corneal neovascularization

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

Hereditary Mucoepithelial Dysplasia

Clinical Characteristics
Ocular Features: 

Impaired epithelial cohesion is the fundamental defect in this disorder.  Photophobia may be present in infants and this is soon evident as secondary to keratitis with eventual formation of a pannus and corneal neovascularization.  Vision is impaired early and as the disease progresses, many patients by early adulthood are severely impaired.  Cataracts are present in the majority of individuals, often present as early as the second decade of life.  Eyelashes and eyebrows may be sparse.  Nystagmus has been reported in some patients.

Systemic Features: 

This is a panepithelial disease of impaired cohesion due, at least in part, to a reduced number of desmosomes and defective gap junctions.  Oral, nasal, vaginal, cervical, perineal, urethral, and bladder mucosa, in addition to external ocular surfaces, are involved.  With exception of the ocular involvement, the lesions are usually not painful, but may be during acute flare-ups.  Demarcated erythematous patches are often seen in the oral mucosa.  Non-scarring alopecia, keratosis pilaris, and perineal intertrigo are usually present.  Histological examination of oral mucosa and skin shows dyskeratotic features, decreased number of desmosomes, and intracytoplasmic vacuoles.

Genetics

Pedigrees suggest autosomal dominant inheritance but few families have been reported.  The location of the responsible mutation, if any, has not been found. 

Somewhat similar genodermatoses are KID syndrome (148210), an autosomal dominant disorder with neurosensory hearing loss and sometimes mental and physical delays secondary to mutations in GJB2, and IFAP (308205), an X-linked condition with mental and physical delays and severe organ deformities.  Cataracts are not features of KID or IFAP syndromes.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been found.

References
Article Title: 

Dyskeratosis Congenita

Clinical Characteristics
Ocular Features: 

The conjunctiva and eyelids are prominently involved as part of the generalized mucocutaneous disease.  Keratinization of the lid margins, absent lacrimal puncta, trichiasis, cicatrizing conjunctivitis, entropion, ectropion, blepharitis, sparse eyelashes, and symblephara are important features.  The cornea is also involved with keratinization of the epithelial surface and vascularization.  The nasolacrimal duct is sometimes blocked.  At least one patient has been reported to have an exudative retinopathy. 

Systemic Features: 

Dyskeratosis congenita consists of a heterogeneous (genetic and clinical) group of inherited bone marrow failure and premature aging syndromes with the common feature of shortened telomeres.  There is considerable variability in the clinical features.  Prominent manifestations include nail dysplasia, oral leukoplakia, abnormal dentition, and reticulated skin pigmentation. Some patients have cognitive impairments.  Liver failure, testicular atrophy, pulmonary fibrosis, aplastic anemia, and osteoporosis along with features of aging such as premature grey hair and loss are typical.  There is an increased risk of malignancies, especially acute myelogenous leukemia.  Bone marrow failure is the major cause of early death.

Genetics

At least three autosomal dominant, three autosomal recessive, and one X-linked form of dyskeratosis congenita are recognized.  Mutations in at least 7 genes have been implicated.

Autosomal dominant disease can result from mutations in the TERC gene (DKCA1; 3q36.2; 127550), the TERT gene (DKCA2; 5p15.33; 613989), and the TINF2 gene (DKCA3; 14q12; 613990).  Mutations in the TINF2 gene are also responsible for Revesz syndrome (268130) with many features of DKC in addition to ocular findings of an exudative retinopathy resembling Coats disease.

Autosomal recessive disease is caused by mutations in the NOP10 (NOLA3) gene (DCKB1; 224230; 15q14-q15), the  NHP2 (NOLA2) gene (DKCB2; 5q35; 613987), and the WRAP53 gene (DKCB3; 17p13; 613988).  Mutations in the TERT gene may also cause autosomal recessive disease known as DKCB4 (613989).  

The X-linked disease (DKCX) (Zinsser-Engman-Cole syndrome) results from a mutation in the DKC1 gene (Xq28; 305000).  The same gene is mutated in Hoyeraal-Hreidarsson syndrome (300240) which some consider to be a more severe variant of dyskeratosis congenita with the added features of immunodeficiency, microcephaly, growth and mental retardation, and cerebellar hypoplasia. 

The majority of mutations occur in genes that provide instructions for making proteins involved in maintainence of telemeres located at the ends of chromosomes.  Shortened telomeres can result from maintainence deficiencies although the molecular mechanism(s) remain elusive.

Pedigree: 
Autosomal dominant
Autosomal recessive
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Treatment for DKC with hematopoietic stem cell transplantation can be curative but its long-term efficacy is poor.  Some advocate androgen therapy first.  Lifelong cancer surveillance and frequent ocular and dental evaluations are important with specific treatment as indicated.

References
Article Title: 

KID Syndrome

Clinical Characteristics
Ocular Features: 

Superficial punctate keratopathy leads to recurrent corneal erosions and eventually scarring and neovascularization.  Progressive opacification requiring PK often occurs.  These individuals may also suffer loss of eyebrows and eyelashes with trichiasis and thickening of the lid margins.  Corneal erosions and keratoconjunctivitis sicca cause incapacitating symptoms.

Systemic Features: 

The skin may be diffusely erythematous and scaly.  This often becomes patchier with well-demarcated areas especially in skin folds of the neck, axillae, and groin.  Older patients with likely autosomal recessive disease have hepatomegaly and may suffer cirrhosis and liver failure.  Short stature and mental retardation have also been noted.  The hearing loss is neurosensory in type.  Epidermal glycogen deposition has been found in one patient with the presumed recessive disorder.

In the presumed autosomal dominant disease, growth failure, mental retardation and liver disease do not seem to be present.  However, oral and skin squamous cell carcinomas, as well as malignant pilar tumors of the scalp may lead to early death.

Genetics

It is uncertain if one or more entities are represented by the KID syndrome.  Many cases are sporadic but others seem to be transmitted in autosomal recessive or autosomal dominant patterns.  The locus of the mutation is unknown in the recessive form.  In the dominant form, a mutation has been found in the connexin-26 gene, GJB2, gene located at 13q12.11.

See Hereditary Mucoepithelial Dysplasia (158310) for a somewhat similar but unique genodermatosis.  Another is IFAP (308205) but cataracts and hearing loss are not features.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

The use of ocular lubricating preparation may supply significant relief from symptoms but scarring may eventually necessitate penetrating keratoplasty.  The threat of skin cancers and fatal hepatic failure requires monitoring throughout life.

References
Article Title: 
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