Table 1.
Clinical and autopsy abnormalities in XP-A (XP12BE) and XP-D (XP18BE) patients compared to two XP-C patients
| Case 1 | Case 2 | Case 3 | Case 4 | |
|---|---|---|---|---|
| |
XP-A (XP12BE) (GM05509)* |
XP-D (XP18BE) (CRL1275)**(XPKABE) |
XP-C (XP24BE) (GM11638)* |
XP-C (XP1BE) (GM10881)* |
| |
late onset juvenile form XP |
XP with neurological degeneration |
no neurological disease |
subclinical neurodegeneration |
| Age at death/Gender/DOB |
d44 yr/F b1965 |
d45 yr/F b1964 |
d35 yr/F b1972 |
d49 yr/F b1944 |
| XP complementation group |
XP-A |
XP-D |
XP-C |
XP-C |
| Mutations (see text for details) |
compound heterozygote |
compound heterozygote |
compound heterozygote |
homozygous |
|
CLINICAL FINDINGS |
|
|
|
|
| Height |
145.5 cm (<3 %ile) |
165 cm (50–75 %ile) |
153.3 cm - 34 yr (10 %ile) |
160 cm (25–50 %ile) |
| Weight |
32 kg (<3 %ile) |
60.6 kg (50 %ile) |
56.7 kg - 35 yr (50 %ile) |
76.6 kg (50–75 %ile) |
| Cachexia? |
yes |
no |
no |
no |
| Acute skin sunburning on minimal exposure? |
yes |
yes |
no |
no |
| Freckle-like skin lesions on sun exposed skin? |
yes |
yes |
yes |
yes |
| Skin cancer?1 |
>200 BCC and 1 SCC |
7 SCC and 2 BCC |
>200 (190-BCC,3 SCC and ~50 MIS) |
>200 (>35 BCC, >37 SCC, 2 soft tissue sarcoma, 28 MIS and 6 Mel) |
| Microcephaly? |
yes (2%ile) |
no |
no |
no |
| Hearing |
progressive high frequency sensorineural hearing loss |
progressive high frequency sensorineural hearing loss |
normal |
subclinical high frequency sensorineural hearing loss at 48 yr |
| Deep tendon reflexes |
absent |
absent (1995) |
normal |
normal at 37 yr, ankle hyporeflexia at 43 yr |
| Able to walk? |
no |
no |
yes |
yes |
| Able to talk? |
no |
no |
yes |
yes |
| Able to care for self? |
no |
no |
yes |
yes |
| Difficulty swallowing? |
yes - G-tube - age 37 yr |
yes - G-tube - age 44 yr |
normal |
normal |
| Primary ovarian failure? |
no |
unknown |
yes |
yes |
| Anterior eye abnormalities |
bilateral pinguecula, exposure keratopathy2 |
bilateral pinguecula, exposure keratopathy2 |
corneal scar, pterygium |
blateral orbital exenterations for infiltrative SCC of globe3 |
| Eye - retinal degeneration |
optic nerve atrophy2 |
no2 |
no |
unknown |
| Imaging of brain |
diffuse cerebral and cerebellar atrophy (41 yr −2006) |
minimal cortical atrophy (19 yr- 1983) |
left frontal lobe tumor |
slight cerebral cortical atrophy and ventricular enlargement (44 yr) |
|
AUTOPSY FINDINGS |
|
|
|
|
| Thick calvarium? |
no |
yes; cortical sclerosis, no tumor seen |
no |
no |
| Brain weight [normal 1240 g (1050–1550)] |
660g (~ 6mo) |
760g (~1 yr) |
1330g [normal] |
1300g [normal] |
| Brain atrophy? |
yes - diffuse |
yes - diffuse |
no atrophy - tumor |
no, except optic nerves secondary to orbital exenteration |
| Dilated brain ventricles? |
yes |
yes |
asymmetric due to tumor |
no |
| Thin corpus callusum? |
yes |
yes |
no remarkable features |
no |
| Histological neuronal loss? |
yes - hippocampus, pons, medulla, midbrain, thinned cortex, small cerebellum |
yes – outer cortex (neuronal loss and vacuolization resembling status spongiosis), hippocampus (CA2 and CA3 regions), basal ganglia, cerebellum |
no remarkable features |
no |
| Histological gliosis? |
yes - midbrain, pons, medulla, basal ganglia, thalamus, hippocampus |
yes - cortex, hippocampus |
no remarkable features |
yes - molecular layer of cerebellum |
| Histological myelin pallor? |
yes - temporal lobe, frontal lobe, cerebellum |
yes - basal ganglia, cerebellum |
no remarkable features |
no remarkable features |
| Cerebellum |
Atrophy, loss of Purkinje cells with axonal swelling, Bergmann astrocytosis |
atrophy, patchy Purkinje cell loss |
no remarkable features |
moderate to marked Purkinje cell loss with Bergmann astrocyte proliferation |
| Dorsal root ganglia |
no remarkable features |
no remarkable features |
no remarkable features |
severe neuronal loss |
| Histology of peripheral nerves |
minimal focal perivascular inflammation in the adjacent connective tissue |
no pathologic changes |
femoral nerve - unremarkable |
median nerve mild focal interstital fibrosis, sural nerve - no pathologic diagnosis |
| EM of peripheral nerves |
axonal neuropathy |
not done |
not done |
not done |
| Eye pathology? |
neovascularization of cornea, optic atrophy2 |
neovascularization of cornea, cataract2 |
not done |
sockets of orbits lined with skin |
| Histology of muscles |
myofiber type -grouping |
no pathologic changes |
unremarkable |
angulated fibers of skeletal muscles |
| Histology of Pharynx |
inflammation and fibrosis |
chronic inflammation |
normal |
normal |
| Esophagus |
no pathologic changes |
T-lymphocyte infiltration of Auerbach's plexus |
no pathologic changes |
no pathologic changes |
| Larynx |
no pathologic changes |
ulceration with chronic and acute inflammation |
pink mucosa |
delicate pink mucosa |
| Lungs |
normal |
bronchopneumonia |
bilateral pneumonia |
pulmonary emboli |
| Thyroid |
normal |
normal |
cystic nodule filled with pink, amprphous material, consistent with goiter |
follicular adenomas |
| Ovaries |
no pathologic changes |
no pathologic changes |
small - microscopic fibrosis, no follicles |
covered by tumor |
| Uterus |
leiomyomas |
adenomyosis |
small - calcified nodules 1 cm, leiomyomas |
covered by tumor |
| Breasts |
fibrocystic changes |
fibrocystic changes |
no masses |
no masses |
| Cause of death | XP-related neurologic degeneration | XP-related neurologic degeneration | Glioblastoma WHO grade IV. Tumor cells positive for GFAP and IDH1, negative for EGFR. P53 positive in <5% tumor cells. | metastasis of well differentiated mucinous adenocarcinoma of uterine endocervix |
1BCC - basal cell carcinoma, SCC -squamous cell carcinoma, MIS - melanoma in situ 2From Ramkumar et al. (reference 26) 3From Gaasterland et al. (reference 48) *Coriell Institute for Medical Research cell culture identification number **American Type Culture Collection cell culture identification number.