Med12-Related Disorders

Clinical 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), Lujan syndrome (LS), and X-linked Ohdo syndrome. 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, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. X-linked Ohdo syndrome (referred to as XLOS in this GeneReview) is characterized by intellectual disability, blepharophimosis, and facial coarsening. A number of individuals with nonsyndromic intellectual disability – including some affected females – have been described.

Diagnosis/testing.

The diagnosis of an MED12-related disorder is established in a male by identification of a hemizygous MED12 pathogenic variant on molecular genetic testing. The diagnosis of an MED12-related disorder in a female would require the identification of a heterozygous pathogenic variant in MED12 by molecular genetic testing along with clinical features consistent with an MED12-related disorder.

Management.

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

Prevention of secondary complications: Physical therapy for joint contractures in individuals with FGS1 or LS.

Surveillance: Routine follow up of growth, development, behavior concerns, gastrointestinal functioning, and neurologic issues; annual eye examination. Annual audiology evaluation for individuals with XLOS. Regular dental evaluations for individuals with XLOS and LS.

Genetic counseling.

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

Suggestive Findings

An MED12-related disorder should be suspected in an individual with a phenotype associated with FG syndrome type 1, Lujan syndrome, or X-linked Ohdo syndrome.

FG syndrome type 1 (FGS1). Formal clinical diagnostic criteria for FGS1 have not been established; however, the following clinical features would be suggestive:

• Neurodevelopmental delays
• A family history consistent with X-linked inheritance
• Characteristic facial features:
  • Absolute or relative macrocephaly
  • Dolichocephaly
  • Frontal hair upsweep
  • Tall forehead
  • Downslanted palpebral fissures
  • Widely spaced eyes
  • Fullness of the upper eyelids
  • Small, simple ears (≤10^th percentile)
  • Open mouth
  • Long narrow face
• Broad thumbs and halluces
• Congenital anomaly (corpus callosum, anal, cardiac, skeletal)
• Hypotonia, constipation, or feeding problems
• Characteristic behavior (affable and eager to please)

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

• Intellectual disability
• Hypotonia
• Large head (occipitofrontal 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

X-linked Ohdo syndrome (referred to as XLOS in this GeneReview). Diagnostic criteria have not been established for XLOS. Common clinical features include the following:

• Intellectual disability
• Blepharophimosis
• Ptosis
• Epicanthal folds
• Facial coarsening at an older age

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

• Triangular face
• Maxillary hypoplasia
• Sparse eyebrows
• Hypertelorism
• Strabismus
• Small ears
• Thick alae nasi
• Wide, low nasal bridge
• Broad nasal tip
• Micrognathia
• Small mouth
• Dental anomalies
• Hypotonia
• Family history consistent with X-linked inheritance

Establishing the Diagnosis

Male proband. The diagnosis of an MED12-related disorder is established in a male proband by identification of a hemizygous pathogenic variant in MED12 by molecular genetic testing (see Table 1).

Female proband. The diagnosis of an MED12-related disorder in a female would require the identification of a heterozygous pathogenic variant in MED12 by molecular genetic testing (see Table 1) along with clinical features consistent with an MED12-related disorder.

Note: Female carriers of a pathogenic variant in MED12 have been unaffected with the exception of seven females with variable cognitive impairment in a family with a novel p.Ser1967GlnfsTer84 frameshift variant [Lesca et al 2013] and a female with a p.Gln1974His pathogenic variant who was described as having language delay [Bouazzi et al 2015].

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

• Single-gene testing. Sequence analysis of MED12 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• A multigene panel that includes MED12 and other genes of interest (see Differential Diagnosis) may also be considered. Notes: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes MED12) fails to confirm a diagnosis in an individual with features of an MED12-related disorder. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Genotype-Phenotype Correlations

FG syndrome type 1 (FGS1). The p.Arg961Trp and p.Gly958Glu pathogenic variants in MED12 are associated with a recognizable phenotype which includes characteristic facial features (tall forehead, frontal hair upsweep, long narrow face, open mouth), small simple ears, absolute or relative macrocephaly, congenital anomalies (corpus callosum, heart, anus, skeleton), behavior issues, and relatively nonspecific features of hypotonia, constipation, and feeding problems [Risheg et al 2007, Clark et al 2009, Lyons et al 2009, Rump et al 2011].

Lujan syndrome (LS). Two families with LS were reported to have the pathogenic missense variant p.Asn1007Ser in MED12 [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.

X-linked Ohdo syndrome (XLOS). Three families with XLOS have been reported with p.Arg1148His, p.Ser1165Pro, and p.His1729Asn hemizygous pathogenic variants in MED12 associated with intellectual disability, hypotonia, behavior issues, blepharophimosis, ptosis, facial coarsening, and thick alae nasi [Vulto-van Silfhout et al 2013]. An additional family with the p.Arg1148His hemizygous pathogenic variant was described with a more severe presentation that included blepharophimosis and short humeri [Isidor et al 2014]. Individuals with XLOS share clinical features of intellectual disability, hypotonia, and behavior issues with FGS1 and LS but can be distinguished by the presence of blepharophimosis, ptosis, facial coarsening, and thick alae nasi [Vulto-van Silfhout et al 2013]. Corpus callosum dysgenesis and macrocephaly are not common in XLOS [Vulto-van Silfhout et al 2013, Isidor et al 2014].

Nonspecific intellectual disability (NSID). A family with a novel p.Ser1967GlnfsTer84 frameshift pathogenic variant in MED12 was reported to have ten affected males with profound intellectual disability along with seven females with variable cognitive impairment [Lesca et al 2013]. The only other affected female had three brothers with NSID and a mother with a history of language delay caused by a p.Gln1974His pathogenic variant – located in the same exon as in the other family with affected females [Bouazzi et al 2015]. A p.Ile1023Val pathogenic variant was described in a male with NSID [Yamamoto & Shimojima 2015]. NSID and microcephaly were reported in a family with a p.Ala1383Thr pathogenic variant and a family with a p.Arg815Gln pathogenic variant [Langley et al 2015, Tzschach et al 2015]. The recent identification of multiple affected families with NSID caused by novel MED12 pathogenic variants not consistent with FGS1, LS, or XLOS indicates that the clinical spectrum of MED12-related disorder is wider than previously reported and the genotype-phenotype correlations will likely evolve over time as additional families are reported.

Penetrance

Penetrance is presumed to be 100% in males with MED12 pathogenic variants associated with FGS1, LS, and XLOS. MED12 pathogenic variants associated with FGS1, LS, and XLOS have not been reported in unaffected males [Risheg et al 2007, Schwartz et al 2007, Graham et al 2008, Clark et al 2009, Lyons et al 2009, Rump et al 2011, Vulto-van Silfhout et al 2013, Isidor et al 2014]. Penetrance is presumed to be 100% in males with MED12 pathogenic variants associated with nonspecific intellectual disability; however, recent reports involve unique variants, and incomplete penetrance may be identified in the future as additional families are described. Affected females with variable clinical expression have been described in two families with nonspecific intellectual disability [Lesca et al 2013, Bouazzi et al 2015].

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 [Risheg et al 2007]. Lujan syndrome is also referred to as Lujan-Fryns syndrome or intellectual disability, X-linked, with marfanoid habitus [Hackmann et al 2016]. X-linked Ohdo syndrome has been referred to as blepharophimosis and mental retardation syndrome, Maat-Kievit-Brunner type [Verloes et al 2006].

Prevalence

The prevalence of FGS is unknown, but FGS1 appears to be an uncommon condition as only 11 families with clinical features of FGS1 have been found with a pathogenic variant in MED12 [Risheg et al 2007, Graham et al 2008, Clark et al 2009, Lyons et al 2009, Rump et al 2011]. Clinically diagnosed FGS has been described as a common disorder [Battaglia et al 2006], but numerous nonspecific findings have led to over-diagnosis [Lyons et al 2009].

The prevalence of LS is unknown; it appears to be uncommon, as only two families with clinical features of LS have been found to have the p.Asn1007Ser pathogenic variant in MED12 [Schwartz et al 2007]. The clinical diagnosis of LS has broadened since the initial description but pathogenic variants in MED12 are rare [Hackmann et al 2016].

The prevalence of XLOS is unknown but it appears to be uncommon: only four families with clinical features of XLOS caused by MED12 pathogenic variants have been described [Vulto-van Silfhout et al 2013, Isidor et al 2014].

Novel pathogenic variants in MED12 have recently been reported in families with nonspecific intellectual disability [Lesca et al 2013, Bouazzi et al 2015, Langley et al 2015, Tzschach et al 2015, Yamamoto & Shimojima 2015]. The prevalence of the broader MED12-related disorder clinical spectrum is unknown but is expected to increase as additional families are identified.

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:

• FGS2 (linked to Xq28) (OMIM 300321) [Briault et al 1999, Briault et al 2000]. A hemizygous p.Pro1291Leu variant was identified in FLNA in one male reported to have FGS2 [Unger et al 2007].
• FGS3 (linked to Xp22.3) (OMIM 300406) [Dessay et al 2002]
• FGS4 (linked to Xp11.4) (OMIM 300422) [Piluso et al 2003]. A hemizygous p.Arg28Leu variant was identified in CASK in one family reported to have FGS4 [Piluso et al 2009].
• 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 chromosomal microarray analysis (CMA) [Lyons et al 2009].

Pathogenic variants 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 (OMIM 300321)
• UPF3B (OMIM 300676)
• CASK (CASK-related disorders)
• MECP2 (Rett syndrome)
• ATRX (ATRX syndrome)

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

Disorders with clinical features that overlap those of FGS include the following.

• Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome. Widely spaced eyes, genitourinary anomalies, hypotonia, and intellectual disability are features of ATRX syndrome that can also be seen in FGS1. 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 FGS1 are X-linked intellectual disability syndromes with common craniofacial features including broad forehead, widely spaced eyes, and downslanted palpebral fissures. Individuals with FGS1 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 FGS1 include large head circumference, prominent forehead, hypotonia, and intellectual disability. FXS is associated with large ears whereas FGS1 is distinguished by small and simple ears. In addition, individuals with FGS1 commonly have constipation with or without anal anomalies. In more than 99% of affected individuals, FXS is caused by an FMR1 allele with greater than 200 CGG repeats. Inheritance is X-linked.
• Phelan-McDermid syndrome. (22q13.3 deletion syndrome) Common features seen in both FGS1 and 22q13.3 deletion syndrome include hypotonia, intellectual disability, and delayed speech. FGS1 can be distinguished by the presence of constipation, small and simple ears, and characteristic behavior. 22q13.3 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 FGS1 include constipation, abnormalities of the corpus callosum, widely spaced eyes, and intellectual disability. Individuals with MWS have characteristic facial features distinct from FGS1 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 FGS1. MWS is typically the result of a de novo dominant pathogenic variant 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 FGS1 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 FGS1. Individuals with FGS1 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 FGS1. The craniofacial features and head size of FGS1 are distinct from RSTS and should allow clinical differentiation. CREBBP and EP300 are the only genes associated with RSTS. RSTS is expressed in an autosomal dominant manner and typically occurs as the result of a de novo pathogenic variant.
• 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 FGS1. Intellectual disability is uncommon in GCPS. Other craniofacial features of FGS1, including small and simple ears, are not associated with GCPS. GCPS either is inherited in an autosomal dominant manner (as a pathogenic variant in GLI3 or as a deletion of 7p13 involving GLI3) or occurs as the result of a de novo or inherited chromosome rearrangement.
• 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 FGS1 are distinct from TBS and should allow clinical differentiation. The only gene associated with TBS is SALL1. TBS is inherited in an autosomal dominant manner.

Lujan Syndrome (LS)

The clinical diagnosis of LS has broadened since the initial description by Lujan et al [1984]. Pathogenic variants in UPF3B were reported in two individuals with a clinical diagnosis of LS [Tarpey et al 2007]. Three families with features that overlap LS were found to have pathogenic variants in ZDHHC9 [Raymond et al 2007].

The evaluation of 28 individuals with clinical features of LS did not identify pathogenic variants in MED12, UPF3B, or ZDHHC9 but did find multiple chromosome and single-gene abnormalities [Hackmann et al 2016]. As a result, further genetic testing including chromosome analysis, CMA, and next-generation sequencing should be considered in individuals with features of LS who have normal MED12 testing.

Disorders with clinical features that overlap those of LS 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 pathogenic variants 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 pathogenic variants in TGFBR1, TGFBR2, SMAD3, or TGFB2. 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. SKI is the only gene in which pathogenic variants are known to cause SGS. SGS is expressed in an autosomal dominant manner and typically occurs as the result of a de novo pathogenic variant.
• Fragile X syndrome (FXS) findings commonly found in individuals with LS include large head circumference, prominent forehead, hypotonia, and intellectual disability. In more than 99% of affected individuals, FXS is caused by an FMR1 allele with greater than 200 CGG 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 pathogenic variants in SMS and inherited in an X-linked manner.

X-linked Ohdo syndrome (XLOS)

XLOS was first clinically described by Maat-Kievit et al [1993] in two unrelated males with blepharophimosis and intellectual disability. XLOS has also been called blepharophimosis and mental retardation syndrome, Maat-Kievit-Brunner type to distinguish it from other syndromes that have blepharophimosis and intellectual disability [Verloes et al 2006].

Disorders with clinical features that overlap those of XLOS include the following:

• Say-Barber-Biesecker-Young-Simpson (SBBYS) syndrome (see KAT6B-Related Disorders). Features in common with XLOS include intellectual disability and blepharophimosis. Individuals with SBBYS have a mask-like face and can have thyroid issues and cleft palate. SBBYS is caused by pathogenic variants in KAT6B and inherited in an autosomal dominant manner.
• Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is characterized by blepharophimosis, ptosis, and epicanthus inversus but the lack of intellectual disability distinguishes BPES from XLOS. The only gene associated with BPES is FOLX2. Deletions of chromosome 3q23 which include FOXL2 along with contiguous genes can present with blepharophimosis and intellectual disability. Inheritance is autosomal dominant.
• Dubowitz syndrome (DS) (OMIM 223370). Affected individuals typically have overlapping features of blepharophimosis, ptosis, and intellectual disability. Microcephaly and eczema are characteristic for DS but are not typically seen in individuals with XLOS. A homozygous variant in NSUN2 was identified in one family with features that overlapped with DS.
• Fetal alcohol spectrum disorders (FASD) are caused by in utero exposure to alchol. They are characterized by short palpebral fissures and intellectual disability. Affected individuals typically have a smooth philtrum and thin upper lip.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FG syndrome type 1 (FGS1), Lujan syndrome (LS), or X-linked Ohdo syndrome (XLOS) the following are recommended:

• Measurement of height, weight, and head circumference
• Developmental and behavioral assessment
• Neurologic history and examination for evidence of seizures and hypotonia
• Evaluation for evidence of spasticity in individuals with FGS1
• Consideration of brain imaging studies in individuals with FGS1 and LS
• Ophthalmologic evaluation for strabismus, visual deficits, and other ophthalmologic features
• Examination for evidence of anal anomalies in individuals with FGS1
• Examination for evidence of genitourinary anomalies
• Cardiology evaluation with echocardiogram
• Audiology evaluation in individuals with XLOS
• Dental evaluation to evaluate for dental anomalies in individuals with XLOS and LS
• Consultation with a clinical geneticist

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
• Ophthalmologic management of strabismus and other ocular anomalies, if present
• Standard management of chronic constipation for individuals with FGS1
• 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 or LS.

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 concerns, gastrointestinal functioning, and neurologic issues
• Annual ophthalmologic evaluation for evidence of strabismus and any visual issues
• Annual audiology evaluation for evidence of hearing loss in XLOS
• Regular dental evaluations for individuals with XLOS and LS

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 in the US and EU Clinical Trials Register in Europe 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.