Hereditary gingival fibromatosis (HGF), also known as idiopathic gingival hyperplasia, is a rare condition of

gingival overgrowth Gingival enlargement is an increase in the size of the gingiva (gums). It is a common feature of gingival disease. Gingival enlargement can be caused by a number of factors, including inflammatory conditions and the side effects of certain medica ...

.Poulami Majumder, Vineet Nair, Malancha Mukherjee, Sujoy Ghosh, and Subrata Kumar Dey, "The Autosomal Recessive Inheritance of Hereditary Gingival Fibromatosis", Case Reports in Dentistry, vol. 2013, Article ID 432864, 4 pages, 2013. doi:10.1155/2013/432864 HGF is characterized as a

benign Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

, slowly progressive, nonhemorrhagic, fibrous enlargement of keratinized

gingiva The gums or gingiva (plural: ''gingivae'') consist of the mucosal tissue that lies over the mandible and maxilla inside the mouth. Gum health and disease can have an effect on general health. Structure The gums are part of the soft tissue lini ...

. It can cover teeth in various degrees, and can lead to

aesthetic Aesthetics, or esthetics, is a branch of philosophy that deals with the nature of beauty and taste, as well as the philosophy of art (its own area of philosophy that comes out of aesthetics). It examines aesthetic values, often expressed th ...

disfigurement.Thomas C. Hart, Yingze Zhang, Michael C. Gorry, P. Suzanne Hart, Margaret Cooper, Mary L. Marazita, Jared M. Marks, Jose R. Cortelli, Debora Pallos Am J Hum Genet. 2002 April; 70(4): 943–954. Published online 2002 February 26. Fibrous enlargement is most common in areas of

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. The t ...

ry and

mandibular 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 tooth, teeth in place. The mandible sits beneath the maxilla. It is the only movabl ...

tissues of both arches in the

mouth In animal anatomy, the mouth, also known as the oral cavity, or in Latin cavum oris, is the opening through which many animals take in food and issue vocal sounds. It is also the cavity lying at the upper end of the alimentary canal, bounded on ...

Phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

and

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

frequency of HGF is 1:175,000 where males and females are equally affected but the cause is not entirely known.K. B. Butchi, K. Pavankumar, B. R. Anuradha, and N. Arora, "Hereditary gingival fibromatosis—a case report and management using a novel surgical technique," Revista Sul-Brasileira de Odontologia, vol. 8, no. 4, pp. 453–458, 2011. It mainly exists as an isolated abnormality but can also be associated with a multi-system syndrome.

Signs and symptoms

There may or may not be any evidence of history of HGF in the family nor any usage of taking long-term medicines for any particular disease when it comes to diagnosing HGF. There also may or may not be any signs of medical and/or family history of

mental retardation 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 signific ...

hypertrichosis Hypertrichosis is an abnormal amount of hair growth over the body. The two distinct types of hypertrichosis are generalized hypertrichosis, which occurs over the entire body, and localized hypertrichosis, which is restricted to a certain area. ...

, nor clinical symptoms that can be associated with gingival enlargement. Although, enlargement of gingiva,

interdental papilla The interdental papilla, also known as the interdental gingiva, is the part of the gums (gingiva) that exists coronal to the free gingival margin on the buccal and lingual surfaces of the teeth A tooth ( : teeth) is a hard, calcified struct ...

, hindered speech, and secondary inflammatory changes taking place in the mouth commonly at the marginal gingiva are all very indicative of this condition. Commonly the patient will have mandibular and maxilliary

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

and overgrowth as opposed to the traditional pink, firm, and fleshy consistency of healthy gingiva. The patient's jaw may also appear distorted because of the gingiva enlargements. Overgrowth of the gingiva can range from slightly covering the surface of teeth or it can even completely cover the surrounding teeth. The patient can also experience damage or loss of teeth.Smith RG (1997) Gingival recession: reappraisal of an enigmatic condition and a new index for monitoring. J Clin Periodontol 24:201–205.Scannapieco FA (1998) Position paper of The American Academy of Periodontology: periodontal disease as a potential risk factor for systemic diseases. J Periodontol 69:841–850.R. D. Coletta and E. Graner, "Hereditary gingival fibromatosis: a systematic review," Journal of Periodontology, vol. 77, no. 5, pp. 753–764, 2006.View at Publisher • View at Google Scholar • View at Scopus.S. L. Singer, J. Goldblatt, L. A. Hallam, and J. C. Winters, "Hereditary gingival fibromatosis with a recessive mode of inheritance. Case reports", Australian Dental Journal, vol. 38, no. 6, pp. 427–432, 1993. View at Scopus.

Obvious signs

* Most obvious sign is gingival overgrowth (overgrowth of the gums) * Hindered chewing efficiency and difficulties eating * Increasing

mobility Mobility may refer to: Social sciences and humanities * Economic mobility, ability of individuals or families to improve their economic status * Geographic mobility, the measure of how populations and goods move over time * Mobilities, a conte ...

of teeth * Abnormally shaped teeth and abnormal movement of teeth * Inflammation and/or swelling of the gums/gingiva * Not necessarily any signs of pain but experiencing pain is possible * Difficulties in speaking, oftentimes can lead to

speech disorders Speech disorders or speech impairments are a type of communication disorder in which normal speech is disrupted. This can mean stuttering, lisps, etc. Someone who is unable to speak due to a speech disorder is considered mute. Speech skills ar ...

* Other dental and oral problems * In some cases, Hereditary Gingival Fibromatosis may cause bleeding from the gums, or gum ulcerations.

Cause

Though much more research needs to be done, researchers have mostly agreed that a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

SOS1 Son of sevenless homolog 1 is a protein that in humans is encoded by the ''SOS1'' gene. Function SOS1 is a guanine nucleotide exchange factor (GEF) which interacts with RAS proteins to phosphorylate GDP into GTP, or from an inactive state to an ...

, son-of-sevenless gene, is responsible for this disease.S. DeAngelo, J. Murphy, L. Claman, J. Kalmar, and B. Leblebicioglu, "Hereditary gingival fibromatosis—a review", Compendium of Continuing Education in Dentistry, vol. 28, no. 3, pp. 138–143, 2007. View at ScopusR. J. Jorgenson and M. E. Cocker, "Variation in the inheritance and expression of gingival fibromatosis", Journal of Periodontology, vol. 45, no. 7, pp. 472–477, 1974. View at ScopusA. Poulopoulos, D. Kittas, and A. Sarigelou, "Current concepts on gingival fibromatosis-related syndromes", Journal of Investigative and Clinical Dentistry, vol. 2, no. 3, pp. 156–161, 2011. View at Publisher • View at Google Scholar

is a

guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...

nucleotide-exchange factor that functions in the transduction of signals that control

cell growth Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...

and differentiation. A mutation in the

gene results in 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 biomolecules wi ...

insertion. Specific linkage studies have localized the

for isolated, nonsyndromic

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

dominant forms of gingival

fibromatosis The term fibromatosis refers to a group of soft tissue tumors which have certain characteristics in common, including absence of cytologic and clinical malignant features, a histology consistent with proliferation of well-differentiated fibroblast ...

chromosomes A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

2 and 5, more specifically 2p21-p22 and 5q13-q22.

Genetic

HGF1 - Caused by a mutation in the

gene localized on chromosome 2p21-p22 HGF2 - Caused by a mutation in the

gene localized on chromosome 5q13-q22 Mutations in the

RE1-silencing transcription factor RE1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a protein which in humans is encoded by the ''REST'' gene, and acts as a transcriptional repressor. REST is expressly involved in the repressi ...

(REST) gene can also cause this syndrome.Bayram Y, White JJ, Elcioglu N, Cho MT, Zadeh N, Gedikbasi A, Palanduz S, Ozturk S, Cefle K, Kasapcopur O, Coban Akdemir Z, Pehlivan D, Begtrup A, Carvalho CMB, Paine IS, Mentes A, Bektas-Kayhan K, Karaca E, Jhangiani SN, Muzny DM, Baylor-Hopkins Center for Mendelian Genomics, Gibbs RA, Lupski JR (2017) REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis. Am J Hum Genet 101(1):149-156

Non genetic

HGF may also be caused by unwanted side effects of pharmacological agents like

phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The intr ...

ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...

, and some calcium-channel blockers, meaning HGF is a disease that can be drug-induced. However, there is little next to no research done in this area to support the claim. *

Inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

U. Khan, S. Mustafa, Z. Saleem, A. Azam, and Z. A. Khan, "Hereditary gingival fibromatosis diagnosis and treatment", Pakistan Oral and Dental Journal, vol. 32, no. 2, pp. 226–231, 2012. *

Hormonal A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required fo ...

Imbalance *

Neoplasia A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

* More commonly associated with an autosomal dominant gene inheritance * Multi-system syndromes: Zimmerman-Laband syndrome, Jones syndrome, Ramon syndrome, Rutherford syndrome, juvenile hyaline fibromatosis, systemic infantile hyalinosis, and mannosidosisT. Ramakrishnan and Manmeet Kaur, "Multispeciality Approach in the Management of Patient with Hereditary Gingival Fibromatosis: 1-Year Followup: A Case Report", Hindawi Publishing Corporation International Journal of Dentistry, Volume 2010, Article ID 575979, doi:10.1155/2010/575979 * Some unknown causes

Mechanism

Genetic linkage studies are among the most popular methods of study to look at the mechanism of this HGF. Genetic linkage studies have found to localize genetic loci for autosomal dominant forms of HGF to chromosome 2p21-p22 (indicative of HGF1) and chromosome 5q13-q22 (indicative of HGF2). Chromosome 2p21-p22 has been refined to an interval of ~2.3 Mb to construct an integrated physical and genetic map of the 16 genes interval. Here, a mutation is found in sequencing these 16 genes. There is an insertion of a cytosine between nucleotides 126,142 and 126,143 in codon 1083 of the

gene, meaning there is a mutation in

. This causes a problem because

introduces a frameshift mutation and creates a premature stop codon. Also, it can segregate over generations, most commonly four. Once it causes a premature stop codon, the chromosome loses four important

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

-rich SH-3 binding domains in the carboxyl-terminal region of 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, respo ...

. As a result, the N-terminal

amino acids 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 am ...

for

is fused into a 22–amino acid carboxyl terminus. Researchers claim that this mutation in the

gene is a probable primary cause of this disease but limited information supports the mechanism of this claim.

Diagnosis

There are very few ways to test a patient for HGF. Currently, the most common way to diagnose a patient is by means of a physical evaluation. The physician can make a physical evaluation of the patient and send them to a dentist or better yet a specialist like a periodontist to evaluate signs of gingival overgrowth, quality of gingiva, inflammation, mechanical difficulties of the mouth, tooth conditions, and any sort of discomfort. Aside from obvious physical symptoms seen in a physical evaluation, molecular tests can be run to check if there is a mutation in the

gene to confirm the diagnosis. If there is indeed a mutation in this gene coupled with the typical physical symptoms, then it is quite probable that a patient suffers from this disease. Also, looking at family history is also becoming more prominent in aiding to diagnose the patient. Otherwise, researchers are working to find new and better ways to test for the presence of HGF.

Prevention

Since this condition is generally agreed upon to be

hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...

, nothing can be done to prevent HGF. However, in some cases where it can develop as a result of rare multi-system syndromes, such as: Zimmerman-Laband, Jones, Ramon Syndrome, Rutherford Syndrome, Juvenile Hyaline Fibromatosis, Systemic Infantile Hyalinosis, and Mannosidosis, it is best for one to simply monitors the possible progression for HGF with regular dental check-ups. If the patient's disease is treated by means of surgery, it is recommended that the patient undergoes post-surgical therapies for maintenance and periodic monitoring of gums for the sake of the possibility of re-occurrence of HGF.

Treatment

This disease has not been shown to be life-threatening or the cause of death in patients. However, treatment is necessary to maintain a healthy lifestyle.

If left untreated

The following can occur if left untreated: * Too much gingiva exposure * * Oral

morbidity A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

* * Chronic

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

of areas between the gums and teeth, or at the gum line * * various degrees of

Periodontitis Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main cau ...

- most likely due to the inability and difficulty of keeping the gingival margin and surrounding tissue clean due to the overgrowth * * Improper

tooth eruption Tooth eruption is a process in tooth development in which the teeth enter the mouth and become visible. It is currently believed that the periodontal ligament plays an important role in tooth eruption. The first human teeth to appear, the decidu ...

and/or complete prevention of tooth eruption as a result of too much gingiva exposure * * Systemic every-day troubles including functional and aesthetic problems of the mouth * *

Malocclusion In orthodontics, a malocclusion is a misalignment or incorrect relation between the teeth of the upper and lower dental arches when they approach each other as the jaws close. The English-language term dates from 1864; Edward Angle (1855-1930), ...

Treatment

Most recent methods of treatment take the form of surgeries such as oral

prophylaxis Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...

, followed by post-surgical therapies to monitor, provide proper oral hygiene, and correct the deformity. Although, the nature of recurrence post-treatment is virtually unknown, let alone what type of treatment is most effective for HGF. (SOURCE 2) In some cases, there is re-growth after surgical removal of the excess gingival tissues, in others there is minimal. No cases yet have shown any particular treatment or form of medicine to permanently remove HGF. One type of procedure that can be executed is as follows: Removal of excess tissue under

anesthesia Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), ...

through an internal bevel

gingivectomy Gingivectomy is a dental procedure in which a dentist or oral surgeon cuts away part of the gums in the mouth (the '' gingiva''). It is the oldest surgical approach in periodontal therapy and is usually done for improvement of aesthetics or p ...

or undisplaced

flap Flap may refer to: Arts, entertainment, and media * ''Flap'' (film), a 1970 American film * Flap, a boss character in the arcade game ''Gaiapolis'' * Flap, a minor character in the film '' Little Nemo: Adventures in Slumberland'' Biology and he ...

followed by gingivoplasty and continuous sling suture placements and periodontal dressing; after about a week of recovery after the surgery, remove sutures and periodically do observational evaluations to look for any signs of re-occurrence.

Recent research

Some researchers suggest that HGF is transmitted as a Mendelian trait since both

autosomal dominant 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 and t ...

and

autosomal 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 and t ...

transmission has been reported since the early 1970s. (SOURCE 1) In more recent scientific literature, there is evidence in which pedigree analyses confirm autosomal dominant, autosomal recessive or even as

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, ...

inherited cases of the HGF trait. In 2002, researchers described the

gene and proved for the first time that a single-nucleotide–insertion mutation of the

gene on codon 1083 is the preliminary cause of HGF1 in humans. (Source 1) Later on in 2010, there was a case study done on a 16-year-old male with severe gingival overgrowth, almost covering all teeth. Researchers approached this issue with

periodontics Periodontology or periodontics (from Ancient Greek , – 'around'; and , – 'tooth', genitive , ) is the specialty of dentistry that studies supporting structures of teeth, as well as diseases and conditions that affect them. The supporting ...

- a partial

and flap surgery. This case study concluded that surgery followed by regular follow-ups is a good way to treat HGF despite the fact that the risks of re-occurrence of the condition remain high. Even more recently, a study was done in 2013 on a family that showed history of autosomal recessive inheritance of HGF. The study did not dismiss the return of HGF after treatment but did claim that general surgical intervention after scaling and

root In vascular plants, the roots are the organs of a plant that are modified to provide anchorage for the plant and take in water and nutrients into the plant body, which allows plants to grow taller and faster. They are most often below the sur ...

planning of teeth supplemented with good

oral hygiene Oral hygiene is the practice of keeping one's mouth clean and free of disease and other problems (e.g. bad breath) by regular brushing of the teeth (dental hygiene) and cleaning between the teeth. It is important that oral hygiene be carried out ...

is good enough to prevent the re-occurrence of HGF. This case study also acknowledged how HGF can be part of a multi-system syndrome associated with disorders such as Zimmermann Laband syndrome (ear, nose, bone, and nail defects with hepatosplenomegaly), Rutherford syndrome (microphthalmia, mental retardation, athetosis, and hypopigmentation), Murray-Puretic Drescher syndrome and Ramon syndrome.

Signs and symptoms

Obvious signs

Cause

Genetic

Non genetic

Mechanism

Diagnosis

Prevention

Treatment

If left untreated

Treatment

Recent research

See also