Table 2. [Disorders That Can Exhibit Features...]. - GeneReviews®

Disorder	Gene(s)	MOI	Overlapping Clinical Features of Disorder	Distinguishing Clinical Features of Disorder
Bloom syndrome ¹	BLM	AR	Rash characterized by an erythematous, sun-sensitive lesion of the face; not true poikiloderma Loss of lower eyelashes & blister & fissure formation of lower lip common Café au lait macules or paired hypopigmented & hyperpigmented macules in some Most common cause of death: cancer (at younger-than-usual ages) Severe pre- & postnatal growth deficiency w/↓ subcutaneous fat	Recurrent infections (otitis media & pneumonia) Chronic pulmonary disease Diabetes mellitus
Werner syndrome	WRN	AR	Initial findings (usually in 3rd decade): loss & graying of hair, alopecia, scleroderma-like skin changes Skin ulcers (4th decade) Cancer predisposition	Premature appearance of features assoc w/normal aging Normal development until end of 1st decade 1st symptom: no growth spurt during early teen years Initial signs: (3rd decade) hoarseness followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, & osteoporosis in 4th decade
Ataxia-telangiectasia	ATM	AR	↑ risk of malignancy, particularly leukemia & lymphoma Unusual sensitivity to ionizing radiation	Progressive cerebellar ataxia beginning ages 1-4 yrs Oculomotor apraxia Frequent infections Choreoathetosis Telangiectasias of the conjunctivae Immunodeficiency
Fanconi anemia	>20 genes ²	AR AD XL	Abnormal skin pigmentation ↑ risk of malignancy: 10%-30% incidence of hematologic malignancies (primarily acute myeloid leukemia); 25%-30% incidence of nonhematologic malignancies (solid tumors, particularly of head & neck, skin, GI tract, & genital tract)	Bone marrow failure in 1st decade; 90% estimated cumulative incidence of bone marrow failure by age 40-50 yrs Physical abnormalities: short stature; malformations of thumbs, forearms, skeletal system, eye, kidneys & urinary tract, ear, heart, GI system, oral cavity, & CNS; hearing loss; hypogonadism; DD
Xeroderma pigmentosum	DDB2 ERCC1 ERCC2 ERCC3 ERCC4 ERCC5 POLH XPA XPC	AR	Sun sensitivity (sunburn w/blistering; persistent erythema on minimal sun exposure in ~60%; severe, marked freckle-like pigmentation of face before age 2 yrs) Greatly ↑ risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) Xerosis (dry skin) Poikiloderma Loss of lashes	Median age of onset of non-melanoma skin cancer: <10 yrs Neurologic manifestations in ~25% Photophobia Keratitis Atrophy of skin of eyelids
Kindler syndrome	FERMT1	AR	Acral bullae at birth & after minor trauma Diffuse poikiloderma w/striate & reticulate atrophy Widespread eczematoid dermatitis Keratotic papules of hands, feet, elbows, knees Marked photosensitivity	Esophageal & urethral strictures Webbing of fingers & toes No ↑ risk for cataract or malignancy
Dyskeratosis congenita	ACD CTC1 DKC1 NHP2 NOP10 PARN RTEL1 TERC TERT TINF2 WRAP53	XL AD AR	Lacy reticular pigmentation of neck & upper chest Nail dystrophy ↑ risk of leukemia & skin cancers	Bone marrow failure Oral leukoplakia w/variable onset Not assoc w/radial ray defects or cataracts
Poikiloderma with neutropenia	USB1	AR	Rash Less common finding: acute myeloid leukemia	Onset of rash differs from that seen in RTS: more eczematous, starting peripherally & spreading centrally Rash affecting the trunk Not assoc w/radial ray abnormalities Clinically significant neutropenia w/recurrent sinopulmonary infection Less common finding: bone marrow failure Paronychias common
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis	FAM111B	AD	Poikiloderma (typically beginning in 1st 6 mos & mainly facial) Chronic erythematous & scaly skin lesions on extremities (distinct from chronic poikiloderma of extremities seen in RTS) Sclerosis of digits Mild palmoplantar keratoderma Scalp hair, eyelashes, &/or eyebrows typically sparse Nail dysplasia in some	Hypohidrosis w/heat intolerance Mild lymphedema of extremities Muscle contractures usually seen in childhood; can be present by age 2 yrs In most: progressive weakness of proximal & distal muscles of all 4 limbs In some adults: progressive interstitial pulmonary fibrosis that can be life threatening w/in 3-4 yrs after respiratory symptoms appear

Disorder

Gene(s)

MOI

Overlapping Clinical Features of Disorder

Distinguishing Clinical Features of Disorder

Bloom syndrome ¹

BLM

Rash characterized by an erythematous, sun-sensitive lesion of the face; not true poikiloderma
Loss of lower eyelashes & blister & fissure formation of lower lip common
Café au lait macules or paired hypopigmented & hyperpigmented macules in some
Most common cause of death: cancer (at younger-than-usual ages)
Severe pre- & postnatal growth deficiency w/↓ subcutaneous fat

Recurrent infections (otitis media & pneumonia)
Chronic pulmonary disease
Diabetes mellitus

Werner syndrome

WRN

Initial findings (usually in 3rd decade): loss & graying of hair, alopecia, scleroderma-like skin changes
Skin ulcers (4th decade)
Cancer predisposition

Premature appearance of features assoc w/normal aging
Normal development until end of 1st decade
1st symptom: no growth spurt during early teen years
Initial signs: (3rd decade) hoarseness followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, & osteoporosis in 4th decade

Ataxia-telangiectasia

ATM

↑ risk of malignancy, particularly leukemia & lymphoma
Unusual sensitivity to ionizing radiation

Progressive cerebellar ataxia beginning ages 1-4 yrs
Oculomotor apraxia
Frequent infections
Choreoathetosis
Telangiectasias of the conjunctivae
Immunodeficiency

Fanconi anemia

>20 genes ²

AR
AD
XL

Abnormal skin pigmentation
↑ risk of malignancy: 10%-30% incidence of hematologic malignancies (primarily acute myeloid leukemia); 25%-30% incidence of nonhematologic malignancies (solid tumors, particularly of head & neck, skin, GI tract, & genital tract)

Bone marrow failure in 1st decade; 90% estimated cumulative incidence of bone marrow failure by age 40-50 yrs
Physical abnormalities: short stature; malformations of thumbs, forearms, skeletal system, eye, kidneys & urinary tract, ear, heart, GI system, oral cavity, & CNS; hearing loss; hypogonadism; DD

Xeroderma pigmentosum

DDB2
ERCC1
ERCC2
ERCC3
ERCC4
ERCC5
POLH
XPA
XPC

Sun sensitivity (sunburn w/blistering; persistent erythema on minimal sun exposure in ~60%; severe, marked freckle-like pigmentation of face before age 2 yrs)
Greatly ↑ risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma)
Xerosis (dry skin)
Poikiloderma
Loss of lashes

Median age of onset of non-melanoma skin cancer: <10 yrs
Neurologic manifestations in ~25%
Photophobia
Keratitis
Atrophy of skin of eyelids

Kindler syndrome

FERMT1

Acral bullae at birth & after minor trauma
Diffuse poikiloderma w/striate & reticulate atrophy
Widespread eczematoid dermatitis
Keratotic papules of hands, feet, elbows, knees
Marked photosensitivity

Esophageal & urethral strictures
Webbing of fingers & toes
No ↑ risk for cataract or malignancy

Dyskeratosis congenita

ACD
CTC1
DKC1
NHP2
NOP10
PARN
RTEL1
TERC
TERT
TINF2
WRAP53

XL
AD
AR

Lacy reticular pigmentation of neck & upper chest
Nail dystrophy
↑ risk of leukemia & skin cancers

Bone marrow failure
Oral leukoplakia w/variable onset
Not assoc w/radial ray defects or cataracts

Poikiloderma with neutropenia

USB1

Rash
Less common finding: acute myeloid leukemia

Onset of rash differs from that seen in RTS: more eczematous, starting peripherally & spreading centrally
Rash affecting the trunk
Not assoc w/radial ray abnormalities
Clinically significant neutropenia w/recurrent sinopulmonary infection
Less common finding: bone marrow failure
Paronychias common

Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis

FAM111B

Poikiloderma (typically beginning in 1st 6 mos & mainly facial)
Chronic erythematous & scaly skin lesions on extremities (distinct from chronic poikiloderma of extremities seen in RTS)
Sclerosis of digits
Mild palmoplantar keratoderma
Scalp hair, eyelashes, &/or eyebrows typically sparse
Nail dysplasia in some

Hypohidrosis w/heat intolerance
Mild lymphedema of extremities
Muscle contractures usually seen in childhood; can be present by age 2 yrs
In most: progressive weakness of proximal & distal muscles of all 4 limbs
In some adults: progressive interstitial pulmonary fibrosis that can be life threatening w/in 3-4 yrs after respiratory symptoms appear

From: Rothmund-Thomson Syndrome

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Adam MP, Feldman J, Mirzaa GM, et al., editors.

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