Table 1 Monogenic disorders with a scleroderma-like phenotype. The clinical features have been summarised as described by the Online Mendelian Inheritance in Man (OMIM) [28] and Genetics Home Reference databases [29]
From: A case of Myhre syndrome mimicking juvenile scleroderma
Disease | Inheritance | Gene | Clinical Features |
|---|---|---|---|
Hutchinson-Gilford Progeria | AD, AR | LMNA | Skin: Sclerodermatous skin disease, loss of subcutaneous fat (lipodystrophy) Skeletal: Osteoporosis, joint restrictions, joint abnormalities Cardiovascular: Atherosclerosis Other: Prematurely aged appearance, postnatal onset growth retardation, hair loss (alopecia) |
Werner syndrome | AR | WRN | Skin: Sclerodermatous skin disease, subcutaneous calcification, ulceration Skeletal: Osteoporosis Cardiovascular: Premature arteriosclerosis Endocrine: Diabetes mellitus, hypogonadism Other: Prematurely aged appearance, short stature, alopecia, juvenile cataracts |
Rothmund Thomson syndrome | AR | RECQL4 | Skin: Erythematous thickened skin lesions in infancy, poikiloderma (atrophic plaques with telangiectasia), telangiectasia, atrophy, sun sensitivity Skeletal: Osteoporosis Central Nervous System: Mental retardation (rare) Endocrine: Hypogonadism Other: Prematurely aged appearance, short stature, alopecia, premature greying of hair, increased risk of malignant disease |
Mandibular hypoplasia, deafness, progeroid features and lipodystrophy syndrome | AD | POLD1 | Skin: Sclerodermatous skin disease, telangiectasias, atrophy, lipodystrophy Skeletal: Osteoporosis, joint contractures Endocrine: Insulin resistance, diabetes mellitus Other: Prematurely aged appearance, mandibular hypoplasia, sensorineural deafness, hepatomegaly, hepatic steatosis |
Nestor-Guillermo Progeria Syndrome | AR | BANF1 | Skin: Sclerodermatous skin disease (patchy) and hyperpigmentation Skeletal: Joint stiffness, joint contractures, osteoporosis, osteolysis Cardiovascular: Sinus tachycardia, prominent subcutaneous venous patterning, pulmonary hypertension Other: Prematurely aged appearance, short stature, lipoatrophy |
Keppen-Lubinsky syndrome | AD | KCNJ6 | Skin: Lipodystrophy, wrinkled appearance Skeletal: Joint contractures Central Nervous System: Severe mental retardation, delayed psychomotor development, hypertonia, hyperreflexia Other: Prematurely aged appearance, generalised lipodystrophy |
Fontaine Progeroid Syndrome | AD | SLC25A24 | Skin: Wrinkled skin, lipodystrophy, sclerodermatous skin disease Skeletal: Low bone density, delayed bone age Cardiovascular: Pulmonary artery hypertension, aortic ectasia Other: Prematurely aged appearance, short stature, intrauterine growth retardation |
Cockayne Syndrome, Type A | AR | ERCC8 | Skin: Cutaneous photosensitivity, scarred, pigmented, atrophy, reduced subcutaneous adipose tissue, sclerodermatous skin disease Skeletal: Flexion contractures, mild-to-moderate joint limitations Cardiovascular: Hypertension Neurological: Impaired or delayed neural development, mental retardation Other: Prematurely aged appearance, cachectic dwarfism, intrauterine growth retardation, sensorineural hearing loss, vision complications, tooth decay, hepatomegaly, splenomegaly, decreased subcutaneous adipose tissue |
Ataxia-telangiectasia | AR | ATM | Skin: Sclerodermatous skin disease, progeric skin changes, cutaneous telangiectasia, cafe-au-lait spots Respiratory: Bronchitis, bronchiectasis Neurological: Cerebellar ataxia, cerebellar cortical degeneration, oculomotor abnormalities, seizures, choreoathetosis, dystonia, reduced/absent deep tendon reflexes Other: Short stature |
Myhre syndrome | AD | SMAD4 | Skin: Sclerodermatous skin disease Skeletal: Skeletal abnormalities, joint restrictions Cardiovascular: Hypertension, congenital heart defects, aortic stenosis, aortic coarctation, pericardial fibrosis Respiratory: Laryngotracheal stenosis, respiratory failure Neurological: Mental retardation, delayed language and motor skill development, behavioural issues (autistic-like) Other: Dysmorphic facial features, short stature, hearing loss, generalised muscle hypertrophy |
Stiff skin syndrome | AD | FBN1 | Skin: Sclerodermatous skin disease (diffuse), lipodystrophy Skeletal: Joint restrictions, flexion contractures Other: Muscle weakness |
Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) | AR | SLC29A3 | Skin: Hyperpigmented and hypertrichotic skin lesions on lower body, sclerodermatous skin disease Skeletal: Joint contractures (elbows, fingers and toes) Abdomen: Hepatomegaly, diabetes mellitus (insulin-dependent), splenomegaly Other: Short stature, hearing loss |
Reynolds syndrome | AD | LBR | Skin: Sclerodermatous skin disease (tightened and shiny skin over the forearms and hands), sclerodactyly, calcinosis cutis, generalized darkening Other: Raynaud phenomenon, hepatomegaly, primary biliary cirrhosis, splenomegaly, esophageal dysfunction |
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome /Nakajo-Nishimura Syndrome | AR | PSMB8 | Skin: Erythematous nodular skin lesions and plaques on the face and extremities, dry, stiff, lipodystrophy Skeletal: Joint contractures (elbow, fingers/hands, toes, feet), joint pain Muscle: Lipodystrophy, muscle weakness Other: Poor growth, hepatomegaly, splenomegaly |
Mucolipidosis III gamma | AR | GNPTG | Skin: Sclerodermatous skin disease Skeletal: Joint restrictions, joint stiffness, joint pain Cardiovascular: Aortic valve thickening, aortic stenosis Neurological: Mental retardation Other: Short stature |
Hurler-Scheie syndrome / Mucopolysaccharidosis Ih/s | AR | IDUA | Skin: Sclerodermatous skin disease Skeletal: Joint stiffness, dysostosis multiplex Cardiovascular: Thickened mitral valve leaflets, aortic valve thickening, dilated left atrium, dilated left ventricle, mild pulmonary hypertension Respiratory: Frequent respiratory infections, nasopharyngeal obstruction, tracheal stenosis Abdomen: Umbilical hernia, hepatomegaly, splenomegaly Neurological: Pachymeningitis cervicalis Other: Short stature, corneal clouding |
Zimmermann-Laband Syndrome 1 | AD | KCNH1 | Skin: Dry, sclerodermatous skin disease Skeletal: Scoliosis, hypoplastic distal phalanges (hands and feet), hyperextensible joints Abdomen: Hepatosplenomegaly, splenomegaly, umbilical hernia Cardiovascular: Cardiomyopathy, patent ductus arteriosus, aortic root dilatation, aortic arch dilatation Muscle: Poor muscle bulk Neurological: Hypotonia, seizures, mental retardation Other: Gingival fibromatosis, dysplastic or absent nails, hirsutism, abnormalities of the cartilage of the nose and/or ears |
Buschke-Ollendorff syndrome | AD | LEMD3 | Skin: Subcutaneous nontender firm nodules, subcutaneous connective tissue nevi, elastin-rich connective tissue nevi (elastoma), collagen-rich connective tissue nevi (dermatofibrosis lenticularis disseminata) Skeletal: Osteopoikilosis, joint stiffness, osteosclerosis, melorheostosis |
Growth Retardation, Alopecia, Pseudoanodontia and Optic Atrophy (GAPO) Syndrome | AR | ANTXR1 | Skin: Sclerodermatous skin disease, redundant, prominent scalp veins, epidermal inclusion cyst Skeletal: Delayed bone age Other: Growth retardation, alopecia, pseudoanodontia, umbilical hernia, hepatomegaly |
Crouzon Syndrome with acanthosis nigricans | AD | FGFR3 | Skin: Hyperpigmentation, acanthosis nigricans, melanocytic nevi, hypertrophy, sclerodermatous skin disease, redundant skin folds Skeletal: Craniosynostosis |
Frontometaphyseal dysplasia 2 | AD | MAP 3 K7 | Skin: Keloid formation, sclerodermatous skin disease Skeletal: Skeletal abnormalities, joint contractures Cardiovascular: Patent ductus arteriosus, bicuspid aortic valve, aortic root dilation, pulmonary valve stenosis Respiratory: Congenital stridor, subglottic stenosis, tracheal stenosis |
Premature aging syndrome, Penttinen type | AD | PDGFRB | Skin: Progressive cutaneous atrophy, thin translucent skin with prominent venous patterning, hypertrophic keloid-like lesions, skin retraction, sclerodermatous skin disease, lipoatrophy Skeletal: Delayed bone maturation, osteopenia, joint contractures |
Farber Lipogranulomatosis | AR | ASAH1 | Skin: Early-onset subcutaneous nodules, lipogranulomatosis Skeletal: Painful and progressively deformed joints, arthritis Respiratory: Laryngeal nodules Abdomen: Hepatomegaly, splenomegaly Neurological: Irritability, motor retardation, mental retardation Other: Hoarseness by laryngeal involvement |
Amyloidosis, Primary Localised cutaneous, 3 (PLCA3) | AR | GPNMB | Skin: Amyloid disposition in the skin, hyper- and hypo-pigmented macules, mild pruritis, dry skin |
Carney Complex, Type 1 | AD | PRKAR1A | Skin: Cutaneous tumors, profuse pigmented skin lesions, nevi Cardiovascular: Tumors (atrial), ventricular myxoma, congestive heart failure Endocrine: Tumors, pigmented micronodular adrenal dysplasia, Cushing disease, acromegaly, thyroid follicular hyperplasia Other: Neoplasia, myxoid subcutaneous tumors, primary adrenocortical nodular hyperplasia, testicular Sertoli cell tumor (calcified), pituitary adenoma, mammary ductal fibroadenoma, schwannoma, psammomatous melanotic schwannomas, thyroid carcinoma, pheochromocytoma |
Porphyria cutanea tarda, Porphyria, hepatoerythropoietic | AD, AR | UROD | Skin: Sclerodermatous skin disease (diffuse), increased mechanical skin fragility after sunlight exposure (photosensitivity), vesicles, bullae and blisters on exposed areas of skin, hyperpigmentation on sun-exposed skin Abdomen: Hepatic hemosiderosis, hepatic cirrhosis, liver biopsy shows red autofluorescence and needle-like cytoplasmic inclusion bodies Other: Neoplasia, increased incidence of hepatocellular carcinoma |
Phenylketonuria, non-PKU mild Hyperphenylalaninemia | AR | PAH | Skin: Sclerodermatous skin disease, pale pigmentation, dry, eczema Neurological: Seizures, delayed development, mental retardation, behavioural problems and psychiatric disorders Other: Head, microcephaly, cataracts |
Porphyria, congenital erythropoietic | AR | UROS | Skin: Sclerodermatous skin disease, photosensitivity, blistering and scarring, hyperpigmentation, hypopigmentation Skeletal: Osteolysis, osteopenia, finger contractures Other: Short stature, conjunctivitis, corneal scarring, hypertrichosis, alopecia, porphyrin-rich gallstones, splenomegaly |
Multicentric osteolysis, nodulosis and arthropathy (MONA) | AR | MMP2 | Skin: Subcutaneous nodules (interphalangeal joints, knees, feet, elbows, pretibial), hyperpigmented erythematous lesions Skeletal: Osteoporosis, flexion contractures |
Winchester syndrome | AR | MMP14 | Skin: Sclerodermatous skin disease (patchy, dark, leathery) Skeletal: Osteopenia, osteoporosis, arthropathy, joint restrictions Cardiovascular: Heart abnormalities Other: Corneal opacity, hypertrichosis, overgrowth of the gums, coarse facial features |
Multisystemic fibrosis-like hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP) | AD | FAM111B | Skin: Congenital poikiloderma (face and exposed skin), telangiectatic lesions, eczema-like lesions, epidermal atrophy Respiratory: Interstitial pulmonary fibrosis Muscle: Tendon contractures, muscle weakness, myopathy Other: Congenital poikiloderma on face |
Weill-Marchesani syndrome 1 | AR | ADAMTS10 | Skin: Sclerodermatous skin disease Skeletal: Joint stiffness, joint restrictions Cardiovascular: Heart defects, aortic valve stenosis, pulmonary valve stenosis, ductus arteriosus, ventricular septal defect Neurological: Mild mental retardation Other: Short stature, brachydactyly, eye anomalies |
Weill-Marchesani syndrome 4 (WMS-like syndrome) | AR | ADAMTS17 | Skin: Sclerodermatous skin disease Skeletal: Joint stiffness Cardiovascular: Cardiac defects (uncommon) Other: Short stature, severe myopia, acute and/or chronic glaucoma, cataract |
Frank-Ter Haar Syndrome | AR | SH3PXD2B | Skin: Sclerodermatous skin disease (face), acne conglobata Skeletal: Osteolysis, osteopenia, osteoporosis, shortened bowed long bones, flexion deformities of fingers Other: Growth retardation, glaucoma, brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, malocclusion |
Geleophysic dysplasia 3 | AD | LTBP3 | Skin: Sclerodermatous skin disease Skeletal: Joint restrictions, delayed bone age Cardiovascular: Pulmonary hypertension Respiratory: Dyspnea, tracheal stenosis, respiratory failure Other: Short stature, marked brachydactyly, hepatomegaly |
Geleophysic dysplasia 1 | AR | ADAMTSL2 | Skin: Sclerodermatous skin disease Skeletal: Osteopenia, shortened long tubular bones, short hands and feet, joint contractures, joint restrictions, delayed bone age Cardiovascular: Progressive cardiac valvular thickening, cardiac failure, mitral stenosis, tricuspid stenosis, aortic stenosis Respiratory: Tracheal stenosis, respiratory insufficiency Neurological: Developmental delay, seizures Other: Short stature, ‘happy’ appearance with full cheeks, shortened nose, wide mouth, hepatomegaly |
Mucolipidosis II Alpha/Beta | AR | GNPTAB | Skin: Sclerodermatous skin disease, cavernous hemangioma Skeletal: Skeletal abnormalities, moderate joint restrictions, osteopenia Cardiovascular: Cardiomegaly, congestive heart failure, hypertrophic cardiomyopathy, cardiac murmur, aortic insufficiency Respiratory: Recurrent bronchitis, recurrent pneumonia Abdomen: Umbilical hernia, hepatomegaly Neurological: Developmental delay, severe psychomotor retardation Other: Progressive failure to thrive, Hurler-like body configuration, marked growth retardation, coarse facial features, abdominal protuberance, hoarse voice |
Hypertrophic Osteoarthropathy, Primary, Autosomal Recessive 1 / Cranioosteoarthropathy | AR | HPGD | Skin: Sclerodermatous skin disease, pachydermia, furrowed, oily, seborrhea, redundant, palmoplantar hyperkeratosis, eczema Skeletal: Digital clubbing, osteoarthropathy, arthralgia, arthritis, swollen joints, decreased joint mobility, osteopenia, osteoporosis Cardiovascular: Congenital heart disease, patent ductus arteriosus Other: Marfanoid habitus, coarse facial features, furrowed forehead, ptosis, thickened eyelids, turtle-backed nails, digital clubbing |