Alström syndrome is a genetic pathology in which obesity, retinitis pigmentosa, type 2 diabetes mellitus, sensorineural hearing loss, cardiopathy, nephropathy develops. Already in the first decade of life, there is a progressive decrease in vision and hearing, in the future, insulin resistance, hypertension, heart failure, proteinuria, hypogonadism are added. To confirm the diagnosis, EchOX, ophthalmoscopy, ERG, audiometry, blood biochemistry, DNA diagnostics are performed. Symptomatic treatment: diet, hypoglycemic drugs, ACE inhibitors, selection of a hearing aid, tinted lenses.
E34.8 Other specified endocrine disorders
Alström syndrome refers to rare genetic disorders with a low population frequency (less than 1 case per 1,000,000 population). Currently, more than 1050 such patients from more than 60 countries are registered in the international registry. Cases of the birth of 2-3 children with this disease in one family are described. The pathology became known and got its name in 1959. Thanks to the Swedish ophthalmologist K. Alström, the molecular genetic basis of the syndrome was discovered in 1997. The clinical significance of the genetic disorder lies in the early onset and development of severe systemic complications.
Alström syndrome is associated with autosomal recessive inheritance of copies of defective genes from both parents, who act as asymptomatic carriers of mutations. The disease gene, ALMS1, is located on the short arm of the 2nd chromosome at the 2p13 locus. The product of this gene is a protein of the same name, which is involved in the formation of microtubules and cilia, the transport of substances inside the cell. Alström syndrome belongs to the group of ciliopathies. At the moment, several dozen mutations of the ALMS1 gene have been described, which in the homozygous state cause the development of a genetic disorder.
The ALMS1 gene is expressed in many tissues of the body: to a greater extent in the gonads, brain, retina of the eye, to a lesser extent – in the kidneys, spleen, liver. Its mutations lead to the synthesis of a defective receptor protein that causes structural and functional abnormalities of cilia. As a result, the cilia are deprived of the ability to perform their sensory and motor functions primarily in those organs where there is an increased expression of ALMS1.
It is assumed that the production of abnormal protein in the rods and cones of the retina causes its pigment infiltration, dystrophy and atrophy of the neuroepithelium. Dysfunction of the gonads is accompanied by the development of hypogonadotropic hypogonadism, pancreas – impaired glucose tolerance. Damage to the cellular structures of the brain, in particular, the olfactory bulb, leads to overeating. The mechanism of development of some disorders in Alstrom syndrome remains unclear.
Most of the clinical signs of Alström syndrome make their debut already in early childhood, the other part – during the first or second decade of life. The earliest symptoms ‒ photophobia and nystagmus ‒ appear by 6-15 months and signal progressive retinal dystrophy. Children with Alstrom syndrome are born with a normal body weight, but closer to 1-2 years they develop obesity. Hearing loss is registered from about 5 years of age. Dilated cardiomyopathy may occur at any age and period of the disease.
Between 1.5 and 5 years, insulin resistance occurs, which by 20-30 years is transformed into type II diabetes mellitus. Other endocrine disorders are also characteristic: hypothyroidism, hypogonadotropic hypogonadism, cryptorchidism in boys, amenorrhea, hirsutism, PCOS in girls, and later endometriosis. In the second decade, hepatolienal syndrome, nephropathy, and macroproteinuria develop. Urinary incontinence is possible.
The growth of a child before puberty is 1-3 years ahead of the bone age, however, due to the early closure of growth zones, the final growth is usually lower than in the population. Of the skeletal anomalies, posture disorders, brachydactyly are often present. Defects of the upper dentition are revealed. Of the skin manifestations, black acanthosis and alopecia are the most typical. Intelligence in Alström syndrome, as a rule, is not reduced, in some patients ZPR is described.
The progression of retinitis pigmentosa leads to complete blindness at the age of 7-8 years. Hyperglycemia, diabetic ketoacidosis may develop. Infertility is noted in all patients. In any age period, there is a high risk of sudden death due to heart failure caused by cardiomyopathy. Kidney failure is the cause of death in adulthood. Life expectancy usually does not exceed 40 years.
Doctors of various specialties are engaged in the management of patients with Alstrom syndrome: pediatricians, oculists, sign language specialists, endocrinologists, cardiologists. Physical examination of patients determines an increased BMI, excessive development of the subcutaneous fat layer, hyperpigmentation of the skin in the folds of the body, often arterial hypertension. To clarify the diagnostic hypothesis , the following is performed:
- Ophthalmological diagnostics. According to visometry data, a decrease in visual acuity is diagnosed. Examination of the fundus reveals signs of retinal pigment degeneration. The electroretinogram demonstrates a weakening of the amplitude of bioelectric waves.
- Surdological examination. Audiometric examination of hearing reveals its bilateral decrease from moderate to severe. When planning a hearing prosthesis, acoustic impedance measurement, electrocochleography is performed.
- Examination of internal organs. According to the results of abdominal ultrasound, hepatosplenomegaly, fatty hepatosis is determined. In order to determine the size and function of the heart, timely detection of DCMP, an EchoCG is prescribed. Adolescents with Alstrom syndrome are recommended to perform ultrasound of the genitals (pelvic organs, scrotum) to assess the condition of the genital glands.
- Laboratory samples. The biochemical analysis of blood determines the elevated level of transaminases, triglycerides, insulin, glucose, glycosylated hemoglobin. Glucosuria, proteinuria, hyperuricemia are registered in the urine. To assess other endocrine disorders, the level of thyroid, gonadotropin and sex hormones is determined.
- Genodiagnostics. Both parents and the sick child are being examined. Molecular genetic analysis of the ALMS1 gene reveals heterozygous carriage of mutations in the mother and father and homozygous in the child.
Alström syndrome must be distinguished from other genetic and congenital pathologies occurring with metabolic disorders, retinitis pigmentosa, dysfunction of internal organs:
- Bardet-Beadle syndrome;
- Leber ‘s amaurosis;
- primary DCMP;
- Prader-Willi syndrome.
Correction of pathology requires the involvement of an interdisciplinary team of specialists. Due to the lack of specific treatment, only symptomatic therapy is possible. Behavioral, medical, surgical methods are used:
- in case of obesity – diet therapy, regular physical activity;
- in diabetes mellitus – taking hypoglycemic drugs, insulin therapy;
- in dilated cardiomyopathy ‒ ACE inhibitors, diuretics, cardiac glycosides, in the terminal stage of HF – heart transplantation;
- with hyperlipidemia – statins;
- in case of sensorineural hearing loss – auditory prosthetics with digital hearing aids, cochlear implants;
- with photophobia – wearing glasses with tinted glasses.
Prognosis and prevention
The life expectancy of patients with Alström syndrome is reduced. The causes of death are severe metabolic complications, heart and kidney failure. Systematic monitoring and implementation of all medical appointments allows you to compensate for symptoms, improve quality and prolong life. Prevention consists in the exclusion of closely related marriages, genetic counseling of families faced with Alström syndrome.