Russell–Silver syndrome is a rare genetic disorder characterized by intrauterine growth retardation and postnatal stunting. Other phenotypic markers of the syndrome are macrocephaly, a triangular face, a violation of the proportions of the body, clinodactyly, pigmented spots on the skin. At the diagnostic stage, clinical symptoms are taken into account, endocrine function is examined, bone age is determined, and genetic studies are carried out. Treatment is limited to symptomatic measures (hormone therapy, corrective surgery, physiotherapy).
Q 87.1 Syndromes of congenital anomalies, manifested mainly by dwarfism
The disease is named after pediatricians who described it almost simultaneously, but independently of each other: G. Silver (1953) and A. Russell (1954). The syndrome occurs with a frequency of 1 case per 30-100 000 newborns. There were no gender and national differences in prevalence. Pathology is distinguished by clinical heterogeneity and a wide range of manifestations affecting almost all organ systems: cardiovascular, endocrine, musculoskeletal, genitourinary, nervous, etc. The management of children with Russell–Silver syndrome requires a qualified interdisciplinary approach.
The genetic anomalies underlying Russell–Silver syndrome are different – it is this factor that determines the heterogeneity of manifestations and severity of pathology. The most common genetic variations are hypomethylation of genes on chromosome 11p15 (observed in 30-60% of patients) and homogenous maternal dysomy on the 7th chromosome (found in 5-10% of patients). Nevertheless, in about 40% of children, the molecular genetic basis of Silver–Russell syndrome remains unclear.
As a rule, genetic defects occur by chance, but there are some cases of hereditary transmission of pathological genes. Random mutations are caused by the pathology of pregnancy or adverse external influences in the early periods of embryogenesis.
Currently, it is believed that the development of Russell–Silver syndrome is due to a violation of genomic imprinting – the activity of genes depending on their maternal or paternal origin. Both chromosomes 7 and 11 contain clusters of imprinted genes. Some children with this pathology have a multilocus imprinting disorder in several areas or on other chromosomes.
In the region of chromosome 11p15. 5. there are two imprinting centers − ICR1 and ICR2. The ICR1 center ensures the activity of genes that play an important role in the regulation of fetal growth. In particular, this is the maternal H19 gene (skeletal muscle gene) and the paternal IGF2 (insulin‒like growth factor 2, IGF2). Hypomethylation leads to their inactivation and growth retardation. It is known that genetic aberrations of this locus are also associated with the development of Beckwith-Wiedemann syndrome, on the contrary, characterized by macrosomia.
About 10% of people with Silver–Russell syndrome have both copies of the maternal chromosome 7, rather than one copy from each parent. This is called homogenous maternal dysomy. On the 7th chromosome in the segment 7p11.2 there are imprinted genes IGFBP1 (protein binding IGF1), IGFR (IGF receptor) and GRB10 (protein binding growth hormone 10), which are also responsible for the growth and development of the body. The exact mechanism by which these genes cause growth disorders is not fully understood.
Literature and scientific publications mention two clinical forms of Russell–Silver syndrome: “severe” and “mild”. It is believed that defects of the seventh chromosome in most cases are associated with a lighter course of the syndrome. This is expressed in the absence of serious abnormalities in the development of internal organs and a not so pronounced deficiency of somatotropic hormone.
Physical and mental development
Children with Russell–Silver syndrome are born small (less than 2500 g), small (less than 45 cm). About a third of them are born prematurely, but even in these cases there is a discrepancy between anthropometric indicators and the gestation period. This condition is regarded as a primordial nanism. Children have a reduced appetite, gain weight poorly.
The physique of patients is more often asymmetric by the type of hemihypoplasia. The growth deficit persists throughout life. The height of adults with Silver–Russell syndrome who have not received growth hormone treatment is approximately 150 cm in men and 140 cm in women.
Patients with Russell–Silver syndrome are distinguished by the presence of a number of characteristic stigmas of dysembriogenesis. These include relative macrocephaly with protruding frontal bumps, a face in the shape of a triangle, lop-eared, Gothic palate, etc. There are often defects of the dental-maxillary system: underdevelopment of the lower jaw, microdentia, crowding of teeth. Children have a small mouth with thin lips with downturned corners (“carp mouth”). Pigmented spots of the “coffee with milk” type are detected on the skin.
Patients have multiple abnormalities in the development of the bone system. Typically, the late overgrowth of the fontanelles. Radiologically, additional metacarpal bones, osteoporosis, bone age delay compared to passport age are determined. Possible congenital dislocation of the hip, flat feet. Characteristic signs of Russell-Silver syndrome are clinodactyly of the little fingers of the hands, syndactyly of the 1st and 2nd toes. The thorax is narrow, funnel-shaped, the tubular bones of the limbs are shortened, there is lumbar hyperlordosis.
Anomalies of internal organs
The syndrome is associated with various pathologies of internal organs. Cardiac disorders are most often represented by sinus arrhythmia, blockage of the legs of the Gis bundle, cardiac defects (mitral or tricuspid valve prolapse, additional ventricular chord). Concomitant gastrointestinal pathologies differ in great variability and severity – from gastroesophageal reflux and dyskinesia of the gastrointestinal tract to hepatocellular carcinoma.
The most common abnormalities of the genitourinary system in Silver–Russell syndrome are underdevelopment of the genitals, hypospadias, cryptorchidism, uterine aplasia. Renal syndromes include renal tubular acidosis, metabolic nephropathy, etc.
In infancy and early childhood, patients may have a delay in motor development due to severe muscle hypotension, limb asymmetry. It is also not uncommon for speech development to lag, especially in patients with chromosome 7 defect, perinatal CNS lesion. In most patients, intelligence is close to normal, but there are cases occurring with DSD, behavioral disorders, autism spectrum disorders.
The hormonal profile of patients shows the presence of somatotropic hormone deficiency, insulin-like growth factor 1, hyperprolactinemia. In about 30% of cases, premature puberty was noted: early menstruation in girls, hair loss and voice mutation in boys. Infants and children are prone to developing nocturnal episodes of hypoglycemia. However, in adulthood, the risk of metabolic disorders and impaired glucose tolerance increases.
Multiple structural pathologies of organs and functional disorders in individuals with Russell–Silver syndrome cause the risk of various complications. Body asymmetry and orthopedic problems are associated with increased injuries due to difficulties with balance and walking. Cardiovascular and renal abnormalities can cause organ failure (CHF, CRF). Due to metabolic disorders, older patients are prone to weight gain, high blood pressure, hyperlipidemia. The correlation of the syndrome with tumor processes (liver cancer, testicular cancer, pituitary adenoma) was noted.
The clinical criteria necessary to establish the diagnosis of Russell–Silver syndrome include microsomy at birth, characteristic phenotypic signs (body disproportions, triangular face, clinodactyly, etc.). At the initial treatment, anthropometry, assessment of the growth and development of the child is carried out. To confirm the diagnostic hypothesis, a geneticist’s consultation is required, as well as laboratory and instrumental follow-up examination:
- Radiography. X-ray of the hands allows you to identify the discrepancy between the biological age and the passport age. Other studies of the skeleton are necessary to detect abnormalities of the musculoskeletal system: skull x-ray, jaws, spine, chest, feet, joints is performed. The functional state of the organs is assessed using stomach radiography, excretory urography.
- Laboratory diagnostics. An analysis of the hormonal profile is prescribed: somatotropin, somatomedin C, prolactin, gonadotropins, TSH. In order to determine the degree of STH deficiency, stimulation pharmacological tests are performed. With a tendency to hypoglycemia, daily glucose monitoring is carried out.
- Genetic research. The karyotype of patients is determined (with Russell-Silver syndrome, a normal female or male karyotype is detected). The key point in establishing a diagnosis is a molecular genetic analysis that allows you to identify chromosomal abnormalities.
- Examination of internal organs. Sonography serves as a screening method for detecting defects of internal organs. The most informative are ultrasound of the abdominal cavity and kidneys, ultrasound of the scrotum, ultrasound of the uterus and appendages, EchoCG. To determine the causes of somatotropic insufficiency, an MRI of the pituitary gland is indicated. Cardiac arrhythmias are recorded during an ECG or XM ECG.
Newborns with Russell-Silver syndrome should be distinguished from children with low weight and short stature caused by other causes:
A radical cure and complete recovery is impossible. Therapy is supportive in nature, aimed at improving the appearance, preventing complications and improving the quality of life. Patients with Silver-Russell syndrome are observed by endocrinologists, orthopedists, urologists, pediatricians. The main areas of treatment include:
- Nutritional support. In the first years of life, the most important task is to ensure the normal nutrition of the child. This is necessary both for adequate growth and weight gain, and for the prevention of hypoglycemia. If the child refuses to eat, parenteral nutrition is used, feeding through a nasogastric probe.
- Hormone replacement therapy. In order to optimize growth, increase muscle mass, and improve motor function, recombinant human growth hormone (HRH) therapy is prescribed. For normal sexual development, treatment with gonadosteroids (testosterone, synestrol, hCG) is used. With TSH deficiency, thyroid hormones are used.
- Symptomatic treatment. Patients with GERD are prescribed therapy with H2 blockers or proton pump inhibitors. It is possible to carry out surgical treatment – fundoplication. Patients with orthopedic problems are shown wearing medical shoes, insoles. Dental problems may require orthodontic treatment. Boys need surgical correction of hypospadias, cryptorchidism.
- Rehabilitation measures. General massage, physiotherapy (electrophoresis, paraffin applications), physical therapy, hydrokinesiotherapy help to improve motor functions, stimulate physical development.
Prognosis and prevention
Most adults with Russell-Silver syndrome who receive the necessary treatment have an acceptable quality of life and normal fertility. A significant part of the anomalies can be corrected, which allows patients to lead a full life. However, the growth of such patients still lags behind the average values in the population.
Prevention is closely related to antenatal measures, primarily prevention of pregnancy complications. Prenatal ultrasound and genetic diagnostics allow to suspect Russell-Silver syndrome in the fetus. In this case, parents are warned about possible deviations in the physical development of the child, but the syndrome is not an absolute indication for early termination of pregnancy. The probability of having a second child with the same pathology in the same family is extremely low.