NORD gratefully acknowledges Mark S. Borchert, MD, Division Head and Director, Eye Birth Defects and Eye Technology Institutes, The Vision Center, Children's Hospital Los Angeles, for assistance in the preparation of this report.
ONH is present at birth, but many symptoms may not be apparent until childhood, or even adolescence. Most infants with ONH have involuntary, rapid eye movements (nystagmus) and/or mild to severe visual impairment of one or both eyes. Vision often improves modestly in early childhood even though there is no growth of the optic nerves after birth. Due to underdevelopment of the optic nerves, the optic disk is smaller than normal size in one or both eyes when viewed by a doctor using an ophthalmoscope. Also referred to as the “blind spot,” the optic disk is the structure in which nerve fibers from the retina combine to form the optic nerve before leaving the back of the eye. The optic nerves meet to form the optic chiasm and optic tracts at the base of the hypothalamus.
Affected individuals may also exhibit symptoms due to underdevelopment of the hypothalamus at the base of the brain. The hypothalamus is divided into several different regions that have different functions. The hypothalamus is responsible for regulating basic body functions such as thirst, hunger, sleep, and body temperature. As a result, children with ONH frequently have problems with these functions. Although the hypothalamus is commonly abnormal in individuals with ONH, the abnormalities are rarely visible on MRI scans.
The hypothalamus also coordinates the function of the pituitary gland by controlling the gland’s release of certain hormones. The pituitary gland, a small structure beneath the hypothalamus produces several hormones and releases them directly into the bloodstream. It is located directly below the optic nerves and is connected to the hypothalamus by a short stalk of nerve fibers and blood vessels. In most individuals with ONH, the hypothalamus does not communicate with the pituitary gland properly, resulting in a failure of the pituitary gland to produce or release the normal levels of certain hormones into the bloodstream.
The specific hormones that are affected and the severity of such hormone deficiencies may vary greatly from case to case. Affected individuals most commonly lack sufficient levels of growth hormone (GH), which stimulates normal growth and development. Growth hormone deficiency is usually apparent during early childhood, when there is a decline in the normal growth rate that may ultimately result in short stature and other maturation delays.
Some individuals with ONH also have abnormally low levels of several other hormones such as adrenocorticotropic hormone (ACTH), which stimulates the adrenal gland to release corticosteroids to maintain blood sugar and blood pressure during times of physical or emotional stress. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH), from the pituitary play a role in coordinating the function of the male and female sexual organs and are essential for normal sexual development. Thyroid stimulating hormone (TSH) stimulates the thyroid gland to release thyroid hormones, which is responsible for energy metabolism. Absence of this hormone during infancy results in intellectual disability. The pituitary also releases antidiuretic hormone (ADH), which controls salt levels in the body by controlling urine output. Deficiencies in these hormone deficiencies may result in: intellectual disability; obesity; delayed sexual maturation; low levels of glucose in the blood (hypoglycemia); seizures; diabetes insipidus, a disorder characterized by excessive excretion of urine and excessive thirst. (For more information on hypothyroidism, hypoglycemia and diabetes insipidus, please see the Related Disorders section of this report.)
Other structures within the brain may also develop improperly. As a result, such brain structures may be absent, incompletely developed (hypoplastic), and/or malformed (dysplastic). For example, individuals with ONH frequently do not have the membrane (septum pellucidum) that normally separates the fluid-filled cavities (lateral ventricles) in both sides of the brain. Absence of the septum pellucidum does not cause any known problems. In many cases, affected individuals also exhibit partial or total absence of the thick band of nerve fibers that connects the left and right hemispheres of the brain (corpus callosum). Such individuals are at increased risk for cognitive or developmental delay.
Many individuals with ONH may also exhibit additional abnormalities. Many affected infants have delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation). Some affected children have normal intelligence and others have learning disabilities and intellectual disability.
The cause of ONH is not known. In most cases, the disorder appears to occur randomly for unknown reasons (sporadic). Rare families have been reported with more than one affected child, suggesting the possibility of autosomal recessive inheritance. A few cases of ONH have been reported to result from a mutation in the HESX1 gene. The vast majority of affected individuals do not have a HESX1 gene mutation, suggesting that other genes and/or environmental factors are involved in the development of this condition.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
ONH is thought to affect males and females in equal numbers. The prevalence is estimated to be 1 in 10,000 children.
ONH is diagnosed by a complete ophthalmologic examination. Imaging studies such as magnetic resonance imaging (MRI) and computerized tomography (CT) are used to examine the corpus callosum and optic nerves. ONH may be suspected, but not diagnosed, based on MRI findings, as other abnormalities can mimic the MRI findings of ONH. Abnormal levels of serum cortisol and growth hormone help to confirm the diagnosis.
The treatment of ONH is directed toward the specific symptoms in each individual. Treatment may require the coordinated efforts of a team of specialists including pediatricians, ophthalmologists, neurologists, endocrinologists and/or other health care professionals.
Specific therapies for ONH are symptomatic and supportive. Hormone deficiencies are treated with hormone replacement therapy. The vision abnormalities are usually not treatable.
Developmental testing should be performed to determine if deficiencies are present in gross or fine motor skills or in intelligence. Early intervention is important to ensure that children with ONH reach their potential. Special services that may be beneficial to affected children may include vision therapy, physical therapy, and occupational therapy.
Genetic counseling may be beneficial for affected children and their families.
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Contact for additional information about optic nerve hypoplasia:
Thomas P. Septooptic Dysplasia. In: The NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott, Williams and Wilkins; 2003:188.
Borchert M. Reappraisal of the optic nerve hypoplasia syndrome. J Neuroophthalmol. 2012; 32:58-67.
McNay DE, Turton JP, Kelberman D, et al. HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab. 2007;92:691-697.
Brickman JM, Clements M, Tyrell R, et al. Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders. Development. 2001;128:5189-5199.
Benner JD, Preslan, MW, Gratz E, et al. Septo-optic dysplasia in two siblings. Am J Opthal. 1990;109:632-637.
Hoyt We, Kaplan SL, Grumbach MM, et al. Septo-optic dysplasia and pituitary dwarfism. Lancet. 1970;1:893-894.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Septooptic Dysplasia. Entry No: 182230. Last Edited 03/12/2013. Available at: http://omim.org/entry/182230 Accessed May 11, 2015.
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