arthritis

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

Singleton-Merten Syndrome 2

Clinical Characteristics
Ocular Features: 

Glaucoma has been diagnosed in multiple members of 4 a generation Korean family in which various features of this disorder were found.  The glaucoma is likely congenital in origin as it has been diagnosed in patients as young as 3 years of age

Systemic Features: 

Calcification of the aorta and other large vessels may be identified in childhood.  The aortic valve and coronary arteries may become calcified in young adults as well, sometimes resulting in aortic stenosis.  Arthritis resulting from calcified tendons as well as ligaments of the interphalangeal and metacarpophalangeal joints may occur in young adults.  The skin is often scaly and dry with psoriatic lesions.  The terminal tufts of the digits have evidence of erosion.

Genetics

Heterozygous mutations in the DDX58 gene (9p21.1) have been associated with this disorder.  Some of the clinical features overlap those of Singleton-Merten Syndrome 2 (182250) but this is a unique disorder caused by a different mutation (IFIH1).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Glaucoma should be treated with pressure-lowering drugs and surgery.  It may be possible to decalcify cardiovascular structures in select patients and to perform valve replacement.

References
Article Title: 

Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome

Jang MA, Kim EK, Now H, Nguyen NT, Kim WJ, Yoo JY, Lee J, Jeong YM, Kim CH, Kim OH, Sohn S, Nam SH, Hong Y, Lee YS, Chang SA, Jang SY, Kim JW, Lee MS, Lim SY, Sung KS, Park KT, Kim BJ, Lee JH, Kim DK, Kee C, Ki CS. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):266-74.

PubMed ID: 
25620203

Alkaptonuria

Clinical Characteristics
Ocular Features: 

Ocular signs of this disease are present in two out of three patients.  Black or bluish pigmented patches may be noted in the sclerae by the fourth decade. The pigmentation is most evident just anterior to the insertion of the medial and lateral rectus muscles.  It is claimed that brown pigment spots resembling 'oil drops' near the opaque portion of the limbus are diagnostic but they are often not present until the 4th or 5th decades.  Nevertheless, these ocular signs on average precede systemic signs by about 15 years and are therefore diagnostically useful.  The pigmentation has no impact on vision. Hyperpigmentation of the anterior chamber angle with elevated intraocular pressure has been reported.  An increased incidence of central vein occlusion has been suggested.  Progressive astigmatism is sometimes seen.  Staining of the tarsal plates may be seen in the eyelids.

Systemic Features: 

Ochronosis (dark pigmentation in connective tissue) as the result of homogentisic acid (HGA) accumulation is a useful sign but does not appear until the 4th decade.  As a result the joint cartilage becomes fragile leading to disabling and chronic symptoms of arthritis especially in the spine and large joints.  Symptoms usually begin in the third or fourth decade and the degeneration of the ochronotic intervertebral disks may result in significant loss of height.  Back pain, kyphosis, and decreased lumbar flexion are common.  Usually smaller joints such as those of the digits are not affected sufficiently to cause symptoms.

Tendons, ligaments, and other fibrous tissue such as sclerae and heart valves are all susceptible to degenerative changes.  The discoloration in skin hue can also be seen in the axillae, nail beds, pinnae, forehead, tympanic membranes, genital areas, and buccal mucosa.  Clothing may become stained from discolored perspiration.

HGA in the urine oxidizes and turns dark and parents may note staining of diapers in the newborn period.  The urine also becomes alkaline.  Plasma levels of HGA are also elevated.  Urolithiasis may occur.

Genetics

This metabolic disease is among the first inborn errors of metabolism described.  Virchow had early described the yellowish discoloration of connective tissue seen under the microscope.  William Bateson at the beginning of the 20th century suggested the heritability of this condition to the British physician Sir Archibald Garrod who then described this syndrome in 1902 as the first human disease whose transmission pattern conformed to mendelian autosomal recessive inheritance based on his understanding of Mendel's laws.

Homozygosity of mutations in the HGD gene (3q13.33) coding for homogentisate 1,2-dioxygenase is responsible for the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Nitisinone reduces the production of HGA and can lower urinary levels up to 95% but may lead to elevated plasma tyrosine that rarely results in the deposition of corneal crystals.  Long-term benefits of nitisinone remain unknown. Others have tried dietary reduction of tyrosine and phenylalanine with reduction in HGA levels but the long term impact on the rate of tissue degradation remains unknown.    

Additional treatment is directed at specific damaged sites.  Calcified valves (often aortic) may need to be replaced.  Large joints such as hips, shoulders, and knees often require replacement for pain relief.  Stones in the urinary tract may need to be removed.  Ophthalmologists should keep such patients under observation for progressive astigmatism and the risk of elevated intraocular pressure.

It may be prudent to avoid contact sports and minimize heavy weight lifting to limit trauma to joint cartilage.

References
Article Title: 

Natural history of alkaptonuria

Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA. Natural history of alkaptonuria. N Engl J Med. 2002 Dec 26;347(26):2111-21.

PubMed ID: 
12501223

The molecular basis of alkaptonuria

Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, Renedo M, Fernandez-Ruiz E, Penalva MA, Rodriguez de Cordoba S. The molecular basis of alkaptonuria. Nat Genet. 1996 Sep;14(1):19-24.

PubMed ID: 
8782815

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: 

Stickler Syndrome, Type II

Clinical Characteristics
Ocular Features: 

Virtually all (85%) patients have a nonprogresssive axial myopia.  The vitreous degeneration has a beaded pattern without the veils of type I, claimed by some to be important in the distinction of the two types.  Paravascular lattice retinopathy is seen in 38% of patients and 64% have cataracts, sometimes with wedge opacities similar to those in type I Stickler syndrome.  Nearly half (42%) of patients are reported to have retinal detachments.

Systemic Features: 

Hearing loss occurs early and many individuals (80%) eventually require hearing aids.    Midline clefting is present frequently with bifid uvula, a highly arched palate, or an actual cleft palate.  Joint laxity is common.

Genetics

There are reasons to classify type II Stickler syndrome as a unique disorder apart from type I (108300).  In addition to phenotypic evidence (vitreoretinal disease, amount of hearing loss, and degree of epiphyseal disease), mutation in two different genes are involved.  Type II results from a mutation in the COL11A1 (1p21) and type I (108300) in COL2A1.  Both types are inherited in autosomal dominant patterns.

Type IV (614234) with vitreoretinal changes, myopia, and a high risk of retinal detachment is inherited in an autsomal recessive pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Patients with type II Stickler disease need lifelong ophthalmologic monitoring because of the risk of retinal detachments and cataracts with treatment as indicated.
 

References
Article Title: 

Clinical features of type 2 Stickler syndrome

Poulson AV, Hooymans JM, Richards AJ, Bearcroft P, Murthy R, Baguley DM, Scott JD, Snead MP. Clinical features of type 2 Stickler syndrome. J Med Genet. 2004 Aug;41(8):e107.

PubMed ID: 
15286167

Stickler Syndrome, Type I

Clinical Characteristics
Ocular Features: 

High myopia and vitreous degeneration dominate the ocular manifestations of Stickler syndrome, type I.  The vitreous often appears optically empty as it liquefies and the fibrils degenerate.  The vitreous is sometimes seen to form 'veils', especially in the retrolenticular region but they may also float throughout the posterior chamber.  They are often attached to areas of lattice degeneration in the retina as well as other areas.  Posterior vitreous detachments are common.  Vitreoretinal degeneration is progressive and by the second decade rhegmatogenous detachments occur in half of affected patients.  As many as three quarters of adult patients have retinal breaks.  The retina has pigmentary changes with deposition circumferentially near the equator and more peripherally.  Hypopigmentation is more common early creating a tessellated appearance.  Lenticular opacities occur also early with cortical flecks and wedge-shaped changes.

The ERG may be normal early but evidence of rod and cone dysfunction soon appears and is progressive.  Dark adaptation is defective later in the course of the disease.  The EOG is virtually always depressed.  The visual field is constricted and may show a ring scotoma coincident with the equatorial chorioretinal atrophy.

Glaucoma is not uncommon and may be infantile in onset and difficult to control.  

Phthisis is a significant risk especially for individuals who have multiple surgical procedures for retinal detachments. 

Systemic Features: 

It has been suggested that there is a nonsyndromic or ocular type of Stickler syndrome lacking many of the extraocular features characteristic of the complete syndrome.  However, the evidence for the ocular type described here as a distinct entity remains slim and the clinical picture may simply reflect variable expressivity of mutations in the same gene.  Type I Stickler syndrome has multiple systemic features such as cleft palate, hearing impairment, premature arthritis, micrognathia, kyphoscoliosis, and some signs such as arachnodactyly that are found in the Marfan syndrome.

Genetics

This is an autosomal dominant disease of collagen formation as a result of mutations in the COL2A1 gene (12q13.11-q13.2). The mutations causing both syndromal and the suggested nonsyndromal ocular type of Stickler disease are in the same gene.  Mutations in the same gene are known to cause autosomal dominant rhegmatogenous retinal detachments in patients who have none of the systemic clinical signs (609508).  These patients may lack the signs of vitreous degeneration seen in Kniest dysplasia (156550)  and in the disorder described here.

There is better evidence for a second type of Stickler syndrome, STL2 or type II (604841) based on phenotypic differences and the fact that a second locus (1p21) containing mutations in COL11A1 has been linked to it. 

Type III is caused by mutations in COL11A2 and has systemic features similar to types I and II but lacks the eye findings since this gene is not expressed in the eye.

Type IV also has important ocular features but is an autosomal recessive disorder caused by mutations in COL9A2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The combination of progressive vitreoretinal degeneration, frequency of posterior vitreous detachments, and axial myopia creates a lifelong threat of retinal tears and detachments.   Half to three quarters of all patients develop retinal tears and detachments.  Certainly all patients with Stickler syndrome deserve repeated and thorough retinal exams throughout their lives.  In addition to prompt treatment of tears and detachments, some have advocated prophylactic scleral banding to reduce vitreous traction, or applying 360 degree cryotherapy.

References
Article Title: 

Stickler syndrome in children: a radiological review

McArthur N, Rehm A, Shenker N, Richards AJ, McNinch AM, Poulson AV, Tanner J, Snead MP, Bearcroft PWP. Stickler syndrome in children: a radiological review. Clin Radiol. 2018 Apr 13. pii: S0009-9260(18)30118-1. doi: 10.1016/j.crad.2018.03.004. [Epub ahead of print].

PubMed ID: 
29661559

High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1

Richards AJ, Laidlaw M, Whittaker J, Treacy B, Rai H, Bearcroft P, Baguley DM, Poulson A, Ang A, Scott JD, Snead MP. High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1. Hum Mutat. 2006 Jul;27(7):696-704. Erratum in: Hum Mutat. 2006 Nov;27(11):1156.

PubMed ID: 
16752401
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