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MED12-Related Disorders

, MD, FAAP, FACMG
Assistant Clinical Geneticist
Greenwood Genetic Center
Charleston, South Carolina

Initial Posting: ; Last Update: June 6, 2013.

Summary

Disease characteristics. The phenotypic spectrum of MED12-related disorders, which is still being defined, includes at a minimum the phenotypes of FG syndrome type 1 (FGS1) and Lujan syndrome (LS). FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, high nasal root, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected.

Diagnosis/testing. The diagnosis of MED12-related disorders relies on molecular genetic testing for common MED12 mutations by sequence analysis of select exons or targeted mutation analysis, followed by sequence analysis of the entire gene as indicated.

Management. Treatment of manifestations: Early individualized education; physical therapy, occupational therapy, and speech therapy for developmental delays; routine management of behavior problems, seizures, strabismus and other ocular anomalies, congenital heart defects, chronic constipation, and imperforate anus.

Surveillance: Routine follow-up of growth, psychomotor development, and behavior; routine attention to gastrointestinal functioning and neurologic findings; annual eye examination.

Genetic counseling. MED12-related disorders are inherited in an X-linked manner. If the mother of a proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected. No male with a MED12-related disorder has reproduced. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family has been identified.

GeneReview Scope

MED12-Related Disorders: Included Disorders
  • FG syndrome type 1
  • Lujan syndrome

For synonyms and outdated names see Nomenclature.

Diagnosis

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). All individuals with FGS1 have been males with neurodevelopmental delays [Clark et al 2009]. A family history consistent with X-linked inheritance is identified in the majority of individuals with FGS1 [Clark et al 2009].

Formal clinical diagnostic criteria for FGS1 have not been established; however, the following clinical features would be suggestive:

  • Small ears (≤10th percentile)
  • Characteristic facial features (dolichocephaly, tall forehead, downslanted palpebral fissures, puffy eyelids, long narrow face, and open mouth)
  • Congenital anomaly (corpus callosum, anal, cardiac, skeletal) in proband or maternally related affected male
  • Absolute or relative macrocephaly
  • Hypotonia, constipation, or feeding problems
  • Characteristic behavior (affable and eager to please)

Additional clinical features helpful in identification of individuals with FGS1:

  • Frontal hair upsweep
  • Widely spaced eyes
  • Broad thumbs and halluces

Lujan syndrome (LS). 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
  • Prominent nasal bridge
  • 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 most common molecular cause of FGS1 [Risheg et al 2007]. In addition, a novel p.Gly958Glu mutation in MED12 was identified in three male cousins with clinical features of FGS1 [Rump et al 2011]. The only known cause of LS is the MED12 mutation p.Asn1007Ser [Schwartz et al 2007].

Clinical testing

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

Gene 1PhenotypeTest MethodMutations Detected 2Mutation Detection Frequency by Test Method and Phenotype 3, 4
MED12FGS1Sequence analysis 5p.Arg961Trp and other sequence variants 6, 7Unknown 8
Sequence analysis of select exons 5, 8p.Arg961Trp and other sequence variants in selected exon 21 7Unknown
Targeted mutation analysis p.Arg961Trp 7,9
Deletion/duplication analysis 10UnknownUnknown; none reported 11
LSSequence analysis 5p.Asn1007Ser and other sequence variants 6, 12Unknown 8
Sequence analysis of select exons 5, 13p.Asn1007Ser and other sequence variants in selected exon 22 7Unknown
Deletion/duplication analysis 10UnknownUnknown; none reported 11

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

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

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

6. Full sequencing of all 45 exons of the MED12 cDNA is possible. However, full sequencing has not been a proven mechanism for identifying novel mutations in MED12.

7. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic, multiexonic, or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

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

9. Individuals with FGS1 typically 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.

10. 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.

11. No deletions or duplications of MED12 have been reported to cause MED12-related disorders.

12. The p.Asn1007Ser mutation in exon 22 of MED12 has been identified in families with LS [Schwartz et al 2007].

13. Exons sequenced may vary by laboratory.

Testing Strategy

To confirm/establish the diagnosis in a proband. To guide the decision to pursue molecular testing of MED12 in individuals with clinical features of FG syndrome, Clark et al [2009] developed an algorithm using the following five clinical features:

  • Small ears (≤10th percentile)
  • Characteristic facial features (dolichocephaly, tall forehead, frontal hair upsweep, downslanted palpebral fissures, puffy eyelids, long narrow face, and open mouth)
  • Congenital anomaly (corpus callosum, anal, cardiac, skeletal) in proband or maternally related affected male
  • Absolute or relative macrocephaly
  • Hypotonia, constipation, or feeding problems

For a male younger than age five years:

  • In the absence of a known family history, all five characteristics should be present.
  • If there is a family history suggestive of X-linked inheritance, four of the five criteria should be met.

For a male over age five years:

  • In the absence of a known family history, all five characteristics should be present in addition to characteristic behaviors (affable and eager to please).
  • If there is a family history suggestive of X-linked inheritance, four of the five criteria should be met in addition to characteristic behaviors (affable and eager to please).

Once a decision is made to pursue molecular genetic testing, the following testing strategy may be employed:

1.

Individuals with an FGS1 or LS phenotype should have targeted mutation analysis of exons 21 and 22. Such testing will detect MED12 mutations p.Arg961Trp and p.Gly958Glu in exon 21 and p.Asn1007Ser in exon 22.

2.

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].

3.

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 and preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

FG Syndrome Type 1 (FGS1)

FGS was initially described by Opitz & Kaveggia [1974] as a rare X-linked disorder associated with intellectual disability, hypotonia, relative macrocephaly, broad and flat thumbs, and imperforate anus. The clinical phenotype attributed to FGS has widened since that initial description. Many of the clinical features in individuals reported to have FGS are nonspecific and may lead to overdiagnosis. A recurrent p.Arg961Trp mutation in MED12 has been reported in ten families with FGS, including the original family described by Opitz and Kaveggia [Clark et al 2009]. A distinct phenotype, termed FGS1, has been identified in individuals with the recurrent p.Arg961Trp MED12 mutation [Clark et al 2009, Lyons et al 2009]. In addition, three male cousins with clinical features of FGS1 were found to have a p.Gly958Glu mutation in MED12 [Rump et al 2011].

Craniofacial. The most characteristic craniofacial feature is small, simple ears. Other common craniofacial features in individuals with FGS1 include tall forehead, dolichocephaly, downslanted palpebral fissures, widely spaced eyes, and frontal hair upsweep [Risheg et al 2007, Clark et al 2009, Lyons et al 2009]. High-arched palate, micrognathia, open mouth, narrow auditory canals, puffy eyelids, and craniosynostosis have also been described in individuals with FGS1 [Opitz & Kaveggia 1974, Graham et al 1998, Clark et al 2009].

Growth. Absolute or relative macrocephaly is frequently associated with FGS1 [Clark et al 2009]. Although most affected individuals have normal height, short stature is not uncommon [Clark et al 2009]. Most individuals with FGS1 have an occipitofrontal head circumference percentile greater than height percentile [Risheg et al 2007]. Individuals with FGS1 occasionally have had failure to thrive [Opitz & Kaveggia 1974, Graham et al 1998].

Development. Although mild to severe cognitive impairment has been reported in the majority of individuals with FGS1, an affected individual may have a borderline to low-normal IQ if other family members have an average to above-average IQ [Clark et al 2009].

Behavior. Characteristic behavior consisting of a hyperactive, friendly, and attention-seeking personality was previously reported in individuals clinically diagnosed with FGS [Graham et al 1999]. Behavior abnormalities are commonly found in individuals with FGS1 [Risheg et al 2007, Graham et al 2008, Graham et al 2010]. Problems with expressive language can contribute to behavior issues including aggression, inattention, and anxiety [Graham et al 1999, Graham et al 2008, Graham et al 2010].

Central nervous system. Hypotonia has been described in the majority of affected individuals [Clark et al 2009]. Progression to spasticity with joint contractures can occur [Graham et al 1999].

Seizures and EEG abnormalities have been described in individuals with FGS1 [Risheg et al 2007].

A number of brain MRI abnormalities have been reported in individuals clinically diagnosed with FGS [Battaglia et al 2006]. The most common brain MRI finding in individuals with FGS1 is partial or complete agenesis of the corpus callosum [Risheg et al 2007, Clark et al 2009].

Tethered spinal cord and Chiari I malformation have been reported in individuals clinically diagnosed with FGS [Gottfried et al 2005, Wang et al 2005, Battaglia et al 2006]. A tethered cord was identified in one individual with the recurrent p.Arg961Trp mutation in MED12 [Clark et al 2009].

Ophthalmologic. Strabismus is relatively common in individuals with FGS1. Large corneas, optic atrophy, nystagmus, cataract, coloboma, phthisis bulbi, retinal detachment, and decreased visual acuity have also been reported [Opitz & Kaveggia 1974, Graham et al 1998, Clark et al 2009].

Gastrointestinal. Constipation, feeding problems in infancy, and gastroesophageal reflux disease are commonly associated with FGS1 [Clark et al 2009]. Anal anomalies are a frequent finding in individuals with FGS1 and can include imperforate anus, anal stenosis, anal fistula, and anteriorly displaced anus [Opitz & Kaveggia 1974, Graham et al 1998, Risheg et al 2007, Clark et al 2009]. Pyloric stenosis and megacolon have also been identified in individuals with FGS1 [Opitz & Kaveggia 1974, Clark et al 2009].

Genitourinary. Cryptorchidism and inguinal hernia are relatively common in individuals with FGS1 [Risheg et al 2007, Clark et al 2009]. Renal cysts and renal stones are less commonly reported in FGS1 [Clark et al 2009]. Hypospadias has been reported in individuals clinically diagnosed with FGS but has not been identified in those with molecularly confirmed FGS1 [Risheg et al 2007].

Musculoskeletal. The most characteristic musculoskeletal feature is broad thumbs and halluces. The thumbs are typically wide and flat. Single transverse palmar creases and short hands and fingers have been less commonly observed in affected individuals [Risheg et al 2007]. Fetal pads on the fingers and toes have been described in individuals clinically diagnosed with FGS and have been identified in two individuals with FGS1 [Clark et al 2009, Lyons et al 2009]. Fingernails have been described as distally adherent to the soft tissue.

Other musculoskeletal features described in individuals with FGS1 include: cutaneous syndactyly, oligodactyly, joint hypermobility, joint contractures, limited elbow supination, ectrodactyly, clinodactyly, duplicated thumbs and halluces, spinal curvature, pectus excavatum, rib anomalies, and hip dysplasia [Opitz & Kaveggia 1974, Graham et al 1998, Clark et al 2009].

Cardiopulmonary. Congenital heart defects were identified in approximately 60% of individuals with FGS1 [Clark et al 2009]. Septal defects are most commonly reported [Opitz & Kaveggia 1974, Graham et al 1998, Graham et al 2008, Clark et al 2009]. Other cardiac features described in individuals with FGS1 include: atrioventricular canal defect, hypoplastic left heart, mitral valve prolapse, pulmonary artery hypertension, and patent ductus arteriosus [Opitz & Kaveggia 1974, Graham et al 1998, Graham et al 2008, Clark et al 2009].

Recurrent upper-respiratory infections were reported in individuals from the original FGS1 family described by Opitz & Kaveggia [1974].

Morbidity and mortality. Early mortality can occur as a result of significant cardiac malformations, pulmonary complications, or gastrointestinal malformations [Opitz & Kaveggia 1974, Graham et al 1998]. Long-term survival has been reported and several individuals with FGS1 have survived beyond age 50 years [Clark et al 2009].

Heterozygous females. Carrier females in families clinically diagnosed with FGS have been reported to have manifestations [Graham et al 1998, Battaglia et al 2006]. However, carrier females in families with FGS1 are typically unaffected [Clark et al 2009]. X-chromosome inactivation ratios in females from six families with FGS1 caused by the p.Arg961Trp MED12 mutation were markedly skewed in three families, moderately skewed in one family, and randomly inactivated in two families [Risheg et al 2007].

Lujan Syndrome (LS)

A p.Asn1007Ser missense mutation in MED12 has been reported in two families with LS, including the original family described by Lujan et al [1984]. One individual with the p.Asn1007Ser mutation was originally diagnosed with FGS [Schwartz et al 2007]. A number of LS features (including intellectual disability, hypotonia, and dysgenesis of the corpus callosum) overlap with FGS1 [Schwartz et al 2007].

Features of LS that distinguish it from FGS1 include tall and thin habitus, prominent nasal bridge, high narrow palate, and short philtrum. Prior to the recognition that LS and FGS1 are allelic, LS was not felt to be in the differential diagnosis of FGS [Schwartz et al 2007].

Craniofacial. Individuals with LS characteristically have a tall narrow face, prominent nasal bridge, malar flattening, short philtrum, high narrow palate, dental crowding, and micrognathia. Hypotelorism is a relatively common finding. Other reported features include: dolichocephaly, prominent forehead, downslanted palpebral fissures, ptosis, narrow nose, open mouth, double row of teeth, and abnormal ears [Lujan et al 1984, Schwartz et al 2007].

Growth. A large occipitofrontal head circumference (>75th percentile) has been reported in most individuals with LS. Affected individuals are typically tall and thin with height greater than 75th percentile. Individuals with LS have been described as having a Marfanoid appearance. However, the arm span percentile was not significantly greater than the height percentile in individuals with the p.Asn1007Ser mutation [Schwartz et al 2007].

Development. Most individuals with LS have mild-moderate intellectual disability. Affected individuals with an IQ above 70 have been reported. Speech is often hypernasal [Schwartz et al 2007].

Behavior. Individuals with LS are commonly hyperactive, aggressive, shy, and attention-seeking. Asperger syndrome has been diagnosed in one individual with LS [Schwartz et al 2007]. Psychotic disorders have been described in individuals clinically diagnosed with LS [Lerma-Carrillo et al 2006].

Central nervous system. Hypotonia is a characteristic feature of LS. In addition, abnormalities of the corpus callosum and seizures have been reported [Schwartz et al 2007].

Ophthalmologic. Strabismus has been identified in individuals with LS [Schwartz et al 2007].

Musculoskeletal. Long hands, long fingers, and hyperextensible digits are common in LS. Broad thumbs, pectus excavatum, long second toe, pes planus, and contractures have also been reported [Schwartz et al 2007].

Genitourinary. Small testes, large testes, and varicoceles have been reported in individuals with LS [Schwartz et al 2007].

Cardiopulmonary. Atrial septal defect was identified in an individual with LS reported by Lujan et al [1984]. Aortic root dilation and ventricular septal defect were reported in an individual and his maternal uncle who were clinically diagnosed with LS [Wittine et al 1999].

Heterozygous females. Carrier females in families with LS caused by the p.Asn1007Ser mutation are typically unaffected. X-chromosome inactivation studies did not detect significant skewing [Schwartz et al 2007].

Genotype-Phenotype Correlations

FG syndrome type 1 (FGS1). The most common gene mutation identified in individuals with FGS1 is the recurrent p.Arg961Trp mutation in MED12 [Risheg et al 2007]. In addition, three male cousins with clinical features of FGS1 have been found to have a p.Gly958Glu mutation in MED12 [Rump et al 2011]. A recognizable phenotype is associated with these mutations [Lyons et al 2009, Clark et al 2009, Rump et al 2011].

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, p.Gly958Glu, and p.Asn1007Ser MED12 mutations. The p.Arg961Trp, p.Gly958Glu, 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 & Kaveggia [1974]. FG syndrome type 1 is also referred to as Opitz-Kaveggia syndrome. Lujan syndrome is also referred to as Lujan-Fryns syndrome or mental retardation, X-linked, with marfanoid habitus.

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.

Differential Diagnosis

FG Syndrome (FGS)

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

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

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 chromosomal microarray analysis (CMA) [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]:

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

Disorders with overlapping clinical features include the following:

  • Alpha-thalassemia X-linked mental retardation (ATRX) syndrome. Widely spaced eyes, 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, widely spaced eyes, and downslanted 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 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, CMA).
  • Mowat-Wilson syndrome (MWS). Features seen in both MWS and FGS include constipation, abnormalities of the corpus callosum, widely spaced eyes, 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 absolute or relative macrocephaly is commonly described in individuals with FGS. MWS is caused by mutations or deletions in ZEB2.
  • X-linked Opitz G/BBB syndrome. Widely spaced eyes 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 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, downslanted 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 absolute or relative macrocephaly 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, widely spaced eyes 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, Clark et al 2009]. 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 overlapping 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Consideration of brain imaging studies
  • Ophthalmologic evaluation for evidence of abnormalities including strabismus and visual deficits
  • Medical genetics consultation

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 and behavioral, gastrointestinal, 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of the proband

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If a 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.

Fetal ultrasonograhy. A level II ultrasound to evaluate for congenital anomalies including congenital heart defects, renal cysts, gastrointestinal anomalies, and skeletal defects may be considered in pregnancies at risk for FGS1.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • FG Syndrome Family Alliance, Inc.
    946 NW Circle Boulevard
    #290
    Corvallis OR 97330
    Phone: 617-577-9050
    Email: info@fgsyndrome.org
  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 800-424-3688 (toll-free); 202-387-1968
    Fax: 202-387-2193
    Email: anam@aaidd.org
  • Medline Plus
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. MED12-Related Disorders: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
MED12Xq13​.1Mediator of RNA polymerase II transcription subunit 12MED12 @ LOVDMED12

Data 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 MED12-Related Disorders (View All in OMIM)

300188MEDIATOR COMPLEX SUBUNIT 12; MED12
305450OPITZ-KAVEGGIA SYNDROME; OKS
309520LUJAN-FRYNS SYNDROME

Gene structure. MED12 was initially described as being 25 kb with 44 exons [Philibert et al 1999]. Risheg et al [2007] later reported that the gene has 45 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. A polymorphism involving a four-amino acid insertion in the Opa domain has been associated with an increased risk for psychosis [Philibert & Madan 2007].

Pathogenic allelic variants. See Table 2. The most common mutation identified in individuals with a distinct FG syndrome (FGS) phenotype is a recurrent p.Arg961Trp missense mutation in exon 21 [Risheg et al 2007]. A p.Gly958Glu missense mutation in exon 21 of MED12 has been reported in three male cousins with features of FGS1 [Rump et al 2011].

Lujan syndrome (LS) is caused by a recurrent p.Asn1007Ser missense mutation in exon 22 of MED12 [Schwartz et al 2007].

Table 2. MED12 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.2873G>Ap.Gly958GluNM_005120​.2
NP_005111​.2
c.2881C>Tp.Arg961Trp
c.3020A>Gp.Asn1007Ser

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. MED12 encodes a subunit of the Mediator complex, which serves as an interface between transcription factors and RNA polymerase II. The Mediator complex comprises multiple subunits organized into a head, middle, and tail module. A fourth module (Cdk8 module) which contains the MED12 protein encoded for by MED12 can also be included in the Mediator complex [Conaway & Conaway 2011]. The Mediator complex can repress transcription through specific action of the MED12 protein when the CdK8 module is present [Ding et al 2008]. MED12 consists of 2212 amino acids and has four domains: Leu-rich (L); Leu-Ser (LS); Pro-, Gln-, and Leu-rich (PQL); and Opa. Transcriptional repression can occur through direct interaction of the PQL domain with a number of transcription factors, including SOX9, GLI3, and β-catenin [Zhou et al 2006, Philibert & Madan 2007].

Abnormal gene product. The p.Arg961Trp missense mutation most commonly associated with FGS1 is located in the Leu-Ser (LS) domain, which has an unclear function [Philibert & Madan 2007]. The p.Arg961Trp mutation leads to conformational changes in the MED12 protein [Risheg et al 2007]. The p.Gly958Glu missense mutation reported in one family with FGS1 is also located in the LS domain. The p.Gly958Glu mutation results in the replacement of a highly conserved glycine residue with a larger, charged glutamic acid which is hydrophilic [Rump et al 2011]. The p.Asn1007Ser missense mutation associated with LS is also located in the LS domain and is predicted to affect MED12 protein folding [Schwartz et al 2007].

References

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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]

Chapter Notes

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

  • 6 June 2013 (me) Comprehensive update posted live
  • 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
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