A genodermatosis refers to a genetic condition that affects the skin. Genodermatoses frequently involve other organs as well. In this month’s column, we review four genodermatoses that involve the heart: pseudoxanthoma elasticum, tuberous sclerosis, nevoid basal cell carcinoma syndrome, and Carney complex.

Pseudoxanthoma elasticum (PXE)

PXE is a rare genodermatosis characterized by calcification and fragmentation of elastic fibres in the skin, eye and arteries.

It’s primarily an autosomal recessive condition due to a mutation in the ABCC6 transporter gene. It’s not known precisely how, but this mutation results in calcification and fragmentation of elastic fibres in the skin, cardiovascular system and eye. It tends to be twice as common in females as males and usually presents in the 2^nd or 3^rd decades.

Skin

Skin folds become lax with redundant skin and yellowish papules giving the impression of a “plucked chicken.” There may also be some cobblestoning of yellow papules in the mucosa. Histology shows calcified and irregular elastic fibres in the mid and lower dermis.

Cardiovascular system

These findings usually don’t present until adulthood but can occur in kids. There’s calcification of the media elastica of arteries with subsequent intimal proliferation.

Other symptoms

• Mucosa: epistaxis
• Coronary arteries and heart: atherosclerosis, angina, myocardial infarction, mitral valve prolapse
• Gastrointestinal: GI bleed, ischemic bowel
• Renal arteries: stenosis leading to hypertension
• Cerebral arteries: subarachnoid hemorrhage, stroke

Eye

The most common eye finding in patients with PXE is angioid streaks. These are red-brown streaks that radiate from the optic disk in the retina. Angioid streaks represent tears in Bruch’s membrane due to calcification of its elastic fibres. They are late findings in PXE, appearing 20 years after the skin lesions.

Other organs

Rarely other organs can be affected. There’s an increased risk of first-trimester miscarriage, hematuria and lung involvement.

Management:

PXE requires a team approach to management. A dermatologist should be involved to consider a skin biopsy demonstrating calcified and fragmented elastic fibers. Surgical cosmetic options may be effective. Patients should see an ophthalmologist regularly to monitor for angioid streaks. They should be followed closely by a cardiologist, internist and neurologist, for cardiovascular involvement and complications. Atherosclerotic risk factors should be minimized. Anticoagulant therapy has to be used with caution due to the risk of GI bleed.

A medical genetics consultation should be arranged for the patient and first-degree relatives. This can be very helpful for patients and family members.

Tuberous sclerosis

Tuberous sclerosis (TS) is a relatively common genodermatosis characterized by the classic triad of seizures, low intelligence and angiofibromas, although only a minority of patients have all three. It’s an autosomal dominant condition, but sporadic in the majority of patients. Its prevalence ranges from 1 in 5,000 to 1 in 10,000, equally present in males and females.

Mutations involve the Hamartin and Tuberin genes. The wild type hamartin and tuberin proteins form a complex that inhibits Rheb and subsequently MTOR, preventing cell proliferation. When either is non-functional, unregulated cell growth can occur.

The cutaneous features are often the first clues to TS. Hypomelanotic macules can be seen at birth. Angiofibromas usually appear later, but often within the first two years. A shagreen patch is a connective tissue nevus that’s usually seen on the buttock. Koenen’s tumours are periungual fibromas present in up to 80% of patients.

There are many extra-cutaneous findings in TS (see Table 1). Neurologic manifestations result in the greatest morbidity. Brain hamartomas lead to seizures in the vast majority of patients, usually in infancy. There can also be behavioural and cognitive dysfunction. Lung lymphangioleiomyomatosis occurs almost exclusively in women, usually after the 3^rd decade. Renal cysts are common in TS, especially when there’s a tuberin mutation. The tuberin gene is very close to the PKD (polycystic kidney disease) gene so these conditions sometimes overlap. Renal cell carcinoma is possible. Endocrine manifestations include hypothyroidism and precocious puberty.

Cardiac manifestations include benign rhabdomyomas in up to 60% of patients. In a child who presents with a rhabdomyoma, 90% may have underlying TS. Rhabdomyomas are usually early findings in TS, and often improve with age. Lesions are rarely symptomatic. Treatment isn’t indicated unless patients are symptomatic with hemodynamic compromise. Wolff-Parkinson-White syndrome can also present early with supraventricular tachycardias and cardiac rhabdomyomata.

Treatment of TS

At the initial visit of a patient with TS, consider referral to dermatology for possible skin biopsies. Neurology should be involved for seizure management as well as considering an MRI of the brain. Involve an ophthalmologist to rule out retinal hamartomas. ECG and echocardiography ought to be done to rule out cardiac involvement. Renal ultrasound should also be done. Refer patients for genetic counselling, and consideration for genetic studies for TSC1/TSC2. Other tests can also be done depending on the patient, such as a bone scan to look for cysts, GI referral for possible hamartomatous rectal polyps, and a CT chest to diagnosis lymphangiomyomatosis in female patients between the ages of 20 and 50 years.

Treatment of skin lesions is important. The lesions can be quite extensive and be a significant source of morbidity. Surgical methods such as electrodessication, dermabrasion, and laser ablation can be helpful. Topical rapamycin may be a non-surgical treatment for angiofibromas of TS, but its use is experimental at this time.

Patients with TS should have regular follow-up. Repeat echocardiography if patients develop cardiac symptoms. Renal ultrasound should be done every one to three years. Brain CT or MRI should be repeated every one to three years until after adolescence.

Family members of affected patients ought to consider genetic testing, CT head and renal ultrasound.

Gorlin’s syndrome

Gorlin’s syndrome is also known as nevoid basal cell carcinoma syndrome. It’s an autosomal dominant condition due to a mutation of the tumour suppressor PTCH gene on chromosome 9.

It has a number of characteristic features including a unique appearance due to skeletal and developmental malformations. Basal cell carcinomas before age 20 are common in these patients.

Patients with Gorlin’s syndrome are at an increased risk of developing cardiac fibromas. Up to 5% of patients who present with a cardiac fibroma may have underlying Gorlin’s syndrome. Cardiac fibromas can present with hemodynamic compromise as well as arrhythmias due to involvement of the conduction system. Consider ECG and echocardiography in symptomatic patients.

Carney complex

Carney complex is a rare autosomal dominant genodermatosis due to a mutation in the PRKAR1A gene. It typically presents in the first few years of life with skin findings such as multiple nevi, lentigines, and myxomas. The lentigines, light brown macules, can occur anywhere including the mucosa and conjunctiva. Myxoma refers to a papule or nodule with increased local mucin deposition. It can be diagnosed on biopsy and confirmed with special stains.

Atrial myxomas are the predominant cardiac manifestation and main source of morbidity and mortality in these patients. They can lead to congestive heart failure and embolization. Consider ECG and echocardiography in suspected patients. Atrial myxomas can be excised in appropriate situations.

Other manifestations of Carney complex include Cushing’s syndrome, acromegaly and precocious puberty. Screen patients carefully for testicular tumours.