Pseudoxanthoma Elasticum:
Inheritance, Difficult Choices
and Cardiovascular Manifestations

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By B. Struk, MD, PhD
Franz-Volhard-Clinic and
Max-Delbrueck-Center Berlin Buch

PXE No Choice

  • PXE patients

  • Can't choose their parents, nobody can

  • Therefore, can't influence their genetic make-up

PXE Disease Definition

  • PXE is a heritable systemic (metabolic?) disorder affecting the elastic tissue, characterized by systemic manifestations, typically first in skin, then in the eyes and cardiovascular system

  • accelerated aging of the organ systems involved

PXE Epidemiology

  • Prevalence approximately 1 in 50,000 to 1 in 100,000

  • Mean age of onset 13 years (range 2-40 yrs)

  • No racial predilection

  • 2 to 1 female preponderance

  • Previously under-diagnosed

  • Now over-diagnosed ??

PXE Clinical Manifestation Sites

  • Skin

  • Eyes

  • Cardiovascular System

PXE Retinopathy Characteristics

PXE Cardiovascular System

  • Heart

    • Coronary artery disease

    • Endocardial thickening

      • Mitral valve prolapse

  • Peripheral Artery Disease

    • Carotid arteries

    • Gastrointestinal arteries

    • Arteries of upper and lower extremities

  • Small Vessel Disease

    • Brain - Mental fatigue syndrome

    • Gut

    • Kidney

PXE Cardiovascular Phenotype

  • Intermittent claudication 20-30% 

  • Hypertension, angina pectoris, heart attacks, stroke 20% 

  • Gastrointestinal hemorrhage 5-13% 

    • Intermittent claudication and angina pectoris in PXE become prevalent 10 to 20 years earlier than in the general population

PXE Pathology

  • Calcification (mineralization) of elastic fibers

  • Increase of elastic fibers in elastic tissue (dermis)

  • Increase in glycosamioglycans in elastic tissue (dermis) (glucosamine, hyaluronic acid, chondroitin sulfate B)

PXE Cardiovascular Pathophysiological Mechanism

  • "vascular stiffening"

PXE Diagnostic Classification Prior to "Molecular Diagnosis"

Category I

(3 major criteria)

Category IIa

(1 major criterion and 2 minor criteria)

Category IIb

(1 major and 1 minor criterion)

Category IIc

(1 major and 1 minor criterion)

Category IId

(2 minor criteria)

1. characteristic flexural skin lesions

1. angioid streaks

1. angioid streaks

1. angioid streaks

1. family history of PXE in first-degree relatives

2. elastic fiber calcification- lesional skin

2. elastic fiber calcification-nonlesional skin

2. elastic fiber calcification- nonlesional skin

2. family history of PXE in first-degree relatives

2. elastic fiber calcification- nonlesional skin

3. ocular disease in adults

3. family history of PXE in first-degree relatives

 

 

 

PXE Angioid Streaks

Disorders other than PXE in which angioid streaks have been observed:

  • Paget's Disease (Osteitis Deformans)

  • Marfan's Syndrome

  • Ehlers-Danlos Syndrome

  • Beta Thalassemia

  • Sickle cell hemoglobinopathies

  • Hereditary spherocytosis

  • Idiopathic thrombocytopenic purpura

  • Tumoral calcinosis

  • Lead poisoning

  • Cowden's Syndrome

  • Pituitary tumors

  • Acromegaly

  • Familial polyposis

  • Nevus of Ota (oculodermal melanocytosis) 

PXE Mutation Analysis

  • Mutation screening in 89 PXE affected individuals

    • representing 170 distinct PXE chromosomes

    • belonging to 81 families

      • 61 families (75%) with PXE in a sibpair of 1 generation (recessive mode of inheritance)

      • 11 families (13.5%) with PXE in 1 person of single generation (sporadic mode of inheritance)

      • 9 families (11%) with PXE either in first degree cousins, or two or three family generations (possible dominant mode of inheritance)

PXE Mutation Detection Rate

  • Potentially disease causing mutations were found in 165 of 170 chromosomes

  • Mutation detection rate of 97%

PXE Mutation Spectrum in ABCC6

  • 5 distinct large deletions

  • 32 missense mutations

  • 8 nonsense mutations

  • 1 small insertion

  • 7 small deletions

  • 6 splice site mutations

PXE Molecular Genetics

  • Interestingly, the frequent PXE mutations originate from founder alleles

PXE From Bench to Bedside

  • Genotype phenotype analysis in the current set of families reveals:

    • All affecteds according to category I diagnostic criteria always carry two mutation alleles (homozygotes, compound heterozygotes)

    • All affecteds according to category II diagnostic criteria always carry one mutation allele (heterozygotes)

  • Homozygotes and compound heterozygotes show the full expression of the disease according to category I diagnostic criteria: 

    • Characteristic flexural skin lesions

    • Elastic fiber calcification of lesional skin

    • Ocular disease in adults (retinal hemorrhages with subsequent central visual field loss

  • Therefore, PXE (full phenotype expression with long term complications) is solely recessively inherited

  • This has profound consequences for the correct genetic counseling of families with PXE

  • Mutations cause loss of protein function

PXE From Bench to Bedside - Conclusions

  • Familial PXE mutation analysis in ABCC6

    • Enhances and refines the clinical diagnostic criteria of the disease

    • Demonstrates a recessive-only mode of inheritance of the full phenotype

    • Allows for the molecular exact discrimination of full phenotype expression against the forme fruste

    • And therefore, allows early individual risk prediction with regard to potential long-term disabling disease complications

  • Pfendner EG, et al.

    • J Med Genet. 2007 Jul 6; [Epub ahead of print] PMID: 17617515 [PubMed - as supplied by publisher]

    • "An interesting observation was the absence of macroscopic skin lesions in 4 patients, although skin biopsy revealed typical histological characteristics of PXE"

    • One patient had significant ophthalmologic complications, suggesting that this individual was not a carrier

    • In three of these patients, a complete genotype was found, confirming the clinical diagnosis and emphasizing that skin features, although present in the majority of PXE patients, are not always mandatory for the diagnosis.

  • Why did Pfendner et al find this, but not us?

    • Selection bias

      • Their patients were referred through ophthalmologists

      • Our patients had to pass the dermatologist first

    • Potentially wrong clinical assessment

    • Missed subtle skin lesions, potentially false positive utation analysis

    • PCR contamination

    • Sample mix-up

  • Is the result by Pfendner et al valid?

  • Yes, it is an important observation, but

      • Further independent observation is needed

      • If it exists it is very rare

      • It is something to keep in mind, but will not change the principal approach towards diagnosing PXE in the first place

PXE From Bench to Bedside - Conclusions in Short

  • Molecular analysis confirms in PXE:

    • The skin might not tell it all

    • Molecular diagnosis is needed for the unambiguous diagnosis and for the safest risk prediction

Choices for Patients With PXE

  • Seek molecular diagnosis

    • If clinical criteria don't fit and PXE is still suspected

  • No disease inheritance to the next generation through a single parent

  • If you suffer from PXE

    • Adjust your life style to minimize your CV risk factors

    • Get monitored for cardiovascular disease manifestations of PXE

PXE Personal Cardiovascular Risk Control

  • Keep normal body weight

  • No BMI greater than 26 for male and 25 for female

  • Do regular exercise

  • Eat healthy

Suggested Reading :

Eat More, Weigh Less by Dean Ornish, MD

Dr. Dean Ornish's Program for Reversing Heart Disease by Dean Ornish, MD

PXE Professional Medical Cardiovascular Risk Management I:

  • Annual lipid profile:

    • Cholesterol (HDL, LDL, VLDL, Chylomicrons)

    • Triglycerid

    • Lipoprotein a [Lp (a)]

    • C-reactive Protein

    • (Homocystein) no longer recommended

PXE Professional Medical Cardiovascular Risk Management II:

  • Annual echocardiography and stress test

  • Two annual 24-hour blood pressure monitorings

  • Exclusion of diabetes mellitus as additional risk factor

PXE Professional Medical Cardiovascular Risk Management III:

  • No causal treatment available

  • Treatment of hyperlipidemia

  • LDL less than 100 mg/dl (statins)

  • Treatment of high blood pressure

  • Treatment of coronary artery disease

  • Treatment of peripheral artery disease