FG syndrome (FGS) is a rare genetic syndrome caused by one or more recessive genes located on the

X chromosome The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...

and causing physical anomalies and developmental delays. FG syndrome was named after the first letters of the surnames of the first patients noted with the disease. First reported by American geneticists John M. Opitz and Elisabeth G. Kaveggia in 1974, its major clinical features include

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

hyperactivity Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple ...

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 it is a potential manifestation of many different dis ...

(low muscle tone), and a characteristic facial appearance including

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 Heredity, familial genetic characteristic. People diagnosed with macrocephaly will receive further medical ...

(an abnormally large head).

Presentation

FG syndrome's major clinical features include physical disability, usually mild; hyperactive behavior, often with a slow personality; severe

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

, with or without structural anomalies in the anus such as

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 unknow ...

;

; severe

; a characteristic facial appearance due to hypotonia, giving a droopy, "open-mouthed" expression, a thin upper lip, a full or pouting lower lip; and most or complete loss of 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 ...

. About a third of reported cases of individuals with FG syndrome die in infancy, usually due to

respiratory infection Respiratory tract infections (RTIs) are infectious diseases involving the lower or upper respiratory tract. An infection of this type usually is further classified as an upper respiratory tract infection (URI or URTI) or a lower respiratory tra ...

; premature death is rare after infancy.

Developmental effects

Associated with agenesis (absence) of the corpus callosum, intellectual disabilities are common among individuals with FG syndrome. Motor ability is also impaired as a result of FG syndrome, and it also affects the development of semen. During childhood, problems arise in the gastrointestinal and gastroesophageal systems of the body. The most common gastrointestinal problems include constipation from an imperforate anus and

gastroesophageal reflux Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or ...

. Cardiopulmonary defects contribute to roughly 60% of premature deaths in infants with FG syndrome. Septal defects are the most common. After infancy, long-term survival has been recorded beyond the age of 50.

Genetics

Most mutations that cause FG syndrome can be found in the ''

MED12 Mediator of RNA polymerase II transcription, subunit 12 homolog (S. cerevisiae), also known as MED12, is a human gene found on the X chromosome. Clinical significance Mutations in ''MED12'' are responsible for at least two different forms of X ...

'' gene. However, mutations have also been found in ''

FMR1 ''FMR1'' (Fragile X Messenger Ribonucleoprotein 1) is a human gene that codes for a protein called ''fragile X messenger ribonucleoprotein'', or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive developmen ...

'', ''

FLNA Filamin A, alpha (FLNA) is a protein that in humans is encoded by the ''FLNA'' gene. Structure The structure of Filamin A, alpha includes an actin binding N terminal domain, 24 internal repeats and 2 hinge regions. Function Actin-binding p ...

'', '' UPF3B'', ''

CASK A barrel or cask is a hollow cylindrical container with a bulging center, longer than it is wide. They are traditionally made of wooden staves and bound by wooden or metal hoops. The word vat is often used for large containers for liquids ...

'', '' MECP2'' and ''

ATRX Transcriptional regulator ATRX also known as ATP-dependent helicase ATRX, X-linked helicase II, or X-linked nuclear protein (XNP) is a protein that in humans is encoded by the ''ATRX'' gene. Function Transcriptional regulator ATRX contains an ...

'' genes. Mutations on these different genes lead to the different types of FG syndrome, all with similar characteristics. The FGS8 type mutation is the most common of the types, and is found in the ''MED12'' gene. Known types and affected genes include:

''MED12'' gene

The ''MED12'' gene codes for the mediator complex subunit 12 protein. The

mediator complex Mediator is a multiprotein complex that functions as a transcriptional coactivator in all eukaryotes. It was discovered in 1990 in the lab of Roger D. Kornberg, recipient of the 2006 Nobel Prize in Chemistry. Mediator complexes interact with tr ...

is composed of around 25 different proteins that all help with the

regulation Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. Fo ...

of gene activity. This mediator complex regulates gene expression by bridging interaction between

RNA polymerase II RNA polymerase II (RNAP II and Pol II) is a Protein complex, multiprotein complex that Transcription (biology), transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNA pol ...

and gene-specific regulating proteins such as

transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...

repressor proteins In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...

, activator proteins, etc. Changes to this complex and the proteins associated can have a severe impact on the production of new proteins. The ''MED12'' gene is also thought to be highly linked to neuron development as well as high usage in the cells

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...

pathway. This explains the slowed intellectual development individuals with FG syndrome have.

Diagnosis

There is no established clinical diagnostic criteria for FG syndrome. A healthcare professional might consider the following clinical features in an individual as indicative for further evaluation: * Neurodevelopmental delays * A family history consistent with X-linked inheritance * Characteristic facial features ** Absolute or relative macrocephaly ** Dolichocephaly ** Frontal hair upsweep ** Very large forehead ** Downslanted palpebral fissures ** far apart eyes ** Missing part of the upper eyelids ** Small, simple ears (≤10th percentile) ** Open mouth ** Long wide face * Broad thumbs and halluces * Congenital anomaly (corpus callosum, anal, cardiac, skeletal) * Hypotonia, constipation, or feeding problems * Characteristic behavior (affable and eager to please)

Treatment

Treatment for FG Syndrome is individualized to each person. It generally involves a team of specialists to manage the symptoms.

History

The name of the syndrome comes from the initials of the surnames of two sisters, who had five sons with the syndrome. The first study of the syndrome, published in 1974, established that it was linked to inheritance of the

References

External links

{{X-linked disorders X-linked recessive disorders Rare syndromes