Premature ageing syndromes

What are the premature ageing syndromes?

Premature ageing syndromes, also known as progeria, include two very rare inherited conditions, Hutchinson-Gilford syndrome and Werner syndrome. In both conditions, skin changes that indicate premature ageing include:

• Atrophy (skin thinning and loss of elasticity)
• Loss of cutaneous fat
• Wrinkling
• Greying hair
• Loss of hair
• Nail dystrophy
• Defective pigmentation
• Ulceration.

These are changes that occur as the normal body ages (see skin ageing) but in progeria, they occur at an accelerated rate.

What are the differences between progeria types?

Hutchinson-Gilford syndrome

Hutchinson-Gilford syndrome occurs in about 1 in 8 million children. Signs of progeria begin to show around 6–12 months when the baby fails to gain weight and skin changes occur.

Characteristic features include:

• Baldness, prominent scalp, veins and eyes, small jaw, delayed tooth formation
• Thin limbs with prominent joints, short stature, joint stiffness, hip dislocations
• Thickened, tight and shiny skin over joints.

The average life expectancy is 13 years, with approximately 75% dying from heart disease.

Werner syndrome

Werner syndrome occurs in about 1 in 1 million individuals. The first sign of the syndrome is around puberty when the child fails to have a normal growth spurt or may be delayed until an individual is as old as 30 years.

Characteristic features include:

• A striking difference between a person's appearance and his/her real age
• Greying hair and/or balding, wrinkling and ageing of the face, sunken cheeks, small jaw
• Small stature (usually less than 1.6m tall), muscle weakness
• Thickened, tight and shiny skin over joints, leading to ulcers
• High-pitched voice.

Death usually occurs in patients between 30–50 years, with most dying from heart disease or cancer.

What is the cause of progeria?

Werner syndrome is an autosomal recessive disorder, which means an individual has inherited a mutated gene from both parents. 1 in 4 offspring would be expected to have the disorder and others may be carriers of the gene. Werner syndrome is caused by a homozygous or compound heterozygous mutation in the RECQL2 geneWS , which provides instructions to a protein called helicase. This is a homolog of the E. coli RecQ DNA helicase and is found on chromosome 8p12. Helicase affects the way DNA and RNA are replicated and repaired in the body.

Hutchinson-Gilford syndrome can be autosomal recessive or autosomal dominant. Autosomal dominant disorders are passed on by one parent, and up to 1 in 2 offspring can have the disorder. Hutchinson-Gilford syndrome is caused by de novo heterozygous mutation in the lamin A gene on chromosome 1q22. The protein Lamin A is the structural scaffolding that holds the nucleus of a cell together. Cellular instability appears to lead to premature ageing.

What are the complications of progeria?

Complications of progeria are related to the diseases that are associated with ageing. In addition to skin changes, patients with Werner syndrome often develop the following conditions:

• Cataracts – rapidly progressing cataracts develop between the ages of 20-40 years in most cases
• Osteoporosis (loss of bone density) – particularly in the legs, caused by disturbances in the parathyroid glands
• Diabetes mellitus – this occurs in at least 30% of patients, and there is abnormal glucose tolerance in many others
• Cardiovascular disease – particularly arteriosclerotic disease, which may lead to a fatal heart attack
• Pituitary gland underactivity
• Hypogonadism or agonadism (absent or underactive ovaries or testes) and premature menopause
• Soft tissue calcification
• Cancer – the incidence of malignancy is high, especially fibrosarcomas which occur in 10% of patients. Other cancers include carcinomas of the thyroid and other organs, blood disorders, meningiomas and skin cancers including squamous cell carcinoma arising in ankle and heel ulcers.

What is the treatment for progeria?

There is no specific treatment for progeria. Management of the syndromes is through symptomatic treatment of related diseases. Genetic counselling is very important.