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]

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

AD Autosomal dominant, AR Autosomal recessive, SSc systemic sclerosis