8.11 Progeria syndromes

LD2B

Progeroid syndrome(s), premature aging syndromes.

Laminopathies are extremely rare disorders. Hutchinson–Gilford progeria syndrome only affects one child per 4,000,000 births worldwide.

Werner syndrome is estimated to occur in 0.5-1 out of 100,000 live births worldwide.

Syndromes characterized by premature aging signs. Hair loss and alopecia. Skin atrophy, sclerotic skin changes, teleangiectasias, poikiloderma and increased prevalence of skin tumors .

The majority of progeria syndromes are rare autosomal recessive genetic conditions and show gene defects in DNA replication, recombination, repair and transcription as well as mitochondrial function. -Several of these syndromes are laminopathies (diseases caused by mutations in components of the nuclear lamina due to Lamin A (LMNA) gene mutations).

• Hutchinson-Gilford progeria syndrome is mainly caused by a sporadic autosomal dominant point mutation in LMNA gene resulting in differently spliced lamin A protein known as progerin.
• Werner syndrome is caused by a truncating mutation in the WRN gene due to the production of a stop codon from a nonsense or frameshift mutation. The WRN gene plays a role in maintaining proper DNA replication and repair through base excision repair, non-homologous end-joining, and homologous recombination. It is also involved in maintaining telomere stability, which is pivotal for genomic stability.

Premature aging only affects certain types of tissues in each syndrome. 

Among the typical signs of premature aging in progeria syndromes is the premature onset of the following symptoms or disorders:

• Graying/loss of hair.

• Hearing loss.

• Cataract.

• Scleroderma-like skin changes.

• Type 2 diabetes mellitus.

• Osteoporosis.

• Atherosclerosis and coronary heart disease.

• Various malignant tumors.

Hutchinson–Gilford progeria syndrome is a systemic disorder that affects the majority of the organs of the body including the skin, bone, skeletal muscle, adipose tissues, heart, and large and small arteries. The children affected start exhibiting the symptoms of the disease at the age of 1–2.

Patients with Werner syndrome develop skin ulcers, cataracts, graying or even loss of their hair, and hypogonadism. The loss of subcutaneous fat and dermal atrophy produces a scleroderma-like appearance. Werner syndrome patients are at an increased risk of tumor formation, with up to 10% of patients developing a malignancy.

More than 100 syndromes with clinical sign(s) of premature aging have so far been described in the scientific literature, but only in recent years the genetic defects causing these syndromes have been identified. The list of the most prominent progeria syndromes includes:

A. Congenital progeroid syndromes

I. Laminopathies
Hutchinson-Gilford progeria syndrome (commonly called progeria)
Restrictive dermopathy
Mandibuloacral dysplasia
LEMD2-associated progeroid syndrome
Atypical Werner syndrome (atypical progeroid syndrome)

II. Other progeroid syndromes
Wiedemann–Rautenstrauch syndrome (neonatal progeroid syndrome)
CAV1-associated neonatal progeroid syndrome
PYCR1-related Cutis laxa syndrome

B. Juvenile/adult progeroid syndromes

Werner syndrome (adult progeria)
Myotonic dystrophy type 1
Cockayne syndrome
Néstor–Guillermo syndrome
Ruijs–Aalfs syndrome
Lessel-Kubisch syndrome (MDM2-associated progeroid syndrome)

Patients diagnosed with Werner syndrome should undergo regular screening tests for hyperlipidemia, breast and colorectal cancer, diabetes, and thyroid abnormalities. Given the number of musculoskeletal abnormalities and high prevalence of soft tissue sarcomas in Werner syndrome patients, clinicians should perform an X-ray, CT, or MRI studies in the appropriate clinical scenario to evaluate for underlying disorders, infections or tumors thoroughly. DEXA (specific scans for osteoporosis) scans should also be performed regularly to evaluate and monitor osteoporosis.

Skin biopsies from patients carrying LMNA or ZMPSTE24 mutations reveal increased nuclear size and an atrophic epidermis with focal hyperkeratosis and hypoplastic sebaceous glands.

• Hutchinson-Gilford progeria syndrome is characterized by accelerated aging in affected children leading to premature death at an average age of 14.5 years due to cardiovascular complications.
• Werner syndrome patients appear unaffected at birth and develop normally until the adolescent period or second decade of life when they start to exhibit signs and symptoms of accelerated aging. Werner syndrome patients typically live into the fifth decade of life. Patients usually die of malignancy or cardiovascular disease.

Werner syndrome patients develop characteristic physical and metabolic abnormalities that result in severe complications more commonly seen in the elderly, including diabetes, hypertension, osteoporosis, myocardial infarction, stroke, and cancer. Caution should be exercised with Werner syndrome patients and chemotherapy treatments. They are at an increased risk of chemotoxicity due to their impaired ability in DNA repair mechanisms.

Classic Hutchinson-Gilford progeria syndrome is identified on the basis of clinical symptoms and the medical history of the patient. Also, its presence can be confirmed by genetic testing for the mutation (c.1824C>T) in the Lamin A gene. However, there is no kit available for its early detection.

Werner syndrome: Genetic testing through nuclear sequencing by reverse transcription-polymerase chain reaction (PCR) with western blot protein analysis can confirm the diagnosis of Werner syndrome. Prenatal testing with amniocentesis and chorionic villus sampling can be performed in patients at high risk for having infants with this disorder.

All syndromes: Normal aging, hormonal deficiencies, metabolic disturbances (internal diseases).

Werner syndrome: systemic sclerosis, dermatomyositis, and other premature aging syndromes.

Hutchinson-Gilford progeria syndrome: No cure has been found for this catastrophic disorder. In several clinical studies, lonafarnib, a farnesyl transferase inhibitor, demonstrated remarkable improvement in weight gain, vascular architecture and bone structure along with a decreased frequency of headaches and strokes and improvement in the life span.

Werner syndrome: Treatment is aimed at symptomatic relief and control of the secondary organ dysfunction. Treatment of atherosclerosis, hypertension, diabetes, and other diseases is achieved through standard conventional monitoring and medical therapy, but the disorder will continue to progress. Bosentan, an endothelin receptor antagonist, can be used to treat severe cutaneous ulcers. Sodium etidronate can help improve symptomatic calcifications in the soft tissue. Orthotics can be used to manage complications with feet deformities. Cataracts should be managed surgically. Sarcopenia can be treated with diets rich in branched amino acids, exercise, vitamin D supplementation, and hormone therapy, although this is controversial given the increased risk of malignancy.

This group of progeria syndromes should be diagnosed and managed in special centers for Orphan diseases and having special interest and expertise in certain types of this rare diseases. Whenever there is any evidence that progeria syndrome could be behind, the patient should be immediately advised to this center.