NORD gratefully acknowledges Braeden Ego, MS, NORD Editorial Intern from the Stanford University MS Program in Human Genetics and Genetic Counseling and MaryAnn Campion, EdD, MS, CGC, Clinical Associate Professor, Director, Stanford University MS Program in Human Genetics and Genetic Counseling, for assistance in the preparation of this report.
Megalocornea-intellectual disability syndrome is an extremely rare disorder that is characterized by distinctive abnormalities of the cornea of the eye (megalocornea) and varying degrees of cognitive impairment (intellectual disability). Most patients also present with diminished muscle tone (hypotonia) and may experience a wide variety of additional symptoms that can vary in severity. Individuals are typically diagnosed during early infancy or early childhood. To date, there have been approximately 40 individuals reported with megalocornea-intellectual disability syndrome in the medical literature. While the exact cause of this condition is unknown, it is suspected to have a genetic basis.
A characteristic symptom of all individuals affected with megalocornea-intellectual disability syndrome is a distinctive eye abnormality known as megalocornea, which is the abnormal, nonprogressive enlargement of the cornea that occurs without the presence of increased pressure within the eye (glaucoma). The cornea is the clear (transparent) outer layer of the eye and has two functions – it protects the rest of the eye from dust, germs and other harmful or irritating material and it acts as the eye’s outermost lens, bending incoming light onto the inner lens, where the light is then directed to the retina (a membranous layer of light-sensing cells in the back of the eye). The retina converts light to images, which are then transmitted to the brain. The cornea must remain clear to be able to focus incoming light. Megalocornea is present at birth (congenital) and usually affects both eyes (bilateral). Although the cornea is abnormally enlarged, it is otherwise normal in structure, curvature and thickness.
Some affected individuals have additional abnormalities affecting the eyes including underdevelopment (hypoplasia) of the colored portion of the eyes (iris), abnormal “unsteadiness” of the irises during eye movements (iridodonesis) and abnormal shaping of the eye so that it does not bend light appropriately (refractive errors).These additional eye abnormalities can potentially lead to varying degrees of visual impairment.
Other characteristic features of all individuals affected with this condition include intellectual disability and delays in the acquisition of motor skills (psychomotor delay). Most (>80%) affected individuals also experience hypotonia. Other neurologic abnormalities may be observed, including delayed speech development, poor coordination and clumsiness, seizures, hyperactivity and involuntary movements of the face, arms and legs (limbs) and trunk consisting of slow, continual, writhing movements (athetosis) occurring in association with more rapid, jerky movements (choreoathetoid movements).
Individuals with megalocornea-intellectual disability syndrome may also have distinctive features in the head and face area (craniofacial region). These include microcephaly, a condition that indicates that the head circumference is smaller than would be expected for an infant’s age and sex, or macrocephaly, a condition in which there is a disproportionally large head circumference. Additional craniofacial findings may include an unusually prominent forehead (frontal bossing), widely spaced eyes (ocular hypertelorism), downward slanting eyelid folds (palpebral fissures), vertical skin folds between the inner corners of the eyes and the nose (epicanthal folds), widening of the top part of the nose (broad nasal bridge), a long upper lip, an abnormally small lower jaw (micrognathia), a high and narrow roof of the mouth (high arched palate) and/or unusually large and/or “cup-shaped” ears.
Rare physical malformations may also be present, including abnormally long and/or permanently flexed fingers (camptodactyly), abnormal sideways curvature of the spine (scoliosis), abnormal forward curvature of the spine (kyphosis) and heart defects. Patients have also been reported with very flexible joints (joint hyperlaxity).
Additionally, affected individuals may experience primary hypothyroidism where the thyroid gland does not produce appropriate levels of hormones. These hormones are required for many bodily functions including growth and metabolism. Some affected individuals experience growth delays ultimately resulting in short stature. Recurrent infections have also been reported in some patients.
The exact cause of megalocornea-intellectual disability syndrome is unknown. However, cases reported in the literature are consistent with an autosomal recessive inheritance pattern or new (de novo) genetic changes (variants) that were not inherited from parents.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working 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 working genes from both parents is 25%. The risk is the same for males and females.
Although megalocornea intellectual disability syndrome is suspected to have an underlying genetic cause, genetic variants in specific genes have not been shown to cause the condition.
Megalocornea-intellectual disability syndrome is typically diagnosed in early childhood or early infancy. Due to the rarity of the condition and the small number of documented cases, there are no accurate estimates for the incidence of this condition. To date, approximately 40 individuals with the condition have been reported in the medical literature. Most are sporadic, meaning that individuals are typically the only ones affected with the condition in their families. An approximately equal number of males and females have been reported. Additionally, individuals across varied races have been reported with this condition.
Megalocornea-intellectual disability syndrome is diagnosed during early infancy or early childhood based on a clinical evaluation, identification of characteristic physical findings and/or a variety of specialized tests. Many researchers agree that the presence of megalocornea and intellectual disability should be considered the minimal criteria upon which to base a diagnosis.
Signs and symptoms such as megalocornea, hypotonia and craniofacial abnormalities may be apparent at birth (congenital). However, certain abnormalities associated with the syndrome, such as intellectual disability, psychomotor delay and/or short stature, may not be confirmed until later during infancy or childhood.
Specialized tests may be conducted to confirm the presence of certain abnormalities that may be associated with the syndrome. For example, thorough examination with or without general anesthesia may be conducted with an instrument that visualizes the interior of the eye (ophthalmoscopy) to detect, confirm and/or characterize megalocornea, iris hypoplasia and/or other ocular abnormalities potentially associated with the disorder.
Additionally, in some affected infants and children, electroencephalography (EEG), which records the brain’s electrical impulses, may reveal epileptic activity. Advanced X-ray studies may be used to confirm craniofacial malformations (e.g., microcephaly or macrocephaly, frontal bossing, micrognathia) and/or skeletal abnormalities (e.g., camptodactyly, scoliosis, kyphosis) potentially associated with the disorder. Brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) scans may reveal structural brain malformations (such as cerebral atrophy, underdeveloped corpus callosum, delayed myelination, mild ventricular dilatation). In some affected individuals, ultrasound imaging of the heart with echocardiography may reveal heart defects.
Treatment is directed towards the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physical therapists and specialists who assess and treat eye problems (ophthalmologists), neurological disorders (neurologists), skeletal disorders (orthopedists) and heart problems (cardiologists) may need to systematically and comprehensively plan an affected child’s treatment.
In affected infants or children with megalocornea, iris abnormalities and/or refractive errors, corrective glasses, contact lenses, surgery and/or other supportive techniques may be used to help improve vision.
In some affected infants and children with neuromuscular abnormalities, physical therapy and/or other supportive therapies may be used to help improve motor skills and coordination. In some patients, treatment with anticonvulsant drugs may help to prevent, reduce or control seizures potentially occurring in association with the disorder. In some patients, hormone replacement therapies can be initiated to treat hypothyroidism and normalize thyroid hormone levels.
Early intervention is important to ensure that children with this syndrome reach their full potential. Special services that may be beneficial to affected children may include special education, special social support and other medical, social, and/or vocational services. Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at https://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:
Tollfree: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., eye abnormalities, visual impairment, intellectual disabilities, neuromuscular abnormalities, short stature, craniofacial abnormalities, etc.].)
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