Lujan–Fryns syndrome (LFS) is an X-linked genetic disorder that causes mild to moderate intellectual disability and features described as

Marfanoid habitus Marfanoid (or Marfanoid habitus) is a constellation of Symptom, symptoms resembling those of Marfan syndrome, including long limbs, with an arm span that is at least 1.03 of the height of the individual, and a crowded oral maxilla, sometimes with a ...

, referring to a group of physical characteristics similar to those found in

Marfan syndrome Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with long arms, legs, fingers, and toes. They also typically have exceptionally flexible joints a ...

. These features include a tall, thin stature and long, slender limbs. LFS is also associated with

psychopathology Psychopathology is the study of abnormal cognition, behaviour, and experiences which differs according to social norms and rests upon a number of constructs that are deemed to be the social norm at any particular era. Biological psychopatholo ...

and behavioral abnormalities, and it exhibits a number of malformations affecting the brain and heart. The disorder is inherited in an X-linked dominant manner, and is attributed to a missense mutation in the '' MED12'' gene. There is currently no treatment or therapy for the underlying ''MED12'' malfunction, and the exact cause of the disorder remains unclear.

Signs and symptoms

Intellectual disability in LFS usually ranges from mild to moderate, but severe cases have also been reported. A relatively common brain anomaly seen with LFS is

agenesis of the corpus callosum Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres ...

, an error of

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

nic development in which the corpus callosum (a structure of the

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

ian brain composed of

nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system. A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the e ...

s that allows communication between the left and right cerebral hemispheres) is not present. Among a number of adverse neurological effects sometimes found with an absence of the corpus callosum, intellectual disability has been shown to occur at a rate of approximately 73 percent. A correlation between agenesis of the corpus callosum and intellectual disability in LFS, however, has not been suggested.

Psychiatric

Psychopathology and related behavioral abnormalities are typically seen in LFS, and they may be considered in the diagnosis of the disorder. The most common of these in LFS is an autism-like spectrum disorder, and LFS is considered one of a number of genetic disorders associated with

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

. Additional alterations of psychopathology with behavioral manifestations that have been observed in LFS include: psychotic behavior, schizophrenia, hyperactivity and attention-deficit hyperactivity disorder,

aggression Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...

, oppositional defiant disorder,

obsessive compulsive disorder Obsession may refer to: Psychology * Celebrity worship syndrome, obsessive addictive disorder to a celebrity's personal and professional life * Fixation (psychology), a persistent attachment to an object or idea * Idée fixe (psychology), a preo ...

, extreme shyness,

learning disability Learning disability, learning disorder, or learning difficulty (British English) is a condition in the brain that causes difficulties comprehending or processing information and can be caused by several different factors. Given the "difficult ...

, cognitive impairment,

short-term memory Short-term memory (or "primary" or "active memory") is the capacity for holding a small amount of information in an active, readily available state for a short interval. For example, short-term memory holds a phone number that has just been recit ...

deficit, low frustration tolerance, social dysfunction, lack of impulse control,

eating disorder An eating disorder is a mental disorder defined by abnormal eating behaviors that negatively affect a person's physical or mental health. Only one eating disorder can be diagnosed at a given time. Types of eating disorders include binge eating d ...

and associated malnutrition, attributed to psychogenic loss of

appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to regu ...

; and pyromania. While psychiatric 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 as

problem solving Problem solving is the process of achieving a goal by overcoming obstacles, a frequent part of most activities. Problems in need of solutions range from simple personal tasks (e.g. how to turn on an appliance) to complex issues in business an ...

, reasoning and normal intelligence. The psychopathology of LFS usually exhibits schizophrenia. When schizophrenia is diagnosed in an individual known to be affected by intellectual disability, LFS may be considered in the

differential diagnosis In healthcare, a differential diagnosis (abbreviated DDx) is a method of analysis of a patient's history and physical examination to arrive at the correct diagnosis. It involves distinguishing a particular disease or condition from others that p ...

of schizophrenia, with confirmation of cause through appropriate psychiatric and genetic evaluation methods.

Marfanoid habitus

LFS is clinically distinguished from other X-linked forms of intellectual disability by the accompanying presence of marfanoid habitus. Marfanoid habitus describes a group of physical features common to Marfan syndrome. Including Marfan syndrome and LFS, marfanoid features of this type have also been observed with several other disorders, one of which is multiple endocrine neoplasia type 2. In LFS, specific features identified as marfanoid include: a long, narrow face; tall, thin

stature Stature may refer to: * Human stature, the distance from the bottom of the feet to the top of the head in a human body, standing erect * Reputation, social opinion about an entity * Respect Respect, also called esteem, is a positive feeli ...

; long, slender limbs, fingers and toes (not unlike arachnodactyly) with joint hyperextensibility, shortened halluces (the big toes) and long second toes. 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 until

adolescence Adolescence () is a transitional stage of physical and psychological development that generally occurs during the period from puberty to adulthood (typically corresponding to the age of majority). Adolescence is usually associated with the t ...

Head and face

Craniofacial and other features of LFS include: maxillary

hypoplasia Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.jaw bone), a small mandible (lower jaw bone) and receding

chin The chin is the forward pointed part of the anterior mandible (List_of_human_anatomical_regions#Regions, mental region) below the lower lip. A fully developed human skull has a chin of between 0.7 cm and 1.1 cm. Evolution The presence of a we ...

, a high-arched palate (the roof of the mouth), with crowding and misalignment of the upper teeth; macrocephaly (enlarged skull) with a prominent

forehead In human anatomy, the forehead is an area of the head bounded by three features, two of the skull and one of the scalp. The top of the forehead is marked by the hairline, the edge of the area where hair on the scalp grows. The bottom of the fore ...

, hypernasal

speech Speech is a human vocal communication using language. Each language uses Phonetics, phonetic combinations of vowel and consonant sounds that form the sound of its words (that is, all English words sound different from all French words, even if ...

( voice), a long nose with a high, narrow nasal bridge; a deep, short philtrum (the indentation in the upper lip, beneath the nose), low-set ears with some apparent retroversion, hypotonia (decreased

muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

tone), pectus excavatum (a malformity of the chest), slightly enlarged to normal testicular size in males, and seizures. Hypernasal speech, or "hypernasality", is primarily the result of velopharyngeal insufficiency, a sometimes

congenital A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

aberration in which the velopharyngeal sphincter allows too much air into the nasal cavity during speech. In LFS, hypernasality may also be caused by failure of the soft palate and uvula to reach the back wall of the pharynx (the interior cavity of the throat where

swallowing Swallowing, sometimes called deglutition in scientific contexts, is the process in the human or animal body that allows for a substance to pass from the mouth, to the pharynx, and into the esophagus, while shutting the epiglottis. Swallowing i ...

generally occurs) during speech, a condition that can be associated with a

submucosa The submucosa (or tela submucosa) is a thin layer of tissue (biology), tissue in various organ (anatomy), organs of the gastrointestinal tract, gastrointestinal, respiratory tract, respiratory, and genitourinary system, genitourinary tracts. It i ...

l cleft palate.

Heart

A number of features involving the heart have been noted in several LFS cases, the most significant being dilation of the aortic root, a section of the

ascending aorta The ascending aorta (AAo) is a portion of the aorta commencing at the upper part of the base of the left ventricle, on a level with the lower border of the third costal cartilage behind the left half of the sternum. Structure It passes obliqu ...

. Aortic root dilation (enlargement) is associated with a greatly increased risk of

dissection Dissection (from Latin ' "to cut to pieces"; also called anatomization) is the dismembering of the body of a deceased animal or plant to study its anatomical structure. Autopsy is used in pathology and forensic medicine to determine the cause o ...

of the

aortic The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes ox ...

wall, resulting in

aortic aneurysm An aortic aneurysm is an enlargement (dilatation) of the aorta to greater than 1.5 times normal size. They usually cause no symptoms except when ruptured. Occasionally, there may be abdominal, back, or leg pain. The prevalence of abdominal aortic ...

. As this presents a possible life-threatening consequence of LFS, routine cardiac evaluation methods such as echocardiogram are implemented when the disorder is first diagnosed, along with MRI scans of the brain to screen for suspected agenesis of the corpus callosum. Additional effects on the heart that have been reported with LFS are ventricular and atrial septal defect.

Cause

A missense mutation in the '' MED12'' gene, located on the human X chromosome, has been established as the cause of LFS. Missense mutations are genetic point mutations in which a single nucleotide in the genetic sequence is exchanged with another one. This leads to an erroneously substitution of a particular amino acid in the protein sequence during translation. The missense mutation in the ''MED12'' gene, that causes LFS, is identified as p.N1007S. This indicates that the amino acid asparagine, normally located at position 1007 along the ''MED12'' sequence, has been mistakenly replaced by

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

. This mutation in ''MED12'' causes incorrect expression and activity of the protein it encodes, resulting in the disorder.

Pathophysiology

MED12, or ''mediator of RNA polymerase II transcription, subunit 12 homolog of S. cerevisiae'', is one of several subunits in the mammalian mediator complex, which regulates RNA polymerase II during mRNA transcription. 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. Currently, the exact mechanism by which dysfunction of ''MED12'' 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, a connective tissue disorder. The finding of aortic root dilation in both disorders suggests that a mutation in an unspecified

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...

regulating gene may contribute to the etiology of LFS. A number of interesting experimental results have been obtained by studying ''MED12'' mutations in the zebrafish, an animal model representing vertebrates. In zebrafish, a mutation in ''MED12'' was found to be responsible for the mutant ''motionless'' (''mot''). Zebrafish with the ''mot'' mutation have neuronal and cardiovascular defects, although not all types of neurons are affected. Introduction of human ''MED12'' mRNA into the zebrafish restores normal development. ''MED12'' is also a critical coactivator for the gene ''

SOX9 Transcription factor SOX-9 is a protein that in humans is encoded by the ''SOX9'' gene. Function SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It is expressed by proliferating but no ...

'', which is involved in the developmental regulation of neurons,

cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...

and bone. In the zebrafish, ''MED12'' defects cause maldevelopment of vertebrate embryonic structures such as the neural crest, which would alter function of the autonomic and peripheral nervous systems; and they also cause malformations of cell types serving as precursors to

and bone, such as osteocytes. Some features found in LFS, like agenesis of the corpus callosum and cartilage-related craniofacial anomalies, are similar to defects found in zebrafish with ''MED12'' and associated mutations.

Genetics

Lujan–Fryns syndrome is inherited in an X-linked dominant manner. 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 normally hemizygous for the X chromosome, having only one copy. As a result, X-linked dominant disorders usually show higher expressivity in males than females. This phenomenon is thought to occur with LFS. As the X chromosome is one of the sex chromosomes (the other being the Y chromosome), X-linked inheritance is determined by the gender of the parent carrying a specific gene and can often seem complex. This is because, typically, females have two copies of the X-chromosome, while males have only one copy. The difference between dominant and recessive 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. A scenario such as this would also be possible with X-linked recessive inheritance, but in this particular case report, the girl was believed to be a manifesting heterozygote 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.

Similarities to other genetic diseases

An individual exhibiting intellectual disability and other symptoms similar to LFS was found to have a terminal deletion of the subtelomeric region in the short arm of chromosome 5. Deletion of this area of chromosome 5 is associated with intellectual disability, psychotic behavior, autism, macrocephaly and hypernasal-like speech, as well as the disorder Cri du chat syndrome. Fryns (2006) suggests a detailed examination of chromosome 5 with FISH should be performed as part of the differential diagnosis of LFS. Mutations in the '' UPF3B'' gene, also found on the X chromosome, are another cause of X-linked intellectual disability. ''UPF3B'' is part of the nonsense-mediated mRNA decay (NMD) complex, which performs

mRNA surveillance mRNA surveillance mechanisms are pathways utilized by organisms to ensure fidelity and quality of messenger RNA (mRNA) molecules. There are a number of surveillance mechanisms present within cells. These mechanisms function at various steps of the ...

, detecting mRNA sequences that have been erroneously truncated (shortened) by the presence of nonsense mutations. Mutations in ''UPF3B'' 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. Individuals from two families diagnosed with LFS and one family with FGS were found to have mutations in ''UPF3B'', confirming that the clinical presentations of the different mutations can overlap.

Diagnosis

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 the ''MED12'' gene.

Differential diagnosis

In the

of LFS, another disorder that exhibits some features and symptoms of LFS and is also associated with a missense mutation of ''MED12'' is Opitz-Kaveggia syndrome (FGS). Common features shared by both LFS and FGS include X-linked intellectual disability, hyperactivity, macrocephaly, corpus callosum agenesis and hypotonia. Notable features of FGS that have not been reported with LFS include excessive talkativeness, consistent strength in socialization skills, imperforate anus (occlusion of the

anus The anus (Latin, 'ring' or 'circle') is an opening at the opposite end of an animal's digestive tract from the mouth. Its function is to control the expulsion of feces, the residual semi-solid waste that remains after food digestion, which, d ...

) and ocular hypertelorism (extremely wide-set

eye Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and conv ...

s). Whereas LFS is associated with missense mutation p.N1007S, FGS is associated with missense mutation p.R961W. 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 be

allelic An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...

. In the context of ''MED12'', this suggests that the phenotype of each disorder is related to the way in which their respective mutations alter the ''MED12'' sequence and its function.

Treatment

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.

Epidemiology

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.

History

Lujan–Fryns syndrome is named after physicians J. Enrique Lujan and Jean-Pierre Fryns. The initial observation of suspected X-linked intellectual disability with Marfanoid features and craniofacial effects such as a high-arched palate was described by Lujan et al. in 1984. In the report, four affected male members of a large kindred (

consanguinous Consanguinity ("blood relation", from Latin '' consanguinitas'') is the characteristic of having a kinship with another person (being descended from a common ancestor). Many jurisdictions have laws prohibiting people who are related by blood fro ...

family) were noted. 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. The disorder soon became known as Lujan–Fryns syndrome.

References

External links

{{DEFAULTSORT:Lujan-Fryns syndrome Syndromes with craniofacial abnormalities Syndromes with intellectual disability X-linked dominant disorders Syndromes affecting stature Syndromes affecting the cardiovascular system Rare syndromes