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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
  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)
  
Respiratory Recurrent respiratory infections
Emphysema
Emphysema Laryngomalacia
Tracheomalacia
Bronchomalacia
Emphysema
Hypoplastic lung
   Laryngomalacia
Bilateral pneumothorax (in early infancy)
   
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
   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)
 
Miscellaneous   Relatively mild cutis laxa, associated with severe vascular abnormalities
Massive aortic aneurysm can cause airway compression in affected infants
  Skin abnormalities tend to decrease with age   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
  
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   Umbilical hernia
Gastroesophageal reflux
Diverticula
Pyloric stenosis
Intestinal dilatation, tortuosity
Rectal prolapsed
Feeding problems in infancy Gastroesophageal reflux   Inguinal hernia
Umbilical hernia
  Hernias
Neurologic   Hypotonia
Brain hemorrhage
  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