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NORD is very grateful to 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.
The syndrome of optic nerve hypoplasia (ONH), also known as septooptic dysplasia (SOD) or DeMorsier syndrome, is a congenital disorder characterized by underdevelopment (hypoplasia) of the optic nerves. The optic nerves transmit impulses from the nerve-rich membranes lining the retina of the eye to the brain. Children with ONH may have brain and pituitary malformations. Abnormalities of structures of the brain may include hypoplasia of the corpus callosum (nerve fibers that connect the two hemispheres of the brain), underdeveloped nerve fibers (white matter) in any other location, and abnormal migration of neurons to the surface of the brain (cortical heterotopia). A common association without any known functional consequence is absence of the septum pellucidum. Abnormal development of the hypothalamus at the base of the brain results in abnormal function of the pituitary gland with or without visible neuroradiographic abnormalities of the pituitary. The pituitary gland is a hormone-producing gland at the base of the brain that controls hormones in the body that are necessary for growth, energy, and sexual development.
Most people with ONH have abnormal eye movements (nystagmus) and vision can range from no light perception to good functional vision, or even full vision in one eye. Some affected children have normal intelligence and others have learning disabilities and developmental delays. Deficiencies of certain hormones may result in growth retardation, poor development, and may be life-threatening without treatment. Hormone deficiencies can be controlled with daily hormone replacement therapy and close monitoring by an endocrinologist (hormone doctor). The cause of ONH is not understood.
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.
Symptoms of the following disorders can be similar to those of ONH. Comparisons may be useful for a differential diagnosis:
Holoprosencephaly (HPE) is the failure of the prosencephalon (a region of the brain in the fetus that develops into parts of the adult brain), or forebrain, to develop normally. Instead of the normal completely distinct left and right halves of the forebrain, there is an abnormal continuity between the two sides. Intellectual disability is associated and seizures are often present. Children with holoprosencephaly may also have defects in the development of the middle of the face such as closely set eyes (hypotelorism), tooth abnormalities (single central incisor), cleft lip/palate, and an abnormally small head (microcephaly). (For more information on this condition, choose "holoprosencephaly" as your search term in the Rare Disease Database.)
The following conditions may be associated with ONH as secondary characteristics. They are not necessary for a differential diagnosis:
Diabetes insipidus, a rare metabolic disorder, is characterized by a deficiency of antidiuretic hormone (ADH), a hormone that is stored in the back (posterior) lobe of the pituitary gland. Major symptoms include excessive excretion of urine (polyuria) and excessive thirst (polydipsia). Diabetes insipidus may have a number of different causes. It may be an inherited condition, occur in association with other underlying disorders, and/or occur as a result of lesions, either congenital or acquired, that damage the posterior lobe of the pituitary gland. (For more information on this disorder, choose "diabetes insipidus" as your search term in the Rare Disease Database.)
Hypothyroidism is a condition characterized by abnormally decreased activity of the thyroid gland and underproduction of thyroid hormones. Symptoms may vary greatly from case to case. Affected individuals may demonstrate mental and physical sluggishness (lethargy); muscle weakness; a slowed heart rate; dry, flaky skin; abnormal hair loss; unusual deepening of the voice; and/or weight gain in association with abnormal thickening of the skin and other body tissues (myxedema). In some cases, individuals with hypothyroidism may exhibit abnormal enlargement of the thyroid gland (goiter). If hypothyroidism occurs during childhood, the condition may cause or contribute to growth retardation, delays in sexual maturation, and/or other abnormalities without appropriate treatment. Hypothyroidism may have a number of different causes. It may be an inherited condition, occur due to or in association with other underlying disorders (such as certain autoimmune diseases and/or disorders affecting the hypothalamus and/or pituitary gland), result from surgery, and/or be due to the use of certain medications. (For more information on this condition, choose "hypothyroidism" as your search term in the Rare Disease Database.)
Hypoglycemia is a condition characterized by abnormally low levels of sugar (glucose) in the blood. Affected individuals may experience faintness, weakness, sweating, excessive hunger, and nervousness. Additional symptoms may include headaches, confusion, visual disturbances, muscle weakness, impaired coordination of voluntary movement (ataxia), marked personality changes, and convulsive episodes (seizures). Hypoglycemia may have a number of causes such as excessive secretion or administration of insulin, prolonged abuse of alcohol without appropriate food intake, and/or deficiencies of certain hormones such as glucocorticoids or growth hormone. In rare cases, hypoglycemia may occur temporarily in some children for unknown reasons. (For more information on this condition, choose "hypoglycemia" as your search term in the Rare Disease Database.)
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. 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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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For information about clinical trials sponsored by private sources, contact:
Contact for additional information about optic nerve hypoplasia:
Mark S. Borchert, MD
The Vision Center at Children’s Hospital Los Angeles
4650 Sunset Blvd, MS #88
Los Angeles, CA 90027
Phone: (323) 361-6219
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., visual impairment, growth hormone deficiency, diabetes insipidus, hypothyroidism, hypoglycemia, mental retardation, etc.].)
(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at email@example.com.)
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 November 30, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed August 31, 2012.
Report last updated: 2012/09/06 00:00:00 GMT+0