NORD gratefully acknowledges Lucia Margari, MD, Professor of Child Neuropsychiatry, Department of Neurological and Psychiatric Sciences, Bari, Italy, for assistance in the preparation of this report.
Affected individuals may not have all of the symptoms discussed below.
The more specific symptom 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 (transparent) to be able to focus incoming light. Megalocornea is present at birth (congenital) and usually is bilateral. Although the cornea is abnormally enlarged, it is otherwise normal in structure, curvature and thickness. Megalocornea may occur as an isolated finding (so-called uncomplicated megalocornea).
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/or other ocular abnormalities. The various eye abnormalities can potentially lead to varying degrees of visual impairment.
In addition to eye abnormalities, affected individuals may also have neurological abnormalities including diminished muscle tone (hypotonia), delays in speech development, varying degrees of cognitive impairment, poor coordination and clumsiness, and delays in the acquisition of motor activities (psychomotor retardation). Less often, additional neurological symptoms may occur including hyperactivity, seizures, 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) including microcephaly, condition that indicates that the head circumference is smaller than would be expected for an infant’s age and sex. In other cases, affected individuals may have a disproportionally large head (macrocephaly). Additional findings may include an unusually prominent forehead (frontal bossing), widely spaced eyes (ocular hypertelorism), downwardly slanting eyelid folds (palpebral fissures), vertical skin folds between the inner corners of the eyes and the nose (epicanthal folds), a broad nasal bridge, a long upper lip, an abnormally small lower jaw (hypoplastic mandible), and/or unusually large and/or “cup-shaped” ears.
Rarely, affected infants and children may have other rare physical malformations such as abnormally long and/or permanently flexed fingers (camptodactyly), abnormal sideways curvature of the spine (scoliosis). Some affected individuals experience growth delays ultimately resulting in short stature.
Because the symptoms have been so variable, researchers believe that the reported cases of megalocornea intellectual disability syndrome may represent similar, yet distinct disorders. However, because of the small number of cases, it is difficult to separate and classify subtypes of the syndrome based on the clinical findings. Additional case reports are necessary to determine specific syndrome subtypes.
The exact cause of megalocornea intellectual disability syndrome is unknown. Megalocornea, when occurring as an isolated finding, is usually inherited as an X-linked recessive trait. 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.
Approximately 37 individuals with megalocornea intellectual disability syndrome have been reported in the medical literature. More males have been reported than females. The disorder is present at birth (congenital). The syndrome was first described in the medical literature in 1975.
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. According to the medical literature, many researchers agree that the presence of megalocornea and intellectual disability should be considered the minimal criteria upon which to base a diagnosis. Abnormally diminished muscle tone (hypotonia) and craniofacial abnormalities may be apparent at birth (congenital). However, certain abnormalities associated with MMR syndrome such as psychomotor retardation, intellectual disability, and/or short stature may not be confirmed until later during infancy or childhood.
In some cases, specialized tests may be conducted to confirm the presence of certain abnormalities that may be associated with the syndrome. For example, thorough examination 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.
In addition, 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, mandibular hypoplasia) and/or skeletal abnormalities (e.g., camptodactyly, scoliosis) potentially associated with the disorder.
Treatment is directed toward 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 asses and treat eye problems (ophthalmologists), neurological disorders (neurologists), and skeletal disorders (orthopedists) as well as other health care professionals may need to systematically and comprehensively plan an affect child’s treatment.
In affected infants or children with megalocornea and/or iris abnormalities, 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 addition, in some cases, treatment with anticonvulsant drugs may help prevent, reduce, or control seizures potentially occurring in association with the disorder.
Early intervention is important to ensure that children with this syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education, special social support, and other medical, social, and/or vocational services. Genetic counseling may be of benefit for affected individuals 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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
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.].)
Stevenson RE, Hall JG, Eds. Human Malformation and Related Anomalies. 2nd ed. Oxford University Press, New York, NY;2006:310.
Porazinski A, Tauber S. Megalocornea and Mental Retardation. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:556.
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McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:190450; Last Update: 09/08/2014. Available at: http://omim.org/entry/249310 Accessed April 28, 2016.
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