bone marrow failure

Révész Syndrome

Clinical Characteristics
Ocular Features: 

This is likely a severe form of dyskeratosis congenita with an exudative retinopathy in addition to the usual lid deformities, corneal opacification, conjunctival scarring.  The exudates are often present in early childhood, and may be of sufficient volume to present as leukocoria mimicking a retrolental mass.  The exudates extend through nearly all layers of the retina and are said to resemble Coats retinopathy. Vitreous hemorrhage and opacification has also been reported.  Severe vision loss and blindness may occur depending on the degree of retinal and vitreous disease.

Systemic Features: 

Patients with Revesz syndrome have cerebral calcifications, and hypoplasia of the cerebellum in addition to mild signs of dyskeratosis congenita such as a reticulated skin pattern, nail dysplasia, and oral leukoplakia.  Ataxia is a prominent sign but is not present in all patients.  Bone marrow failure with pancytopenia and a high risk of malignancies, however, are serious problems.  Aplastic anemia and neutropenia may present in early childhood while other signs may not appear until late childhood.  Sparse hair, intrauterine growth retardation and low birth weight are also features.   

Few patients with Revesz syndrome have been reported and the clinical features have not been fully delineated.  It is important to note that there is a large amount of clinical variation among patients.

Genetics

Heterozygous mutations in the TINF2 gene (14q12) have been found in Revesz syndrome.  Mutations in the same gene have also been found in the autosomal dominant form of dyskeratosis congenita (613990) suggesting that the two disorders, if distinct, are allelic.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Bone marrow failure may respond favorably to hematopoietic stem cell transplantation, at least for some time. Lifelong medical monitoring is required for the systemic and ocular disease.

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
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