Clinical Diagnosis

The phenotypic spectrum of MED12-related disorders, which is currently being defined, includes at a minimum the phenotypes associated with FG syndrome type 1 (FGS1) and Lujan syndrome (LS). The diagnosis of MED12-related disorders relies on Molecular Genetic Testing.

FG syndrome type 1 (FGS1). The phenotype of individuals with the recurrent MED12 mutation p.Arg961Trp can be recognized by the presence of six of the following eight clinical features [Risheg et al 2007, Lyons et al 2009]:

• Intellectual disability
• Hypotonia
• Constipation and/or anal anomalies
• Small and simple ears
• Tall and prominent forehead
• Downslanting palpebral fissures
• Broad thumbs and halluces
• Abnormalities of the corpus callosum

Additional clinical features that are helpful in identification of individuals with FGS1:

• Characteristic behavior (friendly, hyperactive, attention-seeking)
• Frontal hair upsweep
• Relative macrocephaly
• Ocular hypertelorism
• Family history consistent with X-linked inheritance

Lujan syndrome. The phenotype of individuals with the recurrent MED12 mutation p.Asn1007Ser can be recognized by the presence of six of the following eight clinical features:

• Intellectual disability
• Hypotonia
• Large head (occipitofrontal head circumference >75th percentile)
• Tall, thin body habitus (height >75th percentile)
• Long, thin face
• High nasal root
• High, narrow palate
• Short philtrum

Additional clinical features that can assist in recognition of individuals with LS:

• Hypernasal speech
• Micrognathia
• Long hands
• Hyperextensible digits
• Abnormalities of the corpus callosum
• Family history consistent with X-linked inheritance

Molecular Genetic Testing

Gene. A recurrent p.Arg961Trp mutation in MED12 is the only known molecular cause of FGS1 [Risheg et al 2007]. The only known cause of LS is the MED12 mutation p.Asn1007Ser [Schwartz et al 2007].

Clinical testing

• Sequencing of select exons and targeted mutation analysis
  • Individuals with FGS1 have a recurrent p.Arg961Trp mutation in exon 21 of MED12. The published mutation detection frequency in individuals clinically diagnosed with FGS is approximately 13% [Risheg et al 2007] (see Differential Diagnosis). However, subsequent data from laboratory specimens of individuals clinically diagnosed with FGS have yielded a much lower mutation detection frequency [M Friez, personal communication], most likely because of the broad range of clinical features that have been associated with FGS.
  • The p.Asn1007Ser mutation in exon 22 of MED12 has been identified in families with LS [Schwartz et al 2007]. The mutation detection frequency in individuals clinically diagnosed with LS is unknown.
• Sequence analysis of the coding region. Full sequencing of all 45 exons of the MED12 cDNA is clinically available. However, full sequencing has not been a proven mechanism for identifying novel mutations in MED12.

Table 1. Summary of Molecular Genetic Testing Used in MED12-Related Disorders

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Gene Symbol	Phenotype	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method and Phenotype 1,2	Test Availability
MED12	FGS1	Sequence analysis	p.Arg961Trp and other sequence variants 3	Unknown 4	Clinical
		Sequence analysis of select exons 4,5	p.Arg961Trp and other sequence variants in selected exon 21	Unknown
		Targeted mutation analysis	p.Arg961Trp
	LS	Sequence analysis	p.Asn1007Ser and other sequence variants 3	Unknown 4
		Sequence analysis of select exons 5, 6	p.Asn1007Ser and other sequence variants 3 in selected exon 22	Unknown

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Because MED12 testing is at an early stage, the mutation detection frequency for these phenotypes is unknown [M Lyons, personal communication].

3. 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.

4. Sequencing of the entire coding region is clinically available but has not identified any additional mutations associated with these two phenotypes [M Friez, personal communication].

5. Sequencing of select exons 21and 22

6. Exons sequenced may vary by laboratory.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Establishing the diagnosis in a proband

Individuals with an FGS1 or LS phenotype should have targeted mutation analysis of exons 20 and 21. Such testing will detect MED12 mutation p.Arg961Trp in exon 21 and p.Asn1007Ser in exon 22. If no mutation is identified, full sequencing of the remaining 43 exons could be considered. However, the mutation detection rate is low for individuals clinically diagnosed with FGS or LS who do not have a distinct phenotype associated with the specific mutations in MED12 [M Friez, personal communication].

If a mutation in MED12 is not identified, further genetic testing is recommended to search for an alternative diagnosis (see Differential Diagnosis).

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: Carriers are heterozygotes for these X-linked disorders and could develop clinical findings related to the disorders.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No phenotypes other than FGS1 and LS are currently known to be associated with mutations in MED12.

Natural History

Genotype-Phenotype Correlations

FG syndrome type 1 (FGS1). The only gene mutation identified in individuals with FGS1 is the recurrent p.Arg961Trp mutation in MED12 [Risheg et al 2007]. A recognizable phenotype is associated with this mutation [Lyons et al 2009].

Lujan syndrome (LS). Two families with LS were reported to have a p.Asn1007Ser missense mutation in MED12 [Schwartz et al 2007].

Penetrance

Penetrance is presumed to be 100% in males with p.Arg961Trp and p.Asn1007Ser MED12 mutations. The p.Arg961Trp and p.Asn1007Ser MED12 mutations have not been reported in normal males.

Nomenclature

The name FG syndrome represents two surname initials in the family initially described by Opitz and Kaveggia [1974].

Prevalence

The prevalence of FGS is unknown. Clinically diagnosed FGS has been described as a common disorder [Battaglia et al 2006], but numerous nonspecific findings have led to over-diagnosis.

The prevalence of LS is unknown.

FG Syndrome (FGS)

FGS can be a difficult clinical diagnosis because of the broadening of the phenotype since its initial description by Opitz and Kaveggia [1974].

Individuals reported to have FGS have been linked to four additional loci on the X chromosome:

• FGS2 (linked to Xq28) (OMIM 300321) [Briault et al 1999, Briault et al 2000]
• FGS3 (linked to Xp22.3) (OMIM 300406) [Dessay et al 2002]
• FGS4 (linked to Xp11.4-p11.3) (OMIM 300422) [Piluso et al 2003]
• FGS5 (linked to Xq22.3) (OMIM 300581) [Jehee et al 2005]

However, identification of the underlying molecular etiology has been difficult because of the wide range of features reported in individuals clinically diagnosed with FGS. Various alternative diagnoses have been detected, most commonly by chromosome analysis or comparative genomic hybridization (CGH) microarray analysis [Lyons et al 2009].

Mutations in the following genes have been reported in individuals clinically diagnosed with FGS [Piussan et al 1996, De Vries et al 2000, Piluso et al 2007, Tarpey et al 2007, Unger et al 2007, Lyons et al 2009]:

• FMR1 (fragile X syndrome)
• FLNA (FLNA-related disorders)
• UPF3B
• CASK
• MECP2 (MECP2-related disorders)
• ATRX (ATRX syndrome)

Thus, further genetic testing, including FMR1 molecular analysis, chromosome analysis, and CGH microarray analysis, should be considered in individuals with features of FGS who have normal MED12 testing.

Disorders with common clinical features include the following:

• Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome. Ocular hypertelorism, genitourinary anomalies, hypotonia, and intellectual disability are features of ATRX syndrome that can also be seen in FGS. Individuals with ATRX syndrome have characteristic craniofacial features including microcephaly, small nose, tented upper lip, prominent lower lip, and coarsening of facial features. The only gene associated with ATRX syndrome is ATRX (XNP).
• Coffin-Lowry syndrome (CLS) and FGS are X-linked intellectual disability syndromes with common craniofacial features including broad forehead, ocular hypertelorism, and downslanting palpebral fissures. Individuals with FGS can be distinguished by the presence of small and simple ears, relative macrocephaly, constipation with or without anal anomalies, and broad thumbs and halluces. The only gene associated with CLS is RPS6KA3 (RSK2).
• Fragile X syndrome (FXS) findings commonly found in individuals with FGS include large occipitofrontal head circumference, prominent forehead, hypotonia, and intellectual disability. FXS is associated with large ears whereas FGS is distinguished by small and simple ears. In addition, individuals with FGS commonly have constipation with or without anal anomalies. FXS is caused by a loss-of-function mutation in FMR1 that most commonly results from an expansion of CGG trinucleotide repeats.
• 22q13.3 deletion syndrome. Common features seen in both FGS and 22q13.3 deletion syndrome include hypotonia, intellectual disability, and delayed speech. FGS can be distinguished by the presence of constipation, small and simple ears, and characteristic behavior. 22q13 deletion syndrome can often be detected by chromosome analysis but may require further testing (e.g., FISH).
• Mowat-Wilson syndrome (MWS). Features seen in both MWS and FGS include constipation, abnormalities of the corpus callosum, ocular hypertelorism, and intellectual disability. Individuals with MWS have characteristic facial features distinct from FGS including prominent chin, prominent columella, and uplifted earlobes with a central depression. In addition, microcephaly is associated with MWS whereas relative macrocephaly is commonly described in individuals with FGS. MWS is caused by mutations and deletions in ZEB2.
• X-linked Opitz G/BBB syndrome. Ocular hypertelorism and genitourinary abnormalities, including hypospadias and cryptorchidism, are commonly associated with X-linked Opitz G/BBB syndrome. Imperforate anus, abnormalities of the corpus callosum, and congenital heart defects are also relatively common. Intellectual disability is seen in only about half of affected males. Craniofacial features associated with FGS help distinguish the two conditions. MID1 is the only gene associated with X-linked Opitz G/BBB syndrome.
• Rubinstein-Taybi syndrome (RSTS). Broad thumbs and halluces, downslanting palpebral fissures, and intellectual disability are commonly associated with RSTS and FGS. Individuals with FGS often have thumbs and halluces that are broad, but not angulated as in RSTS. RSTS is more commonly associated with microcephaly as opposed to the relative macrocephaly described in FGS. The craniofacial features and head size of FGS are distinct from RSTS and should allow clinical differentiation. CREBBP and EP300 are the only genes associated with RSTS.
• Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly but can be associated with broad thumbs and halluces. In addition, ocular hypertelorism and macrocephaly are common. The head circumference is typically greater than the 97th percentile, which is uncommon in individuals with FGS [Risheg et al 2007]. Intellectual disability is uncommon in GCPS. Other craniofacial features of FGS, including small and simple ears, are not associated with GCPS. GLI3 is the only gene associated with GCPS.
• Townes-Brocks syndrome (TBS) is characterized by imperforate anus, dysplastic ears, and thumb malformations. Congenital heart defects and genitourinary anomalies are commonly described. Intellectual disability is uncommon. Craniofacial features of FGS are distinct from TBS and should allow clinical differentiation. The only gene associated with TBS is SALL1.

Lujan Syndrome (LS)

LS was clinically diagnosed in an individual with a terminal deletion of chromosome 5p [Stathopulu et al 2003].

Disorders with common clinical features include the following:

• Marfan syndrome (MS). Individuals with LS have been described as having a Marfanoid habitus as they may have musculoskeletal features overlapping MS: tall and thin habitus, long hands and fingers, pectus excavatum, narrow palate with dental crowding, and joint hypermobility. LS can be distinguished from MS by the presence of intellectual disability and the absence of significant heart and eye involvement characteristic of MS. The only gene associated with MS is FBN1. Inheritance is autosomal dominant.
• Homocystinuria. Individuals with homocystinuria have features that overlap LS: intellectual disability, tall and thin habitus, pectus deformity, and high arched palate. Ectopia lentis is a characteristic feature of homocystinuria not found in individuals with LS. Homocystinuria is caused by mutations in CBS. Inheritance is autosomal recessive.
• Loeys-Dietz syndrome (LDS) and LS have overlapping features including long face, high arched plate, micrognathia, and pectus deformity. Learning disability has also been described in LDS. LDS has a number of distinguishing features including cleft palate, bifid uvula, hydrocephalus, arterial tortuosity and aneurysms, and easy bruising. LDS is caused by mutations in TGFBR1 or TGFBR2 [Loeys et al 2005]. Inheritance is autosomal dominant.
• Shprintzen-Goldberg syndrome (SGS) and LS are both associated with intellectual disability, pectus deformity, and high arched palate. SGS is associated with craniosynostosis, which has not been described in LS. Although mutations in FBN1 and TGFBR2 have been reported in a minority of individuals with clinically diagnosed SGS [Kosaki et al 2006, van Steensel et al 2008], the underlying cause is unknown. The mode of inheritance is unknown.
• Fragile X syndrome (FXS) findings commonly found in individuals with LS include large occipitofrontal head circumference, prominent forehead, hypotonia, and intellectual disability. FXS is caused by a loss-of-function mutation in FMR1 that most commonly results from an expansion of CGG trinucleotide repeats. Inheritance is X-linked.
• Snyder-Robinson syndrome (SRS) is characterized by intellectual disability, hypotonia, thin habitus, narrow palate, and nasal speech. Affected individuals have an unsteady gait and movement disorder that is not associated with LS. SRS is caused by mutations in SMS [Cason et al 2003]. Inheritance is X-linked.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with FG syndrome type 1 (FGS1) or Lujan syndrome (LS), the following are recommended:

• Measurement of height, weight, and head circumference
• Developmental and behavioral assessment
• Examination for evidence of genitourinary anomalies
• Examination for evidence of anal anomalies in individuals with FGS1
• Cardiac evaluation with echocardiogram
• Neurologic history and examination for evidence of seizures and hypotonia
• Evaluation for evidence of spasticity in individuals with FGS1
• Consider brain imaging studies
• Ophthalmologic evaluation for evidence of abnormalities including strabismus and visual deficits

Treatment of Manifestations

The following measures are appropriate:

• Early individualized education planning and therapies, including physical therapy, occupational therapy, and speech therapy
• Individualized management of behavior problems
• Neurologic management of seizures and consideration of need for further testing (e.g., EEG, brain MRI)
• Standard management of chronic constipation for individuals with FGS1
• Ophthalmologic management of strabismus and other ocular anomalies, if present
• Surgical intervention for imperforate anus, congenital heart defects, and other major malformations, if needed

Prevention of Secondary Complications

Physical therapy can help prevent and manage joint contractures for individuals with FGS1.

Surveillance

The following are appropriate:

• Growth parameters followed on a regular basis and plotted on age-appropriate curves
• Regular follow-up to monitor developmental progress, behavior issues, gastrointestinal issues, and neurologic issues
• Annual ophthalmologic evaluation for evidence of strabismus and any visual issues

Evaluation of Relatives at Risk

See 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

MED12-related disorders are inherited in an X-linked manner.

Risk to Family Members

Parents of the proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
• If a woman has more than one son with a MED12 mutation and the disease-causing mutation cannot be detected in her DNA, she may have germline mosaicism. Germline mosaicism has not been described in the mothers of individuals with a MED12 mutation.
• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation, in which case the mother is not a carrier. The frequency of de novo mutations is unknown.
• When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo disease-causing mutation in MED12 and his mother is not a carrier.
  • His mother has a de novo disease-causing mutation in MED12 either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only).
  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Sibs of the proband

• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.
• If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of the proband. No male with a MED12-related disorder has reproduced.

Other family members of the proband. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the disease-causing mutation has been identified in the family.

Related Genetic Counseling Issues

Assisted reproduction technologies (ART). Donor eggs may be utilized by carrier females to avoid the risk of transmitting a MED12 mutation.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

If the MED12 mutation has been identified in a family member, prenatal testing is possible for pregnancies at increased risk. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Suggested Reading

1. Van Buggenhout G, Fryns JP. Lujan-Fryns syndrome (mental retardation, X-linked, marfanoid habitus). Orphanet J Rare Dis. 2006;1:26–9. [PMC free article: PMC1538574] [PubMed: 16831221]

Author Notes

Web site: www.ggc.org

Acknowledgments

The author would like to thank Drs Roger Stevenson and Michael Friez for their critical review of the manuscript.

Revision History

• 14 July 2009 (cd) Revision: targeted mutation analysis for p.Arg961Trp mutation available clinically
• 23 June 2008 (me) Posted live
• 25 April 2008 (mjl) Original submission