Coffin-Lowry syndrome is a rare genetic disease with an X—linked transmission mechanism, which is characterized by severe mental retardation, multiple phenotypic features. Patients have specific features of appearance: high forehead, hypertelorism, large protruding nose. In addition to intellectual disabilities, growth retardation, hearing loss, and cardiac complications are observed. The basis for the diagnosis of Coffin-Lowry syndrome is a molecular genetic study. Supportive treatment: a special program of neurorehabilitation, correction of bone curvature, hearing prosthetics for hearing loss.
ICD 10
Q87.0 Syndromes of congenital anomalies affecting mainly the appearance of the face
General information
The disease was named after two scientists who independently described its pathognomonic symptoms — American pediatrician Grange S. Coffin (1966) and Canadian geneticist Robert B. Lowry (1971). The molecular genetic foundations of pathology were deciphered in 1996. Coffin-Lowry syndrome in its full clinical form occurs only in male patients. Women who are carriers of the mutant gene may have moderate signs of the syndrome. The disease is registered with a frequency of 1-2 cases per 100,000 live births.
Causes
Coffin-Lowry disease is associated with the presence of a mutation of the RPS6KA3 gene on the X chromosome. Up to 80% of cases of pathology occur sporadically in families without burdened heredity, and the remaining 20% of cases fall on the X-linked recessive type of inheritance. Clinical signs are manifested mainly in men. The factors contributing to spontaneous genetic mutations have not yet been established.
Pathogenesis
Normally, the RPS6KA3 gene encodes the synthesis of the RSK2 kinase protein, which is necessary for the proper course of the processes of proliferation, differentiation, and programmed cell death. The substance is activated with the help of signaling pathway proteins, begins to work with the intake of growth hormones, neurotransmitters, polypeptide hormones.
With RPS6KA3 dysfunction, kinase deficiency is observed in the body, which causes disorders of transmission along the MARK signaling pathway. As a result, the formation of long-term memory and other cognitive functions deteriorates, which is caused by violations of synaptic transmission, and multiple pathologies of the development of the musculoskeletal system also occur.
Symptoms
The most characteristic clinical manifestations are numerous anomalies of the facial skeleton. Children from birth have a high protruding forehead, widely spaced eyes with narrow eye slits. The bridge of the nose is flattened, the wings of the nose are large with the nostrils turned out. Anomalies of the oral cavity include a narrow high palate, changes in bite, median lingual furrow.
Sufferers of Coffin-Lowry syndrome have broad hands with short fingers that taper sharply to the distal parts. In 80% of cases, there is a deformation of the chest, kyphoscoliosis. Men have a serious delay in physical development, the average height of adults is about 143 cm (range 115-158 cm). Heterozygous women often have a normal body length – more than 50% of patients are above the 10th centile.
From the first years of life, patients show a violation of speech function, a lag in intellectual development. The degree of mental retardation varies widely, in different patients the IQ level can be in the range of 15-60. At the same time, the child’s communication skills are partially preserved, the character is usually calm and friendly. Severe forms of mental retardation, as a rule, are formed with concomitant hearing loss.
Complications
Up to 20% of patients suffer from movement coordination disorders, sudden falls (drop attacks) that appear at school age. Up to 15% of patients have cardiovascular complications (mitral valve dysfunction, cardiomyopathy). 5% of people with Coffin-Lowry syndrome have epileptic seizures. Heterozygous women often have obesity, mental problems: depression, schizophrenia, psychopathological type of behavior.
According to literature data, about 13.5% of men die at the age of 13-34, the rest live to middle age. The causes of death are the negative consequences of Coffin-Lowry syndrome — myocarditis, pneumonia, respiratory failure. There is also a risk of death from complications during anesthesia for orthopedic correction of bone abnormalities or performing dental manipulations.
Diagnostics
The characteristic phenotype in combination with disorders of psychomotor development makes it possible to suspect Coffin-Lowry syndrome in infancy. Such patients are examined by a pediatrician together with a pediatric neurologist and a geneticist. To confirm the diagnosis, a comprehensive diagnosis is necessary, including the following methods:
- Genetic testing. Exon sequencing to detect a typical RPS6KA3 mutation is the main way to confirm the presence of the syndrome. Such diagnostics can be carried out by other family members if the hereditary nature of the disease is suspected.
- Radiography of the skeleton. The facial skull images show bone thickening, multiple deformities. Radiography of the spine shows kyphoscoliosis, narrow intervertebral spaces. Examination of the extremities reveals shortening of the tubular bones, wide proximal and narrow distal phalanges of the fingers.
- Consultation of a neurologist. To assess the degree of cognitive and speech disorders, a comprehensive neurological examination is required, special tests and questionnaires are used at preschool and school age. According to the indications, neuroimaging is prescribed (CT brain, neurosonography, EEG).
- Prenatal diagnosis. In a family with a burdened heredity, it is advisable to study the genotype of the fetus during pregnancy. Sampling of the material for the molecular genetic test is performed using amniocentesis, cordocentesis in the second trimester.
Treatment
Conservative therapy
Etiotropic treatment has not been developed, so medical care is reduced to eliminating or reducing symptoms, preventing complications of Coffin-Lowry syndrome. In order to monitor the state of health, patients need dynamic monitoring by a number of specialists (pediatrician /therapist, neurologist, cardiologist, geneticist). Accordingly , the clinical picture is prescribed:
- Psychotropic drugs. Anticonvulsants and serotonin reuptake inhibitors are recommended for frequently repeated drop attacks. Regular intake of anticonvulsants is indicated if the disease is complicated by convulsive seizures.
- Nootropics. The use of drugs that improve energy exchange and blood circulation in the brain, stimulates the formation of intellectual functions, improves short-term and long-term memory.
- Auditory prosthetics. For children with conductive hearing loss, the installation of a hearing aid is performed as early as possible, ideally in the first 6 months of a child’s life, which contributes to the development of speech, the correct formation of communication skills.
Given the mental retardation of most patients, Coffin-Lowry syndrome requires special neurorehabilitation. Classes begin at an early age with the participation of speech therapists, sign language teachers, correctional teachers. Children cannot study in a regular school, they need classes in inclusive classes or special home-schooling programs.
Surgical treatment
Surgical orthopedic care is provided for 3-4 degrees of scoliosis, accompanied by cardiorespiratory disorders. Patients are shown surgical correction of spinal curvature using a mechanical stabilization system
Prognosis and prevention
Women carriers of the damaged gene have a normal life expectancy, symptoms are weak or absent at all, so the prognosis is favorable. Forecasts are less optimistic for male patients, who often die at a young and middle age from somatic or neurological complications. Prevention of Coffin-Lowry syndrome includes medical and genetic counseling for couples with a family predisposition.
