Table 2 Diverse clinical features of autosomal recessive cutis laxa (ARCL) associated with each gene (
From: New insight into clinical heterogeneity and inheritance diversity of FBLN5-related cutis laxa
INHERITANCE | ARCL | ||||||||
|---|---|---|---|---|---|---|---|---|---|
Phenotypes | IA; MIM 219100 | IB; MIM 614437 | IC; MIM 613177 | IIA MIM 219200 | IIB MIM 612940 | IIC MIM 617402 | IID MIM 617403 | IIIA MIM 219150 | IIIB MIM 614438 |
Genes | FBLN5 | FBLN4 | LTBP4 | ATP6V0A2 | PYCR1 | ATP6V1E1 | ATP6V1A | ALDH18A1 | PYCR1 |
Skin | Loose redundant skin Excessive skin folds Normal wound healing No skin hyperelasticity Increased vascularization, reduced collagen bundle size Underdeveloped elastic fibers in dermis | Velvety skin Normal scarring Collagen bundles smaller than normal Vascularization increased in upper dermis Underdeveloped elastic fibers, severe | Skin laxity | Loose redundant skin Excessive skin folds Abnormal, broken, shortened elastic fibers Decreased amount of elastin Sparse, brittle hair Coarse hair | Cutis laxa Loose redundant skin (especially of dorsum of hands and feet and anterior abdominal wall) Reduced skin elasticity Wrinkly skin Prominent veins | Generalized skin wrinkling Reduced elastic fibers Fragmented elastic fibers Loosely packed collagen fibers Variable diameters of collagen fibers | Generalized skin wrinkling Reduced elastic fibers Fragmented elastic fibers Loosely packed collagen fibers Variable diameters of collagen fibers | Thin, translucent skin Prominent superficial blood vessels due to thin skin Reduced number of elastic fibers Thin or fragmented elastic fibers Degenerated elastic fibers Sparse hair | Skin laxity |
Cardiovascular | Supravalvular aortic stenosis Vascular tortuosity Ascending aortic aneurysm | Thickened myocardium (rare) Bradycardia (rare) Aortic aneurysm Pulmonary artery aneurysm Arterial aneurysms, multiple Arterial tortuosity, general Venous tortuosity Arterial stenoses, multiple Vascular fragility Vascularization increased in upper dermis | Pulmonary artery stenosis Patent foramen ovale | Â | No vascular tortuosity | Severe dilation of ascending aortic root Moderate biventricular hypertrophy Mild dilation of right ventricle Reduced diastolic compliance of right ventricle Hypoplastic right ventricle Tricuspid valve stenosis Tricuspid insufficiency Aortic insufficiency Mitral valve prolapse Hypoplastic pulmonary artery Atrial septal defect Incomplete right bundle branch block | Atrial septal defect Dilated ascending aorta Tortuous aortic arch Cardiac failure Cardiomyopathy, hypertrophic Hypertrophy of interventricular septum, mild Long QT interval on electrocardiography (ECG) Incomplete right bundle branch block (ECG) | Â | Â |
Respiratory | Recurrent respiratory infections Emphysema | Emphysema | Laryngomalacia Tracheomalacia Bronchomalacia Emphysema Hypoplastic lung | Â | Â | Laryngomalacia Bilateral pneumothorax (in early infancy) | Â | Â | Â |
Head | Microcephaly Sagging cheeks | Microcephaly (rare) Prominent forehead Prominent premaxilla Micrognathia Dysplastic ears Low-set ears Prominent eyes Small palpebral fissures Downslanting palpebral fissures Hypertelorism, mild Bulbous nasal tip (in some patients) Hooked nose (in some patients) Depressed nasal bridge (in some patients) High-arched palate | Wide fontanels Micrognathia Flat midface Receding forehead Periorbital swelling Hypertelorism Wide nasal bridge Long philtrum Retrognathia | Microcephaly Midface hypoplasia Long philtrum Flat face Low-set ears Downslanting palpebral fissures Strabismus Myopia Short nose Anteverted nares Small mouth High-arched palate Dental caries | Microcephaly Large fontanel Broad, prominent forehead Sagging cheeks Aged appearance Triangular face Midface hypoplasia Prominent ears Blue sclerae Downslanting palpebral fissures (in 2 patients) Hypotelorism (in 2 patients) Deep-set eyes (in 2 patients) Prominent bulbous nose | Progeroid facies Mask-like triangular face Short forehead Long philtrum Prominent nasolabial folds Short pointed chin Low-set ears Misfolded helices Hypertelorism Entropion Nystagmus Prominent beaked nose High nasal root Broad nasal tip Broad columella Narrow nostrils High-arched palate Dental crowding | Progeroid facies Mask-like facies Triangular face Short forehead Receding chin Low-set ears Large ears Prominent ears Simple folded helices Hypertelorism Entropion Blepharophimosis Downslanting palpebral fissures Bilateral cataract Bulbous nose Broad nasal bridge | Brachycephaly Prominent forehead Large fontanelles Progeroid appearance Low-set ears Large ears Corneal opacities Cataracts Hypotelorism Hypertelorism Strabismus Myopia Salt-and-pepper retinopathy (in some patients) Pinched nose Hypoplastic alae Small mouth | Corneal opacification |
Genitourinary | External Genitalia (Male) Inguinal hernia External Genitalia (Female) Inguinal hernia Bladder Bladder diverticula | External Genitalia (Male) Inguinal hernia | External Genitalia (Male) Inguinal hernia Kidneys Hydronephrosis Bladder Bladder diverticula | Â | Â | External Genitalia (Male) Inguinal hernias, bilateral Internal Genitalia (Male) Cryptorchidism, bilateral | External Genitalia (Male) Micropenis Inguinal hernia Internal Genitalia (Male) Cryptorchidism, bilateral | Internal Genitalia (Male) Undescended testes (in some patients) | Â |
Miscellaneous | Â | Relatively mild cutis laxa, associated with severe vascular abnormalities Massive aortic aneurysm can cause airway compression in affected infants | Â | Skin abnormalities tend to decrease with age | Â | One Kuwaiti and one Iranian family with 2 sibs each have been reported (last curated March 2017) Variable congenital heart defects | Based on 3 patients (last curated March 2017) Variable cardiac and skeletal features may be present | Â | Â |
Skeletal | Congenital fractures Joint laxity Arachnodactyly | Joint hypermobility, generalized Fractures at birth Arachnodactyly Contractures of third to fifth fingers Arachnodactyly | Joint laxity Wide sutures Widely spaced first and second toes Plantar crease | Joint hyperextensibility Large anterior fontanel Delayed closure of the fontanel Congenital hip dislocation | Joint hyperextensibility Osteopenia Scoliosis (in 2 patients) Congenital hip dislocation Bowing of long bones Long digits (in 2 patients) Clasped thumb | Joint laxity Recurrent dislocations of temporomandibular joint Kyphoscoliosis Hip dysplasia Flexion contractures of knees Clenched hands Ulnar deviation of fingers Flat feet Club feet | Flexion contractures of all joints Dislocated hips Camptodactyly Club feet | Delayed bone age Hyperextensible joints Dislocated joints Wormian bones Wide cranial sutures Scoliosis Congenital hip dislocation Adducted thumbs Clenched fists Talipes equinovarus Pes calcaneovalgus | Congenital hip dislocation Patent anterior fontanelle Joint laxity -Scoliosis |
Abdomen | Umbilical hernias | Â | Umbilical hernia Gastroesophageal reflux Diverticula Pyloric stenosis Intestinal dilatation, tortuosity Rectal prolapsed | Feeding problems in infancy | Gastroesophageal reflux | Â | Inguinal hernia Umbilical hernia | Â | Hernias |
Neurologic | Â | Hypotonia Brain hemorrhage | Â | Delayed motor development Mental retardation Seizures Hypotonia Partial pachygyria Cobblestone lissencephaly, posterior frontal and parietal regions Board and poorly defined gyri Polymicrogyria Dandy-Walker malformation | Developmental delay Agenesis of the corpus callosum (in 2 patients) Hydrocephalus (in 2 patients) | Hypotonia | Hypotonia Seizures Speech delay Motor delay Enlarged ventricles with white matter involvement Periventricular parietooccipital gliosis Diffuse thickening of cerebral cortex Thin corpus callosum | Developmental delay Hypotonia Athetoid movements Hyperreflexia Seizures Grimacing | -Delayed motor development -Mental retardation -Hypotonia -Athetoid movements |
Other | Fetal overgrowth Pectus excavatum Diaphragmatic hernia | Fetal overgrowth (in some patients) Pectus excavatum Hypoplastic diaphragm Diaphragmatic hernia | Postnatal growth delay Diaphragm hernia or eventration Low muscle tone | Intrauterine growth retardation (IUGR) Failure to thrive Hypotonia Lipodystrophy Abnormal distribution of subcutaneous fat | Intrauterine growth retardation Failure to thrive Poor postnatal growth | Short stature Low weight Marfanoid habitus Sparse subcutaneous fat Marked muscular atrophy Reduced muscular strength | Failure to thrive Marfanoid habitus Abnormal fat distribution | Intrauterine growth retardation (IUGR) Failure to thrive Poor postnatal growth Pectus excavatum | Intrauterine growth retardation Postnatal growth delay |