Heritable disorders of connective tissue Flashcards
(92 cards)
hypermobile Ehlers–Danlos syndrome (hEDS) is the most common form of EDS and the only one without a known genetic marker
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The classical type of Ehlers–Danlos syndrome is most commonly associated with mutations in the COL5A1 and COL5A2 genes.
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These genes encode the α-chains of type V collagen, which is critical for regulating the diameter and assembly of collagen fibrils, especially type I collagen.
Clinical features:
Skin hyperextensibility
Atrophic scarring (cigarette paper scars)
Generalized joint hypermobility
Dominant-negative mutations in COL3A1 are the only genetic cause of vascular Ehlers–Danlos syndrome (vEDS).
True or False?
False
While dominant-negative mutations in the COL3A1 gene are the most common cause of vascular Ehlers–Danlos syndrome (vEDS), they are not the only known cause.
COL3A1 mutations typically lead to type III collagen deficiency, which weakens vessel walls and hollow organs.
Rarely, mutations in other genes like COL1A1 (a glycine substitution near the C-terminus) can produce a vEDS-like phenotype, though this is less common.
Pseudoxanthoma elasticum (PXE) is inherited in an autosomal dominant manner and primarily affects type I collagen.
Pseudoxanthoma elasticum (PXE) is not inherited in an autosomal dominant manner, and it does not involve type I collagen.
Key facts:
Inheritance: PXE is inherited in an** autosomal recessive manner.**
Gene involved:** ABCC6**, a transmembrane transporter expressed primarily in the liver and kidneys, not in affected skin or vessels.
Pathology: Leads to calcification and fragmentation of elastic fibers, particularly in:
- Skin (yellow papules on neck/flexures)
- Retina (angioid streaks → vision loss)
- Vasculature (peripheral arterial disease, GI hemorrhage)
Cutis laxa is a genetically and clinically heterogeneous condition that can be inherited in autosomal dominant, autosomal recessive, or X-linked patterns.
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Inheritance patterns:
- Autosomal dominant (AD): Often mild, late-onset, associated with elastin (ELN) mutations.
- Autosomal recessive (AR): More severe, early-onset; includes:
- ARCL type I: with vascular and pulmonary complications.
- ARCL type II: overlaps with cutis laxa and syndromes like De Barsy syndrome.
-X-linked recessive: Associated with ATP7A mutations (also seen in Menkes disease).
In classical EDS, the presence of skin hyperextensibility without atrophic scarring is sufficient for diagnosis.
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2017 Diagnostic Criteria for cEDS:
To make the diagnosis, both of the following major criteria must be met:
- Skin hyperextensibility with atrophic scarring
- Generalized joint hypermobility (GJH)
Minor criteria can support the diagnosis but are not sufficient alone.
The presence of angioid streaks in the retina is considered a hallmark feature of vascular EDS.
**False **- this is a hallmark, but not pathoneumonic feature of PXE
Histologic examination of classical EDS reveals thickened, well-organized collagen bundles in the dermis.
False
Histopathologic features:
- Disorganized, loosely packed collagen bundles
- Increased inter-fibrillar spacing
- Reduced or fragmented type V collagen
- Elastic fibers may appear normal or slightly reduced
- Often described as having a “moth-eaten” appearance on electron microscopy
Patients with vascular Ehlers–Danlos syndrome are at increased risk of arterial rupture, uterine rupture during pregnancy, and spontaneous bowel perforation.
True
Patients with vascular Ehlers–Danlos syndrome (vEDS) — caused by mutations in COL3A1 — are at very high risk for:
- Arterial rupture or dissection, often spontaneous and catastrophic
- Spontaneous bowel perforation, especially of the sigmoid colon
- Uterine rupture, particularly in the third trimester of pregnancy
These are hallmark features of vEDS, and frequently appear on exams as a triad in young patients presenting with unexpected vascular or visceral emergencies.
In pseudoxanthoma elasticum (PXE), the earliest skin changes typically appear as yellowish papules in flexural areas such as the neck, axillae, and groin.
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What are the clinical and genetic features that distinguish classical Ehlers–Danlos syndrome (cEDS) from hypermobile Ehlers–Danlos syndrome (hEDS)?
Genetics:
* Classical EDS (cEDS): Mutations in COL5A1 or COL5A2. Affects type V collagen, which regulates fibrillogenesis and type I collagen architecture.
* Hypermobile EDS (hEDS): No definitive genetic mutation identified to date (diagnosis is clinical). Likely polygenic or multifactorial etiology.
Inheritance:
Both are typically autosomal dominant (AD).
List three significant complications of vascular Ehlers–Danlos syndrome (vEDS)?
Life-Threatening Complications of vEDS:
* Arterial rupture or dissection (most commonly involving medium-to-large arteries such as carotid, renal, and iliac vessels)
- **Spontaneous bowel perforation **(especially of the sigmoid colon)
- Uterine rupture, particularly in the third trimester of pregnancy
These complications can occur spontaneously and without warning, often in young patients, and may be fatal.
Describe the underlying genetic mutation and its pathophysiologic consequence in vascular EDS
Genetic Mutation:
* Gene: COL3A1
* Type of mutation: Often dominant-negative missense mutations
Protein affected: Type** III collagen, **
This is a major component of: Arterial walls, Hollow organs (bowel, uterus), Skin (less prominently)
Regarding Pseudoxanthoma Elasticum:
- What are the characteristic dermatologic features?
- Thin yellowish papules begin to appear in flexural areas during the first or second decade of life
- Papules coalesce to form cobblestone like plaques
○ Often called a plucked chicken or cobblestone appearance - Papules and plaques can become firm (due to calcification)
- Extrusion of yellowish material through the epidermis = perforating PXE
- Loss of elastic recoil of the skin = sagging of the skin
○ Most notable in the axillae and groin - Mucosa:
○ Yellow papules
○ Most visible on the lower lips - Prominent creases on the chin - highly specific
- Premature aged appearance
- Reticulate pigmentation on the abdomen
- Comedonal lesions
- Chronic granulomatous nodules
- Elastosis serpiginosa perforans
- Papules coalesce to form cobblestone like plaques
Regarding Pseudoxanthoma Elasticum:
- what are the the histopathological features?
**Clumped, fragmented, and thickened elastic fibers **in the mid-dermis
Calcification of elastic fibers, especially in affected dermis
Stains:
- Von Kossa stain (calcium-specific)
- Alizarin Red (also highlights calcium)
- Elastic tissue stains (e.g. Verhoeff–Van Gieson)
Regarding Pseudoxanthoma Elasticum:
* what gene/s and mode of inheritance?
Gene: ABCC6
Protein: An ATP-binding cassette transporter (likely involved in systemic pyrophosphate transport)
Mechanism: ↓ ABCC6 → ↓ ATP → ↓ extracellular inorganic pyrophosphate (PPi) → ↓ inhibition of ectopic mineralization → elastic tissue calcification
Inheritance: Autosomal recessive
Describe the differences in clinical presentation (focus on cutaneous features) between autosomal dominant and autosomal recessive forms of Cutis Laxa.
Describe the differences in systemic features or complicaitons between autosomal dominant and autosomal recessive forms of Cutis Laxa.
What gene/s and inheritance are seen in Cutis laxa
Multiple Genes and inheritance patterns:
Most common = AD
* Gene: ELN
* Mechanism: defective elastin assembly or secretion
AR
* Gene: FBLN5, ATP6VOAV2, EFEMP2
* Defects in elastic fiber assembly or intracellular trafficking
There are also X linked forms
Describe and DDx
Erythematous papules / papulovesicles or pseudovesicles on the back of neck
Male with PT 2
Arranged in an acurate / serpigenous pattern
Overlying scale or crust visible
Dx: elastosis perforans serpiginosa
DDx: Tinea, candida, papular eczema, Insect bite reaction, sarcoidosis,
What is elastosis perforans serpiginosa?
A rare skin disorder in which abnormal elastic tissue fibre passes from the papillary dermis (inner layer of skin) to the epidermis (outer layer of skin), described as transepithelial elimination
How is elastosis perforans serpiginosa classified?
**Idiopathic elastosis perforans serpiginosa: **unknown origin, possibly genetic
**Reactive elastosis perforans serpiginosa: **associated with other inherited disorders such as Down syndrome, Ehlers Danlos syndrome and Marfan syndrome
Drug-induced elastosis perforans serpiginosa: affects 1% of people treated with D-penicillamine
Elastosis Perforans serpiginosa is more common in Males
True 4:1
What are the cutaneous findings of marfans disease?
Striae, elastosis perforans serpiginosa, decreased subcutaneous fat on extremities
