen-Kerkof A, Sibley C, Batu ED, Gul A, Siegel RM, Boehm M, Milner JD, Ozen S, Gadina M, Chae J, Laxer RM, Kastner DL, Aksentijevich I. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016 Jan;48(1):67-73.

PubMed ID: 
266422433

Histiocytic Dermatoarthritis

Clinical Characteristics
Ocular Features: 

This disorder has some ocular similarities to dermochondrocorneal dystrophy of Francois (221800) such as the presence of cataracts, but differs in the absence of corneal opacities.  All patients examined have had glaucoma, uveitis and lens opacities.  Gonioscopy in one patient showed multiple anterior synechiae and another patient, an adult, had buphthalmos.

Systemic Features: 

Skin lesions and stiff, painful joints develop between 4 and 15 years of age.   The cutaneous nodules are found primarily on the hands, ears and the upper extremities.  These are nonulcerating, tender, violaceous to brown in color, and firm in consistency.  Firm subcutaneous plaques apparent only on palpation are also present.  No mucosal lesions or xanthelasmata are present.  Deforming, symmetric arthritis of the hands, feet and elbows is frequently seen with periarticular bony resorption.  The skin of the legs and feet are thick and lichenified.  Histology of the skin lesions shows a granulomatous appearance with a chronic inflammatory infiltrate.  No multinucleated giant cells are seen.

Genetics

A single family with 4 affected sibs born to an affected male parent has been reported which suggests autosomal dominant inheritance.  The mutation, if any, is unknown.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The glaucoma should, of course, be treated but no treatment is available for the systemic disease beyond orthopedic correction of the joint deformities.

References
Article Title: 

Incontinentia Pigmenti

Clinical Characteristics
Ocular Features: 

This is primarily a disorder of skin, teeth, hair, and the central nervous system but 35% of patients have important ocular features.  The iris is variably atrophic and has pigmentary anomalies often with posterior synechiae.  Nystagmus, strabismus, and limited vision are often present.  The majority (up to 90%) of individuals have significant retinal disease.  The retinal vascular pattern is anomalous with tortuosity in some areas and absence of vessels in others.  Preretinal fibrosis and retinal detachments may suggest the presence of a retinoblastoma.  Cataracts are common in patients who have a retinal detachment and some patients have microphthalmia. The retinal pigment epithelium is often abnormal with various-sized patches of sharply demarcated depigmentation.  Cases with uveitis, papillitis and chorioretinitis have been observed and it has been suggested that the observed retinal and choroidal changes result from prior inflammatory disease, perhaps even occurring in utero. There is a great deal of asymmetry in the clinical findings in the two eyes.

Systemic Features: 

Skin changes consisting of erythematous eruptions in a linear pattern are often present at birth and this may be followed by a verrucous stage.  The acute, early findings of inflammatory disease eventually subside, ultimately resulting in pigmentary changes that appear in a 'marbled pattern' in young adults.  Hypodontia and anodontia may be present.  Alopecia and CNS abnormalities are found in nearly half of patients.  Skeletal and structural deformities are common in patients with severe neurological deficits.  The only sign of this disorder in adult women may be a whorled pattern of scarring alopecia.

As many as 30% of patients have neurological features which may be present in the neonatal period.  Seizures of various types occur in 30% of patients.  MRI findings include periventricular and subcortical white matter changes, as well as corpus callosum hypoplasia, cerebral atrophy, and cerebellar hypoplasia.

 

Genetics

The majority of evidence suggests that this is an X-linked dominant disorder with lethality in males although sporadic cases occur.  The mutation occurs as a genomic rearrangement of the IKK-gamma gene, also known as NEMO (IKBKG) located at Xq28.  There is evidence from skin cultures that cells with the mutant X chromosome inactivated are preferentially viable.  It has been proposed that cells with the mutant bearing X chromosome as the active one are gradually replaced by those in which the normal X chromosome is active accounting for the post-natal course of the skin disease.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

No treatment for the generalized disorder is available although ocular surgery might be beneficial in rare cases with cataracts and detachments.

References
Article Title: 
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