A family with several children with Hurler's syndrome. Mucopolysaccharidosis type I in children

Mucopolysaccharidosis, type I (Synonyms: deficiency of the enzyme lysosomal a-L-iduronidase, Hurler, Hurler-Scheie and Scheie syndromes).

Mucopolysaccharidosis, type I is an autosomal recessive disease resulting from a decrease in the activity of lysosomal a-L-iduronidase, which is involved in the metabolism of glycosaminoglycans. The disease is characterized by progressive disorders from internal organs, the skeletal system, neuropsychiatric and cardiopulmonary disorders.

ICD-10 code

• E76 Disorders of glycosaminoglycan metabolism.
• E76.0 Mucopolysaccharidosis, type I.

Epidemiology

Mucopolysaccharidosis I is a pan-ethnic disease with an average incidence of 1 in 90,000 live newborns in the population. The average incidence of Hurler syndrome in Canada is 1 in 100,000 live births, Hurler-Sheye syndrome is 1 in 115,000, and Sheye's syndrome is 1 in 500,000.

Classification

Depending on the severity of the clinical symptoms of the disease, three forms of mucopolysaccharidosis I are distinguished: the Hurler, Hurler-Sheye and Sheye syndromes.

Causes of mucopolysaccharidosis type I

Mucopolysaccharidosis I is an autosomal recessive disease resulting from mutations in the structural gene of lysosomal alpha-L-iduronidase.

Alpha-L-iduronidase gene - IDUA- located on the short arm of chromosome 4 at the 4p16.3 locus. To date, more than 100 different mutations in the gene are known IDUA.The prevailing number of known mutations are point in different exons of the gene IDUA.Caucasians are characterized by two frequent mutations Q70Xand W402X.

The most common mutation among patients from the Russian population is mutation Q70X.Its frequency is 57%, which is comparable to the frequency Q70Xin the Scandinavian population (62%). Mutation frequency W402X,which occurs in 48% of cases of mucopolysaccharidosis I in a number of European populations, in the Russian population it is 5.3%.

Pathogenesis of mucopolysaccharidosis type I

The enzyme a-L-iduronidase is involved in the metabolism of two glycosaminoglycans - dermatan sulfate and heparan sulfate. Since iduronic acid is a part of dermatan sulfate and heparan sulfate, in this disease, the intra-lysosomal breakdown of precisely these glycosaminoglycans is disturbed, which accumulate in lysosomes everywhere: in cartilage, tendons, periosteum, endocardium and vascular wall, liver, spleen and nervous tissue. Edema of the pia mater causes partial occlusion of the subarachnoid spaces, which leads to progressive internal and external hydrocephalus.

The cells of the cerebral cortex, thalamus, trunk, anterior horns are affected. Stiffness of the joints is the result of deformation of the metaphyses, the thickening of the joint capsule is secondary to the deposition of glycosaminoglycans and fibrosis in it. Airway obstruction is a consequence of narrowing of the trachea, thickening of the vocal cords, excess of edematous tissues in the upper airways.

Type I mucopolysaccharidosis symptoms

Mucopolysaccharidosis, type IH (Hurler syndrome)

In patients with Hurler syndrome, the first clinical signs of the disease appear in the first year of life, with a peak of manifestation from 6 to 12 months. In some cases, a slight increase in the liver, umbilical or inguinal-scrotal hernia is observed from birth. Usually, the diagnosis is made between 6 and 24 months of age. Characteristic changes in facial features like gargoilism become apparent by the end of the first year of life: a large head, protruding frontal tubercles, a wide nose bridge, short nasal passages with nostrils turned outward, a half-open mouth, a large tongue, thick lips, gingival hyperplasia, irregular teeth. Other common manifest symptoms are stiffness of small and large joints, kyphosis lumbar spine (lumbar hibus), chronic otitis media and frequent infections of the upper respiratory tract. In almost all patients with Hurler's syndrome, as well as in other types of mucopolysaccharidosis, the skin is dense to the touch. Hypertrichosis is common. In isolated patients under the age of 1 year, the disease debuted with the development of acute heart failure caused by endocardial fibroelastosis. As the disease progresses, symptoms join, indicating the involvement of internal organs, cardiopulmonary, central and peripheral nervous systems in the pathological process. The leading neurological symptoms are a decrease in intelligence, delay in speech development, changes in muscle tone, tendon reflexes, damage cranial nerves, combined conductive and sensorineural hearing loss. Progressive ventriculomegaly often leads to the development of communicating hydrocephalus. By the end of the first and at the beginning of the second year of life, murmurs appear in the heart, and later acquired aortic and mitral heart defects are formed. By the end of the second year of life, hepatosplenomegaly and characteristic skeletal disorders of the type of multiple dysostosis are revealed: a short neck, growth retardation, total platyspondilia, lumbar hibus, stiffness of small and large joints, dysplasia of the hip joints, valgus deformity of the joints, changes in the claw type paws ", deformation chest in the form of a barrel-shaped or bell-shaped. Progressive corneal opacity, megalocornea, glaucoma, congested optic discs and / or partial atrophy are common.

Early radiological signs - rib deformity (of the "rowing" type) and ovoid deformity of the vertebral bodies, excessive trabecularization of the long diaphysis tubular bones in combination with its insufficiency in the area of \u200b\u200bmetaphyses and pineal glands. As the disease progresses, macrocephaly forms with a thickening of the bones of the cranial vault, premature closure of the lambdoid and sagittal sutures of the skull, a decrease in orbits, and expansion of the back of the sella turcica. Patients usually die before the age of 10 years from airway obstruction, respiratory infections, heart failure.

Mucopolysaccharidosis, type I-H / S (Hurler-Sheye syndrome) The clinical phenotype of Hurler-Sheye syndrome occupies an intermediate position between the Hurler and Sheye syndromes, it is characterized by slowly progressive disorders of the internal organs, the skeletal system, a slight decrease in intelligence or lack thereof. The disease usually debuts at the age of 2-4 years. The main clinical disorders are heart damage and the development of obstructive upper respiratory tract syndrome. In some patients, total spondylolisthesis is observed, which can lead to compression of the spinal cord. Most patients survive to the third decade of life. The main cause of death is acute cardiovascular and pulmonary failure.

Mucopolysaccharidosis, type IS (Scheie syndrome)

In the initial classification of mucopolysaccharidosis, before the discovery of the primary biochemical defect in Sheye's syndrome, it was isolated as a separate type - mucopolysaccharidosis V. Scheie's syndrome is the mildest of the disease among other forms of mucopolysaccharidosis I, it is characterized by joint stiffness, aortic heart defects and corneal opacity signs of multiple bone dysostosis. The first symptoms usually appear between the ages of 5 and 15. Leading clinical symptoms - skeletal disorders in the form of joint stiffness with the development of carpal tunnel syndrome. Ophthalmic disorders include corneal opacity, glaucoma, and retinal pigment degeneration. Sensorineural hearing loss - late complication diseases. Obstructive upper airway syndrome often leads to sleep apnea, which in some cases requires a tracheostomy. Myelopathy cervical spinal cord is less common than in Hurler-Scheie syndrome. Aortic stenosis with circulatory failure and hepatosplenomegaly are often noted. Intelligence in this syndrome does not suffer or mild cognitive impairment is observed.

Diagnostics of the mucopolysaccharidosis type I

Laboratory research

Confirmatory biochemical diagnosis of mucopolysaccharidosis I consists in determining the level of excretion of urinary glycosaminoglycans and measuring the activity of lysosomal a-L-iduronidase. The total excretion of Glycosaminoglycans in the urine increases. Hyperexcretion of dermatan sulfate and heparan sulfate is also observed. The activity of a-L-iduronidase is measured in leukocytes or in culture of skin fibroblasts using artificial fluorogenic or chromogenic substrates.

Prenatal diagnosis is possible by measuring the activity of a-L-iduronidase in a biopsy sample of chorionic villi at 9-11 weeks of pregnancy and / or determining the GAG \u200b\u200bspectrum in amniotic fluid at 20-22 weeks of pregnancy. For families with a known genotype, DNA diagnostics are possible.

Functional studies

On radiography, patients with Hurler syndrome show typical signs of so-called multiple bone dysostosis. MRI of the brain reveals multiple cysts in the periventricular areas of the white matter of the brain, corpus callosum, less often the basal ganglia, signs of hydrocephalus; in rare cases - cerebral defects in the form of lissencephaly, Dandy-Walker malformation.

Differential diagnosis

Differential diagnostics is carried out both within the group of mucopolysaccharidoses and with other lysosomal storage diseases: mucolipidosis, galactosialidosis, sialidosis, mannosidosis, fucosidosis, GM1-gangliosidosis.

Treatment of mucopolysaccharidosis type I

In Hurler's syndrome, bone marrow transplantation is indicated, which can radically change the course of the disease and improve its prognosis, however, this procedure has many complications and is carried out in the early stages of the disease, mainly at the age of up to 1.5 years. Currently, a drug for enzyme replacement therapy of mucopolysaccharidosis I has been created - aldurazim (Aldurazyme, Genzyme),which is registered in Europe, USA, Japan; it is used to treat extraneural disorders in mucopolysaccharidosis I. The drug is indicated for the correction of mild forms of mucopolysaccharidosis I (Hurler-Sheye and Sheye syndromes). The drug is administered weekly, intravenously, drip, slowly, at a dose of 100 U / kg. For the treatment of Hurler syndrome with severe neurological complications, the drug is less effective, since the enzyme does not penetrate the blood-brain barrier.

Gargoilism (mucopolysaccharidosis type 1) is a rare hereditary disease caused by impaired metabolism of lipids and mucopolysaccharides due to the absence of the enzyme alpha-L-iduronidase, resulting in connective tissue organs accumulate dermatan sulfate and heparan sulfate. This leads to metabolic disorders. Mucopolysaccharides accumulate in the cells of the brain, retina, peripheral nerves, liver, spleen and other organs.

The disease was first described by the German pediatrician Meinhard von Pfaundler at the beginning of the 20th century. a patient with Gertrude Hurler.

Pfoundler-Hurler syndrome (the second name "gargoilism" the disease got from the designation of the head of a freak spitting out water - decorating drainpipes, churches) has an autosomal recessive inheritance and an unfavorable prognosis: the life expectancy of patients does not exceed 12 years.

The clinical picture. Children suffering from gargoilism are short (stunted growth begins by the end of the first year of life), have a large skull, steep forehead, an inverted root of the nose, thick lips, a large tongue, a characteristic facial expression ("spitting out water"), a short neck, limited mobility joints (mainly the elbow and interphalangeal joints of the fingers), fixed kyphosis at the transition from the thoracic to lumbar vertebrae, shortened limbs due to the proximal parts - the thighs and shoulders, to a lesser extent the legs and forearms. The patient's hand is characteristic: short, equal in length (isodactyly) fingers diverge in a fan-like fashion, resembling a trident. The lower lumbar lordosis causes the abdomen to protrude forward and the buttocks to the back.

On the part of the internal organs, hepatosplenomegaly, a tendency to umbilical hernias, is noted. Characterized by diffuse corneal opacity due to the accumulation of dermatan sulfate in it. Possible dementia, hearing loss or deafness, low hoarse voice, hypertrichosis, dental caries, nails in the form of watch glasses, dry and coarse hair.

Heart damage occurs in most cases of Hurler's syndrome. With this disease, there are: changes in the valves of the heart, myocardium, endocardium, large arteries, and are affected. The heart is enlarged.

Radiographically determined premature ossification of the lambdoid suture, dilated sella turcica, abnormal shape of the vertebrae ("fish vertebrae"), curvature of the radius, deformities of the metaphyseal and epiphyseal sections of long tubular bones, short and blunt metacarpal bones and phalanges.

Children die before the age of 10.

Diagnostics.Prenatal diagnostics is carried out by the method of enzymatic analysis in the amniotic fluid cell culture obtained using transabdominal amniocentesis. Diagnosis after birth is straightforward. In the urine of patients, pathological mucopolysaccharides are determined: chondroitin sulfate B and heparitin sulfate.

Treatment. Stem cell transplant. Surgical correction of glaucoma, skeletal anomalies, carpal-tunnel syndrome. Correction of heart failure with cardiac glycosides and diuretics is performed. Vasodilators are prescribed for the development of arterial hypertension; in nonhypotensive doses, they (angiotensin converting enzyme inhibitors) are used in the complex therapy of congestive heart failure. With the development of severe valvular dysfunction, prosthetics are indicated. For valvular lesions, antibacterial prophylaxis infective endocarditis... They are used (ACTH to enhance growth, thyroid hormones, etc.), as well as symptomatic treatment (vascular drugs, enzymes, vitamins, hepatoprotectors).

Lysosomal storage diseases. It is characterized by a deficiency of alpha-L-iduronidase, an enzyme of lysosomes involved in the catabolism of acidic mucopolysaccharides, which form the basis of the intercellular substance of the connective tissue.

Hurler's syndrome is one of the representatives of the group of mucopolysaccharidoses, united by the term gargoilism .

History reference

The disease originally named pfoundler's disease - Gurler, first described by two pediatricians: Austrian - German. Hurler gertrud (1889-1965) and German - German. Pfaundler Meinhard von (1872-1947) .

The disease described by the authors manifests itself in the first months of life with rough facial features (gargoilism), hepatosplenomegaly, joint stiffness, and deformity of the spinal column. Then the American ophthalmologist Sheye, eng. H. G. Scheie (1909-1990) described the second form of the disease with a later onset and more benign course, called sheye syndrome ... Later, an intermediate form of the disease was described, called hurler-Sheye syndrome .

Eponym

The disease is named after one of the discoverers - an Austrian pediatrician Gertrude Gurler (it. Gertrud hurler), (1889-1965) .

Epidemiology

Hurler syndrome occurs with a frequency of 1 in 100,000.

Inheritance

This group of diseases is inherited, like the vast majority of lysosomal storage diseases, by an autosomal recessive mode of inheritance. Thus, it occurs with the same frequency in both men and women.

see also

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Notes

1. (English). Mucopolysaccharidoses... ninds.nih.gov. Retrieved November 30, 2014.
2. James, William D .; Berger, Timothy G .; et al. Andrews "Diseases of the Skin: clinical Dermatology. - Saunders Elsevier, 2006. - ISBN 0-7216-2921-0. (English)
3. . Chapter 316. Lysosomal storage diseases (p. 250-273)... med-books.info. Retrieved November 30, 2014.
4. . Hurler syndrome... psychology_pedagogy.academic.ru. Retrieved November 30, 2014.
5. Rapini, Ronald P .; Bolognia, Jean L .; Jorizzo, Joseph L. Dermatology: 2-Volume Set. - St. Louis: Mosby, 2007. - ISBN 1-4160-2999-0. (English)
6. (English). en-de-fr.com.ua. Retrieved November 30, 2014.
7. on Who Named It? (English)
8. Hurler, G. (1919). "Über einen Typ multipler Abartungen, vorwiegend am Skelettsystem". Zeitschrift für Kinderheilkunde 24 : 220–234. (German)
9. (English) on the EMedicine website
10. . Hurler Syndrome (Gargoilism)... medpractik.ru. Retrieved December 13, 2014.

Literature

• G. Hurler. Uber einen Typ multipler Abartungen, vorwiegend am Skelettsystem. Zeitschrift fUr Kinderheilkunde, Berlin, 1919; 24: 220-234. (English)
• M. Pfaundler. Demonstrationen Uber einen Typus kindlicher Dysostose. Jahrbuch fUr Kinderheilkunde und physische Erziehung, Berlin, 1920; 92: 420. (English)
• H. G. Scheie, G. W. Hambrick Jr., L. A. Barnes. A newly recognized forme fruste of Hurlers disease (gargoylism). American Journal of Ophthalmology, 1962; 55: 753-769. (English)

Mucopolysaccharidoses (MPS) Mucolipidosis (ML) Sphingolipidoses Oligosaccharidoses Waxy lipofuscinosis neurons Others:

Excerpt from Hurler Syndrome

All in the same position, no worse and no better, broken by paralysis, the old prince lay for three weeks in Bogucharovo in a new house built by Prince Andrey. The old prince was unconscious; he lay like a mutilated corpse. He kept mumbling something, twitching his eyebrows and lips, and it was impossible to know whether he understood or not what surrounded him. One thing for sure was that he suffered and felt the need to express something else. But what it was, no one could understand; Was it some kind of whim of a sick and half-insane, was it related to the general course of affairs, or was it related to family circumstances?
The doctor said that the anxiety he expressed did not mean anything, that it had physical causes; but Princess Marya thought (and the fact that her presence always increased his anxiety confirmed her assumption), thought that he wanted to tell her something. He obviously suffered both physically and mentally.
There was no hope of healing. It was impossible to take him. And what would happen if he died dear? “Wouldn't it have been better the end, the very end! Princess Marya thought sometimes. She watched him day and night, almost without sleep, and, terrible to say, she often watched him, not hoping to find signs of relief, but watching, often wanting to find signs of an approaching end.
Oddly enough it was for the princess to be aware of this feeling in herself, but it was in her. And what was even more terrible for Princess Marya was that since the time of her father's illness (even almost earlier, perhaps when she, expecting something, stayed with him), all those who fell asleep in her woke up in her, forgotten personal desires and hopes. That which had not crossed her mind for years - the thoughts of a free life without the eternal fear of her father, even the thought of the possibility of love and family happiness, like the temptations of the devil, were constantly running through her imagination. No matter how she removed herself from herself, questions constantly came to her mind about how she would now, after that, arrange her life. These were the temptations of the devil, and Princess Marya knew this. She knew that prayer was the only weapon against him, and she tried to pray. She stood in the position of prayer, looked at the images, read the words of the prayer, but could not pray. She felt that now she was embraced by another world - of everyday, difficult and free activity, completely opposite to the moral world in which she had been imprisoned before and in which prayer was the best consolation. She could not pray and could not cry, and the care of life overtook her.
It was becoming dangerous to remain in Vogucharovo. From all sides it was heard about the approaching French, and in one village, fifteen miles from Bogucharov, an estate was plundered by French marauders.
The doctor insisted that the prince should be taken further; the leader sent an official to Princess Marya, persuading her to leave as soon as possible. The police officer, having arrived in Bogucharovo, insisted on the same, saying that the French were forty miles away, that French proclamations were circulating in the villages, and that if the princess did not leave with her father before fifteen, he would not be responsible for anything.
The princess on the fifteenth made up her mind to go. The worries of preparations, the giving of orders, for which everyone turned to her, occupied her all day. She spent the night from fourteen to fifteen, as usual, without undressing, in the room next to the room in which the prince lay. Several times, waking up, she heard his grunting, muttering, the creak of the bed and the steps of Tikhon and the doctor, turning him over. Several times she listened at the door, and it seemed to her that he was muttering louder than usual and tossing and turning more often. She could not sleep and several times approached the door, listening, wanting to enter and not daring to do so. Although he did not speak, Princess Marya saw and knew how unpleasant any expression of fear for him was to him. She noticed how dissatisfied he turned away from her gaze, sometimes involuntarily and stubbornly directed at him. She knew that her arrival at night, at an unusual time, would irritate him.
But she had never felt so sorry for her, so scared to lose him. She recalled her entire life with him, and in every word, deed of him, she found an expression of his love for her. From time to time, between these memories, the temptations of the devil, thoughts of what would happen after his death and how her new, free life would be arranged, burst into her imagination. But with disgust, she drove these thoughts away. By morning he was quiet and she fell asleep.
She woke up late. The sincerity that occurs on awakening showed her clearly what was most of all about her father's illness. She woke up, listened to what was behind the door, and hearing his groaning, with a sigh, said to herself that it was all the same.
- But what should be? What did I want? I want him dead! She cried out in disgust at herself.
She dressed, washed, read prayers and went out onto the porch. Carriages without horses were brought to the porch, into which things were packed.
The morning was warm and gray. Princess Marya stopped on the porch, never ceasing to be horrified at her spiritual filth and trying to put her thoughts in order before entering him.
The doctor stepped down the stairs and walked over to her.
“He’s better today,” said the doctor. - I was looking for you. You can understand something from what he says, the head is fresher. Let's go. He calls you ...
Princess Mary's heart beat so hard at this news that she turned pale and leaned against the door so as not to fall. Seeing him, talking to him, falling under his gaze now, when Princess Mary's whole soul was overflowing with these terrible criminal temptations, was excruciatingly joyful and terrible.
“Come on,” the doctor said.
Princess Marya went to her father and went up to the bed. He lay high on his back, with his small, bony arms covered with lilac knotty veins on the blanket, with his left eye fixed straight on, and with a slanting right eye, with fixed eyebrows and lips. He was all so thin, small and pathetic. His face seemed to be shriveled or melted, crumbling in features. Princess Marya came up and kissed his hand. The left hand squeezed her hand so that it was evident that he had been waiting for her for a long time. He twitched her hand, and his eyebrows and lips moved angrily.
She looked at him frightened, trying to guess what he wanted from her. When she, changing position, moved so that the left eye saw her face, he calmed down, for a few seconds without taking his eyes off her. Then his lips and tongue moved, sounds were heard, and he began to speak, looking timidly and imploringly at her, apparently afraid that she would not understand him.
Princess Marya, straining all her powers of attention, looked at him. The comic work with which he turned his tongue made Princess Marya lower her eyes and with difficulty suppress the sobs that rose in her throat. He said something, repeating his words several times. Princess Marya could not understand them; but she tried to guess what he was saying and repeated the elephant's interrogative words.
- Gaga - fights ... fights ... - he repeated several times. It was impossible to understand these words. The doctor thought he had guessed right, and, repeating his words, asked: is the princess afraid? He shook his head and did the same again ...
“My soul, my soul hurts,” Princess Marya guessed and said. He moaned affirmatively, took her hand and began to press her to various places on his chest, as if looking for a real place for her.

One of the rare inherited genetic diseases that progresses steadily and leads to severe disability early is Hurler's syndrome. It is characterized by metabolic disorders, as a result of which metabolic products are constantly accumulating in the patient's body. They destroy the nervous system, internal organs and the skeleton. This destruction is irreversible, so earlier Hurler's syndrome was incurable, patients died, barely living to 10 years.

But with the modern possibilities of medicine and timely treatment started, it is possible to eliminate the pathology of metabolic processes and return the patient to normal life. True, the already existing deformations of the skeleton and diseases of the internal organs remain, therefore, such patients most often still remain disabled, and they have characteristic anomalies in appearance.

Characteristics of the disease

Hurler's syndrome is a type of mucopolysaccharidosis, a genetic disease associated with a violation of the production of certain lysosomal enzymes. In patients from birth, alpha-L-iduronidase is not produced. This enzyme is responsible for breaking down certain groups of fats and carbohydrates into simpler molecules. As a result, mucopolysaccharides accumulate in the blood and cells, which are destroyed by this enzyme in a healthy body.

This causes dysfunction of various organs, abnormal tissue development. Uncleaved mucopolysaccharides are deposited in meninges, internal organs, nerve cells, cartilage, cornea of \u200b\u200bthe eye. The nervous system, heart, brain, respiratory organs, eyes, liver, bones and joints suffer from this. At birth, children with Hurler's syndrome appear normal, symptoms of pathology begin to appear by the end of the first year of life. Gradually, mucopolysaccharides accumulate, disorders progress, and without treatment, the disease leads to the death of the patient by 10 years.

Causes

One of the most serious hereditary diseases is mucopolysaccharidosis; Hurler's syndrome differs from its varieties in the most severe course. The disease is caused by a genetic mutation that occurs in chromosome 4. Its type of inheritance is autosomal recessive. This means that the child will only get sick if both parents are carriers of the abnormal gene. Moreover, they may not have signs of the disease. But with a probability of 25%, the child will receive exactly the defective gene. This disease is very rare, it occurs in 1 case out of 100 thousand newborns. With the same frequency, pathology occurs in both boys and girls.

This disease is hereditary, so the first signs of it appear immediately after birth.

Symptoms

The manifestations of the disease differ depending on the severity of its course. There are three degrees of type 1 mucopolysaccharidosis. With each type, the symptoms can be more or less pronounced, limited only to bone deformities or be reflected in the work of internal organs and nervous system... Moreover, all these pathologies are progressing every year of the patient's life.

The most severe, characterized by rapid progression and irreversible deformities, is the Hurler syndrome itself. All signs begin to appear in early childhood, and they are very pronounced. A characteristic difference from other varieties is a severe mental retardation and obvious anomalies in appearance. Death usually occurs up to 10 years from serious violations of the internal organs.

The mildest form of type 1 mucopolysaccharidosis is called Sheye's syndrome after the doctor who first described the pathology. Patients can lead a normal life, they retain intelligence. But pathologies of the joints are observed, of cardio-vascular system, visual and hearing impairment, characteristic change in appearance.

An intermediate place is occupied by the Hurler-Scheie syndrome. It combines the signs of both types of the disease. The pathology is characterized by normal intelligence, but multiple deformities in the skeletal system.

In patients after 2-3 years, the disease can be detected by characteristic external signs

Patient appearance

The first symptom of the disease is face dysmorphism. This coarsening of traits like gargoilism begins as early as 3-6 months, and only progresses over time. Therefore, in the most severe forms of the disease, the diagnosis can be made from the patient's photo. All anomalies in appearance are especially clearly visible by the age of 3. These are, first of all, an enlarged skull with strongly pronounced sutures and frontal tubercles, a short neck, short stature, and bone deformities of varying severity.

The facial features of the child also have characteristic features. They become more and more rough by the year. The bridge of the nose is depressed and wide, the nostrils are inverted, and the tip of the nose is unnaturally enlarged. The eyes are set wide apart and appear slightly protruding due to the small sockets. The lips are full, the tongue is so large that it does not fit in the mouth. Therefore, the patient's mouth is constantly in a half-open position. Teeth do not develop properly, grow irregularly, and quickly undergo caries.

Skeleton deformations

With this disease, there are almost always deformities of the child's skeleton. First of all, this can be seen in the change in the shape of the chest. The ribs expand and it takes on a barrel shape. By about one year, all children with Hurler syndrome develop joint dysplasias and mild bone abnormalities. The spine is often bent, kyphosis appears, most often in the lumbar or thoracic region. The vertebrae protrude and acquire the character of "fish". The pelvis is underdeveloped due to the small size of the heads thigh bones dysplasia of the hip joints occurs.

Often, patients develop carpal tunnel syndrome or claw-paw abnormalities of the hand. The toes are rather short and not bend well. Pathologies of small and large joints are manifested by their stiffness, frequent pain already in early age... Hallux valgus may be observed. Patients have short stature, short neck. Due to the irregular constitution, they can only walk on tiptoes, and even on bent legs. In addition, patients have muscle hypotension and motor retardation, which only increases with age.

Serious skeletal deformities, mental and physical retardation often lead to disability

Internal organs

A deficiency in the enzyme responsible for the uncoupling of certain carbohydrates is especially reflected in the condition of the liver and spleen. In patients already in early childhood, these organs are greatly enlarged, so the stomach seems unnaturally large. With the progression of the disease, cirrhosis of the liver may develop. The cardiovascular system also suffers. Most often, aortic valve pathology occurs, therefore, heart murmurs are observed. Hypertension may also develop, narrowing coronary vessels or even a heart attack.

Due to reduced immunity, these children are often susceptible to infectious diseases... It is mainly the respiratory organs that suffer, respiratory failure often develops, and apnea may occur at night. The patient's noisy breathing may also be a characteristic symptom of the disease.

Nervous system

In the second year of the patient's life, intellectual disabilities become noticeable. Until about a year, the child develops normally, but then begins to lag behind his peers, may lose the skills already acquired. Violations are also manifested in speech development... This is associated not only with mental retardation, but also with pathologies of the speech apparatus, as well as with progressive deafness.

Other pathologies

One of the first symptoms of pathology is the appearance of inguinal and umbilical hernias in a child. Often, the accumulation of mucopolysaccharides in the blood causes corneal opacity or the development of glaucoma. It can begin as early as the first year of life and progresses rapidly, leading to blindness. The organ of hearing also suffers - many patients develop progressive sensorineural hearing loss, often otitis media. In patients with Hurler's syndrome, the structure of the nails changes, the hair becomes coarse, the skin becomes thick and rough.

Often, children with Hurler syndrome develop corneal opacities or even glaucoma

Diagnostics

The disease is hereditary, so its prevention is impossible. But it is possible to carry out a genetic analysis of the amniotic fluid during intrauterine development. This is done if the parents had cases of the disease in the family. If you suspect Hurler's syndrome after birth, the following studies are carried out:

• blood tests determine the level of L-iduronidase;
• is found in urine samples elevated level mucopolysaccharides;
• sometimes a genetic blood test is done;
• at an older age, radiography is prescribed to determine the degree of skeletal deformities;
• echocardiography will help identify abnormalities in the cardiovascular system.

With timely diagnosis of the disease, it is possible to slow down serious deformations of the skeleton and disruption of the work of internal organs.

Treatment

With a mild form of pathology, symptoms usually appear only in adolescence. At the same time, the disease is not so difficult, therefore, amenable to conservative treatment. The patient is monitored by many doctors who carry out symptomatic therapy. An orthopedist treats deformities of the skeleton, removes hernias, corrects pathologies of the joints. The pediatrician stops the manifestations of viral infections, monitors the state of the cardiovascular system.

But with a severe form of Hurler's syndrome, most often the main method of therapy is bone marrow or cord blood transplantation from a healthy compatible donor. In this case, the patient's blood cells are replaced with healthy ones that do not contain a genetic defect. Therefore, the enzyme deficiency is no longer detected. The accumulation of harmful metabolic products stops, but the damage already received cannot be restored. Therefore, it is very important that the operation is carried out as early as possible. Usually, transplantation is done in the second year of life.

With a successful operation, the patient's life expectancy and its quality increase significantly. Neurological disorders and intellectual disabilities are eliminated, but bone deformities and visual impairments often persist.

If transplantation is not possible, the patient's condition can be improved with the help of intravenous administration of special drugs.

For mild illness, drug therapy can also help. Drugs are used that replace the desired enzyme. The most effective is "Aldurazim". It is administered intravenously, and such treatment improves the condition of all organs and systems, except for the brain. This is due to the presence of a blood-brain barrier that does not allow this drug to pass through. Aldurazim is also often used in severe disease before bone marrow transplantation to improve the patient's condition.

When conservative treatment a patient with Hurler's syndrome is given glucocorticosteroids, for example, Prednisolone, as well as Corticotropin, Thyroidin, Dextran, vitamin A in large quantities and heart medications. If a bone marrow transplant cannot be performed, a blood plasma transfusion can be done. Physiotherapy is also indicated, which improves the patient's condition. Effective electrophoresis with "Lidaza" on joints, magnetotherapy, paraffin, laser therapy, massage, physiotherapy exercises.

It was only with the development of medicine that it became possible to cure this severe hereditary disease. But for this it is important to make a diagnosis as early as possible, and parents must follow all the doctor's prescriptions. If they show patience and perseverance, the child can develop more or less normally, communicate with peers and self-serve.

Mucopolysaccharidosis I (synonyms: Gurler, Hurler-Scheie syndromes and the mildest in the course of the disease and rare among other clinical phenotypes - Scheie) is a pan-ethnic disease with an average incidence in the population of 1 in 90,000-100,000 live newborns. Mucopolysaccharidosis (MPS) I - H / S or Hurler-Scheie syndrome is a clinical variant of a rare hereditary disease that belongs to the group of lysosomal storage diseases. It occupies an intermediate position between the Hurler and Scheie syndromes and is transmitted in an autosomal recessive manner. It is characterized by more slowly progressive disorders of the internal organs, the skeletal system, with a moderate decrease in intelligence or even the absence of it. Most patients survive to the third decade of life. Its etiology and pathogenesis are caused by mutations in the structural gene of the enzyme alpha-L-iduronidase, which is involved in the catabolism of two glycosaminoglycans (GAGs) - dermatan sulfate and heparan sulfate, which accumulate in the lysosomes of almost all organs and tissues of patients.

Patients with Hurler-Scheie syndrome have rather "striking" phenotypic features. Characterized by changes in the face of the type of "gargoilism", which appear by the end of the first year of life: a large head, protruding frontal tubercles, wide cheekbones, sunken nose bridge, short nasal passages with nostrils turned outward, half-open mouth, large tongue, thick lips. As a rule, patients develop joint stiffness. In particular, due to contractures of the interphalangeal joints and shortening of the phalanges, deformities of the hands are often formed. The vertebrae are widened in diameter, their height is reduced. In areas where kyphosis or kyphoscoliosis is formed, underdevelopment of the transverse processes of the vertebrae or their "lingual" deformity is revealed. In Hurler-Sheye syndrome, the intellect of patients at first practically does not suffer or there are mild cognitive impairments. However, psychomotor development proceeds with a noticeable age lag and reaches its maximum development at the age of 2-4 years, then stops and passes (along with motor development) into the stage of regression, often reaching complete dementia. This syndrome is also characterized by chronic rhinitis, otitis media, sinusitis.

It should be emphasized that all patients develop corneal opacity, which in some cases can be combined with open-angle glaucoma or with partial atrophy of the optic discs (as a consequence of progressive hydrocephalus). In some patients, there is a decrease in visual acuity as a result of retinal pigmentary degeneration and night blindness due to dysfunction of the retinal rods. All patients with MPS are shown annual measurement of intraocular pressure for the timely detection of glaucoma. In rare cases, due to the pronounced opacity of the cornea, the question of its transplant is decided.

The diagnosis is made based on the results of DNA diagnostics. At the same time, a mutation of the Q70X gene is determined, which is the most frequent (diagnosed in 57% of cases) in the Russian population of patients with this syndrome. Disease-confirming biochemical diagnosis of MPS consists in determining the level of excretion of urine glycosaminoglycans and their fractions, as well as measuring the activity of lysosomal α-L-iduronidase in peripheral blood leukocytes or skin fibroblast culture. Today there are two effective method treatment of the syndrome: hematopoietic stem cell transplantation and enzymatic replacement therapy (FZT). Bone marrow transplantation can radically change the course of the disease and improve its prognosis, however, this procedure has many complications and is performed in the early stages of the disease, mainly at the age of up to 1.5 years. At present, a drug for mucopolysaccharidosis I, aldurazim, has been created for FZN, which is indicated for the correction, mainly, of "mild" forms of MPS I (in particular, in Hurler-Sheye and Sheye syndrome). It is administered weekly, intravenously, by drop, slowly, at a dose of 100 units / kg. For the treatment of children with severe neurological complications, it is less effective, since the enzyme does not penetrate the blood-brain barrier.

Prophylactic prenatal diagnosis is possible by measuring the activity of the α-L-iduronidase enzyme in the chorionic villus sampling at 9-11 weeks of gestation, and / or determining the GAG \u200b\u200bspectrum in the amniotic fluid at 20-22 weeks of gestation. Increasing importance is attached to DNA diagnostics of mucopolysaccharidosis.

We had the opportunity to observe a boy S., born in 2012, with Hurler-Sheye syndrome, whose age at the time of the last examination was 3 years 7 months. At the age of 1 year 2 months, the parents first turned to the children's polyclinic of the institute with a complaint of a periodic deviation in the boy's left eye outward.

From the anamnesis: a child from the first pregnancy, which proceeded against the background of placental insufficiency. Delivery of the fetus by caesarean section at 39 weeks, due to breech presentation of the fetus and early discharge amniotic fluid... The child's body weight at birth is 2740 grams, height is 52 cm, according to the Apgar scale 7/8 points. At the maternity hospital, phototherapy was performed for conjugated jaundice. On the 18th day, the child was discharged from the hospital under the supervision of a neurologist at the place of residence with a diagnosis of hypoxic damage to the central nervous system of the 2nd degree, neuroreflex hyperexcitability syndrome, hip dysplasia and hypertensive syndrome. From birth, his mother noted that he had bilateral inguinal hernia, about which surgical treatment was carried out in 1 year. At the age of 6 months, the child developed a petechial rash, to clarify its etiology was prescribed general analysis blood, which showed a low content of hemoglobin and platelets. In this regard, the child was hospitalized in the Department of Hematology, with a diagnosis of immune thrombocytopenic purpura, acute active stage, deficiency anemia.

In addition, at the age of 6 months, the mother noticed a deformity of the spine in her son, and therefore at the age of 9 months he was examined by an orthopedist during hospitalization in the Republican Children's Clinical Hospital. According to the X-ray data of the thoracolumbar spine, congenital anomalies of the spine were diagnosed - kyphosis with a change in the shape of the XII thoracic and L1-L2 vertebrae, systemic dysplasia of the connective tissue. From the first year of the child's life, the parents noted that he had noisy and difficult nasal breathing, in connection with which he was observed by an otolaryngologist with a diagnosis of chronic rhinitis. In 2015, the child underwent adenotomy and hernia repair for recurrent bilateral inguinal and umbilical hernia under endoscopic control. Also, due to the child's anxiety and intermittent vomiting, a computed tomography of the brain was performed in 2015, which revealed the consequences of hypoxic lesions of the central nervous system, moderate hydrocephalus, subatrophy of the medulla and a cyst of the chiasmatic-suprasellar region on the left (without the need for neurosurgical treatment).

Numerous comorbidities in combination with the gradual formation of grotesque facial features were the basis for genetic examination and treatment of a child at the age of 11 months at the Moscow Research Institute of Pediatrics and Pediatric Surgery, and then at the Department of Psychoneurology of the Federal State Budgetary Institution "SCCH" of the Ministry of Health of the Russian Federation. According to the conclusion, the diagnosis was made: mucopolysaccharidosis type I, Q70X mutation in a heterozygous state, Hurler-Sheye syndrome. The examination also revealed hepatosplenomegaly, dysfunction of the biliary tract, osteoporosis, spinal anomalies, and left-sided nephroptosis. After the consultation, it was decided to start ERT with the drug aldurazim.

The examination of the child at the Ufa Scientific Research Institute of GB established the following. Visual acuity - monitors toys, intraocular pressure of both eyes - palpation within normal limits. On examination: both eyes are calm, the left eye is deflected outward by 10 ° according to Hirshberg. When the right eye is closed, the positioning movement of the left is noted. Biomicroscopy: the cornea is somewhat thickened, in the central zone there is a non-intense opacity (which is more pronounced on the left), mainly of its anterior layers, which made it possible to examine the details of the fundus only on the periphery and diagnose retinal vein expansion. A preliminary diagnosis was made - clouding of the cornea of \u200b\u200bboth eyes, retinal angiopathy, divergent concomitant strabismus of the left eye, type I MPS, Hurler-Scheie syndrome.

After 2.5 years, the child was again examined in the children's polyclinic of the institute in connection with the complaints of the parents about his lack of gaze fixation. Visual acuity is reduced - monitors toys from about 4 meters, intraocular pressure is palpably increased by 1+. Both eyes are calm, the eye slits are symmetrical. Movement eyeballs are not substantially limited. Nystagmus is absent. Convergence reduced. With biomicroscopy, a non-intense, but almost diffuse opacity of the cornea of \u200b\u200bboth eyes with signs of minor epitheliopathy is determined. The pupils are rounded (OD \u003d OS), the reaction to light is preserved. Fundus details are not ophthalmoscopic. Considering the development of open-angle glaucoma, local antihypertensive therapy was recommended in the form of permanent instillations of Trusopt eye drops 2 times a day and annual follow-up examinations 2-3 times a year.

A joint examination with a pediatrician showed that the boy had hirsutism (on the skin of the back), disproportionate short stature, macrocephaly (head circumference - 52.2 cm), rough facial features with protruding frontal tubercles, a nose with a sunken bridge and a half-open mouth (Fig.), Kyphoscoliosis , joint stiffness (the range of passive movements is limited), hearing loss, Mongoloid spots on the skin of the back and buttocks, short neck. According to the mother, the skills of neatness are partially formed - during the day he controls urination and defecation, and at night it is necessary to wake him up. Delayed psychoverbal development was noted. Understanding of speech, which consists of separate words and syllables, within the limits of only the usual everyday concepts. Self-care skills are very poorly formed.

In conclusion, it should be noted that early and repeated ERT with aldurazim (in 2013, 2014 and 2015), which he tolerated well, as well as repeated vascular and neurotrophic treatment at the place of residence, contributed not only to stabilization, but also to clinical improvement. the boy's condition. The latter consisted in a reduction in the size of the liver and spleen, as well as the possibility of self-care.

conclusions

Pronounced clinical polymorphism and rare occurrence cause certain difficulties in the early identification of Hurler-Scheie syndrome. The vigilance of pediatric doctors, incl. and ophthalmologists, in relation to hereditary diseases in general and mucopolysaccharidosis, in particular. Timely diagnosis is necessary to refer such children to specialists of an interdisciplinary center with experience in specific treatment, which is most effective in the early stage of the disease - before the development of irreversible changes. Medical genetic counseling of families will significantly reduce the occurrence of new cases of this severe hereditary disease.