Lujan–Fryns syndrome (LFS) is an

X-linked Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

that causes mild to moderate

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...

and features described as

Marfanoid habitus Marfanoid (or Marfanoid habitus) is a constellation of 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 high arc ...

, 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 psychopathol ...

and

behavioral Behavior (American English) or behaviour (British English) is the range of actions and mannerisms made by individuals, organisms, systems or artificial entities in some environment. These systems can include other systems or organisms as we ...

abnormalities, and it exhibits a number of malformations affecting the

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

and

heart The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...

. The disorder is inherited in an

X-linked dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type ...

manner, and is attributed to a

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

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

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 The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental m ...

(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 ...

ian

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 ...

s that allows communication between the left and right cerebral hemispheres) is not present. Among a number of adverse

neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...

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 Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

hyperactivity Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inappr ...

and

attention-deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inappr ...

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 pr ...

, extreme

shyness Shyness (also called diffidence) is the feeling of apprehension, lack of comfort, or awkwardness especially when a person is around other people. This commonly occurs in new situations or with unfamiliar people; a shy person may simply opt ...

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 Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. The term may describe * deficits in overall intelligence (as with intellectual disabilities), * specific and restricted defici ...

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 Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues ...

, attributed to

psychogenic A psychogenic effect is one that originates from the brain instead of other physical organs (i.e. the cause is psychological rather than physiological) and may refer to: * Psychogenic pain *Psychogenic disease * Psychogenic amnesia *Psychogenic co ...

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 Pyromania is an impulse control disorder in which individuals repeatedly fail to resist impulses to deliberately start fires, to relieve some tension or for instant gratification. The term ''pyromania'' comes from the Greek word (''pyr'', 'fi ...

. While

psychiatric Psychiatry is the medical specialty devoted to the diagnosis, prevention, and treatment of mental disorders. These include various maladaptations related to mood, behaviour, cognition, and perceptions. See glossary of psychiatry. Initial psy ...

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 Intelligence has been defined in many ways: the capacity for abstraction, logic, understanding, self-awareness, learning, emotional knowledge, reasoning, planning, creativity, critical thinking, and problem-solving. More generally, it can ...

. 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; long, slender limbs,

finger A finger is a limb of the body and a type of digit, an organ of manipulation and sensation found in the hands of most of the Tetrapods, so also with humans and other primates. Most land vertebrates have five fingers ( Pentadactyly). Chamber ...

s and toes (not unlike arachnodactyly) with

joint A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw- ...

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 ...

Head and face

Craniofacial and other features of LFS include:

maxilla The maxilla (plural: ''maxillae'' ) in vertebrates is the upper fixed (not fixed in Neopterygii) bone of the jaw formed from the fusion of two maxillary bones. In humans, the upper jaw includes the hard palate in the front of the mouth. T ...

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 bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

), a small

mandible In anatomy, the mandible, lower jaw or jawbone is the largest, strongest and lowest bone in the human facial skeleton. It forms the lower jaw and holds the lower teeth in place. The mandible sits beneath the maxilla. It is the only movable bone ...

(lower jaw bone) and receding

chin The chin is the forward pointed part of the anterior mandible ( 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 well-developed chin is considered to be one ...

, a high-arched

palate The palate () is the roof of the mouth in humans and other mammals. It separates the oral cavity from the nasal cavity. A similar structure is found in crocodilians, but in most other tetrapods, the oral and nasal cavities are not truly separ ...

(the roof of the mouth), with crowding and misalignment of the upper

teeth A tooth ( : teeth) is a hard, calcified structure found in the jaws (or mouths) of many vertebrates and used to break down food. Some animals, particularly carnivores and omnivores, also use teeth to help with capturing or wounding prey, ...

;

macrocephaly Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...

(enlarged

skull The skull is a bone protective cavity for the brain. The skull is composed of four types of bone i.e., cranial bones, facial bones, ear ossicles and hyoid bone. However two parts are more prominent: the cranium and the mandible. In humans, th ...

) 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 fo ...

, hypernasal

speech Speech is a human vocal communication using language. Each language uses 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 they are th ...

(

voice The human voice consists of sound made by a human being using the vocal tract, including talking, singing, laughing, crying, screaming, shouting, humming or yelling. The human voice frequency is specifically a part of human sound producti ...

), a long

nose A nose is a protuberance in vertebrates that houses the nostrils, or nares, which receive and expel air for respiration alongside the mouth. Behind the nose are the olfactory mucosa and the sinuses. Behind the nasal cavity, air next passe ...

with a high, narrow nasal bridge; a deep, short

philtrum The philtrum ( la, philtrum from Ancient Greek ''phíltron,'' lit. "love charm"), or medial cleft, is a vertical indentation in the middle area of the upper lip, common to therian mammals, extending in humans from the nasal septum to the tuberc ...

(the indentation in the upper lip, beneath the nose), low-set ears with some apparent retroversion,

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...

(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 mus ...

tone), pectus excavatum (a malformity of the

chest The thorax or chest is a part of the anatomy of humans, mammals, and other tetrapod animals located between the neck and the abdomen. In insects, crustaceans, and the extinct trilobites, the thorax is one of the three main divisions of the crea ...

), slightly enlarged to normal

testicular A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testosteron ...

size in males, and

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...

s. Hypernasal speech, or "hypernasality", is primarily the result of

velopharyngeal insufficiency Velopharyngeal insufficiency is a disorder of structure that causes a failure of the velum (soft palate) to close against the posterior pharyngeal wall (back wall of the throat) during speech in order to close off the nose (nasal cavity) during o ...

, 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 A sphincter is a circular muscle that normally maintains constriction of a natural body passage or orifice and which relaxes as required by normal physiological functioning. Sphincters are found in many animals. There are over 60 types in the h ...

allows too much air into the

nasal cavity The nasal cavity is a large, air-filled space above and behind the nose in the middle of the face. The nasal septum divides the cavity into two cavities, also known as fossae. Each cavity is the continuation of one of the two nostrils. The nasal ...

during speech. In LFS, hypernasality may also be caused by failure of the

soft palate The soft palate (also known as the velum, palatal velum, or muscular palate) is, in mammals, the soft tissue constituting the back of the roof of the mouth. The soft palate is part of the palate of the mouth; the other part is the hard palat ...

and

uvula The palatine uvula, usually referred to as simply the uvula, is a conic projection from the back edge of the middle of the soft palate, composed of connective tissue containing a number of racemose glands, and some muscular fibers. It also conta ...

to reach the back wall of the

pharynx The pharynx (plural: pharynges) is the part of the throat behind the mouth and nasal cavity, and above the oesophagus and trachea (the tubes going down to the stomach and the lungs). It is found in vertebrates and invertebrates, though its st ...

(the interior cavity of the

throat In vertebrate anatomy, the throat is the front part of the neck, internally positioned in front of the vertebrae. It contains the pharynx and larynx. An important section of it is the epiglottis, separating the esophagus from the trachea (windpip ...

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 in various organs of the gastrointestinal, respiratory, and genitourinary tracts. It is the layer of dense irregular connective tissue that supports the mucosa (mucous membrane) and j ...

cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...

Heart

A number of features involving the

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 aorti ...

. As this presents a possible life-threatening consequence of LFS, routine

cardiac The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

evaluation methods such as

echocardiogram An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart. It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound. Echocardiography has become routinely used in th ...

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 Atrial septal defect (ASD) is a congenital heart defect in which blood flows between the atria (upper chambers) of the heart. Some flow is a normal condition both pre-birth and immediately post-birth via the foramen ovale; however, when this d ...

Cause

in the '' MED12'' gene, located on the human

X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex ...

, has been established as the cause of LFS. Missense mutations are genetic

point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...

s in which a single

nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...

in the genetic sequence is exchanged with another one. This leads to an erroneously substitution of a particular

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

in the

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

sequence during

translation Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...

. The missense mutation in the ''MED12'' gene, that causes LFS, is identified as p.N1007S. This indicates that the amino acid

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

, 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 − for ...

. 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 RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of euka ...

during

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

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 A connective tissue disease (collagenosis) is any disease that has the connective tissues of the body as a target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds togeth ...

. 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 The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...

, an

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

representing

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with ...

s. 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 n ...

'', 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 ...

and

. In the zebrafish, ''MED12'' defects cause maldevelopment of vertebrate embryonic structures such as the

neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...

, which would alter function of the autonomic and

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brai ...

s; and they also cause malformations of

cell type A cell type is a classification used to identify cells that share morphological or phenotypical features. A multicellular organism may contain cells of a number of widely differing and specialized cell types, such as muscle cells and skin cell ...

s serving as precursors to

and

, such as

osteocyte An osteocyte, an oblate shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide an ...

s. 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

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 Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

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 chromosome A sex chromosome (also referred to as an allosome, heterotypical chromosome, gonosome, heterochromosome, or idiochromosome) is a chromosome that differs from an ordinary autosome in form, size, and behavior. The human sex chromosomes, a typical ...

s (the other being the

Y chromosome The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abs ...

), X-linked inheritance is determined by the

gender Gender is the range of characteristics pertaining to femininity and masculinity and differentiating between them. Depending on the context, this may include sex-based social structures (i.e. gender roles) and gender identity. Most culture ...

of the parent carrying a specific gene and can often seem complex. This is because, typically,

female Female ( symbol: ♀) is the sex of an organism that produces the large non-motile ova (egg cells), the type of gamete (sex cell) that fuses with the male gamete during sexual reproduction. A female has larger gametes than a male. Fema ...

s have two copies of the X-chromosome, while

male Male (symbol: ♂) is the sex of an organism that produces the gamete (sex cell) known as sperm, which fuses with the larger female gamete, or ovum, in the process of fertilization. A male organism cannot reproduce sexually without access to ...

s have only one copy. The difference between dominant and

recessive In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...

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 X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...

inheritance, but in this particular case report, the girl was believed to be a manifesting

heterozygote Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. M ...

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 Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. Ch ...

. 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 Cri du chat syndrome is a rare genetic disorder due to a partial chromosome deletion on chromosome 5. Its name is a French term ("cat-cry" or " call of the cat") referring to the characteristic cat-like cry of affected children. It was first de ...

. Fryns (2006) suggests a detailed examination of chromosome 5 with

FISH Fish are Aquatic animal, aquatic, craniate, gill-bearing animals that lack Limb (anatomy), limbs with Digit (anatomy), digits. Included in this definition are the living hagfish, lampreys, and Chondrichthyes, cartilaginous and bony fish as we ...

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 Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberrant ...

(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 An imperforate anus or anorectal malformations (ARMs) are birth defects in which the rectum is malformed. ARMs are a spectrum of different congenital anomalies which vary from fairly minor lesions to complex anomalies. The cause of ARMs is unkno ...

(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, ...

) and ocular hypertelorism (extremely wide-set eyes). 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 chrom ...

. 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

physician A physician (American English), medical practitioner (Commonwealth English), medical doctor, or simply doctor, is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through th ...

s 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

was described by Lujan et al. in 1984. In the report, four affected male members of a large kindred ( consanguinous 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