Diagnosis Clinical Diagnosis Formal diagnostic criteria do not exist. The clinical findings of Lenz microphthalmia syndrome (LMS) include: Unilateral or bilateral microphthalmia and/or anophthalmia that may be symmetric or asymmetric Anophthalmia refers to the histologic diagnosis of complete absence of the globe in the presence of ocular adnexae (eyelids, conjunctiva, and lacrimal apparatus). CT or MRI scan of the orbit shows absence of ocular tissue, optic nerve, and extraocular muscles.
Note: The term "clinical anophthalmia" should be used for severe microphthalmia when the globe is not detectable on physical examination. "Simple microphthalmia" or "pure microphthalmia" describes a globe that is reduced in total axial length (TAL), has all structural elements intact, and retains some vision. Mild simple microphthalmia can be identified by measuring the axial length of the globe with A-scan ultrasonography. Total axial length of the neonatal eye is normally near 17 mm; an age-adjusted total axial length below the fifth centile defines microphthalmia. The mean total axial length of the adult eye is 23.8 mm; a total axial length of less than 18.5 mm defines microphthalmia. Coloboma is present in approximately 60% of microphthalmic eyes [Ng et al 2002], with severity ranging from isolated iris coloboma to coloboma of the ciliary body, choroid, and optic disk. Congenital cystic eye has not been observed in LMS. Extraocular malformations that vary within and among families Hypospadias, cryptorchidism, renal aplasia/hypoplasia, hydroureter (77% of individuals) Simple, anteverted, abnormally modeled ears (63%) Abnormal shape of incisors, irregularly spaced teeth (48%) Duplicated thumbs, syndactyly, clinodactyly, camptodactyly (44%) Microcephaly (37%) Narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindrical thorax, webbed neck (26%) Cleft lip/palate (7%) Intellectual disability ranging from mild to severe (63%) Family history consistent with X-linked recessive inheritance Testing Karyotype is normal. Molecular Genetic TestingBCOR mutation p.Pro85Leu, the only mutation found in individuals with LMS to date, is identified by targeted mutation analysis. Gene. BCOR (MCOPS2 locus) is the only gene known to be associated with Lenz microphthalmia syndrome [Ng et al 2004]. Thus far, only two males with a mutation in BCOR have been identified [Ng et al 2004, Hilton et al 2009]. Evidence of locus heterogeneity. One additional locus on the X chromosome, MCOPS1, is known to be associated with LMS. Identification of the gene at Xq27-q28 (MCOPS1) in which mutation is causative has remained elusive. Graham et al [1991] mapped the gene in a family with X-linked clinical anophthalmos to Xq27-q28. The authors reported extraocular features of preauricular skin tags and cleft palate; however, they considered the disorder present in this family to be distinct from LMS. Forrester et al [2001] mapped the gene in a family with the LMS phenotype (anophthalmia, moderate-to-severe intellectual disability, delayed motor development, hypotonia, and ear, dental, digital, skeletal, cardiac, and renal abnormalities) to a 17.65-cM region in Xq27-q28. The linkage data demonstrating locus heterogeneity suggest that LMS, previously thought to be a single disorder, may actually be either:Two distinct disorders that are difficult to distinguish clinically; or A single disorder with a phenotypic spectrum caused by mutations in two different genes on the X chromosome. Clinical testing Sequencing of the entire coding region. A missense mutation, 254C>T, resulting in a change of amino acid at position 85 from proline to leucine (p.Pro85Leu) in BCOR, was found in affected males of the family used to map the MOCPS2 locus [Ng et al 2002, Ng et al 2004] and in a male reported by Hilton et al [2009]. The low frequency of BCOR mutations does not allow determination of the mutation detection frequency.Table 1. Summary of Molecular Genetic Testing Used in Lenz Microphthalmia SyndromeView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityAffected MalesCarrier FemalesBCORSequence analysisSequence variants 2UnknownUnknownClinicalExonic and whole-gene deletions0% 3Deletion / duplication analysis 4Exonic and whole-gene deletionsNot neededUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. Sequence analysis of genomic DNA cannot detect exonic or whole-gene deletions on the X chromosome in carrier females.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here. Testing StrategyTo confirm/establish the diagnosis in a male with features of LMS 1.Perform targeted sequencing for the BCOR mutation p.Pro85Leu. 2.If negative for the p.Pro85Leu mutation, consider sequencing the entire gene. Carrier testing for at-risk relativesCarriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. Identification of female carriers requires either Prior identification of the disease-causing mutation in the family; or If an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) Disorders Oculofaciocardiodental (OFCD) syndrome is also associated with mutations in BCOR [Ng et al 2004, Horn et al 2005, Oberoi et al 2005]. OFCD syndrome is inherited in an X-linked dominant pattern with male lethality. Females with OFCD syndrome may have congenital cataracts as the sole ocular manifestation or unilateral/bilateral microphthalmia with congenital cataracts. Microphthalmia is less severe in OFCD syndrome than in LMS. Extraocular features include long narrow face, broad nasal tip with separated nasal cartilage, cleft palate, submucous cleft palate, cardiac anomalies (ventricular septal defect, atrial septal defect, floppy mitral valve) and dental anomalies (retained deciduous teeth, canine radiculomegaly, root dilacerations, and oligodontia). Females with OFCD syndrome have normal intelligence, in contrast to males with LMS, who often have developmental delay/intellectual disability, microcephaly, and structural CNS abnormalities. The majority of individuals with OFCD syndrome analyzed thus far have detectable BCOR mutations [Ng et al 2004, Horn et al 2005, Hilton et al 2009]. Two BCOR deletions that encompass several exons have been observed and can be detected by targeted array CGH. Individuals with OFCD syndrome have mutations that are predicted to prematurely truncate the BCOR protein. In hemizygous males, truncating mutations are hypothesized to lead to a complete loss of BCOR function and are presumed to be lethal. Truncating BCOR mutations in females lead to haploinsufficiency and a milder phenotype. All families with OFCD syndrome have unique mutations. Based on the known cases of OFCD syndrome scanned for BCOR mutations, penetrance is complete. Three females with features of OFCD syndrome but with notable absence of dental radiculomegaly did not have identifiable BCOR mutations [Hilton et al 2009].Other. Isolated (nonsyndromic) forms of microphthalmia have been mapped to the proximal p to q arm of the X chromosome [Lehman et al 2001].}

Natural History The phenotype of Lenz microphthalmia syndrome, microphthalmia with developmental delay and skeletal and urogenital anomalies, linked to the MCOPS1 locus cannot be distinguished from the LMS phenotype caused by mutations in BCOR (MOCPS2 locus). Lenz microphthalmia syndrome has a wide spectrum of ocular and extraocular abnormalities. Eyes. The eyes may be asymmetrically affected. One globe can be of normal size while the other is microphthalmic. Severity can range from mild microphthalmia with retained vision to severe microphthalmia or clinical anophthalmia with blindness. Microphthalmia is often accompanied by microcornea and reduction in the size of the anterior segment of the eye, which predispose to the development of glaucoma. Since mild microphthalmia may not be obvious on clinical examination, individuals with LMS with retained vision may not be identified until the first ophthalmologic examination when high hyperopia (+7 to +11 diopters) secondary to a foreshortened posterior segment of the globe is diagnosed. Cataracts may be present. Nystagmus may be present secondary to impaired vision. Absence or diminished size of the globe may cause secondary underdevelopment of the bony orbits, shortened palpebral fissures, and fusion of the eyelid margins (ankyloblepharon). Craniofacial. The occurrence of congenital microcephaly is variable. Affected individuals may be normocephalic or dolichocephalic. Ears may be low set, anteverted, posteriorly rotated, simple, cup shaped, or abnormally modeled. Preauricular tags may be present. Hearing loss has been observed. Cleft lip/palate or high arched palate is present in approximately 40% of individuals [Ng et al 2002]. Dental development may be delayed. Nonspecific dental findings include irregularly shaped, missing, or widely spaced teeth. Genitourinary. Urogenital anomalies are the most frequent associated findings, reported in approximately 77% of individuals [Ng et al 2002]. These include hypospadias, cryptorchidism, renal hypoplasia/aplasia, and hydroureter. Limbs. Hand findings include duplicated and/or proximally placed thumbs, cutaneous syndactyly, clinodactyly, and camptodactyly. Skeletal. Long cylindrical thorax with sloping, narrow shoulders, underdeveloped clavicles, or thinning of the lateral third of the clavicles on x-ray as well as kyphoscoliosis and exaggerated lumbar lordosis have been seen in some families. Cognitive/neurologic. Cognitive impairment varies within and among families. Approximately 60% of affected males have mild-to-severe intellectual disability or developmental delay [Ng et al 2002]. Motor development may be delayed. Seizures, behavioral disturbance, and self-mutilation may manifest in males with severe intellectual disability. Sleep-wake cycles can be disturbed because of lack of normal diurnal variation. Cranial MRI often reveals absent or hypoplastic optic nerves and optic chiasm. In addition, hypoplasia of the corpus callosum and cingulate gyrus has been noted. The latter is often clinically silent.

Genotype-Phenotype Correlations No genotype-phenotype correlations are known. Both males reported with LMS and a BCOR mutation had the p.Pro85Leu mutation; however, the second reported male exhibited radioulnar synostosis, which occurs in 32% of those with oculofaciocardiodental (OFCD) syndrome (see Genetically Related Disorders). Thus, the presence of radioulnar synostosis in a male with LMS may indicate the presence of a BCOR mutation [Hilton et al 2009].

Differential Diagnosis See Anophthalmia/Microphthalmia Overview.

Management Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Lenz microphthalmia syndrome (LMS), the following evaluations are recommended: Physical examination for the presence of anomalies associated with the disorder Cranial MRI to estimate the size of the globes for prognosis regarding potential visual function and to detect concurrent CNS malformations such as hypoplastic corpus callosum and cingulate gyrus Visual evoked response testing and ophthalmologic examination to help determine visual acuity and/or the potential for vision Renal ultrasound examination to evaluate for renal aplasia, hypoplasia, and hydroureter Consideration of hearing evaluation during infancy if: Head and neck examination reveals malformations of the auricle or ear canal, presence of skin tags or dimples around the ear, presence of cleft lip or palate, asymmetric facies, and microcephaly; The parents have concerns that the child cannot hear (i.e., infant does not startle to loud noises, awaken to sound, etc). The type of examination should be adjusted for the individual's cognitive level to allow for cooperation and maximize the chance of an informative test (see Deafness and Hereditary Hearing Loss Overview). Consideration of sleep evaluation if parents report excessive daytime somnolence, altered sleep-wake cycles, difficulty awakening the child or getting the child to fall asleep, apnea, loud snoring, and/or difficulty breathing while asleep Treatment of Manifestations Individuals with anophthalmos or extreme microphthalmos benefit from regular evaluations by an ocularist for placement of serial enlarging orbital expanders to prevent deformation of facial structures and to encourage normal development of eye lashes and lid margins. Early intervention with physical therapy and occupational therapy helps to address disturbances of the sleep-wake cycle caused by lack of light perception and problems of delayed gross motor development often observed in children with visual impairment. Early intervention with special education maximizes cognitive development. Referral to services for the blind is recommended. Treatment for hearing loss and sleep disorders is dependent on the specific defect and similar to the general population. Referral to a sleep disorder specialist may be necessary depending on the individual's history and presentation to determine the appropriate tests. Dental examinations and cleaning should be instituted to monitor dental hygiene, especially when the affected individual has cognitive developmental delay. Missing and irregularly shaped teeth and wide spacing of teeth are common. Treatment is the same as for the general population in restoring masticatory function. Prevention of Secondary Complications If cardiac valvular abnormalities are present, antibiotic prophylaxis prior to dental care and specific medical procedures is necessary as for the general population. SurveillanceThe following are appropriate:Annual ophthalmologic examination for those with residual vision given the predisposition to glaucoma and high hyperopia from foreshortening of the globe Monitoring of renal function (BUN, creatinine, and urine analysis) in those with known renal/ureteral anomalies Developmental assessments performed with each well-child visit as recommended by the American Academy of Pediatrics. More frequent and specialized assessments are tailored to each child if development is not on track. Lifelong case management to help affected individuals gain access to social services and assistive devices for the blind. Agents/Circumstances to Avoid In those with residual vision, dilating drops and medications that may dilate the pupils (i.e., antihistamines, decongestants, tricyclic antidepressants) should be used in consultation with an ophthalmologist, because of the narrow anterior chamber and risk for angle closure glaucoma. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Therapies Under Investigation Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Lenz Microphthalmia Syndrome: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMCOPS1UnknownXq27-q28Unknown MCOPS2BCORXp11​.4BCL-6 corepressorBCOR @ LOVDBCORData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Lenz Microphthalmia Syndrome (View All in OMIM) View in own window 300166MICROPHTHALMIA, SYNDROMIC 2; MCOPS2 300485BCL6 COREPRESSOR; BCOR 309800MICROPHTHALMIA, SYNDROMIC 1; MCOPS1Normal allelic variants. BCOR extends over approximately 55 kb and includes 15 exons. The reference cDNA for BCOR isoform 1 is 6182 bp (NM_017745). The open reading frame is 5163 bp. BCOR isoform 2 is 3676 bp. BCOR long isoform, alternatively spliced is 5810 bp (AY316592.1). Pathologic allelic variants. Two mutations have been reported in individuals with LMS (MCOPS2) 254C>T (p.Pro85Leu) [Ng et al 2004, Hilton et al 2009]. Normal gene product. BCOR isoform 1 encodes a protein of 1721amino acids. BCOR isoform 2 encodes a protein of 1004 amino acids. BCOR long isoform, alternatively spliced encodes a protein of 1755 amino acids. Abnormal gene product. The p.Pro85Leu mutation is expressed and results in perturbation of ocular and extraocular organ development. Truncated and abnormally spiced variants of BCOR have not been detected in individuals with OFCD syndrome and are hypothesized to be eliminated by nonsense-mediated mRNA decay.