Inherited Connective Tissue Disorders Flashcards
What is the most common form of cutis laxa/generalized elastolysis?
Autosomal Recessive
What genes are involved in the AD form of cutis laxa/generalized elastolysis?
Elastin (ELN) and fibulin 5 (FBLN5)
What do the mutations in ELN or FBLN5 in cutis laxa/generalized elastolysis lead to?
Dysregulation of elastic fiber network in skin mainly (uncommon to get internal involvement)
What age do patients with AD cutis laxa/generalized elastolysis present?
Early adulthood
What is one major difference between AD and AR cutis laxa/generalized elastolysis?
The AR form has severe internal organ involvement
What genes are involved in the AR forms of cutis laxa/generalized elastolysis?
FBLN5, EFEMP2/FBLN4, LTBP4, ATPase, ATP6V0A2 and others
What is the XLR form of cutis laxa?
Was called occipital horn syndrome (previously know as EDS IX)
- Caused from mutations in ATPase, Cu2+ transporters, alpha polypeptide (ATP7A) (allelic to menkes dz)
Clinical appearance of cutis laxa?
Loose, sagging skin w/ reduced elasticity and resilience
- Pts also get deep voice from vocal cord laxity
Histology of cutis laxa?
Sparse and or fragmented elastic fibers
Clinical findings of AD cutis laxa?
Loose, sagging skin w/ reduced elasticity and resilience, cardiac valve abnormalities, aortic dilation (variable), emphysema (uncommon), and hernias
Clinical findings in AR cutis laxa type I?
Potentially fatal involvement of the lungs (hypoplastic and emphysema)
- cardiovascular abnormalities (aortic tortuosity and aneurysms)
- Inguinal/diaphragmatic/umbilical hernias
- GI diverticula or genitourinary diverticula
- Joint laxity, arachnodactyly, and fractures
Clinical findings in AR cutis laxa type II?
Craniofacial abnormalities, delayed growth and development, cutaneous findings can be mostly acral, pachygyria (IIA) and absent corpus callosum (IIB), translucent skin (IIB), joint laxity, strabismus/myopia, improves with age
Clinical findings in AR cutis laxa type III?
- Developmental delay/dystonia/neurologic deterioration
- Progeroid appearance
- Reduced subcutaneous fat
- Reduced subcutaneous fat
- Athetosis
- Hyperammonemia
- Corneal clouding/cataracts
Clinical findings in XLR cutis laxa (Occipital horn syndrome)?
- Easy bruising and coarse hair
- Tortuous arteries
- Genitourinary diverticula
- Inguinal, diaphragmatic and umbilical hernias
- Long face w/ high forehead and hooked nose
- Wedge-shaped occipital calcifications
- Hip dislocations
What is acquired cutis laxa?
Primarily in adults w/ sagging skin and little associated internal involvement
- Cutaneous involvement tends to be primarily acral; generalized involvement usually occurs on face/neck
- Can be associated with drugs (penicillamine and isoniazid), other disorders (cutaneous lymphoma, Sweet syndrome-like eruption, interstitial granulomatous dermatitis, and cutaneous mastocytosis and systemic dz (RF, sarcoidosis, SLE, and infectious disorders
What are the genetics of pseudoxanthoma elasticum?
AR
-Mutations in ABCC6 (ATP-binding cassette, subfamily C, member 6) gene –> secondary mineralization of the elastic tissue of the eyes, skin and arteries
When does pseudoxanthoma elasticum tend to present?
Childhood or the 2nd/3rd decade of life
Cutaneous manifestations of pseudoxanthoma elasticum?
- Thin, yellowish papules in flexural areas arising in the first or second decades of life
- typically first appear on the lateral aspects of the neck
- Papules coalesce to form cobblestone-like plaques resembling “plucked chicken skin”
- Antecubital and popliteal fossae, wrists, axillae, groin, and periumbilical area (in multiparous women) are involved
- Loss of recoid and sagging skin in axillae and grown
- Can get yellow papules in the oral/anogenital mucosa
What is perforating pseudoxanthoma elasticum?
Happens in advanced dz: increased dermal calcium deposition and extrusion of yellowish material through the epidermis
What are the ocular manifestations of pseudoxanthoma elasticum?
- Asymptomatic angioid streaks, usually occur in the first decade. This usually looks like “owl’s eyes” paired areas of hyperpigmented spots straddling an angioid streak
- macular degeneration, optic drusen, retinal hemorrhage, mottling of the retinal pigment epithelium (most prevalent ophthalmologic finding, can precede the formation of angioid streaks
What other conditions can have angiod streaks?
Paget’s disease of bone, sickle cell anemia, thalassemia, EDS, lead poisoning, and age-related degeneration
What are the cardiovascular manifestations of pseudoxanthoma elasticum?
Intermittent claudication, loss of peripheral pulses, renovascular hypertension, mitral valve prolapse, angina/myocardial infarction, and stroke
-Progressive clacification of elastic media and intima –> atheromatous plaques involving predominantly medium-sized arteries (esp in extremities)
What are the GI manifestations of pseudoxanthoma elasticum?
Gastric artery hemorrhage (aneurysms), hematemesis, epistaxis
What are the obstetric pseudoxanthoma elasticum?
Increased risk of first trimester miscarriage and maternal cardiovascular complications
What is the histology of pseudoxanthoma elasticum?
Distorted, basophilic, and fragmented calcified elastic fibers in mid/deep reticular dermis
What are the main causes of morbidity and mortality in pseudoxanthoma elasticum?
GI hemorrhage, cerebral hemorrhage, atherosclerotic dz and myocardial infarction
What stains would be useful for pseudoxanthoma elasticum?
Von kassa for calcium and Giemsa for the elastic fibers
What are the mutations in osteogenesis imperfecta?
Type I collagen –> fragile bones (poor cortical modeling and less trabecular bone formation)
What are the different types of osteogenesis imperfecta?
There are 8 types, but 4 main ones
I: most common (50%), generally mild
II: Most severe form, fatal in the perinatal period
III: Progressive and deforming
IV: normal lifespan, we don’t discuss in derm much
What are the cutaneous findings of osteogenesis imperfecta?
Thin, atrophic, and translucent skin
- Easy bruisability
- Scars can be atrophic or hypertrophic
MSK findings in osteogenesis imperfecta?
Hyperlaxity of ligaments and hypermobility of joints
- Brittle bones + fractures (often of skull, long bones and vertebrae) This can happen in utero in severe forms
- Scoliosis
- Beaded ribs (from multiple fractures)
- Limb deformities
Eyes/ears findings in osteogenesis imperfecta?
Blue sclerae in 90% of pts
- otosclerosis w/ hearing loss can happen during adolescence
- fragile disoclered teeth too
Cardiac findings in osteogenesis imperfecta?
Mitral and aortic valve prolapse/dilation and regurgitation
- cystic medionecrosis of aorta
Neurologic findings associated with osteogenesis imperfecta?
Macrocephaly, hydrocephalus, syringomyelia, and basilar invagination
What is the prognosis for the main 4 types of osteogenesis imperfecta?
I and IV = normal life span
II = death in perinatal period
III= Increased mortality in 3rd/4th decade due to respiratory failure from Kyphoscoliosis
What genes are mutated in classical (formally type I and II) ehlers-danlos syndrome (EDS)
COL5A1, COL5A2
What is the inheritance of classic type Ehlers-Danlos syndrome?
AD
Skin findings in classical type Ehlers-Danlos syndrome?
Velvety, soft, and doughy consistency of skin, marked hyperextensibility of skin, poor wound healing (cigarette paper scars), widened atrophic cutaneous scares (“fishmouth sounds”), piezogenic pedal papules, fragile blood vessels leading to hematomas and easy bruising, subcutaneous spheroids (fat lobules that have calcified after losing blood supply, Molluscoid pseudotumors –> associated with scars over knees and elbows , blue sclerae, Gorlin’s sign: ability to touch tip of nose with tongue
What are the joint changes in the classical type of Ehlers-Danlos syndrome?
Double-jointed figures, generalized joint hypermobility, frequent subluxation of larger joints, chronic pain, kyphoscoliosis, pes planus
What MSK findings can be seen in classical type Ehlers-Danlos syndrome?
Hypermobility, double-jointed fingers, frequent subluxation of larger joints, chronic joint and limb pain
- Kyphoscoliosis
- Pes planus
GI manifestations of classical type Ehlers-Danlos syndrome?
Hiatal/inguinal hernia, postoperative hernias, and anal prolapse
-GI bleeding/rupture
Cardiac findings of classic-type Ehlers-Danlos syndrome?
Mitral valve prolapse
- Aortic root dilation
What gene is mutated in the vascular type of Ehlers-Danlos syndrome?
COL3A1
What is the inheritance pattern of vascular type of Ehlers-Danlos syndrome?
AD
What are the cutaneous findings of vascular type of Ehlers-Danlos syndrome?
Easy bruising, thin and translucent skin with visible underlying blood vessels
- Skin is not hyperextensible, but can be fragile
- Lack of subcutaneous fat
- Blue sclera (>90%)
- Acrogeria
What are the facial features associated with vascular type of Ehlers-Danlos syndrome?
thin, pinched nose; prominent sunken eyes, thin upper lip; and lobeless ears
MSK findings of vascular type of Ehlers-Danlos syndrome?
Small joint hypermobility
What are the vascular complications seen in vascular type of Ehlers-Danlos syndrome?
Arterial (including aorta) dissection, rupture, and aneurysm of medium-sized vessels
- Spontaneous ruepture of arteries may occur during childhood and incidence peaks during 3rd and 4th decades
- Intestinal rupture is common, sigmoid colon is the most common site
- Can get intracranial aneurism and CVA
What are the obstetric complications of vascular type of Ehlers-Danlos syndrome?
Uterine and arterial rupture, massive postpartum hemorrhage, and severe laceration from tearing at vaginal delivery
Important prognostic considerations in the vascular type of Ehlers-Danlos syndrome?
Life-threatening risk of the blood vessel and oran rupture can happen in the 3rd or 4th decade of life. Maternal mortality can occur from uterine or arterial rupture
What is the most life-threatening form of Ehlers-Danlos syndrome?
The vascular type of Ehlers-Danlos syndrome
What is the gene and inheritance pattern of the hypermobility form of Ehlers-Danlos syndrome?
TNXB, AD/AR
What are the main findings in the hypermobility form of Ehlers-Danlos syndrome?
Not prone to life-threatening complications
- Severe joint laxity, recurrent dislocations/subluxations, and chronic pain/arthritis
- Mitral valve prolapse
- autonomic dysfunction: postural orthostatic tachycardia syndrome (POTS)
- GI and urinary sx’s.
What is the gene mutated and the form of inheritance in the kyphoscoliotic type of Ehlers-Danlos?
Lysyl hydroxylase 1 (PLOD1), AR
What are the findings in the kyphoscoliotic type of Ehlers-Danlos?
Severe scoliosis
- Severe muscle hypotonia
- Ruptured globe, blindness, retinal detachment, or keratoconus
- Marfanoid appearance
- Osteopenia
- Ascorbic acid supplementation may help
What are the genes involved and the mode of inheritance for the arthrochalasic form of Ehlers-Danlos syndrome?
COL1A1, COL1A2, AD
What are the findings in the arthrochalasic form of Ehlers-Danlos syndrome?
- Severe joint hypermobility with frequent dislocations
- Congenital hip dislocations
- Skin hyperextensibility
- Easy bruising and vascular fragility
- Muscle hypotonia
- Kyphoscoliosis (spinal curvature)
- Fragile skin with atrophic (thin) scarring
What is the gene mutation and mode of inheritance for the dermatosparaxis type of Ehlers-Danlos syndrome?
ADAMTS2, AR
Cutaneous findings in the dermatosparaxis type of Ehlers-Danlos syndrome?
Severe fragility, sagging, redundant skin and bruising
What should you think of if you see hyperextensible skin with scaring (especially pre-tibial area) and bruising with bad tooth loss and periodontal dz?
Periodontitis type of Ehlers-Danlos
What is the mutation and inheritance pattern of Marfan Syndrome?
FBN1 gene (fibrillin-1), AD
What are the “marfanoid” features seen in Marfan syndrome?
Tall w/ long extremities
- can also include large arm span (greater than height)
- after puberty, upper segment (vertex to pubis) to lower segment (pubis to sole) ratio is <0.86
Cutaneous findings of Marfan syndrome?
Lack of subcutaneous fat, presence of striae on upper chest, arms, thighs, and abdomen, and increased risk of elastosis perforans serpiginosa
Skeletal findings of Marfan syndrome?
Arachnodactyly
- Kyphoscoliosis, precuts excavatum, and dolichocephaly
- Pes Planus
- Joint laxity, patellar discoloration, and hip dislocation
What are the ocular findings of Marfan syndrome?
Ectopia lentis (upward lens displacement; 60% of patients)
- Ocular globe elongation leading to myopia (40%)
- Retinal detachment, cataracts, and glaucoma
Cardiovascular findings of Marfan syndrome?
Dilation of ascending aorta –> regurgitation, CHF, dissection/aneurysm, and rupture
-Mitral valve prolapse
-left ventricular dilation
Pulmonary manifestations of Marfan syndrome?
Spontaneous pneumothorax, apical blebs, and bullous emphysema
What is the gene and the inheritance pattern involved in Buschke-Ollendorf syndrome?
AD
mutation in LEMD3/MAN1 –> increased TGF-beta signaling
What lesion is classically associated with Buschke-Ollendorf syndrome?
Dermatofibrosis lenticularis disseminata
- This is a collagen-type nevus on buttocks, proximal trunk and limbs. Looks like symmetric small, uniform, yellow to skin-colored dermal papules coalescing into plaques
What is the bone finding classically associated with Buscke-Ollendorf?
Osteopoikilosis (“spotted bones”)
- Asymptomatic circular densities in carpal bones, tarsal bones, phalanges of hands and feet, pelvis and epiphyses and metaphyses of long bones
- Often noted incidentally on plain films (1-10mm round opacities)
Histology of Buschke-Ollendorf syndrom?
Abundant thickened collagen fibers and elastic fibers (often fragmented and lcusted into nets)
What genes are involved in infantile systemic hyalinosis and juvenile hyaline fibromatosis?
AR, ANTXR2/CMG2 gene —> abundance of hyalinized fibrous tissue in skin and internal organs
Presentation of infantile systemic hyalinosis?
Presents within the first 6 months of life w/ cutaneous, mucosal, skeletal and internal organ involvement and death in early childhood
What is the presentation of juvenile hyaline fibromatosis?
Presents during early childhood with cutaneous, mucosal, and skeletal/joint (often debilitating) involvement only; survival into adulthood
What are the cutaneous findings of infantile systemic hyalinosis and juvenile hyaline fibromatosis?
Thickened skin and hyperpigmentation overlying bony prominences is characteristic of the ISH
- Perianal nodules
- Small pearly papules on ears and face (perinasal and perioral)
- Scalp nodules are characteristic of JHF
Oral findings of infantile systemic hyalinosis and juvenile hyaline fibromatosis?
Thickening of oral mucosa
- gingival hypertrophy
- marked curvature of dental roots
- Replacement of periodontal ligament by hyaline fibrous material
- Feeding difficulty
What are the MSK findings in infantile systemic hyalinosis and juvenile hyaline fibromatosis?
Debilitating joint contractures and tumors
- Osteolytic bone lesions are characteristic of JHF
Which condition, infantile systemic hyalinosis or juvenile hyaline fibromatosis, involves visceral findings?
Infantile systemic hyalinosis
Histology of infantile systemic hyalinosis and juvenile hyaline fibromatosis?
Increased # of of fibroblasts embedded in hyalinized connective tissue stroma that is homogenous, amorphous, and acidophilic (PAS +)
Prognosis of infantile systemic hyalinosis and juvenile hyaline fibromatosis?
ISH: death within 2 years of age from recurrent pulmonary infection and GI complications
JHF: survival into adulthood, but death often by 4th decade
What is the inheritance pattern and gene mutations in lipoid proteinosis?
AR due to mutations in extracellular matrix protein 1 (ECM1) gene
What are the characteristic findings of lipoid proteinosis?
Thickening of basement membrane and deposition of hyaline material in dermis –> characteristic thickening of the skin, mucous membranes and certain viscera
What is the first clinical sign of lipoid proteinosis?
Horse cry or weak cry from infiltrated vocal cords
What are the two stages of cutaneous lesion emergence in lipoid proteinosis and when do they occur?
Occurs during the first 2 years of life
- Stage I: Vesicles and hemorrhagic crusts involving the face, extremities, and oral mucosa develop in association with trauma and resolve w/ “ice-pick” scars
- Stage II: Increased hyaline deposition within the dermis which turn to yellow, waxy and coalescing papules/nodules on the face/neck and extremities; beaded eyelid papules resembling “string of pearls” (50%); verrucous nodules on elbows/knees/hands
Other cutaneous manifestations of lipoid proteinosis?
Infiltrating by yellow papules/plaques of mucosa of pharynx, soft palate, tonsils, and lips
- Thickened “woody” tongue; inability to protrude tongue (shortened frenulum)
- Respiratory difficulty a/w upper respiratory tract infections may require tracheostomy; occasionally fatal in infancy
Neurology findings in lipoid proteinosis?
Seizures and neuropsychiatric sx’s, a/w pathognomonic sickle or “bean-shaped” calcifications in temporal lobes or hippocampus
Histology of lipoid proteinosis?
Deposition of amorphous or laminated basement membrane-like material containing collagen (types II and IV) and laminin around blood vessels, dermal-epidermal junction, adnexal epithelia, and in connective tissues (appears as vertically oriented pink dermal deposits)
- Deposits are PAS +
What is the inheritance pattern and gene involved in Focal dermal hypoplasia (Goltz syndrome)?
X-linked dominant (XLD) and the gene PORCN (porcupine) –> regulates of WNT, signaling proteins which are critical for skin, bone, teeth, and other structures
What sex predominantly gets Focal dermal hypoplasia (Goltz syndrome)?
Women (90%); lethal in males
Cutaneous manifestations of Focal dermal hypoplasia (Goltz syndrome)?
Widely distributed linear/Blaschkoid areas of hypoplasia/atrophy of the skin, with telangiectasias
- Soft, yellow to reddish-yellow nodular outpouchings caused by herniation of subcutaneous fat through the thinned dermis
- Dysmorphic facies (notched nasal ala and malformed ears)
- Large cutaneous ulcers (from congenital absence of skin) that heal w/ atrophic scarring
- Streaky hyper- and or hypopigmentation
- Rdd (“raspberry-like”) papillomas; favors lips, anogenital region, larynx and acral
Skeletal findings in Focal dermal hypoplasia (Goltz syndrome)?
Oligodactylyl, syndactyly, ectrodactyly (lobster claw deformity) and polydactyly
- Microcrania, asymmetric development of the skull, pointed mandible and deviated nasal septum
- Scoliosis kyphosis, spina bifida occulta, rudimentary tail and fusion of vertebral bodies
- Osteopathia stirata: vertical striations in long bone metaphyses on x-ray (celery bones)
What are the ophthalmologic manifestations Focal dermal hypoplasia (Goltz syndrome)?
Colobomas of iris/choroid/retina/optic disc
- strabismus
- Anophthalmia, microphthalmia, and incomplete development of the retinal and optic nerve
- Hypopigmented/hyperpigmented retina, cloudy vitreous and subluxation of lens
Dental abnormalities in Focal dermal hypoplasia (Goltz syndrome)?
Underdeveloped, hypoplastic, or absent teeth
- Delayed eruption of primary dentition
- Notched incisors
- Enamel hypoplasia
- Severe malocclusion if the mandible is malformed
Histology of Focal dermal hypoplasia (Goltz syndrome)?
Markedly decreased/absent dermis with herniated fat located abnormally close to epidermis
What is the inheritance pattern and gene involved in Congenital contractual arachnodactyly (Beals syndrome and distal arthrogyrposis type 9)?
AD, fibrillin 2 (FBN2) gene
What are the findings in Congenital contractual arachnodactyly (Beals syndrome and distal arthrogryposis type 9)?
Crumpled ears, marfanoid habitus, arachnodactyly, congenital contractures of small and large joints that usually improve over time, kyphoscoliosis, and pectus excavatum
- Facial features: High forehead, down-slanting palpebral fissures hypertelorism, anteverted nostrils, low-set and abnormal auricles, retromicrognathia, short neck
- Cardiac manifestations: mitrial valve prolapse and aortic root dilation
What is the inheritance pattern and mutated gene in restrictive dermopathy (tight skin contracture syndrome)?
AR, Lamini-A (LMNA gene) or zinc metalloproteinase STE24 (ZMPSTE24) –> increased prelamin A (accumulates in the nucleus –> nuclear membrane toxicity
Prenatal manifestations in restrictive dermopathy?
Intrauterine course characterized by fetal akinesia and hypokinesia deformation sequence
- Polyhydramnios with reduced fetal movements noted at about 31 weeks
- Clavicular hypoplasia develops in utero
- Birth typically occurs before 35 weeks of gestation as a result fo PROM
Cutaneous manifestations in restrictive dermopathy?
- Taut translucent, thin skin with erosions and fissures
- skin tears in response to the stress of delivery
- complications from infection and dehydration
- Increased transepidermal water loss leads to hypoalbuminemia and electrolyte imbalance
Dysmorphic facies seen in restrictive dermopathy?
- Fixed round open mouth and micrognathia
- Small pinched nose
- Hypertelorism
- Enlarged fontanelles
- Widened cranial sutures
Cause of death in restrictive dermopathy?
Restrictive pulmonary dz from thoracic stiffness and severely restricted movements –> occurs shortly after birth
What is the gene and inheritance pattern of stiff skin syndrome?
AD, mutations in fibrillin-1 (FBN1)
Clinical findings in stiff skin syndrome?
The progressive development of stony-hard skin on thighs, buttocks, lower back, and shoulder
- Joint contractures (esp large joints), scoliosis, tiptoes gait, narrow thorax in relation to arm girdle, restrictive pulmonary changes, growth retardation, and postural and thoracic wall irregularities
What is the histology of stiff skin syndrome?
Fascial sclerosis, increased fibroblast cellularity, thickened sclerotic horizontally oriented collagen bundles in the deep reticular dermis and or subcutaneous septa
