Progeria syndrome

Definition

Progeria syndrome is an extremely rare genetic disorder of unknown origin that manifests as premature aging in children. Progeria affects many parts of the body including the skin, bones, and arteries.

Description

Dr. Jonathan Hutchinson in 1886 and Dr. Hastings Gilford in 1904 first described this syndrome. The word progeria is coined from the Greek word geras, which means old age. Progeria syndrome is also known as Hutchinson-Gilford progeria syndrome, HGPS or Gilford syndrome.

Most patients appear normal at birth. Signs and symptoms usually begin to develop within the first one to two years of life. Changes in skin and failure to thrive (failure to gain weight) are usually evident first, the exception being four reported cases of possible neonatal progeria. All four infants died before twenty months of age. Death in these cases appears to be related to intrauterine growth retardation and presentation of progeria signs and symptoms at birth. The neonatal cases did not exhibit the development of arteriosclerosis (hardening of the arteries). Arteriosclerosis is the most serious complication of progeria. Complications secondary to arteriosclerosis in childhood, adolescence, or adulthood are the leading cause of death.

Patients with progeria syndrome develop many other signs and symptoms which present a classical appearance. The majority of patients with progeria resemble each other. Common external findings include aging at an accelerated rate, alopecia (hair loss), prominent scalp veins, absence of fat under the skin (subcutaneous fat), scleroderma (thickening of the skin), a pinched nose, small face and jaw (micrognathia) relative to head size (bird face), delayed tooth formation, high pitched voice, and impaired or absence of sexual development. Patients are also known to experience stiffening of various joints, bone structure abnormalities, and the development of arteriosclerosis. Patients with progeria syndrome experience average intelligence and their cognitive abilities are usually not affected.

Genetic profile

Evidence suggests that the gene for progeria may be located on chromosome 1. Progeria is believed to be passed on in an autosomal dominant new mutation fashion. The disorder is transmitted to children by autosomal dominant inheritance . This means that either affected parent (father or mother) has a 50% chance of having a child (regardless of gender) with the disorder. New mutation refers to the chance change in the structure of a gene resulting in alterations in its function. This new mutation is believed to happen at conception sporadically and permanently (since neither parent is affected). New mutations occur as a result of both genetic and environmental factors. New mutations can be either chromosomal abnormalities or point mutations (specific alterations in the building blocks of genes called nucleotides). Research is ongoing to identify a more specific genetic mutation that causes progeria syndrome.

Demographics

Occurrence of progeria is sporadic and rare, though studies suggest frequency may be related to increased parental age and increased average difference in age of parents. Approximately 100 cases have been reported to date in the world with the reported incidence (number of absolute occurrence) being one in eight million.

Signs and symptoms

Progeria syndrome is progressive. Signs develop over time.

• General—Patients are short and weigh less than is appropriate for height. Patients usually do not grow taller than 3.7 ft (1.15 m) or weigh over 40 lb (15 kg). Patients with progeria do not usually exhibit mental impairment.
• Skin—Skin is usually thin, dry and wrinkled. The skin in the hands and feet is pushed inwards. The skin also exhibits color (pigmentation) changes, which presents clinically as yellow-brownish spots. Patients also have a decrease in fat below the skin (subcutaneous) except in the area below the navel. The nails of patients with progeria are small, thin, and poorly developed. Patients experience alopecia (hair loss) of the scalp, eyelashes, and eyebrows. Scalp veins become visible and prominent as hair loss progresses.
• Bones—There are several abnormalities in the skeletal structure. Refer to complete description under diagnosis heading.
• Eyes—Patients often appear to have prominent eyes. This is in part secondary to the alterations in bone structure of the face. Patients also may experience far-sightedness (hyperopia) and astigmatism. Astigmatism refers to changes in the structure of the lens and cornea (parts of the internal structure of the eyes), which alter the eyes' ability to focus incoming visual images.

Diagnosis

Diagnosis is based upon physical appearance. Diagnosis is usually made within the first two years of life when patients develop skin changes and fail to grow.

Patients with progeria eventually develop skeletal system (bone and joint) changes. Patients show characteristic radiographic (x ray) findings. In general the skeleton is hypoplastic (underdeveloped). Patients have persistent anterior fontanelles (soft spots of skull in newborn children). Patients with progeria may also develop deterioration of the collarbone and end of the fingers. Hip joints are affected because of alteration in the bone structure of the femur (the bone which extends from the knee upwards to the pelvis). This causes the femur to sit in more of a straight-line relationship to the hip joint. This is abnormal and causes a wide-based gait (walking) and the appearance of a horse-riding stance. It is described as coxa valga. Some patients also show an increase in the amount of hyaluronic acid secreted in the urine. Hyaluronic acid is a substance in the body that is found in tissues such as cartilage. Cartilage is a flexible connective tissue that works as a joint stabilizer.

Treatment and management

There is no cure for progeria. Treatment is symptomatic and aimed at providing psychological support. Palliative measures such as wearing a wig may be beneficial. Relief from chest pain due to changes in arteries can be accomplished by nitroglycerin. Nitroglycerin is a medication that relaxes muscle fibers in blood vessels causing them to expand or dilate. This permits proper blood flow to affected areas, which enables cells and tissues to receive adequate amounts of the oxygen necessary for cell maintenance.

Experimental research management

Recent evidence suggested the benefit of giving nutritional therapy and growth hormone supplementation. The combination treatment of nutritional therapy and growth hormone supplementation demonstrated an increase in growth of Progeria patients, an increase in growth factors (chemicals which promote formation) within the blood, and a decrease in the patient's basal metabolic rate. Basal metabolic rate is the minimum amount of energy (calories) that an individual needs to ingest on a daily basis in order to execute normal activities and tasks.

Arteriosclerosis is most prominent in coronary (heart) arteries and the aorta (the largest artery in the body, which has many branches supplying oxygen filled blood to cells and tissues). Research indicates successful outcome from aggressive treatment of arteriosclerosis utilizing techniques such as coronary artery bypass (reconstruction of the heart arteries) or coronary artery balloon dilation (stretching the heart arteries in an attempt to allow increased blood flow).

Prognosis

Age of death ranges from seven to 27 years. One documented case reports an individual living to be 45 years of age. Death is usually secondary to arteriosclerosis complications such as heart failure, myocardial infarction (heart attack), or coronary thrombosis (when a clot from the heart moves to another location cutting the flow of blood to the new location).

Resources

BOOKS

Nora, J.J., and F.C. Fraser. Medical Genetics: Principles and Practice. Philadelphia: Lea & Febiger, 1989.

Wiedemann, H.R., J. Kunze, and F.R. Grosse. "Progeria." In Clinical Syndromes. 3rd ed. Edited by Gina Almond, 306–7. St. Louis: Mosby, Inc., 1997.

PERIODICALS

Sivaraman, D.M. Thappa., M. D'Souza, and C. Ratnakar. "Progeria (Hutchinson-Gilford): A Case Report." Journal of Dermatology 26, no. 5 (May 1999): 324–28.

ORGANIZATIONS

Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR. UK 127 025 0221. Fax: 0870-7700-327. <http://www.climb.org.uk>.

International Progeria Registry. IBR Dept. of Human Genetics, 1050 Forest Hill Rd., Staten Island, NY 10314. (718) 494-5333. wtbibr@aol.com.

WEBSITES

The Council of Regional Networks for Genetic Services. <http://www.cc.emory.edu/PEDIATRICS/corn/corn.htm>.

The National Society of Genetic Counselors. <http://www.nsgc.org/Resource>.

Laith Farid Gulli, MD

Nicole Mallory, MS