| Lujan–Fryns syndrome | |
|---|---|
| Other names | X-linked mental retardation with Marfanoid habitus, Lujan syndrome[1][2][3] |
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| Lujan–Fryns syndrome in a young adult male, with features that include a long, narrow face and recessed chin. | |
| Specialty | Medical genetics |
Lujan–Fryns syndrome (LFS) is anX-linkedgenetic disorder that causes mild to moderateintellectual disability and features described asMarfanoid habitus, referring to a group of physical characteristics similar to those found inMarfan syndrome.[4][5] These features include a tall, thin stature and long, slender limbs.[5] LFS is also associated withpsychopathology andbehavioral abnormalities, and it exhibits a number of malformations affecting thebrain andheart.[6][7][8] The disorder is inherited in anX-linked dominant manner, and is attributed to amissense mutation in theMED12 gene.[3] There is currently no treatment or therapy for the underlyingMED12 malfunction, and the exact cause of the disorder remains unclear.[9]
Intellectual disability in LFS usually ranges from mild to moderate, but severe cases have also been reported.[10][11] A relatively commonbrain anomaly seen with LFS isagenesis of the corpus callosum, an error ofembryonic development in which thecorpus callosum (a structure of themammalianbrain composed ofnerves that allows communication between theleft and right cerebral hemispheres) is not present.[7][12] Among a number of adverseneurological effects sometimes found with an absence of the corpus callosum, intellectual disability has been shown to occur at a rate of approximately 73 percent.[12] A correlation between agenesis of the corpus callosum and intellectual disability in LFS, however, has not been suggested.[13]
Psychopathology and related behavioral abnormalities are typically seen in LFS, and they may be considered in the diagnosis of the disorder.[7] The most common of these in LFS is anautism-like spectrum disorder, and LFS is considered one of a number of genetic disorders associated withautism.[7][14] Additional alterations of psychopathology with behavioral manifestations that have been observed in LFS include:psychotic behavior,[15]schizophrenia,[16]hyperactivity andattention-deficit hyperactivity disorder,[13][17]aggression,[17]oppositional defiant disorder,[13][18]obsessive compulsive disorder,[13] extremeshyness,[17]learning disability,[13]cognitive impairment,[13]short-term memory deficit,[13]low frustration tolerance,[13]social dysfunction,[13]lack of impulse control,[13]eating disorder and associatedmalnutrition, attributed topsychogenicloss ofappetite;[6] andpyromania.[7][13][18]
Whilepsychiatric conditions like these are to be expected with LFS, there have also been cases of the disorder with some preservation of mental and behavioral abilities, such asproblem solving, reasoning and normalintelligence.[19]
The psychopathology of LFS usually exhibits schizophrenia.[16] When schizophrenia is diagnosed in an individual known to be affected by intellectual disability, LFS may be considered in thedifferential diagnosis of schizophrenia, with confirmation of cause through appropriate psychiatric and genetic evaluation methods.[16]
LFS is clinically distinguished from other X-linked forms of intellectual disability by the accompanying presence of marfanoid habitus.[10] Marfanoid habitus describes a group of physical features common to Marfan syndrome.[5] Including Marfan syndrome and LFS, marfanoid features of this type have also been observed with several other disorders, one of which ismultiple endocrine neoplasia type 2.[20]
In LFS, specific features identified as marfanoid include: a long,narrow face;[5][9] tall, thinstature;[3][9] long, slenderlimbs,fingers andtoes (not unlikearachnodactyly)[3][21][22] withjointhyperextensibility,[17] shortenedhalluces (the big toes) and long second toes.[9]
The diagnosis of marfanoid habitus in LFS is often delayed because many of the physical features and characteristics associated with it are usually not evident untiladolescence.[2]
Craniofacial and other features of LFS include:maxillaryhypoplasia (underdevelopment of the upperjawbone),[9] a smallmandible (lower jaw bone) and recedingchin,[3][17] a high-archedpalate (the roof of the mouth), with crowding and misalignment of the upperteeth;[5][7]macrocephaly (enlargedskull) with a prominentforehead,[3][9]hypernasalspeech (voice),[5][7] a longnose with a high, narrownasal bridge;[9] a deep, shortphiltrum (the indentation in the upper lip, beneath the nose),[9] low-setears with some apparentretroversion,[9]hypotonia (decreasedmuscletone),[3]pectus excavatum (a malformity of thechest),[9] slightly enlarged to normaltesticular size in males,[9][17] andseizures.[9]
Hypernasal speech, or "hypernasality", is primarily the result ofvelopharyngeal insufficiency, a sometimescongenital aberration in which the velopharyngealsphincter allows too much air into thenasal cavity during speech.[23][24] In LFS, hypernasality may also be caused by failure of thesoft palate anduvula to reach the back wall of thepharynx (the interior cavity of thethroat whereswallowing generally occurs) during speech, a condition that can be associated with asubmucosalcleft palate.[13][25]
A number of features involving theheart have been noted in several LFS cases, the most significant being dilation of theaortic root, a section of theascending aorta.[8] Aortic root dilation (enlargement) is associated with a greatly increased risk ofdissection of theaortic wall, resulting inaortic aneurysm.[26] As this presents a possible life-threatening consequence of LFS, routinecardiac evaluation methods such asechocardiogram are implemented when the disorder is first diagnosed, along withMRI scans of the brain to screen for suspected agenesis of the corpus callosum.[7] Additional effects on the heart that have been reported with LFS areventricular andatrial septal defect.[8][17]
Amissense mutation in theMED12 gene, located on the humanX chromosome, has been established as the cause of LFS.[3][27] Missense mutations are geneticpoint mutations in which a singlenucleotide in the genetic sequence is exchanged with another one. This leads to an erroneous substitution of a particularamino acid in theprotein sequence duringtranslation. The missense mutation in theMED12 gene, that causes LFS, is identified as p.N1007S.[3] This indicates that the amino acidasparagine, normally located at position 1007 along theMED12 sequence, has been mistakenly replaced byserine.[27] This mutation inMED12 causes incorrect expression and activity of the protein it encodes, resulting in the disorder.[3][9]
MED12, ormediator of RNA polymerase II transcription, subunit 12 homolog of S. cerevisiae, is one of several subunits in the mammalianmediator complex, which regulatesRNA polymerase II duringmRNAtranscription.[28][29]
The Mediator complex is required for polymerase II transcription and acts as a bridge between the polymerase II enzyme and different gene-specific transcription factors. Mediator can contain up to 30 subunits, but some of the subunits are only required for regulation of transcription in particular tissues or cells.[30] Currently, the exact mechanism by which dysfunction ofMED12 results in LFS and its associated neuropsychopathic and physical characteristics is unclear. Marfanoid habitus, a highly arched palate and several other features of LFS can be found with Marfan syndrome, aconnective tissue disorder.[4] The finding of aortic root dilation in both disorders suggests that a mutation in an unspecifiedconnective tissue regulating gene may contribute to the etiology of LFS.[1][5][8][13]
A number of interesting experimental results have been obtained by studyingMED12 mutations in thezebrafish, ananimal model representingvertebrates.[31][32][33] In zebrafish, a mutation inMED12 was found to be responsible for the mutantmotionless (mot). Zebrafish with themot mutation have neuronal and cardiovascular defects, although not all types of neurons are affected. Introduction of humanMED12 mRNA into the zebrafish restores normal development.[34]MED12 is also a criticalcoactivator for the geneSOX9, which is involved in the developmental regulation of neurons,cartilage andbone. In the zebrafish,MED12 defects cause maldevelopment of vertebrate embryonic structures such as theneural crest, which would alter function of theautonomic andperipheral nervous systems; and they also cause malformations ofcell types serving as precursors tocartilage andbone, such asosteocytes.[34][35][36] Some features found in LFS, like agenesis of the corpus callosum and cartilage-related craniofacial anomalies, are similar to defects found in zebrafish withMED12 and associated mutations.[3]
Lujan–Fryns syndrome is inherited in anX-linked dominant manner.[9][13][37] This means the defective gene responsible for the disorder (MED12) is located on the X chromosome, and only one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who has the disorder. Males are normallyhemizygous for the X chromosome, having only one copy. As a result, X-linked dominant disorders usually show higherexpressivity in males than females. This phenomenon is thought to occur with LFS.[13][37]
As the X chromosome is one of thesex chromosomes (the other being theY chromosome), X-linkedinheritance is determined by thekaryotype of the parent carrying a specific gene and can often seem complex. This is because, typically,females have two copies of the X-chromosome, whilemales have only one copy. The difference betweendominant andrecessive inheritance patterns also plays a role in determining the chances of a child inheriting an X-linked disorder from their parentage.
In LFS, X-linked dominant inheritance was suspected, as boy and girl siblings in one family both exhibited the disorder.[13][37] A scenario such as this would also be possible withX-linked recessive inheritance, but in this particular case report, the girl was believed to be a manifestingheterozygote[13][37] carrying one copy of the mutated gene.
Sporadic cases of LFS, where the disorder is present in an individual with no prior family history of it, have also been reported in a small number of affected males.[13][15][38]
An individual exhibiting intellectual disability and other symptoms similar to LFS was found to have aterminal deletion of thesubtelomeric region in theshort arm ofchromosome 5.[25] Deletion of this area of chromosome 5 is associated with intellectual disability, psychotic behavior, autism, macrocephaly and hypernasal-like speech, as well as the disorderCri du chat syndrome.[25][39] Fryns (2006) suggests a detailed examination of chromosome 5 withFISH should be performed as part of the differential diagnosis of LFS.[9]
Mutations in theUPF3B gene, also found on the X chromosome, are another cause of X-linked intellectual disability.[40]UPF3B is part of thenonsense-mediated mRNA decay (NMD) complex, which performsmRNA surveillance, detecting mRNA sequences that have been erroneously truncated (shortened) by the presence ofnonsense mutations.[41] Mutations inUPF3B alter and prevent normal function of the NMD pathway, resulting in translation and expression of truncated mRNA sequences into malfunctioning proteins that can be associated with developmental errors and intellectual disability.[41][42] Individuals from two families diagnosed with LFS and one family with FGS were found to have mutations inUPF3B, confirming that the clinical presentations of the different mutations can overlap.[42]
Although LFS is usually suspected when intellectual disability and marfanoid habitus are observed together in a patient, the diagnosis of LFS can be confirmed by the presence of the p.N1007S missense mutation in theMED12 gene.[3][9][10]
In thedifferential diagnosis of LFS, another disorder that exhibits some features and symptoms of LFS and is also associated with a missense mutation ofMED12 isOpitz-Kaveggia syndrome (FGS).[3][43] Common features shared by both LFS and FGS include X-linked intellectual disability, hyperactivity, macrocephaly, corpus callosum agenesis and hypotonia.[3] Notable features of FGS that have not been reported with LFS include excessive talkativeness, consistent strength in socialization skills,imperforate anus (occlusion of theanus) and ocularhypertelorism (extremely wide-seteyes).[44][45]
Whereas LFS is associated with missense mutation p.N1007S, FGS is associated with missense mutation p.R961W.[3][46] As both disorders originate from an identical type of mutation in the same gene, while exhibiting similar, yet distinct characteristics; LFS and FGS are considered to beallelic.[3][9][13][43] In the context ofMED12, this suggests that the phenotype of each disorder is related to the way in which their respective mutations alter theMED12 sequence and its function.[3][27][43]
While there is no specific treatment for the underlying genetic cause of LFS, corrective procedures, preventive intervention measures, and therapies may be considered in the treatment and management of the many craniofacial, orthopedic, and psychiatric problems associated with the disorder. More pressing issues such as cardiac involvement or epileptic seizures should be routinely examined and monitored. Close attention and specialized follow-up care, including neuro-psychological evaluation methods and therapies, and special education, should be given to diagnose and prevent psychiatric disorders and related behavioral problems such as psychosis and outbursts of aggression.[9]
Lujan–Fryns syndrome is a rare X-linked dominant syndrome and is more common in males than females. Its prevalence within the general population has not yet been determined.[9]
Lujan–Fryns syndrome is named afterphysicians J. Enrique Lujan and Jean-Pierre Fryns.[21] The initial observation of suspected X-linked intellectual disability with Marfanoid features and craniofacial effects such as a high-archedpalate was described by Lujan et al. in 1984.[17] In the report, four affected male members of a largekindred (consanguinous family) were noted.[3][13][17] Additional investigations of combined X-linked intellectual disability and Marfanoid habitus in other families, including two brothers, were reported by Fryns et al., beginning in 1987.[5] The disorder soon became known as Lujan–Fryns syndrome.[37]
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