Inherited Vascular Disorders Flashcards
What is the gene and mode of inheritance for Sturge-Weber syndrome?
Gene: GNAQ
- Somatic mosaic mutation
What is the clinical manifestation of Sturge-Weber syndrome?
Capillary malformation in V1 (ophthalmic branch of trigeminal nerve) and V2 (>V3) distribution
- Only 10% of pts w/ malformation in V1 will have SWS
- Combo of V2 and V3 = increased risk, 30% (also bilateral increases risk)
- Under the malformation, due to increased blood flow you get soft tissue and skeletal hypertrophy
What are some associated findings in Sturge-Weber syndrome?
Ipsilateral leptomeningeal capillary malformation (angiomatosis) of brain and eye
- Seizures (usually in first year of life if they happen)
- Developmental delay/intellectual disability
- Focal neurologic deficits
- Ophthalmologic: Glaucoma (most common) optho issues occur in 60%
What cutaneous finding portends to worse prognosis in Sturge-Weber syndrome?
Bilateral facial capillary malformations involving V1 distribution
This portends to an increased risk of seizures and more profound developmental delay
Workup for a pt w/ Sturge-Weber syndrome?
Optho consult, EEG (consider), MRI
What neuropathology can occur in Sturge-Weber syndrome?
Ipsilateral leptomeningeal capillary malformation (angiomatosis) of the brain and eye
What can be seen on CT exam in Sturge-Weber syndrome?
Cortical calcifications that resemble “tram track lines”
What is the most common ophthalmologic complication in Sturge-Weber syndrome? ?
Glaucoma
What is the main driver of prognosis in Sturge-Weber syndrome?
Leptomeningeal involvement
How many phakomatosis pigmentovascularis syndromes are there?
5
What are the phakomatosis pigmentovascularis syndromes?
They are widespread capillary malformation in addition to other cutaneous findings
Can have extracutaneous features like neurologic, MSK, and ocular findings
What is phakomatosis pigmentovascularis syndrome type I?
Port-wine stain + Epidermal nevus
What is phakomatosis pigmentovascularis syndrome type II?
Phakomatosis cesioflammea
PWS + dermal melanocytosis +/- nevus anemicus; most common form (85%); roughly 50% have major complications (Sturge-Weber, Parkes-Weber, or KTS
What is phakomatosis pigmentovascularis syndrome type III?
Phakomatosis spilorosa
PWS + nevus spills +/- nevus anemicus
What is phakomatosis pigmentovascularis syndrome type IV?
PWS + dermal melanocytosis + nevus spilus +/- nevus anemicus
What is phakomatosis pigmentovascularis syndrome type V?
Phakomatosis cesiomarmorata
Cutis marmorata telangiectatica congenita + dermal melanocytosis
What is the gene and inheritance of phakomatosis pigmentokeratotica?
HRAS, 2/2 post-zygotic mutation
What is the presentation of phakomatosis pigmentokeratotica?
Speckled lentiginous nevus (nevus spilus) in conjunction w/ nevus sebaceous
- Neurologic abnormalities may include: seizures, hemiparesis, and intellectual impairment
What vitamin deficiency can develop in phakomatosis pigmentokeratotica?
Hypophosphatemic vitamin D-resistant rickets
What is the gene involved in Klippel-Trenaunay syndrome?
PIK3CA
What is the clinical presentation in Klippel-Trenaunay syndrome?
Capillary malformation, venous malformation, and or lymphatic malformation with soft tissue and /or bone hypertrophy of one limb
Most common on lower extremitites (95%)
What are the potential complications in Klippel-Trenaunay syndrome?
Complications include the deep vein thrombosis and thrombophlebitis, GI bleeding, PE, vascular blebs and pain, and high-output cardiac failure
What is the gene and inheritance found in Proteus syndrome?
AKT1 (previously thought to be PTEN), and it is a somatic activating mutation (leads to progressive overgrowth)
What are the cutaneous lesions seen in Proteus Syndrome?
Cerebriform connective tissue nevus (often plantar collagenoma form) [This is pathognomonic if seen]
Capillary/venous/lymphatic malformation
Epidermal nevi
Lipomas
CALM
Focal atrophy/dermal hypoplasia
Varicosities
Partial lipohypoplasia
What are the CNS findings in Proteus Syndrome?
Hemimegalencephaly and impaired intelligence
What is the ophthalmologic findings in Proteus Syndrome?
Nystagmus, strabismus, cataracts, and myopia
What are the MSK findings in Proteus Syndrome?
Distinctive facies: dolichocephaly, down-slanting palpebral fissures, depressed nasal bridge, anteverted nares, and open mouth position
- Also can have an overgrowth of soft tissue and bone of the extremities, digits, cranium, vertebrae, and external auditory meatus
- Can also lead to hyperostoses and scoliosis
What tumors can be seen in Proteus Syndrome?
Bilateral ovarian cystadenoma and parted monomorphic adenoma
What organ findings are seen in Proteus Syndrome?
Organomegaly
- Restrictive lung disease, pulmonary emphysema, recurrent pneumonia
What is the gene associated with Beckwith-Wiedemann syndrome?
p57(KIP2) gene
What are the clinical findings in Beckwith-Wiedemann syndrome?
Macrosomia/gigantism (eight and weight >97%)
- Facial capillary malformation of glabella, mid-forehead and upper eyelid
- macroglossia
- Omphalocele/exomphalos
- Hemihyperplasia
- Anterior linear earlobe creases and posterior helical ear pits
- Visceromegaly
Neonatal hypoglycemia
There is an increased risk of which tumors in Beckwith-Wiedemann syndrome?
Embryonal tumors like Wilms’ tumor (#1), rhabdomyosarcoma, neuroblastoma, and hepatoblastoma
What are the genes involved in macrocephaly capillary malformation syndrome?
AKT3, PIK3CA, or PIK3R2
What are the clinical findings in macrocephaly capillary malformation syndrome?
Macrocephaly and frontal bossing
- Widespread reticulated capillary malformation, often in the mid-face (philtrum and glabella)
- Hemihypertrophy in the contralateral side of body from the capillary malformation
- progressive neurologic dysfunction –> developmental delay, seizures, hypotonia
- Syndactyly (especially w/ the 2 and 3 toes
There is an increased risk of what tumor in macrocephaly capillary malformation syndrome?
Increased risk of Wilms’ tumor
What is familial cutaneous and mucosal venous malformation syndrome?
TIE2 mutation
- Has a lot of overlap w/ blue rubber bleb syndrome (also TIE2 mutations)
What is the gene involved in Maffucci syndrome?
Most cases (80%) are 2/2 to mutations in isocitrate dehydrogenase (IDH1 and IDH2)
What is the first sign of Maffucci syndrome?
Deep venous malformations (soft, compressible, and bluish nodules) on the hands and feet
What bone tumors are associated with Maffucci syndrome?
Enchondromas –> develop on the phalanges and long bones, and predispose to short stature, fractures, and limb length differences
can also get neurologic issues from spine and skull deformities
What is the clinical course seen in Maffucci syndrome?
Bone fractures 2/2 to non ossification: 50% risk of chondrosarcoma; lymphangiosarcoma can also occur
What is the presentation of Blue-rubber bleb nevus syndrome?
Sporadic usually
- Presents @ birth/early childhood
- Presents w/ venous malformations that are multiple, blue-violaceous, compressible papules and nodules w/ hyperhidrosis overlying lesions
- These are located on the trunk and extremities, mucosa GI tract, liver and CNS
- Size and # increases with age
What is seen on histology in blue-rubber bleb nevus syndrome?
Ectatic vascular spaces w/ single-layer endothelial wall surrounded by fibrous tissue
- Seen in the deep dermis or sub-cutis
What are some of the most serious complications in blue-rubber bleb nevus syndrome?
Small intestinal blebs can lead to GI bleed or occult/chronic bleeding
What is the gene involved in congenital lymphedema (Nonne-Milroy syndrome)?
FLT4 gene, AD
What is the clinical presentation of congenital lymphedema?
Presents @ birth or soon after persists for life
- Painless pitting edema of b/l lower extremities
- can often have hydrocele, prominent veins and upslanting toenails
Treatment options in congenital lymphedema?
Good skin hygiene, massage, use of compression garments, and sometimes surgical interventions
What is a lymphedema-distichiasis syndrome?
Also hereditary lymphedema, peripubertal onset (10-30) yrs; AD inheritance; FOXC2 mutation
- Has the lower extremity edema + distichiasis (extra eyelashes)
What is the mutation involved in Parkes-Weber syndrome?
RASA1
What are the clinical manifestations in Parkes-Weber syndrome?
Capillary malformations, venous malformations, lymphatic malformations, and multiple fast-flow arteriovenous malformations/shunts
What is the main thing that seperates Parkes-Weber syndrome from Kleppel-Trenaunay syndrome?
KTS only has the slow-flow malformations, not the fast flow
What areas are usually affected in Parkes-Weber syndrome?
Usually the lower extremities, you get soft tissue and bone involvement
What tests can be done to differentiate Parkes-Weber syndrome from Kleppel-Trenaunay syndrome?
Duplex ultrasound and MRI/MRA
Prognosis in Parkes-Weber syndrome?
Can lead to high output cardiac failure in infancy or later in life
- Also can get lytic bone lesions
Ultimately bad prognosis after puberty w/ continued growth of the arteriovenous malformations
In what conditions can you see angiokeratoma corporis diffusum?
Fabry disease, fucosidosis, GM1 gangliosidosis, silicosis, galactosialidosis, aspartyl-glycosaminuria, and Kanzaki dz
What is Cobb syndrome?
Spinal hemangioma or AVM (most common) + cutaneous capillary malformation of the same metamere of the torso
Cutaneous manifestations in Cobb syndrome?
Faint erythema (elicited w/ rubbing affected area or Valsalva maneuver
- On the lumbar back
- Painful throbbing can develop
What are the neurologic abnormalities seen in Cobb syndrome?
These are due to the enlarging AVM
-Includes back pain or headache, muscle atrophy, weakness/numbness, and bowel/bladder dysfunction
Get MRI
What is the affected gene and the mode of inheritance for Fabry’s dz?
XLR, lysosomal storage dz 2/2 deficiency of alpha-galactosidase (GLA mutation)
What is the pathophysiology of Fabry Disease?
Glycosphingolipids accumulate in the vascular endothelium and in epithelial, perithelial, and smooth muscle cells of multiple organs (skin, eye, heart, brain, kidney, and periphery nerves
What is the clinical manifestation of Fabry’s dz?
Thousands of angiokeratomas in the “bathing suite” distribution between umbilicus and knees, as well as oral mucosa/conjunctiva; a/w hypohidrosis
- “Whorl-like” corneal opacities, and posterior capsular cataracts
What is a “Fabry Crisis”
Episodic or chronic paresthesias that can be triggered by stress or temperature/fatigue.
- this can be an initial manifestation in early childhood
- Can go on to lead to peripheral neuropathy
Systemic noncutaneous sx’s in Fabry’s dz?
Cardiac rhythm, conduction issues, cardiomegaly, congestive heart failure, cerebrovascular accidents
What classic urinary finding can be seen in Fabry’s disease?
Maltese crosses in the urine (birefringent lipid globules)
Tx of Fabry’s dz?
Recombinant enzyme therapy which can delay organ damage
Prognosis of Fabry’s dz?
Median age of death is 50 years –> cardiac or neuro complications
What is fucosidosis?
AR
Mutation/deficiency in alpha-L-fucosidase
Hypo/hyperhidrosis, coarse facies, progressive neuromotor and cognitive deterioration/seizures, growth failure, viseromegaly, recurrent infections, and dysostosis multiplex
- fatal
What is GM1 gangliosidosis?
AR lysosomal storage dz
- Mutation in beta-galactosidase-1
- There are 3 forms (infantile), (late infantile/juvenile), and Adult-onset form
- Infantile type is rapidly progressive hypotonia and neurogednerative dz, coarse facies, corneal opacities, w/ cherry-red spots on fundoscopy, hepatosplenomegaly and dysostosis multiplex
- The late form is more gradually progressive
- The adult form is progressive extrapyramidal sx’s
- Cardiomyopathy can develop in any type, ultimately fatal
