Differentials
Cerebro-oculo-facio-skeletal syndrome (COFS)
SIGNS / SYMPTOMS
Congenital joint contractures (arthrogryposis), extreme microcephaly, facial dysmorphism, and congenital cataracts. Many of the signs are present at birth.
Ocular findings (microcornea, cataracts, and optic atrophy) often present earlier in life than XP.
Intrauterine growth is often normal but after birth, growth deficiency is striking and unrelenting (similar to Cockayne syndrome, below).[35]
Cutaneous photosensitivity was not noted in patients originally reported with COFS syndrome.[36]
INVESTIGATIONS
The distinction between XP and COFS is mainly clinical. Genetic testing is useful to narrow the diagnosis, but will not differentiate between the conditions.[37]
Trichothiodystrophy
SIGNS / SYMPTOMS
Presence of brittle hair and/or hair shaft abnormalities.
Ichthyosis.
Recurrent infections due to immunodeficiency.
Absence of freckle-like skin lesions (lentigines).
Decreased levels of sulfur-containing amino acids in hair shafts.
No increased risk of cancer.
INVESTIGATIONS
Microscopic examination of hair shafts shows alternating transverse dark and light “tiger tail” banding with polarized microscopy.
Identification of biallelic pathogenic variants in TTDA and TTDN1 on molecular genetic testing (pathogenic variants in XPD and XPB may occur, but if so this will not help differentiate from XP).[14]
Cockayne syndrome
SIGNS / SYMPTOMS
Pigmentary retinal degeneration.
Calcification of basal ganglia on x-ray in some patients.
Postnatal growth failure (height and weight <5th centile by age 2 years).
No increased risk of cancer.
INVESTIGATIONS
Identification of biallelic pathogenic variants in ERCC6 or ERCC8 on molecular genetic testing.[14]
Xeroderma pigmentosum/Cockayne syndrome complex
SIGNS / SYMPTOMS
Clinical features of both XP and Cockayne syndrome complex.
INVESTIGATIONS
Identification of biallelic pathogenic variants in ERCC5 on molecular genetic testing.[14]
Erythropoietic protoporphyria
SIGNS / SYMPTOMS
Tingling, burning, pain, and itching occur within 30 minutes after sun exposure.
Patients do not develop early and extensive freckle-like lesions (lentigines).
INVESTIGATIONS
Markedly increased free erythrocyte protoporphyrin.
Identification of biallelic pathogenic variants in FECH on molecular genetic testing.
Noonan syndrome with multiple lentigines (Leopard syndrome)
SIGNS / SYMPTOMS
Lentigines (freckle-like lesions) present in non-sun-exposed areas, such as the upper chest.
Short stature.
Pectus deformity.
Dysmorphic facial features including widely spaced eyes and ptosis.
Signs of hypertrophic cardiomyopathy.
INVESTIGATIONS
Identification of a heterozygous pathogenic variant in one of four genes (BRAF, MAP2K1, PTPN11, and RAF1) on molecular genetic testing.
Dyschromatosis symmetrica hereditaria
SIGNS / SYMPTOMS
Hyper- and hypopigmented macules are not progressive nor strictly on sun-exposed areas.
Positive family history for dyschromatosis symmetrica hereditaria.
INVESTIGATIONS
Identification of a pathologic variant of the ADAR1 gene on molecular genetic testing.
Poikiloderma with neutropenia
SIGNS / SYMPTOMS
Midfacial hypoplasia, palmar/plantar hyperkeratosis.
Post-inflammatory poikiloderma (atrophy, telangiectasia, and dyspigmentation).
Recurrent infections.
INVESTIGATIONS
Congenital chronic neutropenia on complete blood count.
Identification of biallelic USB1 pathogenic variants on molecular genetic testing.
Bloom syndrome
SIGNS / SYMPTOMS
Severe pre- and post-natal growth deficiency with sparse subcutaneous fat.
Photodistributed erythematous rash.
Insulin resistance at a young age.
INVESTIGATIONS
Cytogenetic findings of an increased frequency of sister-chromatid exchanges.
Identification of biallelic pathogenic variants in BLM on molecular genetic testing.
Low plasma immunoglobulins (usually IgM and IgA).
Rothmund-Thompson syndrome
SIGNS / SYMPTOMS
Small stature.
Poikiloderma, especially over the cheeks, but not limited to sun-exposed areas.
Juvenile cataracts.
Skeletal abnormalities.
INVESTIGATIONS
Identification of biallelic pathogenic variants in ANAPC1 or RECQL4 on molecular genetic testing.
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