Pseudoxanthoma Elasticum:
Inheritance, Difficult Choices
and Cardiovascular Manifestations

Click to listen (1.60 MB)

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"

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