Premature Aging Syndromes and Poikilodermas Flashcards
What is the inheritance pattern and genes involved in Hutchinson-Gilford progeria?
AD caused by the 1824C>T in the LMNA gene (encodes lamin A)
Pathophysiology of Hutchinson-Gilford progeria?
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.
What do the cutaneous findings of Hutchinson-Gilford progeria begin and what are they?
Starts at 6-18 months
- Localized sclerodermatous changes of lower trunk/thigh
- Cyanosis around the mouth or nasolabial folds
- Dyspigmentation
- Early failure to thrive
Later findings in Hutchinson-Gilford progeria?
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
What are some systemic signs of Hutchinson-Gilford progeria?
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
The most common cause of death in Hutchinson-Gilford progeria?
Cardiovascular disease (mean age is 13)
What is the inheritance pattern and genes involved in Werner sydrome?
AR, mutations in RECQL2/WRN gene (encodes a DNA helices that helps maintain genomic stability)
Pathophysiology of Werner syndrome?
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
When do the sx’s and signs of Werner syndrome usually occur?
Third to fourth decades
What are the cutaneous findings Werner syndrome?
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
What are some extracutaneous findings in Werner syndrome?
Short stature, muscle wasting, atherosclerosis (can progress to CVA/MI), diabetes mellitus, hypogonadism, osteoporosis, arthritis, posterior subcapsular cataracts, DM2, and hypogonadism
What tumors are those with Werner syndrome at increased risk for?
Breast cancer, ovarian cancer, thyroid adenocarcinoma, fibrosarcoma, osteogenic sarcoma, meningioma, skin cancers, and hepatoma
What are the major causes of death in Werner syndrome?
Cerebrovascular/cardiovascular events (mid 50’s)
What is the inheritance and involved genes in Xeroderma pigmentosum?
AR, mutations in XPA to XPG genes (as well as variant XPV) (nucleotide excision repair pathway)
What is the pathophysiology of Xeroderma pigmentosum?
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)
What are the downstream effects of Xeroderma pigmentosum?
Poikiloderma, numerous cutaneous malignancies (1000 fold increase)
- Includes BCC, SCC, melanoma, and fibrosarcoma
- Also ophthalmologic and neurodevelopmental issues
What is the most common type of Xeroderma pigmentosum in the US?
XPA and XPC, XPA alone is most common subtype in Japan
What overlap syndromes can be seen with Xeroderma pigmentosum and why are they seen?
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
What is the increase in risk of cutaneous malignancies seen in Xeroderma pigmentosum?
1000x increase
- Usually occurs in pts <20 y/o
- Often is BCC, SCC, melanoma, and fibrosarcoma
mean onset of malignancy is 8 y/o
Systemic/non-cutaneous complications in Xeroderma pigmentosum?
Photophobia, conjunctivitis, ectropion, symblepharon, neurodevelopmental complications (developmental delay, intellectual impairment, sensorineural hearing loss, hyporeflexia, and ataxia) (20-30% of pts)
What Xeroderma pigmentosum subtypes do not have neurologic findings?
XPV related (remember different pathophysiology there)
What is De Sanctis-Cacchione syndrome?
Rare XP phenotype w/ severe neurologic deficits (severe mental, retardation, deafness, ataxia and paralysis)
Most common cause of death in those with Xeroderma pigmentosum?
Complications from metastatic melanoma or invasive SCC
- Usually occurs by ~20 years of age
What is the inheritance pattern and genes mutated in Bloom syndrome (congenital telangietatic erythema)?
AR due to mutations in BLM/RECQL3 genes (DNA helicase)
What is the pathophysiology of Bloom syndrome?
Increased rates of sister chromatid exchange and chromosomal instability due to mutations in DNA helicase
When does Bloom syndrome start to present?
Early in life w/ prenatal and postnatal growth impairment (short stature; do not exceed 5 feet in height)
Cutaneous manifestations of Bloom syndrome?
Photosensitivity, telangiectatic erythema in malar distribution, cheilitis, CALM, and hypopigmentation
What are the facial features of Bloom syndrome?
Bird-like nose, narrow face w/ prominent ears, and malar hypoplasia
Systemic findings in Bloom syndrome?
Primary hypogonadism (men are sterile, women have decreased fertility), high pitched voice, decreased IgA and IgM which leads to bronchiectasis/chronic lung disease/ recurrent respiratory and GI infections, increased risk of lymphoma and leukemia (150-300x risk), increased risk of some solid tissue tumors like SSC and GI adenocarcinomas
Prognosis of Bloom syndrome?
The cutaneous and immunologic findings improve w/ age but mortality comes from malignancy (#1 cause of death, especially leukemia) in the 2nd or 3rd decades, these pts do not survive beyond 50 years of age
What population is at the highest risk of Bloom syndrome?
Ashkenazi jews, there is a 1% carrier rate among this population
What is the inheritance pattern and gene mutated in Rothmund-Thompson syndrome (poikiloderma congenitale)?
AR, mutations in RECQL4 DNA helicase
What are the cutaneous manifestations of Rothmund-Thompson syndrome (poikiloderma congenitale)?
Presents in the first years of life
- Erythema, edema, blisters that start on the cheeks and go to involve the extensor surfaces of the extremities and buttocks
- Poikiloderma (hypo + hyperpigmentation + atrophy) is noted on these sites after
- Acral verrucous keratoses which may progress to SCC
- Photosensitivity (30%), alopecia of scalp/lashes/brows, and dystrophic nails
Systemic findings in Rothmund-Thompson syndrome (poikiloderma congenitale)?
Short stature, skeletal dysplasia (absence or hypoplasia of thumbs, radius, and ulna); triangular appearing face w/ frontal bossing/saddle nose/micrognathia; juvenile cataracts; dental anomalies, and hypogonadism
- Malignancy can happen early (osteosarcoma and non-melanoma skin cancer
Prognosis of Rothmund-Thompson syndrome (poikiloderma congenitale)?
Malignancy can cause premature death
- Osteosarcoma has a mean onset of 14 years of age in 30% of pts
- SCC mean age is 34 yrs
What is the inheritance pattern and gene mutated in Cockayne syndrome?
AR due to transcription-coupled NER (nucleotide excision repair) (Ercc6 and 8)
What is the pathophysiology of Cockayne syndrome?
The damage in nucleotide excision repair leads to the inability to resume RNA synthesis after UV exposure (different from XP, which has defective global genomic NER issues).
What are the two genes in Cockayne syndrome?
Cockayne syndrome-A (20%): Mutations in excision repair, cross-complementing group (ERCC8)
Cockayne syndrome-B (80%): mutations in ERCC6
What is the difference between type I and type II Cockayne syndrome?
Type I: Presents at the end of first decade
Type II: Presents at birth; progresses more rapidly
Cutaneous findings in Cockayne syndrome?
Photosensitivity, with telangiectatic erythema; unlike XP, has NO increased risk of skin cancer and there are NO pigmentary changes
Facial differences in Cockayne syndrome?
Pinched, narrow “bird-like” face w/ beaked nose, large protuberant ears, and sunken eyes; growth failure and cachexia
Neurologic manifestations of Cockayne syndrome?
Basal ganglia calcifications, progressive deterioration/demyelination of CNS/PNS w/ ataxia and spasticity, intellectual impairment, progressive sensorineural hearing loss
What are the skeletal manifestations of Cockayne syndrome?
Short stature + cachectic/thin body (cachectic dwarfism), joint contractures, and kyphosis
What are the ophthalmologic manifestations of Cockayne syndrome?
Salt and pepper retinopathy, pupils are hard to dilate, optic atrophy, cataracts, and nystagmus
Prognosis of Cockayne syndrome?
Most pts die in the 4th decade from progressive neurologic disease complications
What is the inheritance pattern and gene involved for Trichothiodystrophy (Tay syndrome and PIBIDS)?
AR, Heterogeneous group of genetic abnormlaities depending on phenotype
- TrIchothiodystrophy w/ photosensitivity = mutations in 3 genes (ERCC2, ERCC3, and GTF2H5)
- TrIchothiodystrophy, non-photosensitive = mutations in C7Orf11 gene and M-phase-specific PLK1 interacting protein (MPLK1P)
Cutaneous manifestations of Trichothiodystrophy (Tay syndrome and PIBIDS)?
Photosensitivity (except in non-photosensitive type), ichthyiosis (except the non-photosensitive type), brittle hair and nails, neurodevelopmental disability
- NO increased risk of skin cancer
- Short/sparse hair on the scalp/brows/lashes/ with alternating light and dark bands on polarizing light microscopy (tiger-tail abnormalities)
- Can also see trichoschisis and trichorrhexis nodosa
Systemic findings in Trichothiodystrophy (Tay syndrome and PIBIDS)
Intellectual impairment and ataxia, decreased fertility/hypogonadism, short stature
- Other: palmoplantar keratoderma, keratosis pilaris, atopic dermatitis, cataracts, osteosclerosis, joint contractures, aged facial appearance, and hypogammaglobinemia w/ recurrent infections
