72 - Genetic Disorders affecting Dermal Connective Tissue Flashcards
A variety of genetically and clinically heterogeneous inherited conditions characterized by varying degrees of skin fragility and hyperextensibility, and joint hypermobility
Ehlers-Danlos syndromes
Most clinically significant EDS subtype because of the risk of arterial or major organ rupture
Vascular EDS
Overlap with joint hypermobility syndrome interferes with prevalence estimates, but it inclusive definitions are used, it may be the most common subtype of EDS
Hypermobility type
The skin in classical EDS patients is hyperextensible, but recoils easily to its normal position after stretching, in contrast to the skin in
Cutis laxa
Hyperextensibility is present if the skin can be stretched beyond _____ cm on the distal forearms and/or dorsal hands and beyond _____ cm at the neck, elbow, and/or knees
1.5
3
Joint hypermobility is frequent in cEDS and often greatest at the
Fingers and/or wrists
Chronic and excessive joint hypermobility frequently leads to
Early-onset osteoarthritis
Most patients with cEDS or hypermobile EDS are able to extend the tongue to touch the tip of the nose
Gorlin sign
Gorlin sign can be displayed by approximately _____% of individuals without inherited disorders of connective tissue
10
AR form of EDS resembling a mild version of cEDS
Classical-like EDS
Classic quadrad of vEDS
Characteristic facial appearance
Thin, transluscent skin with a prominent venous pattern
Extensive bruising or hematomas
Vascular or visceral rupture (or both)
The development of _____ before the age of 20 years can be a clinical indicator of vEDS
Superficial venous insufficiency
Have soft, velvety skin with occasional mild hyperextensibility but no fragility
Have abnormal skin, with changes similar to, yet more subtle than cEDS or vEDS
Hypermobility EDS
Used to distinguish hEDS skin from normal
Rubber glove skin test
Three distinct phases of clinical progression of hEDS
Hypermobility phase
Pain phase
Stiffness phase
More than 90% of cEDS cases are caused by AD mutations in the alpha1 or alpha2 chain of
Type V collagen
Type V collagen is a minor fibrillar collagen that relates
Collagen fibril diameter
Patients with features of cEDS exhibiting defective Type I collagen are at high risk for
Vascular rupture, similar to the complications of the vEDS subtype
Electron microscopy of the skin in EDS reveals
Thickened collagen fibrils
vEDS is associated with dominant negative mutations in the _____ gene, resulting in reduced amounts of _____ in the dermis, vessels, and viscera
Type III collagen
Type _____ collagen plays an important role in the integrity of the walls of both blood vessels and hollow organs, in addition to the upper dermis
III
Routine histopathologic examination from EDS
Typically normal
Electron microscopy demonstrates
Abnormalities in the appearance of collagen fibrils
The kyphoscoliotic and hypermobility forms of EDS must be distinguised from
Marfan syndrome
Molluscoid pseudotomors of the lower legs may mimic
Subcutaneous granuloma annulare
vEDS exhibits significant clinical similarities to _____, an aortic aneurysm syndrome caused by mutations in TGF-beta receptors 1 and 2
Loeys-Dietz syndrome type 2
Fatigue is present in more than 75% of EDS patients of most types. It appears most often in
hEDS
Marfan syndrome is a generalized connective tissue disorder exhibiting abnormalities of 3 primary organ systems
Ocular
Skeletal
CV
Ocular findings in Marfan syndrome
Typically lens dislocation
Skeletal findings in Marfan syndrome
Excessive extremity length
Loose joints
Anterior chest deformities
Kyphoscoliosis
CV findings in Marfan syndrome
Classically
Aortic aneurysm
Mitral valve redundancy
The “marfanoid habitus” is characteristically _____ (tall and thin), with a lower-body segment (pubic symphysis to floor) that is longer than the upper segment (height minus lower segment)
Dolichostenomelic
Distal bones are excessively long
Arachnodactyly
Sternal depression
Pectus excavatum
Sternal projection
Pectus carinatum
Often detected during the newborn period
May be the first sign of Marfan syndrome
Dislocation of the hip
Thumb extends well beyond the ulnar border of the hand when overlapped by the fingers
Thumb or Steinberg sign
Thumb overlaps the fifth finger as they grasp the opposite wrist
Wrist or Walker-Murdoch sign
Most common CV abnormality in Marfan syndrome
Medial necrosis of the aorta
Death in Marfan patients usually occurs in adulthood as a result of CV sequelae, most commonly secondary to _____, leading to aortic dissection or rupture and pericardial tamponade
Dilation of the aortic root
Most common cutaneous manifestation of Marfan syndrome
Lack of subcutaneous fat
Presence of striae
Y/N: Pediatric patients often do not meet international criteria for the diagnosis if Marfan syndrome at the time of first examination
Yes
Standard histopathology of affected skin in Marfan syndrome
Normal
Electron microscopy findings in Marfan syndrome
Abnormal thickness, array, and shape of dermal collagen
Marfan syndrome results from heterozygous mutations in the
Profibrillin 1 gene
350-kDa glycoprotein that is a major component of extracellular matrix microfibrils, which are structural components of the zonular fibers of the suspensory ligament of the lens and associated with elastic fibers in the aorta and skin
Fibrillin
Also known as Gronblad-Strandberg syndrome
Pseudoxanthoma elasticum
Rare heritable ectopic mineralization disorder exhibiting progressive deposition of calcium hydroxyapatite on elastic tissue
Pseudoxanthoma elasticum
Mode of inheritance of pseudoxanthoma elasticum
AR
PXE is more severe in
Female patients
Yellowish, flat-topped, discrete, and confluent papules in the skin creases of the sides and nape of the neck, perineum, axillae, umbilicus, and flexural folds with skin redundancy that increases with advancing age
PXE
Cutaneous changes of PXE are often termed
Plucked chicken skin
Dermatologic features of PXE generally begin in the ______ decade
Second
Prominence of the horizontal and oblique mental creases (which separate the lower lip from the chin) prior to 30 years if age is highly specific for
PXE
Atrophoderma reported in patients with PXE
Elastosis perforans serpiginosa
Most common ophthalmologic finding in PXE
Angioid streaks
Precede angioid streaks and are the more common ocular finding in children with PXE
Peau d’orange retinal changes
Mutated gene in typical PXE
ABCC6
Putative efflux transporter expressed primarily in the basolateral plasma membrane of liver hepatocytes and proximal tubules of the kidney, 2 sites not affected by PXE
ABCC6 protein
The histologic changes on biopsy of lesional skin with PXE are diagnostic, showing
Distinctive broken curls of basophilic elastic fibers
Electron microscopy of PXE shows
Calcification in a centripetal pattern with elastic fibers
Most common forms of cutis laxa
Recessive
Skin is inelastic and appears pendulous; hyperextensible, but does not resume or slowly resumes its normal shape after strerching
Bloodhound-like facial appearance
Signs of skin fragility, easy bruising, or abnormal scarring are typically absent in contrast to EDS
Cutis laxa
Has been termed Walt Disney dwarfism
Loose skin acrally, as well as on the face and stomach
Oblique furrows from the lateral border of the supraorbital ridge to the outer canthus are a recently reported distinguishing finding
Gerodermia osteodysplastica
Abnormalities in _____ synthesis, stabilization, or degradation may all lead to the clinical phenotype of CL
Elastic fiber
Special stains for elastic tissue of skin biopsy specimens of CL demonstrate
Significantly decreased or absent dermal elastic fibers
Remaining fibers are often clumped, short, granular, and fragmented
Involve the head and neck and progress in a cephalocaudal direction
Development of CL is preceded by an inflammatory eruption (urticaria, erythema multiforme, eczematous eruption) in approximately 50% of cases
Usually begins In adulthood
Type I-acquired CL
Most frequent cause of death in acquired CL
Emphysema
Postinflammatory elastolysis characterized by more localized, well-demarcated, nonpruritic erythematous plaques that extend peripherally and have a hypopigmented center
Type II-acquired CL (Marshall syndrome)
Acquired CL may develop after drug exposure to
Penicillin
D-penicillamine
Isoniazid
Acquired CL is one of the primary presenting features of _____, an AD condition resulting from mutations in gelsolin, an actin-modulating protein
Hereditary gelsolin amyloidosis (AGel amyloidosis)
Generalized skin laxity and inguinal hernias in infants born to mothers who were administered D-penicillamine during pregnancy
Resolved during the first year of life
Neonatal CL
Mode of inheritance of Bushcke-Ollendorff syndrome
AD
Characteristic connective tissue nevi appear as collections of skin-colored to yellow papules or plaques (dermatofibrosis lenticularis disseminata) most commonly located on the buttocks, proximal trunk, and limbs
Buschke-Olendorff syndrome
Histopathologic examination of lesional skin may show increased amounts of elastic tissue (elastoma) or collagen
Buschke-Olendorff syndrome
Discrete spherical areas of increased radiodensity, most frequently noted in the epiphysed and metaphyses of long bone, pelvis, scapulae, carpal, and tarsal bones
Osteopoikilosis
Buschke-Olendorff syndrome
Complications of Buschke-Olendorff syndrome
None reported
Buschke-Olendorff syndrome results from loss-of-function mutations in
LEMD3 gene
Also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease
Lipoid proteinosis
Lipoid proteinosis is relatively common in
Namaqualand area of Northern Cape Province in South Africa
Most reliable clinical signs of diagnosing LP
Hoarse voice
Thickened sublingual frenulum
Earliest finding in LP
One of the most striking and consistent features
Hoarseness (noted as faint or weak cry)
Beaded papules along the eyelid margins
Considered a pathognomonic clinical finding of LP
Moniliform blepharosis
LP has been used as a model disorder for investigation of the function of the
Amygdala
Mode of inheritance of LP
AR
LP is caused by mutations in the gene encoding
ECM-1
Light microscopic evaluation of lesional sections reveals deposition of amorphous eosinophilic material at the DEJ, perivascularly, and along adnexal epithelia
Deposition of hyaline material in the dermis, often perpendicular to the basement membrane
LP
