Hutchinson-Gilford Progeria Syndrome (HGPS): Causes, Symptoms, Complications, And Treatment

Hutchinson-Gilford progeria syndrome (HGPS) or Progeria fatal, a rare genetic illness where a child has striking features resembling premature aging. Patients with HGPS start to reflect the signs and symptoms of aging around 24 months of age, but seem normal during the early stages of infancy. 2 years of age the child starts to experience profound growth delays, short stature, and low weight.

The root cause of progeria is the mutation of the single-letter misspelling in a gene on chromosome 1 called the LMNA gene. The LMNA gene is responsible to code lamin A protein in the body which creates a temporary membrane surrounding that holds the nucleus of a cell together. Scientists believe that defective mutations in the LMNA gene can make the nucleus unstable causing aging.

Unlike any other genetic disorder, HGPS does not pass through your ancestors' genetics. The genetic condition is considered to be extremely rare due to its sporadic autosomal dominant mutation; it is always a chance occurrence more than a genetic pass. This mutation comes only when there is a new genetic change in the family that mutates a copy of the gene like:

• Parents who never have progeria have 1 in 4 – 8 million to deliver mutated genes to offspring.
• If the first child is born with HGPS, there is a 2-3% chance that the second child will also develop this condition.

Furthermore, it is a proven fact that an individual is born with every genetic imprint which is inherent in a small proportion of their cells which is known as mosaicism. Individuals with a small proportion of progeria that does not affect them can pass the mutation to the offspring.

The specific reason for how and why the genetic mutation happens in the gene is still unknown. But there is a hypothesis that researchers believe. Scientists believe that an abnormal aging process occurs via cumulative cellular damage which results in a metabolic process within the body in which free radicals are being produced. The increased amount of free radicals causes damage and impair functioning in the cell.

On the other hand, antioxidant enzymes are certain enzyme that is responsible for the overall aging process in the human body by keeping the production of free radicals in balance. Lower production of antioxidant enzymes can accelerate the production of free radicals resulting in HGPS.

Other studies suspect that fibroblasts or the skin cells obtained from individuals with progeria have activity levels of certain primary antioxidants like gluthathione peroxidase [GPx] and catalase [CAT] which results in decreased levels of healthy fibroblasts.

Studies have also shown that progerin has a much lower rate in healthy individuals yet it creates deposits in your coronary arteries over a while. This clears the view towards the relation between progerin and its contribution to the risk of atherosclerosis and other cardiovascular diseases.

Newborns with HGPS may seem to be normal although some symptoms can show at the early stages of lifelike:

• Unusually taut, shiny, hardened (i.e., “scleroderma-like”) skin over the buttocks, upper legs, and lower abdomen of the infant’s body.
• Midfacial cyanosis - bluish discoloration of the skin and mucous membranes within the mid-portion of the face or/and nose.
• Growth delay
• Short stature as compared to the general growth milestones.
• Underweight and short height.
• Loss of subcutaneous adipose tissue (layer of fat beneath the skin) and veins over the scalp and thighs.
• Brownish skin blotches over sun-exposed areas of the skin.
• yellowish, thin, brittle, and curved fingernails and toenails.

By the second year of life, some additional symptoms may show like:

• General symptoms:
  • Micrognathia - Underdevelopment of the facial bones and the lower jaw.
  • Frontal and parietal bossing - disproportion of the head, bones, and cranium (sides of the skull).
  • Small, thin, potentially pointed nose
  • Unusually prominent eyes
  • Small ears with absent lobes
  • Thin lips
  • High-pitched voice
• Dental symptom:
  • Delayed eruption of the primary (deciduous) and secondary (permanent) teeth.
  • Irregularly formed, small, discolored, and/or absent teeth.
  • Dental caries - unusually increased incidence of tooth decay
  • Dental crowding due to abnormal smallness of the jaw.
• Hair related symptoms:
  • Alopecia - hair loss replaced by fine, downy, white, or blond hairs.
  • Lost of eyebrows and eyelashes
• Skeletal symptoms:
  • Delayed closure of the anterior fontanelle (soft spot at the front of the skull) and calvaria ( thin dome-like portion of the skull).
  • Paranasal or frontal sinuses (absence of air-filled cavities within the skull that open into the nose).
  • Short and thin collarbones, shoulders, ribs.
  • Narrow or “pear-shaped” chest.
  • Prominent abdomen.
  • Thin and fragile arms and legs.
  • Osteoporosis - loss of bone density
• Further skeletal complications may include:
  • Osteolysis - progressive destruction of periprosthetic bony tissue generally affecting clavicles, terminal phalanges, and acetabulum.
  • Coxa valga - hip deformity which increases the angle of the thigh bone.
  • Periarticular fibrosis - abnormal formation of fibrous tissue around joints like knees, hands, feet, elbows, and spine.
  • Abnormal walk style which resembles “horse-riding stance” position.

From the infancy stage to adolescence one, further complications with the patient may include:

• General symptoms:
  • Absence of the breast or nipple
  • Absence of sexual maturation
  • Hearing impairment
• Cardiovascular symptoms:
  • Arteriosclerosis - loss of elasticity in artery walls, especially in coronary arteries and aorta
  • Cardiomegaly - Heart enlargement
  • Cardiac murmurs - Abnormal heart sounds
  • Anginal attacks - episodes of chest pain due to lack of oxygen supply in the heart muscle
  • Cerebrovascular occlusion - Low blood flow in the brain vessels
  • Heart failure
  • Myocardial infarction or heart attack

After 24 months of birth, the symptoms of HGPS are quite visible and easy to diagnose. Yet disorder can easily be confused with the following disorder:

1. Hallermann-Streiff syndrome: Rare genetic disorder which characters are quite identical to the HGPS like:
   • Distinctive craniofacial malformations
   • Hypotrichosis
   • Dental defects
   • Ocular abnormalities
   • Atrophy deformities
   • Dwarfism
   • Brachycephaly
   • Hypoplastic mandible
   • Palate
   • Thin, high pinched, tapering nose
   • Congenital cataracts
   • Microphthalmia
   • Natal teeth or Partial Adonia

   Unlike HGPS, the key reason behind the occurrence of the Hallermann-Streiff syndrome is still unknown although scientists believe that it happens due to GJA1 gene mutation.

2. Gottron’s syndrome or acrogeria: Can be described as a mild form of premature aging which can be identified by the appearance of small feet and hands with thin and parchment-like delicate skin. Like HGPS, the symptoms will start to appear from the early stages of life ( infancy stage). Even though scientists do not know the actual reason, studies suspect LMNA, ZMPSTE24, or COL3A1 genes for the genetic mutation.
3. Wiedemann-Rautenstrauch syndrome (WRS) or Neonatal progeroid syndrome: Another rare genetic disorder identified by prenatal and postnatal growth delay following early aging along with the absence of subcutaneous lipoatrophy which started to appear at the time of birth. Unlike HGPS, the life expectancy of WRS is up to 20 yrs of age max. The specific reason for WRS is still unknown although scientists believe that disturbances in lipid and bone maturation may be the reason.
4. De Barsy syndrome: It is a rare disorder that is inherited in the pattern called autosomal recessive. The key symptoms may include:
   • Degeneration of cutis laxa (elastic tissue in the skin).
   • Athetosis ( involuntary movements of the arms and legs).
   • Cloudy corneas of the eyes.
   • Frontal bossing.
   • Loss of muscle tone.
   • Large prominent ears.
   • Unusual flexibility of the small joints.

   The root cause of de Barsy syndrome is the deformities in the PYCR1 or ALDH18A1 genes which makes it different from HGPS as all the symptoms are identical to each other.

5. Progeroid syndrome with Ehlers-Danlos: An extremely rare genetic disorder “progeria-like appearance. The only difference that makes it apart from spEDS as it occurs is due to the mutation in the B4GALT7 gene. Which can only be medically diagnosed.

The medical diagnosis depends upon the medical history of the patient along with clinical evaluation followed by condition-specific physical findings and genetic testing.

Since most of the symptoms of HGPS is quite identical to some of the genetic disorders that have been mentioned above, some signs may help an individual to figure out the difference like“scleroderma-like” skin over the lower abdomen, buttocks, and thighs, along with midfacial cyanosis and “sculptured” nose.

The medical diagnosis of Hutchinson-Gilford Progeria Syndrome includes a series of specialized imaging tests like X-ray studies, specialized cardiac tests to monitor certain skeletal abnormalities which are associated with the disease. Also, regular cardiac evaluations may be conducted to manage cardiovascular abnormalities.

Scientists have recently discovered a new methodology for the treatment of the HGPS. Zokinvy or lonafarnib is a type of farnesyltransferase inhibitor (FTI) that earlier was used for cancer treatment but now shows successful results on Hutchinson-Gilford Progeria Syndrome too.

In addition to that, the treatment of HGPS is designed around the signs and symptoms the patient shows. Treatment may require a team of specialists to systematically and comprehensively deal with all kinds of conditions. Such experts may include pediatricians, orthopedists, cardiologists, physical therapists, and other health care professionals.

Therapies may include the treatment of the condition that is symptomatic and supportive. For instance, cardiac attacks due to lack of oxygen in the heart muscles may require a combination course of specific medications to minimize the life threat.

Even though it is hard to cure the medical condition, here are some of the steps that one can follow in order to have a healthy lifestyle.

• Dehydration is one of the most common yet serious conditions in children suffering from Hutchinson Gilford progeria syndrome. It is important to keep the patient hydrated, especially during an illness or during hot weather.
• Small frequent and wholesome meals are preferred for the patient with HGPS as it aids better digestion and optimum nutrition. Add high-calorie foods that are healthy and rich in nutrients.
• Keep the patient physically active, indulge the child in regular physical activity that is safe and appropriate as per the doctor.
• Since there is a loss of body fat in HGPS, it is important to get accessories like cushioned shoes and sunscreen SPF of at least 15 to protect the child from external damage.
• Keep your child fully immunized as a child with progeria is quite vulnerable to bacterial, fungal, or viral infections.
• It is important to keep the learning and social opportunities open for the patient for their overall mental health. Progeria may lower the oxygen level in the brain vessels but it does not hinder the child's intellect.
• Make certain changes at home like easily accessible switches and extra cushioned bedding and chairs to make the patient safe and comfortable at home. Other lifestyle adaptations like clothing with soft fabrics and easy handling can make the patient's life easy and manageable.

Summary: Hutchinson-Gilford progeria syndrome (HGPS) or Progeria fatal, a rare genetic illness where a child has striking features resembling premature aging. Caused by a mutation in the LMNA gene, it can be detected via signs like abnormal skin texture followed by massive growth delays.