Septo-optic dysplasia is a congenital disease related to the defects of the prosencephalic group, characterized by abnormalities in the development of the optic nerve, pituitary gland and transparent septum. Symptoms of this condition are nystagmus and other visual disturbances, signs of endocrine disorders (growth retardation and puberty), possible development of mental retardation. Diagnosis is made on the basis of data from a general examination of the patient, ophthalmological studies, computer and magnetic resonance imaging of the brain, as well as molecular genetic analyses. Specific treatment has not been developed, symptomatic measures include vision correction and hormone replacement therapy for endocrine disorders.
Septo-optic dysplasia (de Morsier syndrome) is a congenital disorder of the development of the brain and visual apparatus of various (including genetic) nature. The causes of this condition, in addition to genetic mutations, may be infections of the mother during pregnancy, the young age of the parents, vascular disorders in a woman. The name “septo-optic dysplasia” was introduced by the French pediatrician De Morsier, who in 1956 compiled the most extensive and complete description of this condition. Currently, under De Morsier syndrome, geneticists mean only a hereditary form of septo-optic dysplasia. To date, the total incidence of this disease (both acquired and hereditary forms) is approximately 1 case per 10,000 newborns, boys and girls are affected with the same frequency. The severity of septo-optic dysplasia can vary significantly in different patients – from the almost complete absence of symptoms to severe disorders complicated by cerebral palsy, lag in physical and mental development.
Septo-optic dysplasia of a hereditary nature develops due to mutations in the HESX1 gene located on the 3rd chromosome. This gene belongs to an extensive class of homeobox genes that are actively involved in the regulation of embryogenesis processes. In particular, HESX1 regulates the embryonic development of brain structures (transparent septum, pituitary gland, chiasm, optic nerve), so its mutations lead to the development of septo-optic dysplasia. In addition, the participation of this gene in the regulation of the axial and bilaterally symmetrical structure of the body has been proven. To date, four types of HESX1 gene missense mutations have been identified, the presence of which causes the appearance of signs of septo-optic dysplasia, all of them are inherited by autosomal recessive type.
The severity of the symptoms of the disease can vary significantly – from minor visual disturbances (myopia, strabismus) to a bright clinical picture with blindness, hypopituitarism and severe mental retardation. Researchers have not yet found a relationship between the type of HESX1 mutation and the severity of symptoms of septo-optic dysplasia. Perhaps the development of this disease is the result of the combined influence of both internal (genetic) and external factors. It also remains unclear that in children of young mothers (aged less than 23 years), septo-optic dysplasia occurs more often, and its hereditary variety is much more severe.
The pathogenesis of septo-optic dysplasia is a violation of the process of differentiation of embryonic tissues in the area of the rudiments of the pituitary gland, chiasm, corpus callosum and other brain structures. For this reason, this disease in severe cases may be accompanied by other neurological symptoms – cerebral palsy, mental retardation. Almost always, with septo-optic dysplasia, certain visual disturbances and endocrine disorders caused by pituitary malformations are detected. Because of this, secondary pathologies may occur caused by abnormal function of the endocrine glands.
The age of onset of symptoms of septo-optic dysplasia varies greatly in different patients, in severe cases, the diagnosis can be made in the first days and months of life, with the erased form of the disease – only in younger or even older childhood. Usually, the first manifestation of pathology is the development of horizontal nystagmus caused by hypoplasia of the optic nerve. Even earlier, when examining a child, signs of endocrine insufficiency of the pituitary gland can be determined: hypoglycemia, reduced size of the genitals, abnormal jaundice. In rare cases, in the first months of life with septo-optic dysplasia, convulsive seizures occur, long-term preservation of transient reflexes and other neurological disorders.
As a child suffering from septo-optic dysplasia grows, a lag in both physical and intellectual development may be revealed. Visual pathologies are increasing, epileptic seizures often occur. In such patients, the process of puberty usually begins earlier than in their peers, due to endocrine disorders. However, in some cases, endocrine disorders may be expressed rather weakly or completely absent. The same situation is with the mental retardation of patients with septo-optic dysplasia – it ranges from normal intelligence to deep mental retardation. The latter may indicate the presence of concomitant malformations of the brain – holoprosencephaly, hypoplasia of the corpus callosum. The variability of symptoms and the varying degree of their severity significantly complicates the diagnosis of septo-optic dysplasia.
Diagnosis and treatment
To determine septo-optic dysplasia, the results of a general examination of the patient, neurological and ophthalmological studies, magnetic resonance and computed tomography, molecular genetic analyses are used. Upon examination, there may be a lag in physical development (in young children), early onset of puberty (in adolescents), signs of multiple hormonal insufficiency. An ophthalmological examination can reveal nystagmus and signs of optic nerve hypoplasia – a decrease in the size of the optic disc, a weakening of all peaks on the ERG, complete blindness. However, according to the clinical picture, it is quite problematic to diagnose septo-optic dysplasia, since this condition is characterized by a significant variability of symptoms.
Magnetic resonance imaging determines the absence or pronounced underdevelopment of the transparent septum, aplasia or hypoplasia of the optic nerve, in some cases – underdevelopment of the corpus callosum. Disorders in the formation of the pituitary gland are detected, in especially severe cases of septo-optic dysplasia, other defects of the central nervous system may be detected, for example, holoprosencephaly. A biochemical blood test allows you to confirm the presence of insufficiency of growth hormone (somatotropin) and other pituitary hormones. Molecular genetic diagnostics is carried out by a geneticist, direct sequencing of the HESX1 gene is performed in order to confirm mutations. The absence of genetic defects is not a reason to exclude septo-optic dysplasia, since the disease can occur due to non-hereditary causes. The “gold standard” in the diagnosis of this condition is MRI and CT data.
There is no specific treatment for septo-optic dysplasia, symptomatic and palliative therapeutic measures are used. In the presence of endocrine disorders, substitution therapy is prescribed, the scheme of which depends on the nature of hormonal dysfunction, which is determined as part of a blood test. In most cases of septo-optic dysplasia, visual impairments are practically impossible to correct. Symptomatic therapy includes the use of anticonvulsants (for epileptic seizures) and nootropic drugs, the work of child psychologists with a sick child with mental retardation.
Prognosis and prevention
The prognosis of septooptic dysplasia is often uncertain due to the strong variability of the manifestations of the disease. In the presence of severe hypoplasia of the optic nerves, pituitary gland, transparent septum, there is an extremely high risk of death in early childhood due to numerous disorders. Similarly, concomitant pathologies – cerebral palsy, holoprosencephaly – worsen the prognosis of septo-optic dysplasia. In many cases, the disease proceeds quite favorably – the symptoms are limited to minor visual impairments, sometimes the presence of mild mental retardation, an increased risk of seizures. Prevention of septo-optic dysplasia is possible only with respect to forms of the disease caused by non–hereditary causes – infectious diseases of the mother, her young age, vascular disorders during pregnancy.