72: Genetic Disorders Affecting Dermal Connective Tissue Flashcards
1
Q
What is the prevalence of Classical Ehlers-Danlos Syndrome (cEDS) in newborns?
A
Classical Ehlers-Danlos Syndrome (cEDS) occurs in 1 in 10,000 to 20,000 newborns.
2
Q
What are the key clinical features of Classical Ehlers-Danlos Syndrome?
A
Key clinical features include:
- Skin hyperextensibility and fragility
- Atrophic scarring
- Generalized joint hypermobility
3
Q
What are the characteristics of skin in patients with Classical Ehlers-Danlos Syndrome?
A
The skin in cEDS patients is:
- Velvety, thin, and bruises easily.
- Hyperextensible, but recoils easily to its normal position after stretching, unlike the skin in cutis laxa.
4
Q
What complications may fetuses exhibit if affected by Ehlers-Danlos Syndrome?
A
Fetuses may exhibit:
- Growth retardation
- Hernias
- Joint dislocations
5
Q
What is the most clinically significant subtype of Ehlers-Danlos Syndrome and why?
A
The vascular subtype is the most clinically significant because of the risk of arterial or major organ rupture.
6
Q
A patient with Ehlers-Danlos Syndrome (EDS) presents with a large, painless skin tear after minor trauma. What subtype of EDS is most likely, and what are the characteristic skin features?
A
Classical EDS (cEDS) is most likely. Characteristic skin features include hyperextensibility, fragility, atrophic scarring, and easy bruising.
7
Q
What is the Beighton scale and how is it used in assessing joint hypermobility?
A
The Beighton scale is a tool used to assess joint hypermobility in suspected patients, including older children and adolescents. A score of 5 or greater out of 9 confirms joint hypermobility.
8
Q
What are common complications associated with joint hypermobility?
A
Common complications associated with joint hypermobility include:
- Sprains, dislocations, or subluxations
- Scoliosis
- Pes planus
- Early-onset osteoarthritis due to chronic and excessive joint hypermobility.
9
Q
What are some clinical features of hypermobile EDS (hEDS)?
A
Clinical features of hypermobile EDS (hEDS) include:
- Ability to extend the tongue to touch the tip of the nose (Gorlin sign)
- Muscle hypotonia and delayed gross motor development
- Chronic fatigue syndrome or fibromyalgia
- Temporomandibular joint dysfunction
- Lack of lingual and labial frenula, particularly in patients with vascular type EDS.
10
Q
What are the characteristics of classical-like Ehlers-Danlos syndrome?
A
Classical-like Ehlers-Danlos syndrome is characterized by:
- Caused by heterozygous COL1A1 c.934C>T, p.(Arg312Cys) substitutions.
- Increased risk for vascular rupture mimicking COL3A1-vascular Ehlers-Danlos syndrome (vEDS) due to substitution of arginine for cysteine in COL1A1.
11
Q
What are the features of the vascular type of Ehlers-Danlos syndrome (vEDS)?
A
The vascular type of Ehlers-Danlos syndrome (vEDS) includes the classic quadrad of features:
- Thin translucent skin
- Prominent venous pattern
- Extensive bruising or hematomas
- Vascular or visceral rupture
Joint hypermobility is usually minimal and limited to the digits.
12
Q
A 25-year-old patient presents with a history of frequent joint dislocations and hypermobility. They also report chronic pain and fatigue. What diagnostic criteria and tools would you use to confirm hypermobile Ehlers-Danlos Syndrome (hEDS)?
A
The Beighton scale is used to assess joint hypermobility, with a score of 5 or greater out of 9 confirming hypermobility. Additionally, a 5-point questionnaire can help confirm the diagnosis. Chronic fatigue and pain are common in hEDS.
13
Q
What are the facial features commonly associated with vascular Ehlers-Danlos Syndrome (vEDS)?
A
The facial features include a thin nose, upper lip, small earlobes, and sunken, pigmented periocular regions.
14
Q
What is a clinical indicator of vascular Ehlers-Danlos Syndrome (vEDS) before the age of 20?
A
The development of superficial venous insufficiency before the age of 20 years can be a clinical indicator of vEDS.
15
Q
What are the three discrete phases of clinical progression recognized in hypermobile Ehlers-Danlos Syndrome (hEDS)?
A
- Hypermobility phase: Infants first exhibit hypermobility.
- Pain phase: In the second decade, joint hypermobility decreases, and pain progressively impacts quality of life.
- Stiffness phase: Characterized by progressive limitation of joint mobility and a dramatic impact on quality of life, often accompanied by depression and anxiety.
16
Q
What skin characteristics are associated with hypermobile Ehlers-Danlos Syndrome (hEDS)?
A
Patients with hEDS have abnormal skin that is:
- Soft, velvety skin with occasional mild hyperextensibility but no fragility.
- May show easy bruising and piezogenic papules.
- Skin may be slightly transparent with more visible veins and tendons.
17
Q
What genetic mutations are primarily responsible for Classical Ehlers-Danlos Syndrome?
A
Over 90% of Classical Ehlers-Danlos Syndrome cases are caused by autosomal dominant (AD) mutations in the α1 or α2 chain of Type V collagen (COL5A1 and COL5A2), with the majority occurring in COL5A1.
18
Q
A 30-year-old patient with vascular Ehlers-Danlos Syndrome (vEDS) presents with acute abdominal pain. What is the most likely cause, and what other complications should be considered?
A
The most likely cause is arterial or intestinal rupture, particularly in the sigmoid colon. Other complications include stroke and spontaneous vascular rupture.
19
Q
A patient with hypermobile Ehlers-Danlos Syndrome (hEDS) reports chronic musculoskeletal pain and fatigue. What are the three phases of clinical progression in hEDS?
A
The three phases are: 1) Hypermobility phase in infancy, 2) Pain phase in the second decade with worsening pain and joint hypermobility, and 3) Stiffness phase with progressive joint mobility limitation and significant quality-of-life impact.
20
Q
A patient with hypermobile Ehlers-Danlos Syndrome (hEDS) is diagnosed with fibromyalgia. What overlapping symptoms might contribute to this diagnosis?
A
Overlapping symptoms include chronic musculoskeletal pain, fatigue, and sleep disturbances, which are common in both hEDS and fibromyalgia.
21
Q
A patient with hypermobile Ehlers-Danlos Syndrome (hEDS) reports atypical chest pain and heart palpitations. What cardiovascular findings are common in hEDS?
A
Common cardiovascular findings include aortic root dilation, orthostatic intolerance, and heart palpitations.
22
Q
A patient with vascular Ehlers-Danlos Syndrome (vEDS) has a history of spontaneous vascular rupture. What is the median life span for vEDS patients, and what is the most common cause of death?
A
The median life span for vEDS patients is approximately 51 years. The most common cause of death is arterial rupture.
23
Q
A patient with vascular Ehlers-Danlos Syndrome (vEDS) has a history of bowel rupture. What part of the bowel is most commonly affected, and what are the implications?
A
The sigmoid colon is most commonly affected. Bowel rupture can lead to acute abdominal pain and requires immediate medical intervention.
24
Q
What are the key histological findings in Ehlers-Danlos Syndrome (EDS) as observed through electron microscopy?
A
Electron microscopy of the skin in EDS reveals thickened collagen fibrils, highlighting the role of Type V collagen in regulating their size. Less than 5% of fibrils may exhibit ‘collagen flowers,’ which are rare composite fibrils.
25
What genetic mutation is primarily associated with vascular type Ehlers-Danlos Syndrome (vEDS)?
vEDS is associated with dominant negative mutations in the Type III collagen gene (COL3A1), resulting in reduced amounts of Type III collagen in the dermis, vessels, and viscera.
26
How does the management of Ehlers-Danlos Syndrome (EDS) typically approach prevention and treatment?
A multidisciplinary preventive strategy is the most productive approach to managing EDS patients, which includes:
1. Early identification of affected patients.
2. Appropriate interventions (pain management, physical therapy, surgery).
3. Non-weight-bearing exercises (e.g., swimming) to promote muscle development.
4. Avoiding and preventing injuries.
5. Proper wound care with sutures and pressure bandages to aid healing and reduce scarring.
27
What distinguishes Ehlers-Danlos Syndrome (EDS) from classical lichen (CL) in terms of skin elasticity?
In classical lichen (CL), the hyperelastic skin does not return to its normal position after stretching, which is a key distinguishing feature from EDS.
28
What are the clinical similarities between vascular type EDS (vEDS) and Loeys-Dietz syndrome?
vEDS exhibits significant clinical similarities to Loeys-Dietz syndrome Type 2, including:
- Aortic aneurysm syndrome caused by mutations in TGF-β receptors 1 and 2 (TGFBR1 and TGFBR2).
- Skin findings such as velvety translucent skin, easy bruising, and widened, atrophic scars.
29
A patient with suspected vascular Ehlers-Danlos Syndrome (vEDS) has a family history of arterial rupture. What genetic mutation is most commonly associated with vEDS, and how does it affect collagen?
vEDS is most commonly associated with dominant negative mutations in the COL3A1 gene, leading to reduced amounts of Type III collagen and impaired structural integrity of blood vessels and hollow organs.
30
A patient with Ehlers-Danlos Syndrome (EDS) presents with recurrent joint dislocations and scoliosis. What preventive strategies and treatments should be considered?
Preventive strategies include physical therapy, bracing, and low-resistance exercises. Vertebral fusion may be required for severe scoliosis. Joint dislocations can often be remedied with closed reduction.
31
A patient with Ehlers-Danlos Syndrome (EDS) has a history of poor wound healing and atrophic scars. What specific surgical techniques should be used to manage their wounds?
Wounds should be sutured using both subcuticular and cuticular sutures, which are tightly spaced and left in place for a prolonged duration. Adhesive tapes, bolsters, or pressure bandages are also recommended.
32
A patient with vascular Ehlers-Danlos Syndrome (vEDS) presents with a large hematoma after minimal trauma. What diagnostic tests can confirm vEDS?
Diagnostic tests include analysis of Type III procollagen and collagen chains, as well as direct genetic testing of the COL3A1 gene.
33
A patient with Ehlers-Danlos Syndrome (EDS) has a history of arterial rupture. What subtype of EDS is most likely, and what genetic mutation is associated with it?
Vascular EDS (vEDS) is most likely. It is associated with dominant negative mutations in the COL3A1 gene.
34
A patient with Ehlers-Danlos Syndrome (EDS) has a history of recurrent ecchymoses and hematomas. What preventive measures should be taken to minimize these complications?
Preventive measures include avoiding trauma, using protective padding, and ensuring proper wound care with tightly spaced sutures and pressure bandages.
35
A patient with hypermobile Ehlers-Danlos Syndrome (hEDS) has pes planus and frequent joint dislocations. What physical therapy interventions are recommended?
Low-resistance exercises for muscle toning and myofascial release therapies are recommended. Bracing may also be helpful for joint stabilization.
36
A patient with Ehlers-Danlos Syndrome (EDS) has a history of slow wound healing and frequent infections. What surgical precautions should be taken to improve outcomes?
Surgical precautions include using both subcuticular and cuticular sutures, leaving them in place for a prolonged duration, and using adhesive tapes or pressure bandages to aid healing.
37
What are the major criteria for diagnosing Classical Ehlers-Danlos Syndrome (cEDS)?
1. Skin hyperextensibility
2. Atrophic scarring
3. Easy bruising
4. Joint hypermobility
5. Family history of cEDS
38
What are the minor criteria for Vascular Ehlers-Danlos Syndrome (vEDS)?
1. Thin, translucent skin
2. Easy bruising
3. Arterial rupture
4. Spontaneous pneumothorax
5. Family history of vEDS
39
What is a key clinical feature of Hypermobility Ehlers-Danlos Syndrome (hEDS)?
Joint hypermobility is a key clinical feature, often accompanied by musculoskeletal pain and a history of joint dislocations.
40
What are the major criteria for diagnosing Hypermobile Ehlers-Danlos Syndrome (hEDS)?
1. Generalized joint hypermobility
2. Musculoskeletal pain in two or more limbs
3. Family history of hEDS
4. Exclusion of other connective tissue disorders
41
What are the diagnostic criteria for the Vascular Ehlers-Danlos Syndrome (vEDS)?
Major criteria include:
1. Family history of vEDS
2. Characteristic facial features
3. Arterial rupture or dissection
4. Thin, translucent skin
5. Easy bruising
Minor criteria include:
1. Spontaneous pneumothorax
2. Uterine rupture during pregnancy
3. Arterial aneurysms
42
What are the major criteria for diagnosing Musculocontractural Ehlers-Danlos Syndrome (mEDS)?
1. Congenital muscle contractures
2. Characteristic craniofacial features (charleston fin)
3. Skin hyperextensibility, easy bruising, skin fragility with atrophic scars, increased palmar wrinkling
43
What are the minor criteria for Musculocontractural Ehlers-Danlos Syndrome (mEDS)?
1. Recurrent joint dislocations
2. Palate deformities
3. Prolonged healing
4. Large subcutaneous hematomas
5. Scoliosis
6. Hypermobility/neuropathy
7. Skin fragility
8. Soft, doughy skin
9. Developmental delay
10. Muscle biopsy showing abnormal findings
44
What are the minimal diagnostic criteria for Musculocontractural Ehlers-Danlos Syndrome (mEDS)?
Major criteria 1 plus either minor criteria or:
- Confirmatory molecular testing is necessary to confirm diagnosis.
45
What are the major criteria for diagnosing Myopathic Ehlers-Danlos Syndrome (mEDS)?
1. Congenital muscle hypotonia and/or atrophy
2. Improves with age
3. Proximal joint contractures
46
What are the minimal diagnostic criteria for Musculocontractural Ehlers-Danlos Syndrome (mEDS)?
Major criteria 1 plus either minor criteria or confirmatory molecular testing is necessary to confirm diagnosis.
47
What are the major criteria for diagnosing Myopathic Ehlers-Danlos Syndrome (mEDS)?
1. Congenital muscle hypotonia and/or atrophy
2. Improves with age
3. Proximal joint contractures
4. Distal joint hypermobility
48
What are the minimal diagnostic criteria for Myopathic Ehlers-Danlos Syndrome (mEDS)?
Major criteria 1 plus 1 other major criterion and 2 minor criteria or confirmatory molecular testing is necessary to confirm diagnosis.
49
What are the major criteria for diagnosing Periodontal Ehlers-Danlos Syndrome (pEDS)?
1. Severe, intractable periodontitis—early onset
2. Lack of attached gingiva
3. Peeling papules
4. Family history: first-degree relative meeting diagnostic criteria
50
What are the primary organ systems affected by Marfan syndrome?
Marfan syndrome primarily affects the following organ systems:
1. **Ocular** - typically involves lens dislocation.
2. **Skeletal** - characterized by excessive extremity length, loose joints, anterior chest deformities, and kyphoscoliosis.
3. **Cardiovascular** - most important, often leading to aortic aneurysm and mitral valve redundancy.
51
What is the significance of the 'marfanoid habitus' in Marfan syndrome?
The 'marfanoid habitus' is characterized by:
- **Dolichostenomelic** body type (tall and thin).
- A lower-body segment (pubic symphysis to floor) that is longer than the upper segment (height minus lower segment).
- The arm span exceeds the person's height by several centimeters, indicating excessive length of distal bones (arachnodactyly).
52
What are the common skeletal features associated with Marfan syndrome?
Skeletal features of Marfan syndrome include:
- **Kyphoscoliosis**
- **Pectus excavatum** (sternal depression) and **carinatum** (sternal projection)
- **Joint laxity** leading to flat feet, knee or elbow hyperextensibility (genu recurvatum)
- **Patellar dislocation**
- **Hip dislocation**, often detected during the newborn period, may be the first sign of Marfan syndrome.
53
What ocular abnormalities are commonly seen in patients with Marfan syndrome?
Common ocular abnormalities in Marfan syndrome include:
- **Myopia** caused by flattening of the corneas and an abnormally long anterior-posterior orbital axis.
- **Ectopia lentis** - estimated to occur in 50% to 70% of patients, typically with upward lens displacement.
- Secondary ocular issues such as ametropia, acute glaucoma, and increased risk of retinal detachment due to lens subluxation or dislocation.
54
What cardiovascular abnormalities are associated with Marfan syndrome and their implications?
Cardiovascular abnormalities in Marfan syndrome are significant as they account for the majority of morbidity and mortality. Key points include:
- **Medial necrosis of the aorta** is the most common defect.
- **Diffuse dilation** of the proximal segment of the ascending aorta often occurs, leading to aortic regurgitation.
- Death typically occurs in adulthood as a result of cardiovascular sequelae.
55
A pediatric patient presents with a tall and thin body habitus, a lower body segment longer than the upper, and an arm span exceeding their height. What condition should be suspected, and what skeletal features would you examine further?
Marfan syndrome should be suspected. Skeletal features to examine include kyphoscoliosis, pectus excavatum or carinatum, joint laxity, and patellar or hip dislocations.
56
A patient with Marfan syndrome presents with upward lens displacement. What is the term for this condition, and what are the associated risks?
The condition is called ectopia lentis. Associated risks include ametropia, myopia, acute glaucoma, and increased risk of retinal detachment.
57
What are the common cutaneous findings in individuals with Marfan syndrome?
The most common cutaneous findings in individuals with Marfan syndrome include:
- Lack of subcutaneous fat
- Presence of striae, particularly on the upper chest, arms, thighs, and abdomen
- Elastosis perforans serpiginosa
- Skin findings are considered minor diagnostic features in the revised diagnostic criteria.
58
What are the clinical features of Neonatal Marfan Syndrome?
Neonatal Marfan Syndrome is characterized by:
- Body disproportion
- Lax skin
- Emphysema
- Ocular abnormalities
- Joint contractures
- Kyphoscoliosis
- Adducted thumbs
- Crumpled ears
- Micrognathia
- Muscle hypoplasia
- Deficient subcutaneous fat over joints
- Severe cardiac valve insufficiency and aortic dilation, which can result in death during the first 2 years of life.
59
What is the significance of the ratio of collagen Type I to collagen Type III in Marfan syndrome?
In Marfan syndrome, the ratio of collagen Type I to collagen Type III is decreased, indicating defects in the architecture of the collagen microfibrils of large vessels rather than in collagen content or crosslinking. This alteration contributes to the vascular complications associated with the syndrome.
60
What are the diagnostic criteria for Marfan syndrome in pediatric patients?
Pediatric patients often do not meet international criteria for the diagnosis of Marfan syndrome at the time of first examination. Follow-up examination is critical to identify affected patients. The presence of features such as ectopia lentis, a systemic score of 7 or higher, or significant aortic root dilation (Z-score ≥2 if older than 20 years and ≥3 if younger than 20 years) can aid in diagnosis.
61
What are the laboratory investigation criteria for diagnosing Marfan syndrome?
The diagnosis of Marfan syndrome is based on a constellation of clinical findings, as there is no specific diagnostic laboratory test or histologic abnormality. Diagnosis can be made with:
- Detection of a FBN1 pathogenic variant of known association along with:
- Aortic root enlargement (Z-score ≥2)
- Ectopia lentis
Alternatively, a positive Z-score along with enough additional clinical features to yield a systemic score of 7 or higher is diagnostic.
62
A patient with Marfan syndrome has a Z-score of 2.5 for aortic root enlargement. What additional clinical features would confirm the diagnosis in the absence of a family history?
The diagnosis can be confirmed with the detection of an FBN1 pathogenic variant of known association along with ectopia lentis or a systemic score of 7 or higher.
63
A neonate presents with body disproportion, lax skin, and severe cardiac valve insufficiency. What condition is likely, and what is the prognosis?
The condition is likely neonatal Marfan syndrome. The prognosis is poor, with death often occurring during the first 2 years of life due to severe cardiac valve insufficiency and aortic dilation.
64
A patient with Marfan syndrome has mitral valve prolapse (MVP). What are the potential complications of MVP in this condition?
Complications of MVP in Marfan syndrome include mitral valvular regurgitation, cardiac arrhythmias, and sudden death.
65
A patient with vascular Ehlers-Danlos Syndrome (vEDS) has a history of gum fragility and tooth loss. What other oral findings are common in connective tissue disorders like vEDS?
Other oral findings include a high-arched palate and crowding of anterior teeth, particularly in Marfan syndrome.
66
A patient with Marfan syndrome has emphysema and lung bullae. What is the associated risk, and what precautions should be taken?
The associated risk is pneumothorax, particularly in the upper lobes. Patients should avoid smoking and situations with rapid changes in air pressure.
67
A patient with Marfan syndrome has a systemic score of 8 but no family history. What additional diagnostic criteria would confirm the diagnosis?
The diagnosis can be confirmed with the detection of an FBN1 pathogenic variant of known association or aortic root enlargement (Z-score ≥2).
68
A patient with Marfan syndrome has a high-arched palate and crowded anterior teeth. What other oral findings are common in connective tissue disorders?
Other oral findings include gum fragility and tooth loss, particularly in vascular Ehlers-Danlos Syndrome (vEDS).
69
A patient with Marfan syndrome has a systemic score of 6 and a Z-score of 2.5 for aortic root enlargement. What additional findings would confirm the diagnosis?
The diagnosis can be confirmed with the detection of an FBN1 pathogenic variant of known association or ectopia lentis.
70
What is the recommended management for patients with Marfan syndrome to ensure life expectancy is similar to the general population?
Appropriate management includes coordination with a multidisciplinary team composed of cardiology, ophthalmology, orthopaedics, and cardiothoracic surgery.
71
What are the ocular considerations for patients with Marfan syndrome?
Patients require early and regular ophthalmologic examinations to detect correctable amblyopia and retinal detachment. Ectopia lentis and complete subluxation may be tolerated for decades, and lens extraction may be necessary for treating diplopia, glaucoma, cataracts, or retinal detachment. LASIK surgery is contraindicated.
72
What are the skeletal management options for adolescents with Marfan syndrome?
Management options include:
1. Repair of pectus excavatum if cardiopulmonary compromise develops, delayed until skeletal maturation is nearly complete.
2. Scoliosis may be lessened by estrogen therapy in adolescent girls, though this may decrease height.
3. Bracing, physical therapy, and vertebral fusion may be required to prevent severe scoliosis.
73
What cardiovascular monitoring is recommended for patients with a family history of early aortic dissection?
Aggressive monitoring is mandated, and patients should undergo yearly monitoring to prevent complications.
74
What is the role of long-term propranolol therapy in managing Marfan syndrome?
Long-term propranolol therapy is administered to prevent aortic dilation by decreasing myocardial contractility, although it may not affect survival.
75
What are the indications for replacing the aortic root in patients with Marfan syndrome?
Replacement of the aortic root is indicated when the maximal measurement is greater than 5 cm in adults and older children, the rate of size increase is approximately 1 cm/year, or progressive aortic regurgitation develops.
76
What precautions should patients with pulmonary involvement in Marfan syndrome take?
Patients should avoid situations with rapid changes in air pressure, such as scuba diving or flying, and should not smoke.
77
What is the significance of doxycycline in the management of Marfan syndrome?
Doxycycline inhibits matrix metalloproteinases and has been shown in mouse models to improve aortic wall architecture and delay aortic dissection.
78
What physical activity restrictions are recommended for children with Marfan syndrome?
Children should be excused from participation in physical education to avoid potentially harmful exertion, contact sports, and isometric exercises, which could lead to aortic rupture or congenital heart failure.
79
A patient with Marfan syndrome is undergoing yearly monitoring for aortic dilation. What pharmacological treatments could be considered, and what are their limitations?
Long-term propranolol therapy can be used to prevent aortic dilation by decreasing myocardial contractility, but it may not affect survival. Angiotensin II receptor blockers like losartan have shown mixed results in trials.
80
A patient with Marfan syndrome is advised against certain physical activities. What types of activities should they avoid, and why?
Patients should avoid activities involving rapid changes in air pressure (e.g., scuba diving, flying), contact sports, and isometric exercises to prevent aortic rupture or congenital heart failure.
81
A patient with Marfan syndrome has aortic root dilation measuring 5.2 cm. What surgical intervention is indicated, and what are the criteria for this intervention?
Replacement of the aortic root is indicated when the maximal measurement exceeds 5 cm, the rate of size increase is approximately 1 cm/year, or progressive aortic regurgitation develops.
82
A patient with Marfan syndrome is considering LASIK surgery for myopia. What advice should be given, and why?
LASIK surgery is contraindicated in Marfan syndrome due to the risk of corneal complications and structural instability.
83
A patient with Marfan syndrome has a family history of early aortic dissection. What monitoring and preventive measures should be implemented?
Yearly monitoring of the aortic root diameter is essential. Long-term propranolol therapy or angiotensin II receptor blockers may be considered to prevent aortic dilation.
84
A patient with Marfan syndrome has scoliosis and pectus excavatum. What treatments are recommended for these skeletal abnormalities?
Bracing, physical therapy, and vertebral fusion may be required for scoliosis. Repair of pectus excavatum is appropriate if cardiopulmonary compromise develops but should be delayed until skeletal maturation is nearly complete.
85
A patient with Marfan syndrome has aortic root dilation and mitral valve prolapse. What pharmacological treatment could be considered to manage these cardiovascular complications?
Long-term propranolol therapy or angiotensin II receptor blockers like losartan may be considered to manage aortic root dilation and mitral valve prolapse.
86
A patient with Marfan syndrome has aortic root dilation and a family history of early aortic dissection. What monitoring frequency is recommended?
Yearly monitoring of the aortic root diameter is recommended for patients with a family history of early aortic dissection.
87
What is the incidence rate of Pseudoxanthoma elasticum (PXE)?
The incidence of Pseudoxanthoma elasticum is approximately 1 in 25,000 to 100,000 live births.
88
What are the common skin features associated with Pseudoxanthoma elasticum?
Common skin features include yellowish, flat-topped, discrete, and confluent papules in skin creases, particularly in the neck, axillae, and flexural folds, often described as 'plucked chicken skin'.
89
What is the average age of diagnosis for individuals with a positive family history of Pseudoxanthoma elasticum?
The average age of diagnosis in patients with a positive family history of Pseudoxanthoma elasticum is between 8 to 12 years.
90
What are some of the extraneous manifestations of Pseudoxanthoma elasticum?
Extraneous manifestations include angioid streaks, vascular impairment, cardiovascular disease, and bleeding, as well as breast and testicular microcalcifications that may be mistaken for malignancy.
91
What is the most common ophthalmologic finding in patients with Pseudoxanthoma elasticum?
The most common ophthalmologic finding in patients with Pseudoxanthoma elasticum is angioid streaks, observed in 87% of patients, which develop during the third or fourth decade of life.
92
What genetic mutation is associated with Pseudoxanthoma elasticum?
Pseudoxanthoma elasticum is associated with mutations in the ABCC6 gene located on chromosome 16q13.1.
93
A patient presents with yellowish, flat-topped papules in the skin creases of the nape and axillae, along with skin redundancy. What is the likely diagnosis, and what is the genetic basis of this condition?
The likely diagnosis is Pseudoxanthoma Elasticum (PXE). It is caused by mutations in the ABCC6 gene, which is located on chromosome 16p13.1.
94
A 35-year-old patient develops radial curvilinear extensions of reddish coloration from the optic disc. What is this finding called, and what condition is it associated with?
This finding is called angioid streaks, and it is associated with Pseudoxanthoma Elasticum (PXE).
95
A patient with PXE is experiencing prominent horizontal and oblique mental creases. At what age is this finding highly specific for PXE?
Prominence of the horizontal and oblique mental creases prior to 30 years of age is highly specific for PXE.
96
A patient with PXE is undergoing an ophthalmologic examination. What is the most common finding in PXE patients?
The most common ophthalmologic finding in PXE patients is angioid streaks, observed in 87% of cases.
97
What are the characteristic ocular findings in Pseudoxanthoma Elasticum (PXE)?
- **Calcification** of the outer layer, the lamina elastica, leads to fragility and fissuring.
- Rarely interferes with **visual acuity** and may progress or remain stationary.
- **Characteristic irregular retinal epithelial mottling** known as 'peau d’orange'.
- **Loss of vision** tends to occur later in life, with central visual loss while peripheral vision often remains intact.
98
What are the common gastrointestinal manifestations in patients with Pseudoxanthoma Elasticum (PXE)?
- **GI tract** and renal vasculature are sites of early manifestations.
- Often presents as **acute-onset hemorrhage** in the second to fourth decade.
- **10% to 15%** of PXE patients will have at least 1 GI hemorrhagic event.
- Other common issues include **subarachnoid hemorrhage** and intermittent claudication.
99
What are the associations and risks related to cardiovascular health in Pseudoxanthoma Elasticum (PXE)?
- Patients may experience **severe coronary artery disease**.
- Physical signs may include:
- Diminished peripheral pulses
- Hypertension (3 times more common in PXE patients)
- Murmurs related to **mitral valve prolapse (MVP)** and/or congestive heart failure
- Peripheral gangrene.
- **Rec tovesical prolapse** may also occur.
100
How does pregnancy affect patients with Pseudoxanthoma Elasticum (PXE)?
- **Pregnancy is not contraindicated** in PXE patients.
- However, miscarriage rates may be higher in the first trimester.
- Multiple pregnancies may accelerate the pace of the disease.
101
A patient with PXE is experiencing central visual loss but retains peripheral vision. What is the underlying cause of this visual impairment?
The central visual loss is caused by disc-shaped degeneration of the central visual area due to calcification and hemorrhage in the elastic tissue of the retina.
102
A patient with PXE is diagnosed with severe coronary artery disease. What physical signs might be observed?
Physical signs may include diminished peripheral pulses, hypertension, murmurs related to mitral valve prolapse (MVP) or congestive heart failure, and peripheral gangrene.
103
A patient with PXE has calcification of the internal lamina of blood vessels. What are the potential complications of this finding?
Potential complications include subarachnoid hemorrhage, intermittent claudication, myocardial infarction, and severe coronary artery disease.
104
A patient with PXE presents with peau d’orange and drusen-like lesions in the posterior pole of the retina. What do these findings indicate?
These findings indicate characteristic retinal changes in PXE, including irregular retinal epithelial mottling and past hemorrhagic events.
105
A patient with PXE is experiencing intermittent claudication. What is the underlying cause of this symptom?
Intermittent claudication is caused by calcification and subsequent narrowing of blood vessels, leading to reduced blood flow.
106
A patient with PXE is found to have diminished peripheral pulses and hypertension. What is the likely explanation for these findings?
These findings are likely due to severe coronary artery disease and vascular calcification associated with PXE.
107
A patient with PXE is experiencing recurrent GI hemorrhagic events. What percentage of PXE patients experience at least one GI hemorrhagic event?
Approximately 10% to 15% of PXE patients experience at least one GI hemorrhagic event.
108
A patient with PXE is found to have breast and testicular microcalcifications. Does this finding increase the risk of cancer?
No, breast and testicular microcalcifications in PXE do not increase the risk of cancer.
109
A patient with PXE is experiencing calcification of degenerated elastic tissue in the GI tract. What are the clinical implications of this finding?
Calcification in the GI tract can lead to acute-onset hemorrhage, which is a common early manifestation in PXE.
110
A patient with PXE is experiencing subarachnoid hemorrhage. What is the underlying cause of this complication?
Subarachnoid hemorrhage in PXE is caused by calcification and fragility of blood vessels.
111
A patient with PXE is experiencing calcification of the lamina elastica in the eye. What are the potential complications of this finding?
Calcification of the lamina elastica can lead to fragility, fissuring, and hemorrhagic complications in the eye.
112
A patient with PXE is found to have peau d’orange in the retina. What does this finding represent?
Peau d’orange represents characteristic irregular retinal epithelial mottling in PXE.
113
What is the mutated gene associated with typical Pseudoxanthoma elasticum (PXE) and its location?
The mutated gene in typical PXE is **ABCC6**, located on chromosome **16p13.1**.
114
What are the histologic changes observed in Pseudoxanthoma elasticum (PXE)?
Histologic changes in PXE include:
- **H&E or Verhoeff-van Gieson stain**: distinctive broken curls of basophilic elastic fibers
- **Von Kossa stain**: calcium deposition on elastic fibers can be easily detected
- **Electron microscopy**: calcification in a centripetal pattern within elastic fibers.
115
What are the clinical features that differentiate classical Pseudoxanthoma elasticum (PXE) from other conditions?
Classical PXE is characterized by:
- **Pebbly pattern** and **yellow discoloration** of flexural skin
- Later development of **redundancy** may be confused with the sagging skin of **Cutis Laxa (CL)**.
116
What is the relationship between GACI and Pseudoxanthoma elasticum (PXE)?
**GACI** (generalized arterial calcification of infancy) is an **autosomal recessive disorder** characterized by widespread arterial calcification in infancy, with extracardiac findings such as skin and retinal findings that are identical to those seen in PXE.
117
What are the common conditions associated with angioid streaks that can be confused with Pseudoxanthoma elasticum (PXE)?
Conditions associated with angioid streaks include:
- **Ehlers-Danlos syndrome (EDS)**
- **Marfan syndrome**
- **Lead poisoning**
- **Sickle cell anemia**
- **Thalassemia**
- **Paget disease of bone**
- **Acromegaly**
- Other pituitary disorders and familial hyperphosphatemia.
118
A patient with PXE is undergoing genetic testing. What are the most common mutations associated with PXE?
The most common mutations are R1141X in Europe and ABCC6del23-29, which has an overall frequency of 12.9% and is most prevalent in U.S. patients.
119
A patient with PXE is found to have calcification in a centripetal pattern within elastic fibers. What diagnostic method was likely used to observe this?
Electron microscopy was likely used to observe the centripetal pattern of calcification within elastic fibers.
120
A patient with PXE is undergoing a histopathological examination. What staining techniques might reveal calcium deposition on elastic fibers?
H&E or Verhoeff-van Gieson stain can reveal distinctive broken curls of basophilic elastic fibers, and Von Kossa stain can detect calcium deposition.
121
A patient with PXE is found to have a deficiency of inorganic pyrophosphate. What is the role of this compound in PXE?
Inorganic pyrophosphate is a potent mineralization inhibitor, and its deficiency leads to ectopic mineralization as seen in PXE.
122
A patient with PXE is undergoing a soft-tissue radiograph. What findings might be observed?
Soft-tissue radiographs may reveal vessel wall calcification.
123
A patient with PXE is found to have angioid streaks. What other conditions might also present with angioid streaks?
Angioid streaks can also be seen in Ehlers-Danlos syndrome (EDS), Marfan syndrome, lead poisoning, sickle cell anemia, thalassemia, Paget disease of bone, and acromegaly.
124
A patient with PXE is experiencing calcification of elastic fibers in the skin. What histologic changes might be observed?
Histologic changes include distinctive broken curls of basophilic elastic fibers and calcium deposition, which can be detected using Von Kossa stain.
125
A patient with PXE is experiencing calcification in the renal vasculature. What diagnostic imaging technique might reveal this finding?
Ultrasonography might reveal dotted increased echogenicity of renal arteries, pancreas, and spleen.
126
A patient with PXE is experiencing calcification of elastic fibers in the skin. What is the clinical appearance of this finding?
The clinical appearance includes a pebbly pattern and yellow discoloration of flexural skin.
127
What are the key clinical features of Cutis Laxa?
- Skin is **inelastic** and appears **pendulous**.
- Bloodhound-like facial appearance with **loose skin** on the face, neck, shoulders, and thighs.
- Infants exhibit **unusually soft and loose hyperextensible skin** that does not resume its normal shape after stretching.
- Young children may appear **aged**.
- Absent signs of skin fragility, easy bruising, and abnormal scarring (which are present in EDS).
- **Joint hypermobility** and potential internal organ involvement may be observed.
128
What are the recommended treatment strategies for managing Cutis Laxa?
- **No cure** for PXE; plastic surgery may improve sagging skin.
- **Extrusion of calcium particles** through surgical wounds may lead to delayed healing.
- **Fillers or autologous fat** can soften prominent facial creases.
- For GI bleeding, **iced saline lavage** and transfusion are recommended.
- Avoid **anticoagulants** (NSAIDs/aspirin).
- **Eye protection** and consultation with a retina specialist are crucial.
- Treatments under investigation include **bisphosphonates** and **aluminum hydroxide** for improvement in PXE.
129
What is the inheritance pattern and epidemiology of Cutis Laxa?
- Inheritance can be **autosomal dominant (AD)**, **autosomal recessive (AR)**, or **X-linked recessive (XLR)**.
- Most commonly associated with **1 in 1,000,000 live births** incidence.
130
A patient with PXE is prescribed intravitreal injections of bevacizumab. What is the mechanism of action of this drug?
Bevacizumab is a VEGF inhibitor that stops choroidal neovascularization in PXE.
131
A patient with PXE is advised to follow a specific diet. What dietary modifications are recommended?
A diet with fivefold the standard magnesium intake is recommended to prevent connective tissue mineralization.
132
A patient with PXE experiences acute-onset gastrointestinal hemorrhage. What is the recommended initial management?
The recommended initial management includes iced saline lavage and transfusion. Rarely, balloon embolization or surgery may be required.
133
A patient with PXE is advised to avoid certain medications. Which medications should be avoided and why?
Patients with PXE should avoid anticoagulants such as NSAIDs and aspirin to reduce the risk of hemorrhage.
134
A pregnant woman with a history of generalized arterial calcification of infancy (GACI) is seeking treatment. What investigational therapy might be considered?
Bisphosphonates, such as etidronate, have been used as prenatal therapy for pregnant mothers with a history of GACI.
135
A patient with PXE is undergoing laser photocoagulation. What is the purpose of this treatment?
Laser photocoagulation is used to treat choroidal neovascularization, a complication of PXE.
136
A patient with PXE is experiencing prominent facial creases. What cosmetic treatments might be considered?
Fillers or autologous fat can be used to soften the prominent facial creases.
137
A patient with PXE is advised to avoid high-intensity cardiovascular exercise. Why is this recommendation made?
High-intensity cardiovascular exercise is avoided to reduce the risk of vascular complications, such as hemorrhage or arterial rupture.
138
A patient with PXE is undergoing regular evaluation with a cardiologist. What is the purpose of this follow-up?
Regular evaluation with a cardiologist is necessary to monitor and manage cardiovascular complications, such as coronary artery disease and hypertension.
139
A patient with PXE is experiencing visual symptoms. What tool can be used to detect early symptoms of retinal hemorrhage?
The Amsler grid can be used to detect early symptoms of retinal hemorrhage in PXE.
140
A patient with PXE is prescribed oral ascorbic acid and tocopherol. What is the expected outcome of this treatment?
The expected outcome of this treatment is to improve connective tissue health.
141
What is the purpose of regular evaluation with a cardiologist for a patient with PXE?
Regular evaluation with a cardiologist is necessary to monitor and manage cardiovascular complications, such as coronary artery disease and hypertension.
142
What tool can be used to detect early symptoms of retinal hemorrhage in a patient with PXE?
The Amsler grid can be used to detect early symptoms of retinal hemorrhage in PXE.
143
What is the expected outcome of prescribing oral ascorbic acid and tocopherol to a patient with PXE?
Oral ascorbic acid and tocopherol have shown an apparent positive response after several years in PXE patients.
144
What are the common clinical features associated with Autosomal Dominant Cutis Laxa (ADCL)?
Common clinical features of ADCL include:
- Beaked nose, long philtrum, high forehead, and large ears
- Hypotonia and skin laxity
- Internal involvement is less common
- Occipital horn syndrome and Menkes disease may be present.
145
What are the life expectancy and developmental outcomes for patients with X-linked Cutis Laxa?
Patients with X-linked Cutis Laxa may experience:
- Failure to thrive and developmental delays
- Normal or near-normal life expectancy, but may die within the first decade due to complications.
- Early intervention with copper replacement therapy can be helpful.
146
What are the key characteristics of ARCL Type 1?
Key characteristics of ARCL Type 1 include:
- Loose, hanging, pendulous skin
- Emphysema, hernias, pulmonary artery stenosis
- Cardiopulmonary insufficiency and early lethality due to profound elastic tissue defects.
147
What are the notable features of ARCL2B?
Notable features of ARCL2B include:
- Severe wrinkling of the dorsal hands and feet
- Lipodystrophy and cataracts
- Life-threatening complications such as pneumothorax and congenital heart defects.
148
What are the developmental and cognitive outcomes for patients with ARCL2A?
Patients with ARCL2A often exhibit:
- Microcephaly and neuroregression in the first decade of life
- 80% of patients show intellectual disabilities
- Failure to thrive and growth delays are common.
149
What is the role of copper-dependent lysyl oxidase in the synthesis of elastic fibers?
Copper-dependent lysyl oxidase mediates the formation of intermolecular crosslinks, stabilizing the alignment of individual tropoelastin molecules in the network of elastic fibers.
150
What are the consequences of mutations in the elastin gene?
Mutations in the elastin gene can lead to a shift in the reading frame, abnormal protein deposition in the ECM, premature activation of tropoelastin monomers, and cases of Acquired Cutis Laxa (ADCL).
151
How do mutations in fibulin 4 and fibulin 5 affect elastic fiber assembly?
Mutations in fibulin 4 and fibulin 5 lead to abnormal protein folding, decreased secretion, and reduced interaction with elastin and fibrillin, which are critical for elastic fiber assembly.
152
What are the clinical features associated with ARCL Type 1c (Urban-Rifkin-Davis syndrome)?
ARCL Type 1c is characterized by lung, gastrointestinal, and genitourinary abnormalities, along with mutations in LTBP4 that affect TGF-β sequestration and microfibril guidance.
153
What is the impact of loss-of-function mutations in ATP6V0A2 on glycosylation?
Loss-of-function mutations in ATP6V0A2 result in CDG-II due to defective serum protein N- and O-linked glycosylation, leading to increased intravesicular pH and impaired crosslinking of elastin.
154
What are the symptoms of MACS/RIN2 syndrome?
MACS/RIN2 syndrome presents with macrocephaly, alopecia, cutis laxa, scoliosis, hyperextensible skin, distinct facies, and mild protein hypoglycosylation.
155
What is the role of the ALDH18A1 gene in ARCL3B?
The ALDH18A1 gene encodes the mitochondrial enzyme Δ1-P5C synthase, which converts glutamic acid to P5C, and mutations can lead to thin translucent skin and increased sensitivity to oxidative stress.
156
How does the ATP7A gene mutation affect copper transport?
Mutations in the ATP7A gene disrupt copper transport into the Golgi apparatus, leading to X-linked cutis laxa and conditions like Menkes disease and occipital horn syndrome.
157
What are the characteristics of acquired forms of cutis laxa (CL)?
- Present after skin inflammation and structural damage of elastic fibers.
- Increased neutrophil elastase disrupts elastic fiber integrity.
- Genetic mutations may contribute to acquired forms of CL.
- Special stains show decreased or absent dermal elastic fibers.
- Electron microscopy may reveal increased elastin-associated microfibrils and abnormal elastic fiber branching.
158
What laboratory investigations are used for diagnosing cutis laxa?
- **Special Stains**: Verhoeff-van Gieson stain shows decreased or absent dermal elastic fibers.
- **Electron Microscopy**: Diagnostic for most cases, revealing increased elastin-associated microfibrils and abnormal fiber branching.
- **Transferrin Isoelectric Focusing**: Should be considered in patients with AR or sporadic CL, especially with typical facies and developmental delays.
159
What are the differential diagnoses for cutis laxa?
| Condition | Key Features |
|----------|---------------|
| Ehlers-Danlos Syndrome (EDS) | Skin regains normal appearance after stretching; joint laxity, increased bruising, poor wound healing. |
| Pseudoxanthoma Elasticum (PXE) | Laxity of skin, especially in flexural areas; pebbly, yellow appearance. |
| Hereditary Gelsolin Amyloidosis | Acquired CL is a primary feature; mutations in gelsolin; develops with age, initially affecting eyelid and scalp skin.
160
What are the clinical features of Type I acquired cutis laxa?
- Usually begins in adulthood; children can also be affected.
- Ill-defined areas of loose skin appear progressively with elastolysis.
- Involves the head and neck, progressing in a cephalocaudal direction.
- 50% of cases preceded by inflammatory eruptions.
- Most frequent cause of death: pulmonary involvement (emphysema).
161
What are the characteristics of Type II acquired cutis laxa (Marshall syndrome)?
- Postinflammatory elastolysis with localized, well-demarcated erythematous plaques.
- Plaques extend peripherally with a hypopigmented center.
- Appears in crops over days to weeks, often with fever and malaise.
- Systemic involvement is rare, but fatal aortitis has been reported.
162
What additional clinical features might be observed in a patient with PXE who has mutations in the GGCX gene?
Mutations in the GGCX gene can lead to features of both PXE and CL, including mineralized elastic fibers, abnormal bleeding tendency, and atherosclerosis.
163
What is the transient form of neonatal CL and its characteristics?
The transient form of neonatal CL is characterized by **generalized skin laxity** and **inguinal hernias** in infants born to mothers who were administered **d-penicillamine** during pregnancy. The loose skin typically resolves during the **first year of life**.
164
What multidisciplinary approaches are recommended for managing complications of neonatal CL?
A multidisciplinary approach to manage complications of neonatal CL includes:
1. Addressing **psychological trauma** and **emotional aspects**.
2. Conducting **genetic testing** to identify underlying genetic defects.
3. Avoiding **environmental exposures** that may exacerbate CL-related changes, such as UV light and smoking.
4. Regular **cardiac and pulmonary evaluations** and monitoring.
5. Considering **plastic surgery** for vascular and wound healing capabilities, which are typically normal.
165
What treatment options are available for neonatal CL?
Treatment options for neonatal CL include:
1. **Dapsone** to control acute swelling, potentially supporting neutrophil elastase.
2. **Botulinum toxin** to improve facial cosmesis.
3. **Surgical repair** of herniations when clinically indicated.
4. Regular monitoring and evaluations to manage complications effectively.
166
What is the estimated incidence of Buschke-Ollendorff syndrome?
The estimated incidence of Buschke-Ollendorff syndrome is 1 in 20,000 people.
167
What are the cutaneous findings associated with Buschke-Ollendorff syndrome?
Cutaneous findings include collections of skin-colored to yellow papules or plaques known as dermatofibrosis lenticularis disseminata, commonly located on the buttocks, proximal trunk, and limbs.
168
What are the noncutaneous findings associated with Buschke-Ollendorff syndrome?
Noncutaneous findings include bony lesions that appear after 15 years of age, discrete spherical areas of increased radiodensity, and osteopoikilosis, which is asymptomatic but may lead to functional limitations. Other findings include short stature, otosclerosis, and rare cataracts and peptic ulcer disease.
169
What is the inheritance pattern of Buschke-Ollendorff syndrome?
Buschke-Ollendorff syndrome follows an autosomal dominant inheritance pattern with usually complete penetrance.
170
What histopathological findings are associated with the cutaneous manifestations of Buschke-Ollendorff syndrome?
Histopathological findings may show increased amounts of elastic tissue (elastoma) or collagen, although decreased or normal amounts of elastic tissue and abnormalities of collagen can also be described.
171
What is the role of the LEMD3 gene in bone signaling pathways?
The LEMD3 gene antagonizes both bone morphogenetic protein and TGF-β signaling pathways in human cell lines. Loss of LEMD3 leads to enhanced TGF-β signaling.
172
What are the clinical features associated with Lipoid Proteinosis?
Clinical features include:
- Hoarseness (most frequent finding)
- Skin fragility and blistering in affected children
- Infiltrated lesions with scar-like appearance
- Development of infiltrated papules and plaques, especially on elbows and lower legs
- Beaded papules on the eyelid margin (moniliform blepharosis)
- Calcification of temporal lobes and amygdala, potentially leading to neurologic or psychiatric symptoms.
173
What is the epidemiology of Lipoid Proteinosis?
Lipoid Proteinosis is rare worldwide, with the greatest incidence in the Namaqualand region of South Africa. Fewer than 500 cases have been reported globally, and it is relatively common in this region due to a founder effect from a German settler who arrived in 1652.
174
What is the differential diagnosis for conditions associated with LEMD3 mutations?
The most frequent disorders considered in the differential diagnosis include:
- Connective tissue nevi without associated bony changes
- Morphea
- Pseudoxanthoma elasticum (PXE)
175
What are the most reliable clinical signs for diagnosing Lipoid Proteinosis (LP)?
The most reliable clinical signs for diagnosing LP include:
- **Hoarse voice**
- **Thickened sublingual frenulum**, which prevents protrusion of the tongue.
176
What are the secondary features associated with Lipoid Proteinosis (LP)?
Secondary features of Lipoid Proteinosis (LP) include:
- **Beaded eyelid papules**
- **Infiltration of warty papules** of the skin around the elbows and extensor forearms
- **Mild alopecia**
- **Increased scarring and photoaging** of sun-exposed skin
- Scars or scar-like lesions in areas of minor trauma that are not increased at sites of surgery or vaccination.
177
What is the earliest finding in Lipoid Proteinosis (LP) and when does it occur?
The earliest finding in Lipoid Proteinosis (LP) is **hoarseness** due to vocal cord infiltration, which occurs at birth or in the first few years of life.
178
What are the stages of cutaneous lesions in Lipoid Proteinosis (LP)?
The stages of cutaneous lesions in Lipoid Proteinosis (LP) are:
1. **1st Stage**:
- **Erosions**: Underappreciated clinical feature that develops during childhood in up to 50% of patients.
- **Blistering**: May mimic epidermolysis bullosa, typically noninflammatory, heals slowly with hemorrhagic crusting and resultant scarring.
- Blistering is worse during warmer weather, with skin fragility and easy wounding.
- Spontaneous development of extrafacial pustular lesions.
- Shedding of sheets of skin, leaving red oozing areas.
2. **2nd Stage**:
- Pathognomonic clinical finding: **Beaded papules along the eyelid margins** (moniliform blepharosis).
179
What are some other cutaneous stigmata associated with Lipoid Proteinosis (LP)?
Other cutaneous stigmata associated with Lipoid Proteinosis (LP) include:
- **Generalized skin thickening** with a waxy, yellow appearance and areas of distinct papules and nodules.
- **Hyperkeratosis** in areas subject to repeated friction or trauma, such as elbows, halluces, and extensor aspects of the arms and lower legs.
180
What are the common skin manifestations associated with ECM-1 mutations?
- **Scarring**: Begins during childhood, often worst on the face; may follow trauma or occur spontaneously.
- **Pock-like and acneiform scarring**: Some areas may resemble solar elastosis.
- **Flexural lichenification**: May be misdiagnosed as atopic dermatitis.
- **Increased photosensitivity**: Sun-exposed areas exhibit the greatest amount of scarring.
- **Pruritus**: Alterations in the ability to sweat and abnormal pain sensation.
181
What are the related physical findings in the mucosa for patients with ECM-1 mutations?
- **Oral erosions**
- **Thickening of the lingual frenulum**: Leads to inability to protrude the tongue.
- **Involvement of pharynx, tongue, soft palate, tonsils, and lips**.
- **Loss of the tongue papillae**: Results in a smooth surface.
- **Respiratory difficulty**: Swelling of the salivary glands (submandibular and parotid).
- **Xerostomia**: Dry mouth and dental abnormalities, such as absent permanent upper lateral incisors.
182
What neurological symptoms are associated with CNS involvement in ECM-1 mutations?
- **Abnormal perception and appraisal of fear**.
- **Judgment of facial expression and emotion**: Memory for negative and positive pictures, and in odor-figure association tests.
- **Seizures**: Often temporal lobe, memory deficits, social and behavioral changes, paranoid symptoms, mental retardation, and aggressiveness.
- **Severe generalized dystonia**: Has also been reported.
- **Brain imaging**: May show calcification of the temporal lobes in the region of the amygdala or hippocampi.
183
What are the laboratory findings in light microscopy for patients with ECM-1 mutations?
- **Deposition of amorphous eosinophilic material** at the DEJ, perivascularly, and along adnexal epithelia.
- **Deposition of hyaline material in the dermis**: Perpendicular to the basement membrane.
- **Periodic acid–Schiff positive and diastase resistant**.
- Arranged in concentric, "onion-skin" layers around vessels.
- Layers include Type III and IV collagen, and laminin.
184
What are the key differences between ECM-1a and ECM-1b?
| Feature | ECM-1a | ECM-1b |
|---------|---------|---------|
| Exon Binding | Binds to fibulin | Lacks exon 7, does not bind fibulin |
| Expression | Expressed in basal keratinocytes | Only expressed in terminally differentiated keratinocytes |
185
What are the histologic features of early bullous lesions in Lipoid Proteinosis (LP)?
The histologic features include acantholysis of keratinocytes and enlarged vessels in the mid and deep dermis with an orientation parallel to the dermal-epidermal junction. The dermal papillary plexus lacks capillary loops, and vascular abnormalities may reflect a disturbance of ECM-1 function during angiogenesis.
186
What are the common findings in a Brain CT scan of patients with Lipoid Proteinosis (LP)?
Common findings include bilateral anterior medial temporal lobe calcifications, often bean-shaped, especially within the amygdala, observed in 50-75% of LP patients.
187
What are the treatment options for Lipoid Proteinosis (LP) and their effectiveness?
Treatment options include topical and systemic corticosteroids, oral dimethyl sulfoxide, intralesional heparin, acitretin (shows improvement in various aspects of LP), photoprotection, avoiding friction or trauma, and surgical modalities (dermabrasion and CO2 laser surgery for vocal cord lesions and eyelid papules). However, none of these agents has demonstrated any sustained benefits, except for acitretin which shows some improvement.
188
What is the clinical course of Lipoid Proteinosis (LP)?
The clinical course of LP is characterized by progressive worsening of cutaneous features, clearance during childhood of blistering lesions, development of infiltrative lesions over time, and hoarseness and mucosal lesions may progress with time. Most patients lead a normal life, but the disfiguring nature of skin lesions and abnormal voice can impact social interactions and job holding.
189
What is the significance of prenatal genetic testing in families at risk for Lipoid Proteinosis (LP)?
Prenatal genetic testing in families at risk for LP is theoretically possible using DNA-based analysis, which can help in early identification and management of the condition.
190
What are the key differences between ECM-1a and ECM-1b?
ECM-1a binds to fibulin, is expressed in basal keratinocytes, and is important in keratinocyte differentiation. ECM-1b lacks exon 7, does not bind fibulin, is only expressed in terminally differentiated keratinocytes, and may stimulate blood vessel endothelial cell proliferation and promote angiogenesis.
191
What are the structural characteristics of the ECM?
Schiff positive and diastase resistant; arranged in concentric, 'onion-skin' layers around vessels, which include Type III and IV collagen, and laminin.
