Premature Aging Syndromes and Poikilodermas Flashcards

AD caused by the 1824C>T in the LMNA gene (encodes lamin A)

Mutation produces a splice site that results in the protein being abnormally farnesylated. The lamin A protein contributes to the structure/function of the nuclear envelope

• So with the abnormal farnesylation, lamin A cannot insert normally into the nuclear envelope.

Starts at 6-18 months

• Localized sclerodermatous changes of lower trunk/thigh
• Cyanosis around the mouth or nasolabial folds
• Dyspigmentation
• Early failure to thrive

Early skin wrinkling and xerosis, hair loss (scalp, eyebrows, and eyelashes, non-scarring), atrophy w/ prominant veins, atherosclerosis and angina, bone density loss, osteolysis of distal phalanges, lipodystrophy, onychodystrophy, breast hypoplasia

• Facial: enlarged head, micrognathia w/ dental crowding, small ears, and beaked nose
• High pitched voice

Rapid and progressive premature aging, with complications like cerebrovascular and cardiovascular events, limited mobility and exercise tolerance due to joint stiffness/arthritis, and poor growth

Cardiovascular disease (mean age is 13)

AR, mutations in RECQL2/WRN gene (encodes a DNA helices that helps maintain genomic stability)

Mutations in the RECQL2/WRN leads to increased expression of inhibitors of DNA synthesis and increased telomere-driven replicative senescence and leads to accelerated aging

Third to fourth decades

Premature canities, progressive alopecia, bird-like facial appearance, sclerodermatous/atrophic change acrally/facially, mottled pigmentation, telangiectasias, hyperkeratotic ulcers over pressure points, leg ulcers, calcinosis cutis, and loss of subcutaneous fat

Short stature, muscle wasting, atherosclerosis (can progress to CVA/MI), diabetes mellitus, hypogonadism, osteoporosis, arthritis, posterior subcapsular cataracts, DM2, and hypogonadism

Breast cancer, ovarian cancer, thyroid adenocarcinoma, fibrosarcoma, osteogenic sarcoma, meningioma, skin cancers, and hepatoma

Cerebrovascular/cardiovascular events (mid 50’s)

AR, mutations in XPA to XPG genes (as well as variant XPV) (nucleotide excision repair pathway)

Mutations in the nucelotide decision pathway are the underlying cause of pathology

• XPA encodes DNA damage binding protein 1 (DDB1), XPB encodes ecision-repair cross-complementing 3 (ERCC3), and XPC encodes endonuclease, XPD encodes ERCC2, XPE encodes DDB2, XPF encodes ERCC4, XPG encodes endonuclease, and XPV is unique and it encodes a DNA polymerase.
• The variant pathway is important because it affects a polymerase which is involved in the post-replication repair pathway (mutation in DNA polymerase)

Poikiloderma, numerous cutaneous malignancies (1000 fold increase)

• Includes BCC, SCC, melanoma, and fibrosarcoma
• Also ophthalmologic and neurodevelopmental issues

XPA and XPC, XPA alone is most common subtype in Japan

Because different mutations in XP genes can lead to different phenotypes you can also get overlaps

• XPB, XPD and XPG: is a/w an XP-Cockayne overlap syndrome that has the signs of both XP (skin cancers lentigines) and Cockayne syndrome (retinal degeneration, basal ganglia calcification)
• XPB, XPD: also a/w trichothiodystrophy

1000x increase

• Usually occurs in pts <20 y/o
• Often is BCC, SCC, melanoma, and fibrosarcoma

mean onset of malignancy is 8 y/o