Beckwith-Wiedemann syndrome is a complex multigenic pathology, which is manifested by multiple congenital malformations. The disease occurs with various genetic abnormalities of chromosome 11 in combination with epigenetic disorders. The triad of signs of Beckwith-Wiedemann disease includes macroglossia, omphalocele, macrosomia. Various somatic pathologies are also observed. Diagnostics is represented by genetic research, visualization of internal organs by ultrasound, MRI, CT. The treatment and rehabilitation plan is selected individually, according to the severity of the syndrome, the number and nature of clinical symptoms.
Q87.3 Syndromes of congenital anomalies manifested by excessive growth [gigantism] in the early stages of development
The disease bears the names of American pathologist John Bruce Beckwith and German pediatrician Hans-Rudolf Wiedemann, who described its clinical signs in 1963-1964. The syndrome occurs with a frequency from 1:10000 to 1:13700 newborns. Information on the prevalence may be inaccurate due to unregistered cases with mild phenotypic symptoms. In modern genetics, the diagnosis of Beckwith-Wiedemann syndrome is associated with significant difficulties, due to its genetic heterogeneity, wide variability in the expression of mutant genes.
Pathology occurs when genetic causes (various DNA mutations) and epigenetic factors (DNA methylation, biochemical changes in histones) are combined. Up to 85% of cases of the syndrome are manifested sporadically, and the remaining 15% are inherited from parents in an autosomal dominant type with incomplete penetrance. Disorders of the structure of the 11th chromosome in patients with Beckwith-Wiedemann disease are divided into the following groups:
- Violation of IC2 methylation. The most common type of epigenetic mutation, which is detected in 50% of patients. In most cases, such disorders appear in children without burdened heredity.
- Paternal parent dysomy. In this variant of the syndrome, the child inherits both chromosomes from a specific pair from one parent, which is fraught with the development of severe birth defects.
- CDKN1C mutation. Such a gene anomaly has a 50% chance of transmission from a sick mother to a child, sporadic mutations are extremely rare.
- Hypermethylation of IC1 (H19). This type of epigenetic disorders accounts for up to 5% of all cases of Beckwith-Wiedemann syndrome. It happens without deletion (sporadic variants) or with deletion (inherited from the mother).
- Anomalies of locus 11p15. Less than 1% of patients are people with cytogenetically visible chromosome duplication or translocation/inversion. Such mutations are mostly inherited from the father and mother.
At the heart of all emerging defects are molecular disorders in the genes of the short arm of chromosome 11. Here are the imprinting centers, which are responsible for the correct expression of genes received from the mother and father. In healthy people, these genes control the growth of organs and tissues, inhibit excessive cell proliferation. Accordingly, with their mutation, multiple organ disorders occur in the fetus, congenital skeletal defects are formed.
The disease is manifested by a pathognomonic triad of symptoms (“large” criteria), which includes omphalocele (umbilical hernia), macroglossia (too large tongue), macrosomy (large fetus). Typical clinical signs of Beckwith-Wiedemann syndrome include a proportional increase in the length of the upper and lower extremities on one side (hemihyperplasia), divergence of the rectus abdominal muscles, additional folds on the earlobe.
Among the disorders of internal organs, medullary dysplasia of the kidneys, cytomegaly of the fetal adrenal cortex, visceromegaly — an increase in the size of the liver, spleen, pancreas prevail. Heart malformations, congenital cardiomyopathy, cardiomegaly are less common. After birth, a baby usually has severe neonatal hypoglycemia with a characteristic symptom complex.
The presence of epigenetic mutations creates prerequisites for the development of embryonic tumors. The most common types of oncopathology in patients with Beckwith-Wiedemann syndrome are hepatoblastoma, nephroblastoma, rhabdomyocarcinoma, adenocarcinoma. Due to multiple congenital anomalies, which are aggravated by multiple organ disorders, patients have a high probability of death. Up to 20% of patients die in childhood.
To establish a clinical diagnosis of Beckwith-Wiedemann syndrome, the patient must identify at least 3 “large” criteria or 2 “large” + 1 “small”. With a combination of magroglossia and umbilical hernia, it is worth considering the possibility of the disease, even if there is no other typical symptomatology. The extended diagnostic plan includes the following methods:
- Molecular genetic testing. When carrying out genetic diagnostics, the possibility of heterogeneity of the syndrome is taken into account, so studies are done on several typical mutations, epigenetic anomalies at once. All children with manifestations of Beckwith-Wiedemann syndrome also undergo mandatory karyotyping.
- Instrumental visualization. A specific sign of the syndrome is considered to be visceromegaly, for the detection of which ultrasound, CT or MRI of the abdominal organs is performed. Echocardiography is indicated for the diagnosis of cardiomegaly, and concomitant cardiac disorders are recorded on an ECG.
- Neurological examination. Examination of a newborn by a pediatric neurologist is necessary to exclude concomitant lesions of the central nervous system, birth injuries on the background of macrosomia. In the future, an assessment of cognitive abilities that may have suffered due to neonatal hypoglycemia is required.
Specific therapy for the disease has not yet been developed. Treatment is carried out by a multidisciplinary team of doctors and is aimed at eliminating or reducing individual manifestations of Beckwith-Wiedemann syndrome. According to clinical protocols, the plan of medical care for this genetic pathology includes:
- Correction of hypoglycemia. This is the most important moment of treatment in the neonatal period, since a normal level of glycemia is necessary for the functioning of the brain. Correction is performed with 10% glucose solutions, if necessary, glucocorticoids are injected.
- Chemoradiotherapy. Such treatment is prescribed for oncological diseases, which often occur in young children as a result of hereditary predisposition.
- Plastic correction. The participation of orthopedists and plastic surgeons is required to eliminate deformities and abnormal length of the limbs, restore the correct proportions of the body, increase the functionality of the musculoskeletal system.
Taking into account the typical signs and possible complications of the syndrome, a comprehensive program of dispensary observation of the patient is being developed, for which orthopedists, endocrinologists, neurologists, cardiologists are involved. According to the indications, rehabilitation measures are used with the participation of speech pathologists, speech therapists, physical therapy specialists and massage therapists.
Prognosis and prevention
Beckwith-Wiedemann syndrome is associated with a high risk of disabling complications, and 1/5 of patients have a fatal outcome. The prognosis is doubtful, it is determined by the degree of severity of phenotypic changes, the number of congenital somatic pathologies. Since the disease belongs to the category of multigenic with predominantly sporadic development, effective preventive measures have not yet been developed.