Wolf-Hirschhorn syndrome is a rare genetic anomaly in which a part of the short arm of the 4th chromosome is deleted, which is accompanied by mutations of the genes WHSC1, WHSC2, LETM1. The disease is manifested by multiple defects in the formation of the facial skeleton, congenital cardiovascular abnormalities, and delayed psychomotor development. The syndrome is diagnosed using genetic tests (routine chromosomal analysis, FISH hybridization), a comprehensive instrumental examination. Symptomatic treatment: nutritional support, medical correction of complications, surgical assistance in severe congenital malformations.
ICD 10
Q93.3 Deletion of the short arm of chromosome 4 (Wolf-Hirschorn syndrome)
General information
The syndrome was first isolated as an independent disease in 1961, and in 1965, scientists W. Wolf and K. Hirschhorn described a characteristic symptom complex in newborn children, so the disease is named after them. The prevalence of pathology is about 1 case per 96,000 population, while boys get sick 2 times more often. Despite the low frequency of occurrence, Wolf-Hirschhorn syndrome does not lose its relevance in modern pediatrics and therapy, which is due to the need for lifelong comprehensive rehabilitation of such patients.
Causes
Wolf-Hirschhorn syndrome is caused by a chromosomal anomaly in which the short arm of chromosome 4 loses some of its part at the 4p16 locus. The size of the defect ranges from small (up to 3.5 megabases), in which there are no gross defects and a mild phenotype is observed, to terminal, associated with the death of a child in utero or immediately after childbirth. In most cases, the mutation is new, and only in 13% of situations, the chromosomal deletion is inherited from parents.
Pathogenesis
The syndrome is formed due to a mutation of the WHSC1 gene (Wolf-Hirschhorn Syndrome Candidate 1), also known as NSD2 (Nuclear Receptor Binding SET Domain Protein 2 or histone-lysine-N-methyltransferase). It is responsible for the formation of histone group proteins necessary for DNA replication processes. In addition, a high level of MMSET gene expression disrupts DNA repair processes after the action of carcinogens.
Wolf-Hirschhorn syndrome also has a mutation in WHSC2 (Wolf-Hirschhorn Syndrome Candidate 2), which is located in all tissues of the body. Convulsive syndrome is most likely caused by the pathology of the LETM1 gene (Leucine zipper-EFhand containing transmembrane protein 1), which is expressed in mitochondria and has regulatory activity. It disrupts the depolarization of cell membranes, affecting the operation of ion pumps.
Symptoms
The syndrome manifests itself immediately after birth. Babies are usually born prematurely with a body weight of about 2 kg. The head has a small size relative to the trunk (microcephaly), the nose has a beak-shaped shape, the ears are deformed and low. Often there is a small mouth with drooping corners of the lips, vertical skin folds near the eyes, cleft upper lip and palate. The shape of the feet has been changed: clubfoot, flat-footed foot are pronounced.
The Wolf-Hirschhorn syndrome is characterized by cardiovascular defects: stenosis of the superior vena cava, defects of the interventricular or atrial septum. Kidney damage is manifested by hypoplasia, the presence of multiple cysts. Due to cerebral pathologies, convulsive seizures often occur in children. As the patient grows older, mental retardation, growth retardation and motor development become noticeable.
Complications
Deletion of the WHSC1 gene plays a key role for violations of the immune defense of the body, therefore, immunodeficiency conditions are observed in all children. Due to the high susceptibility to pathogens, patients suffer from recurrent tonsillitis, bronchitis, sinusitis, frequent pneumonia, gastrointestinal infections. In infancy, aspiration pneumonia may develop, which is associated with high mortality.
In 60-70% of cases, the syndrome is accompanied by disorders of the skeletal structure in the form of pronounced scoliosis, kyphosis, clubfoot, in some patients a split hand is formed. Up to 50% of patients suffer from pathologies of the visual apparatus — exotropia (a form of strabismus), coloboma, excessive lacrimation. In 40% of children, hearing loss is detected, which is associated with disorders of the formation of the inner ear apparatus.
About 20% of patients die from multiple organ complications during infancy, and half of the deceased are children of neonatal age. Due to gross malformations, the addition of infections, central nervous system damage, life expectancy is sharply reduced in patients, the maximum age of an adult suffering from Wolf-Hirschhorn syndrome is 25 years in Russia, up to 30 years in other European countries.
Diagnostics
Wolf-Hirschhorn syndrome can be suspected immediately in a newborn child, since most patients have specific facial abnormalities, dysembriogenesis stigmas. During the examination by a neonatologist, the physical condition of the cardiovascular system is assessed to confirm or exclude congenital malformations. To verify this hereditary syndrome, the following are prescribed:
- Molecular genetic testing. With the help of routine chromosomal analysis, it is possible to identify up to 58% of cases of the disease. To improve the accuracy of diagnostics at the present stage, the technique of fluorescent hybridization (FISH) is used, the results of which have 95% reliability.
- Antenatal diagnostics. It is advisable for parents with a chromosomal anomaly to do an analysis during pregnancy by amniocentesis or biopsy of chorionic villi. After invasive sampling of the material, a genetic study is recommended. If conception occurs by IVF, reproductologists perform preimplantation genetic diagnosis (PGD).
- Instrumental methods. Given the high frequency of heart defects in sufferers of Wolf-Hirschhorn syndrome, echocardiography and ECG are necessarily performed to determine anomalies. If a CNS lesion is suspected, neurosonography, CT or MRI of the brain is indicated. To assess hearing, tonal audiometry and acoustic impedance measurement are performed.
Treatment
There is no specific therapy. The actions of medical workers are aimed at correcting existing problems in order to improve the quality of life of the patient. To help patients, a multidisciplinary team of specialists is involved, which includes a pediatrician (family doctor), a geneticist, specialized specialists — a pediatric cardiologist, a pulmonologist, a gastroenterologist. The following methods are included in the treatment regimen:
- Nutritional support. Given the frequent problems with feeding, orogastric or nasogastric probes are used in infancy. In severe cases, percutaneous endoscopic gastrostomy is resorted to.
- Drug therapy. Taking valproic acid is required for the relief of convulsive seizures. In case of infections, antibiotics are prescribed, in order to increase the reactivity of the body, immunomodulators are shown.
- Cardiac surgical correction. The help of a pediatric cardiac surgeon is required for life-threatening heart defects that disrupt blood circulation. Surgical treatment in such cases is carried out in the first months of a child’s life.
Great importance is given to rehabilitation programs. To correct speech delay and increase the child’s socialization, classes with a children’s speech therapist are recommended. Skeletal anomalies with concomitant motor disorders require the help of qualified massage specialists, physical therapy instructors, rehabilitologists. Swimming and spa treatment show good health-improving results in the rehabilitation of patients with Wolf-Hirschhorn syndrome.
Prognosis and prevention
Changes in Wolf-Hirschhorn disease are irreversible, associated with a significant reduction in life expectancy, so the prognosis is unfavorable. Even if the patient lives to adulthood, he suffers from mental retardation, has severe somatic diseases. Prevention of the syndrome includes medical and genetic counseling of families from risk groups, preimplantation diagnosis of embryos during IVF procedure.