Premature Aging Syndromes and Poikilodermas

Question 1

What is the inheritance pattern and genes involved in Hutchinson-Gilford progeria?

Answer 1

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

Question 2

Pathophysiology of Hutchinson-Gilford progeria?

Answer 2

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.

Question 3

What do the cutaneous findings of Hutchinson-Gilford progeria begin and what are they?

Answer 3

Starts at 6-18 months

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

Question 4

Later findings in Hutchinson-Gilford progeria?

Answer 4

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

Question 5

What are some systemic signs of Hutchinson-Gilford progeria?

Answer 5

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

Question 6

The most common cause of death in Hutchinson-Gilford progeria?

Answer 6

Cardiovascular disease (mean age is 13)

Question 7

What is the inheritance pattern and genes involved in Werner sydrome?

Answer 7

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

Question 8

Pathophysiology of Werner syndrome?

Answer 8

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

Question 9

When do the sx’s and signs of Werner syndrome usually occur?

Answer 9

Third to fourth decades

Question 10

What are the cutaneous findings Werner syndrome?

Answer 10

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

Question 11

What are some extracutaneous findings in Werner syndrome?

Answer 11

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

Question 12

What tumors are those with Werner syndrome at increased risk for?

Answer 12

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

Question 13

What are the major causes of death in Werner syndrome?

Answer 13

Cerebrovascular/cardiovascular events (mid 50’s)

Question 14

What is the inheritance and involved genes in Xeroderma pigmentosum?

Answer 14

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

Question 15

What is the pathophysiology of Xeroderma pigmentosum?

Answer 15

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)

Question 16

What are the downstream effects of Xeroderma pigmentosum?

Answer 16

Poikiloderma, numerous cutaneous malignancies (1000 fold increase)

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

Question 17

What is the most common type of Xeroderma pigmentosum in the US?

Answer 17

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

Question 18

What overlap syndromes can be seen with Xeroderma pigmentosum and why are they seen?

Answer 18

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

Question 19

What is the increase in risk of cutaneous malignancies seen in Xeroderma pigmentosum?

Answer 19

1000x increase

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

mean onset of malignancy is 8 y/o

Question 20

Systemic/non-cutaneous complications in Xeroderma pigmentosum?

Answer 20

Photophobia, conjunctivitis, ectropion, symblepharon, neurodevelopmental complications (developmental delay, intellectual impairment, sensorineural hearing loss, hyporeflexia, and ataxia) (20-30% of pts)

Question 21

What Xeroderma pigmentosum subtypes do not have neurologic findings?

Answer 21

XPV related (remember different pathophysiology there)

Question 22

What is De Sanctis-Cacchione syndrome?

Answer 22

Rare XP phenotype w/ severe neurologic deficits (severe mental, retardation, deafness, ataxia and paralysis)

Question 23

Most common cause of death in those with Xeroderma pigmentosum?

Answer 23

Complications from metastatic melanoma or invasive SCC

• Usually occurs by ~20 years of age

Question 24

What is the inheritance pattern and genes mutated in Bloom syndrome (congenital telangietatic erythema)?

Answer 24

AR due to mutations in BLM/RECQL3 genes (DNA helicase)

Question 25

What is the pathophysiology of Bloom syndrome?

Answer 25

Increased rates of sister chromatid exchange and chromosomal instability due to mutations in DNA helicase

Question 26

When does Bloom syndrome start to present?

Answer 26

Early in life w/ prenatal and postnatal growth impairment (short stature; do not exceed 5 feet in height)

Question 27

Cutaneous manifestations of Bloom syndrome?

Answer 27

Photosensitivity, telangiectatic erythema in malar distribution, cheilitis, CALM, and hypopigmentation

Question 28

What are the facial features of Bloom syndrome?

Answer 28

Bird-like nose, narrow face w/ prominent ears, and malar hypoplasia

Question 29

Systemic findings in Bloom syndrome?

Answer 29

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

Question 30

Prognosis of Bloom syndrome?

Answer 30

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

Question 31

What population is at the highest risk of Bloom syndrome?

Answer 31

Ashkenazi jews, there is a 1% carrier rate among this population

Question 32

What is the inheritance pattern and gene mutated in Rothmund-Thompson syndrome (poikiloderma congenitale)?

Answer 32

AR, mutations in RECQL4 DNA helicase

Question 33

What are the cutaneous manifestations of Rothmund-Thompson syndrome (poikiloderma congenitale)?

Answer 33

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

Question 34

Systemic findings in Rothmund-Thompson syndrome (poikiloderma congenitale)?

Answer 34

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

Question 35

Prognosis of Rothmund-Thompson syndrome (poikiloderma congenitale)?

Answer 35

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

Question 36

What is the inheritance pattern and gene mutated in Cockayne syndrome?

Answer 36

AR due to transcription-coupled NER (nucleotide excision repair) (Ercc6 and 8)

Question 37

What is the pathophysiology of Cockayne syndrome?

Answer 37

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).

Question 38

What are the two genes in Cockayne syndrome?

Answer 38

Cockayne syndrome-A (20%): Mutations in excision repair, cross-complementing group (ERCC8)

Cockayne syndrome-B (80%): mutations in ERCC6

Question 39

What is the difference between type I and type II Cockayne syndrome?

Answer 39

Type I: Presents at the end of first decade

Type II: Presents at birth; progresses more rapidly

Question 40

Cutaneous findings in Cockayne syndrome?

Answer 40

Photosensitivity, with telangiectatic erythema; unlike XP, has NO increased risk of skin cancer and there are NO pigmentary changes

Question 41

Facial differences in Cockayne syndrome?

Answer 41

Pinched, narrow “bird-like” face w/ beaked nose, large protuberant ears, and sunken eyes; growth failure and cachexia

Question 42

Neurologic manifestations of Cockayne syndrome?

Answer 42

Basal ganglia calcifications, progressive deterioration/demyelination of CNS/PNS w/ ataxia and spasticity, intellectual impairment, progressive sensorineural hearing loss

Question 43

What are the skeletal manifestations of Cockayne syndrome?

Answer 43

Short stature + cachectic/thin body (cachectic dwarfism), joint contractures, and kyphosis

Question 44

What are the ophthalmologic manifestations of Cockayne syndrome?

Answer 44

Salt and pepper retinopathy, pupils are hard to dilate, optic atrophy, cataracts, and nystagmus

Question 45

Prognosis of Cockayne syndrome?

Answer 45

Most pts die in the 4th decade from progressive neurologic disease complications

Question 46

What is the inheritance pattern and gene involved for Trichothiodystrophy (Tay syndrome and PIBIDS)?

Answer 46

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)

Question 47

Cutaneous manifestations of Trichothiodystrophy (Tay syndrome and PIBIDS)?

Answer 47

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

Question 48

Systemic findings in Trichothiodystrophy (Tay syndrome and PIBIDS)

Answer 48

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