NORD gratefully acknowledges John M. Opitz, MD, Department of Human Genetics, University of Utah School of Medicine, for assistance in the preparation of this report.
Lenz Microphthalmia syndrome is an extremely rare inherited disorder characterized by abnormal smallness of one or both eyes (unilateral or bilateral microphthalmos) and/or droopy eyelids (blepharoptosis), resulting in visual impairment. In rare cases, affected infants may exhibit complete absence of the eyes (anophthalmia). Most affected infants also exhibit developmental delay and mental retardation, ranging from mild to severe. Additional physical abnormalities are often associated with this disorder such as an unusually small head (microcephaly) and/or malformations of the teeth, ears, and/or fingers and/or toes (digits). The range and severity of findings may vary from case to case.
Lenz microphthalmia syndrome, which is inherited as an X-linked recessive genetic trait, is fully expressed in males only. However, females who carry one copy of the disease gene (heterozygotes) may exhibit some of the symptoms associated with the disorder, such as an abnormally small head (microcephaly), short stature, and/or malformations of the fingers and/or toes.
BCOR (MAA2 locus) is the only gene known to be associated with this syndrome.
Lenz Microphthalmia syndrome, also known as microphthalmia or anophthalmos with Associated Anomalies, is an extremely rare inherited disorder that is apparent at birth (congenital). It is fully expressed in males only; however, the range and severity of symptoms in affected males may vary from case to case. Some females who carry a single copy of the disease gene (heterozygous carriers) may exhibit some of the symptoms associated with Lenz Microphthalmia syndrome.
In affected males, the primary physical characteristic associated with Lenz microphthalmia syndrome is abnormal smallness of one or both eyes (unilateral or bilateral microphthalmos). In most cases, both eyes are affected, and the eyes maybe of different size (bilateral, asymmetrical microphthalmos). The front (anterior), clear portion of the eye through which light passes (cornea) may be unusually small (microcornea). In addition, some tissue from the colored portion of the eye (iris) may be absent (coloboma), giving the iris a “keyhole” appearance. Colobomas may also affect other eye tissues including the ciliary body, choroid, and/or optic disc. In many cases, the upper eyelids may droop due to paralysis of muscles that control the eyelids (blepharoptosis). In rare cases, affected infants may exhibit absence or rudimentary (vestigial) portions of the eyes (anophthalmia). Such eye abnormalities may result in varying degrees of visual impairment or, in some cases, blindness. The degree of visual impairment depends upon the severity and/or combination of eye abnormalities present.
In most cases of Lenz microphthalmia syndrome, affected males may exhibit a mild to severe delay in attaining certain developmental milestones (e.g., crawling, sitting up, walking, etc.). Affected males may also exhibit mental retardation, ranging from mild to severe.
Most infants with Lenz microphthalmia syndrome also exhibit additional physical abnormalities, such as malformations of the head and facial (craniofacial) area. These usually include an abnormally small head (microcephaly) and malformations of the ears and teeth. In most infants with this disorder, the ears are flared forward (anteverted) and the ear lobes may be abnormally large; however, in some cases, the ears may be abnormally small and underdeveloped (hypoplastic). Hearing impairment may be present in some cases. The teeth may be widely spaced or abnormally crowded. In addition, front teeth (incisors) may be absent (agenesis) or malformed. In some cases, affected males may also exhibit incomplete closure of the roof of the mouth (cleft palate) and/or a vertical groove in the upper lip (cleft lip). (For more information on this disorder, choose “Cleft Lip and Cleft Palate” as your search terms in the Rare Disease Database.)
Most males with the disorder also have skeletal abnormalities. These may include a sideways and front-to-back curvature of the spine (kyphoscoliosis), narrow and/or sloping shoulders, underdeveloped collarbones (hypoplastic clavicles), and/or a “barrel-shaped” rib cage (thoracic cage).
In addition, infants with Lenz microphthalmia syndrome often exhibit malformations of the fingers and/or toes (digits). They may be abnormally bent (clinodactyly), permanently flexed (camptodactyly), and/or webbed or fused (syndactyly). In some cases, double thumbs may also be present.
Approximately half of affected males may also have abnormalities of the reproductive and urinary (genitourinary) systems. These malformations may include failure of the testes to descend into the scrotum (cryptorchidism), placement of the urinary opening (meatus) on the underside of the penis (hypospadias), and/or underdevelopment (hypoplasia) or absence of a kidney (renal agenesis).
Females who carry a single copy of the disease gene for Lenz microphthalmia syndrome (heterozygous carriers) may exhibit some of the symptoms associated with the disease. Such symptoms are milder than those associated with the fully expressed disorder. Such heterozygous females may have abnormalities of the fingers and/or toes (digital anomalies), an unusually small head (microcephaly), and/or short stature.
Lenz microphthalmia syndrome is inherited as an X-linked recessive trait. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is turned off and most of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males can not pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% to have a son affected with the disease, and a 25% chance to have an unaffected son.
In some females who inherit a single copy of the disease gene for Lenz microphthalmia syndrome (heterozygotes), disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, in such cases, some females may exhibit some of the symptoms associated with the disorder.
Some cases of Lenz microphthalmia syndrome may be caused by disruption or changes (mutations) of a gene located on the X chromosome between bands Xq27-q28. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq27” refers to band 27 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Another gene locus has been identified in some individuals with Lenz microphthalmia syndrome. In these cases, the disorder may be caused by changes (mutations) of the BCL-6-interacting corepressor (BCOR) gene located on X chromosome between bands Xp11.4-p21.2. These cases may be referred to as microphthalmia with associated anomalies 2 (MMA2).
Some researchers speculate that severe cases of Lenz microphthalmia syndrome may result from deletions of genetic material from two or more adjacent genes (contiguous gene syndrome) located on the X chromosome.
Lenz microphthalmia syndrome is an extremely rare inherited disorder that is fully expressed in males only and is apparent at birth. However, females who carry a single copy of the disease gene (heterozygous carriers) may exhibit some milder symptoms associated with the disorder. Approximately 12 affected males with the fully expressed disorder have been reported. The disorder was first described by Lenz in 1955.
In some familial cases, Lenz microphthalmia syndrome may be detected before birth (prenatally). For example, ultrasound studies during pregnancy may reveal characteristic findings suggestive of Lenz microphthalmia syndrome in siblings of affected children. In fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus.
The diagnosis of Lenz microphthalmia syndrome may be confirmed at birth, based upon a thorough clinical evaluation, characteristic physical findings, and imaging techniques. Ultrasonography studies of the internal structure of the eye may demonstrate that the length from the front to the back of the eye (anteroposterior axis) is smaller than normal, confirming a diagnosis of microphthalmia. In some cases, however, it may be difficult to distinguish severe microphthalmia from anophthalmia. Therefore, magnetic resonance imaging (MRI) may sometimes be used to help confirm which condition is present. When MRI scanning is unable to clarify which malformation is present, other diagnostic steps may sometimes be taken to determine whether rudimentary (vestigial) portions of the eyes are present or absent.
Additional diagnostic steps may also be taken to confirm the presence of other conditions often associated with Lenz microphthalmia syndrome. Examination with an instrument that visualizes the interior of the eye (ophthalmoscopy) may be used to determine the absence of ocular tissue in certain structures of the eyes (colobomas). Drooping of the upper eyelid (blepharoptosis) may be diagnosed by clinical evaluation, including comparison with the other eyelid (if the malformation is unilateral) or examination of the infant's upper gaze. Imaging techniques may confirm the presence of dental, skeletal, genitourinary, and/or other abnormalities associated with Lenz microphthalmia syndrome.
The treatment of Lenz microphthalmia syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; physicians who diagnose and treat diseases of the eye (ophthalmologists); dental specialists who diagnose, prevent, and/or correct abnormalities of the teeth (orthodontists); specialists who diagnose and treat skeletal abnormalities (orthopedists); and/or others may need to work together to ensure a comprehensive approach to treatment.
Specific therapies for the treatment of Lenz microphthalmia syndrome are symptomatic and supportive. In some cases, corrective glasses, contact lenses, and/or surgery may be used to help improve vision. Artificial teeth (dentures), dental implants, braces, dental surgery, and/or other corrective procedures may be undertaken to correct dental abnormalities. Sideways and front-to-back curvature of the spine (kyphoscoliosis) may be treated with a combination of exercises and physical therapy, other supportive techniques, braces, casts, and/or corrective surgery. Surgery may also be performed to correct cleft lip and palate; digital, skeletal, and/or genitourinary malformations; or other abnormalities associated with the disorder.
Early intervention is important to ensure that children with Lenz microphthalmia syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education and other medical, social, and/or vocational services.
Genetic counseling will be of benefit for affected individuals and their families. Family members of affected individuals should also receive regular clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Lenz microphthalmia syndrome or heterozygosity for the disorder. Other treatment for Lenz microphthalmia syndrome is symptomatic and supportive.
Albert Einstein Medical Center’s National Anophthalmia/Microphthalmia (A/M) Registry is assembling a national database of individuals with A/M and conducting an analysis of the registry population. Recent advances in gene research have identified several genes associated with development of the mammalian eye. This study will try to learn more about the genetic cause and conditions related to anophthalmia and microphthalmia; to better understand the conditions that may be associated with A/M; and to identify genetic mutations associated with the condition.
For further information, please contact:
Tanya M. Bardakjian, MS, CGC
Coordinator of anophthalmia/microphthalmia Research Project
Einstein Medical Center Philadelphia
5501 Old York Rd
Genetics Levy 2 West
Philadelphia, PA 19141
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
For information about clinical trials sponsored by private sources, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., visual handicaps, mental retardation, etc.].)
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