Progeria is a rare genetic disease characterized by premature aging of the body, corresponding changes in internal organs. It is manifested by hyperpigmentation, thinning and loss of elasticity of the skin, graying and hair loss, an increase in the size of the skull, a decrease in its facial part, exophthalmos, the development of vascular atherosclerosis, myocardial infarction and fibrosis, osteoporosis, diabetes mellitus, the formation of malignant tumors. Diagnosis is based on the collection of clinical data, laboratory DNA testing. Treatment is aimed at eliminating the symptoms of the disease: prevention and therapy of atherosclerosis, myocardial infarction, diabetes, osteoporosis, cancer.
E34.8 Other specified endocrine disorders
The term “progeria” in translation from ancient Greek means “premature aging”. The childhood form of progeria is called Hutchinson-Guilford syndrome according to the surnames of the researchers who independently described this pathology for the first time: the British doctor J. Hutchinson – in 1889, his compatriot H. Guilford – in 1897. The adult form is called “Werner’s syndrome”, since in 1904 the German doctor O. Werner was the first to officially observe the symptoms of aging in adolescents aged 14-19 years. Both variants of the disease are extremely rare. The prevalence of pediatric progeria is 1 case per 7-8 million people, since the beginning of pathology studies, about 150 sick children have been identified. Adult progeria is more common, the average epidemiological indicators are 1 patient per 100 thousand population.
The disease is based on a genetic mutation. The cause of the children’s type of progeria is a defect in the LMNA gene, which encodes a special protein lamin A, which builds the shell of the cell nucleus. As a rule, mutation occurs sporadically – during the maturation of germ cells in parents or at conception. However, researchers have identified several cases of pathology in siblings, some of whom were in families with closely related marriages. This indicates the possibility of inheriting an autosomal recessive mutation (parents are carriers of a defective gene, but do not get sick and are capable of procreation).
Progeria of adults is a hereditary disease. It develops in the presence of a defect in the RECQL2 gene, which is responsible for the production of the WRN protein, which maintains the stability of the genome, the integrity and structure of DNA. The mutation is transmitted in an autosomal recessive way, the disease manifests itself in people who have received two defective genes in one allele (from the mother and from the father).
In the children’s version of progeria, a genetic defect leads to a violation of the synthesis of structurally correct protein lamin A, which forms the inner framework of the nuclear envelope. As a result of the mutation, the production of a shortened precursor protein of prelamin A is established, and the structure of the matured final protein differs from the normal one. Protein molecules are embedded in the nuclear membrane, change its shape and increase fragility. The nucleus cannot maintain its integrity, the cell dies prematurely.
In Werner’s disease, there is a deficiency of WRN protein, a genetically determined instability of chromosomes is determined. Their structure very often changes spontaneously or under the influence of certain factors. As a result, the ability of cells to divide worsens, the proliferative potential becomes 3-5 times less than it should be normal. The frequency of spontaneous mutations increases by 10 times, telomeres – the end sections of chromosomes that protect genes from damage – are abnormally shortened.
Hutchinson’s progeria debuts after a period of normal development at the age of 6 months to 2 years. The appearance of children changes: growth slows down, the size of the skull increases, but the front part remains small, the lower jaw is underdeveloped. A beak-shaped thin nose and exophthalmos (protruding eyes) are formed. Hair loss out completely – on the head and body, eyelashes and eyebrows. With alopecia, hair follicles are destroyed, so further hair growth becomes impossible. Veins bulge out on the scalp. The dermis and subcutaneous tissue undergo atrophic changes: the skin is thinning, drying out, covered with wrinkles. Lipodystrophy develops – a noticeable decrease in the amount of subcutaneous fat. It remains relatively intact on the cheeks and pubis.
Scleroderm–like foci are formed on the trunk – seals in the lower abdomen, buttocks and thighs. Pigmented spots appear on exposed areas of the skin. The nails are underdeveloped, brittle, thickened, roundly convex – they have the shape of “watch glasses”. By the age of 2, fibrosis of organs and periarticular tissues develops. Passive movements in the elbow and knee joints are limited (contractures), a characteristic position of the leg bones is formed – the “rider’s pose”. The skeleton undergoes hypoplasia, dysplasia and degenerative changes. Milk and permanent teeth erupt late, partially absent, crowded, curved, prone to caries. By the age of 5-6, atherosclerosis of blood vessels, cardiac murmurs, hypertrophy of the left ventricle, cataract, insulin resistance are diagnosed. The genitals remain underdeveloped. The level of mental development is usually higher than that of peers.
Clinical manifestations of Werner’s syndrome are detected from 14 to 18 years of age. The teenager begins to lag behind in growth, his hair turns gray and falls out. By the age of 20, patients are balding. The skin of the face and limbs pales, becomes thinner, tightens. A network of blood vessels is visible under it. Muscle and adipose tissues atrophy, arms and legs become disproportionately thin, the skin over the articular protrusions ulcerates. By the age of 30, cataracts appear, the voice weakens and wheezes, ulcers form on the feet, calluses, vascular asterisks, keratosis form on the soles. The appearance of patients is specific: low height, moon-shaped face, protruding chin, narrowed mouth opening, pseudoexophthalmos.
The sebaceous and sweat glands atrophy. Bone and joint changes include metastatic calcification, generalized osteoporosis, erosive osteoarthritis, limited mobility and deformity of the fingers, flexion contractures, pain in the extremities, arthritis and osteomyelitis. Atherosclerotic vascular changes are noted, cataracts slowly progress, intellectual abilities decrease. After 30 years, endocrine diseases manifest themselves – diabetes mellitus, hypogonadism, thyropathies. In 5-10% of patients, malignant tumors of various organs, bones and skin are detected. The cause of death is oncopathology or severe cardiovascular disease.
The diagnosis of progeria is established on the basis of clinical and anamnestic data. Depending on the existing symptoms, endocrinologists, neurologists, dermatologists, therapists, and geneticists can participate in the diagnosis. Children’s and adult progeria should be differentiated with systemic scleroderma, poikiloderma, Rotmund-Thomson syndrome, Wiedemann-Rautenstrauch syndrome. The main methods of examination of patients include:
- Survey. During the conversation, doctors specify the time of the appearance of symptoms, their severity, the degree of physical and social maladaptation, the presence of a period of normal development (6-24 months for children, 14-20 years for adults). Collect family and genealogical history data, identifying genetic pathology or its absence in the genus.
- Inspection. Specialists evaluate the neurological status, passive and active mobility of joints, bone deformities, skin and subcutaneous tissue condition, preservation of vision, intellectual functions. Patients can be referred for instrumental examinations: bone radiography, ultrasound and MR tomography of organs, ECG, ophthalmoscopy.
- Biogenetic research. Genetic material is analyzed by DNA sequencing. The sections of genes in which defects lead to the development of progeria are investigated. Mutations in homozygous and compound-heterozygous states are found in patients with childhood and adult forms of the disease.
Specific methods of progeria therapy have not been developed. Medical care for patients is to alleviate the symptoms of the disease. Atherosclerosis, osteoporosis, osteomyelitis, cataracts, diabetes, heart pathologies and oncological diseases are treated. There is a known case when the patient’s condition noticeably improved for several years after a heart transplant operation.
Scientific research is being conducted in the field of genetic engineering – attempts are being made to isolate a mutated gene from DNA and replace it with a healthy one. In parallel, a method of etiotropic therapy is being developed. Scientists from Sweden have found a way to neutralize defective lamin A molecules that penetrate the membrane of cell nuclei and contribute to cell death. Positive results were obtained in experiments with rat muscle tissue, the drug has not yet been tested on humans. In the USA, since 2012, the effectiveness of the use of a farnesyltransferase inhibitor (a drug developed for the treatment of cancer) has been studied. After therapy, the children from the experimental group felt better, the stiffness and elasticity of the arteries, bone density increased, cases of transient ischemic attacks, cardiac pathologies, loss of vision and hearing decreased. Life expectancy increased by 1.6-6 years.
Prognosis and prevention
On average, patients with childhood progeria live up to 13 years, deaths have been recorded at 7 and 27 years. Life expectancy in the adult type of the disease is 30-40 years. The cause of death is atherosclerotic complications and malignant neoplasms. There are no preventive measures. It is possible to prevent the birth of a sick child with the hereditary nature of the disease – with Werner syndrome, in some cases Hutchinson syndrome, when the pathology is detected in the family, future parents are classified as a high-risk group. Such couples are assigned medical and genetic counseling.