premature aging

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: 

Rothmund-Thomson Syndrome

Clinical Characteristics
Ocular Features: 

Patients have been reported with juvenile and infantile cataracts.  Reported prevalence varies possibly because the diagnostic criteria have not been established and more than one disorder may be represented by the title.  Rothmund (an ophthalmologist) originally reported two families of 5 children in which lens opacities were found, but Thomson, who was a dermatologist, in a later report did not mention cataracts.  The lens opacities are usually nuclear or posterior cortical in location and may be evident in 50% of patients.  Iris stromal changes such as hypoplasia have also been reported.  Eyelashes and/or eyebrows may be sparse.  This is likely the same disorder as the previously described ‘mesodermal dysgenesis of the iris and skeletal dysplasia’ and formerly listed as 270240 in OMIM.

Systemic Features: 

This is a clinically heterogeneous disorder.  Skin atrophy with pigmentary changes, telangiectasia, short stature, premature aging, and skeletal abnormalities are characteristic.  There is an increased risk of malignancy, particularly osteosarcomas and skin cancer.  Saddle nose, sparse hair, hypogonadism, dysplastic nails, and teeth anomalies have also been described.

The skin is usually normal at birth but an erythematous rash typically appears in the first six months of life accompanied by swelling and blistering.  Eventually areas of hypo- and hyperpigmentation appear in a reticulated pattern with spots of punctate atrophy and telangiectasia.  Hyperkeratosis of the soles of the feet is common.  The skeletal abnormalities of dysplasia, radial ray defects, and missing bones are often evident at birth while osteopenia and delayed bone maturation are evident later.

Genetics

This is an autosomal recessive disorder in which most patients have mutations in the RECQL4 gene (8q24.3).

Mutations in the same gene cause Baller-Gerold syndrome (218600) suggesting that the two disorders are allelic but the phenotypes are considerably different.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the primary disorder but patients must be monitored for malignancies.  Visually significant cataracts should be removed.  It has been recommended that patients avoid excessive sun exposure to reduce the risk of skin cancers.

References
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