Fumarase deficiency (or fumaric aciduria) is an autosomal recessive metabolic disorder characterized by a deficiency of the enzyme fumarate hydratase, which is indicated by a build up of fumaric acid in the urine.

Fumarase deficiency is caused by a mutation in the fumarate hydratase (FH) gene in humans, which encodes the enzyme that converts fumarate to malate in the mitochondria. Other mutant alleles of the FH gene, located on human Chromosome 1 at position 1q42.1, cause multiple cutaneous and uterine leiomyomata, hereditary leiomyomatosis and renal cell cancer. [1] Fumarase deficiency is one of the few known deficiencies of the Krebs cycle or tricarboxylic acid cycle, the main enzymatic pathway of cellular aerobic respiration.[2]

The condition is an autosomal recessive disorder,[3] and it is therefore usually necessary for an affected individual to receive the mutant allele from both parents. A number of children diagnosed with the disorder have been born to parents who were first cousins.[4][5] It can also be associated with uniparental isodisomy.[6]

Fumarase deficiency causes encephalopathy,[7] severe mental retardation, unusual facial features, brain malformation, and epileptic seizures[8] due to an abnormally low amount of fumarase in cells.

Fumarase deficiency is extremely rare, with only thirteen diagnosed and identified cases worldwide until roughly 1990. Since then an additional twenty cases have been documented in the Arizona/Utah border towns of Colorado City, Arizona, and Hildale, Utah, settled in the 1930s by the Fundamentalist Church of Jesus Christ of Latter Day Saints a church that gradually split from The Church of Jesus Christ of Latter-day Saints beginning in 1890.[9] [10]

Theodore Tarby, a pediatric neurologist who has treated some of the community’s fumarase deficient residents, has been quoted as estimating the IQ of his patients as around 25.[11]. While treating a child with a developmental disability Tarby sent off a urine sample for testing and learned the child had a disorder so rare that only 13 other current cases were known worldwide.[12] Tarby later learned the child he treated had a sibling who had been diagnosed with cerebral palsy, a disease commonly associated with developmental difficulties. This sibling also turned out to have fumarase deficiency.[9]

According to the Phoenix New Times, the rare disease appeared when Martha Jessop, the daughter of Joseph Smith Jessop, one of the founders of the community, married her second cousin, John Yeates Barlow, in 1923.[9] Tarby and fellow researchers at Barrow Neurological Institute at St. Joseph’s Hospital in Phoenix have found that the highest incidence of the disease recorded anywhere appears in the population of polygamists living in these two towns.[9]

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Fucosidosis, also called alpha-l-fucosidase deficiency,[1] is a rare autosomal recessive[2] lysosomal storage disease[3] in which the enzyme fucosidase is not properly used in the cells to break down fucose. This enzyme normally cleaves long sugar chains known as oligosaccharides in the lysosome. When the enzyme is absent, sugar chains accumulate and eventually lead to the clinical features of Fucosidosis. The symptoms of this disorder may progress in degrees of severity over time.

Focosidosis is one of nine identified Glycoprotein Storage Diseases. The gene encoding the alpha-fucosidase, FUCA 1, was found to be located to the short arm of chromosome 1, by Carrit and co-workers, in 1982.

There are two different types of Fucosidosis, Type I and Type II, characterized by the age of onset and by the types of physical and mental manifestations of the disorder.

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Freeman-Sheldon syndrome (FSS), also termed distal arthrogryposis type 2A (DA2A), craniocarpotarsal dysplasia (or dystrophy), or whistling-face syndrome, was originally described by Freeman and Sheldon in 1938.[1] Freeman-Sheldon syndrome is a rare form of multiple congenital contracture (MCC) syndromes (arthrogryposes) and is the most severe form of distal arthrogryposis (DA).[2][3][4]

The symptoms of Freeman-Sheldon syndrome include drooping of the upper eyelids, strabismus, low-set ears, a long philtrum, gradual hearing loss, scoliosis, and walking difficulties. Gastroesophageal reflux has been noted during infancy, but usually improve with age. The tongue may be small, and the limited movement of the soft palate may cause nasal speech. Often there is an H- or Y-shaped dimpling of the skin over the chin. There is no laboratory test that can diagnose Freeman-Sheldon syndrome– research continues. Chromosome tests are usually normal.

Freeman-Sheldon syndrome is a type of distal arthrogryposis, related to distal arthrogryposis type 1 (DA1).[5] In 1996, more strict criteria for the diagnosis of Freeman-Sheldon syndrome were drawn up, assigning Freeman-Sheldon syndrome as distal arthrogryposis type 2A (DA2A).[4]

On the whole, DA1 is the least severe; DA2B is more severe with additional features that respond less favourably to therapy. DA2A (Freeman-Sheldon syndrome) is the most severe of the three, with more abnormalities and greater resistance to therapy.[4]

Freeman-Sheldon syndrome has been described as a type of congenital myopathy.[6]

In March 2006, Stevenson et al. published strict diagnostic criteria for distal arthrogryposis type 2A (DA2A) or Freeman-Sheldon syndrome. These included two or more features of distal arthrogryposis: microstomia, whistling-face, nasolabial creases, and ‘H-shaped’ chin dimple.[3]

FSS is caused by genetic changes. Krakowiak et al (1998) mapped the distal arthrogryposis multiplex congenita (DA2B; MIM #601680) gene, a syndrome very similar in phenotypic expression to classic FSS, to 11p15.5-pter.[7][8] Other mutations have been found as well.[9][10] In FSS, inheritance may be either autosomal dominant, most often demonstrated.[11][12][13] or autosomal recessive (MIM 277720).[14][15][16][17] Alves and Azevedo (1977) note most reported cases of DA2A have been identified as new allelic variation.[18] Toydemir et al (2006) showed that mutations in embryonic myosin heavy chain 3 (MYH3; MIM *160270), at 17p-13.1-pter, caused classic FSS phenotype, in their screening of 28 (21 sporadic and 7 familial) probands with distal arthrogryposis type 2A.[19][20] In 20 patients (12 and 8 probands, respectively), missense mutations (R672H; MIM *160270.0001 and R672C; MIM *160270.0002) caused substitution of arg672, an embryonic myosin residue retained post-embryonically.[19][20][20] Of the remaining 6 patients in whom they found mutations, 3 had missense private de novo (E498G; MIM *160270.0006 and Y583S) or familial mutations (V825D; MIM *160270.0004); 3 other patients with sporadic expression had de novo mutations (T178I; MIM *160270.0003), which was also found in DA2B; 2 patients had no recognized mutations.[19][20]

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Follicular thyroid cancer is a form of thyroid cancer which occurs more commonly in women of over 50 years old. Thyroglobulin (Tg) can be used as a tumor marker for well-differentiated follicular thyroid cancer.

It is not possible to distinguish between follicular adenoma and carcinoma on cytological grounds. If fine needle aspiration cytology (FNAC) suggests follicular neoplasm, thyroid lobectomy should be performed to establish the histopathological diagnosis.

HMGA2 has been proposed as a marker to identify malignant tumors.[1]

Treatment is usually surgical, followed by radioiodine.

Minimally invasive thyroidectomy has been used in recent years in cases where the nodules are small.[3]

Some studies have shown that thyroglobulin (Tg) testing combined with neck ultrasound is more productive in finding disease recurrence than full- or whole-body scans (WBS) using radioactive iodine. However, current protocol (in the USA) suggests a small number of clean annual WBS are required before relying on Tg testing plus neck ultrasound. When needed, whole body scans consist of withdrawal from thyroxine medication and/or injection of recombinant human Thyroid stimulating hormone (TSH). In both cases, a low iodine diet regimen must also be followed to optimize the takeup of the radioactive iodine dose. Low dose radioiodine of a few millicuries is administered. Full body nuclear medicine scan follows using a gamma camera. Scan doses of radioactive iodine may be I131 or I123.

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Flat feet (also called pes planus or fallen arches) is an informal reference to a medical condition in which the arch of the foot collapses, with the entire sole of the foot coming into complete or near-complete contact with the ground. In some individuals (an estimated 20–30% of the general population) the arch simply never develops in one foot (unilaterally) or both feet (bilaterally).[citation needed] It should be noted that being flatfooted does not decrease footspeed; having flat feet does not affect one’s response to the plantar reflex test.[citation needed]

The appearance of flat feet is normal and common in infants, partly due to “baby fat” which masks the developing arch and partly because the arch has not yet fully developed. The human arch develops in infancy and early childhood as part of normal muscle, tendon, ligament and bone growth. Training of the feet, especially by foot gymnastics and going barefoot on varying terrain, can facilitate the formation of arches during childhood, with a developed arch occurring for most by the age of four to six years. Flat arches in children usually become proper arches and high arches while the child progresses through adolescence and into adulthood.

Because young children are unlikely to suspect or identify flat feet on their own, it is a good idea for parents or other adult caregivers to check on this themselves. Besides visual inspection, parents should notice whether a child begins to walk oddly, for example on the outer edges of the feet, or to limp, during long walks, and to ask the child whether he or she feels foot pain or fatigue during such walks.

Children who complain about calf muscle pains or any other pains around the foot area, may be developing or have flat feet. Pain or discomfort may also develop in the knee joints. A recent randomized controlled trial found no evidence for the treatment of flat feet in children either for expensive prescribed orthoses (shoe inserts) or less expensive over-the-counter orthoses.[1]

Going barefoot, particularly over terrain such as a beach where muscles are given a good workout, is good for all but the most extremely flatfooted, or those with certain related conditions such as plantar fasciitis. One medical study in India with a large sample size of children who had grown up wearing shoes and others going barefoot, found that the longitudinal arches of the barefooters were generally strongest and highest as a group, and that flat feet were less common in children who had grown up wearing sandals or slippers than among those who had worn closed-toe shoes.[2] Flat feet can be treated by insoles.[citation needed] Flat feet can also occur from genetics.

Flat feet can also develop as an adult (“adult acquired flatfoot”) due to injury, illness, unusual or prolonged stress to the foot, faulty biomechanics, or as part of the normal aging process. Flat feet can also occur in pregnant women as a result of temporary changes, due to increased elastin (elasticity) during pregnancy. However, if developed by adulthood, flat feet generally remain flat permanently.

If a youth or adult appears flatfooted while standing in a full weight bearing position, but an arch appears when the person dorsiflexes (stands on heel or pulls the toes back with the rest of the foot flat on the floor), this condition is called flexible flatfoot. Muscular training of the feet, while generally helpful, will usually not result in increased arch height in adults, because the muscles in the human foot are so short that exercise will generally not make much difference, regardless of the variety or amount of exercise.[citation needed] However, as long as the foot is still growing, it may be possible that a lasting arch can be created.

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Fissured tongue, also known as scrotal tongue or lingua plicata, is a benign condition characterized by deep grooves (fissures) in the dorsum of the tongue.

Fissured tongue is seen in Melkersson-Rosenthal syndrome, in most patients with Down syndrome, and in association with geographic tongue.

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Fibromas (or fibroid tumors or fibroids) are benign tumors that are composed of fibrous or connective tissue. They can grow in all organs, arising from mesenchyme tissue. The term “fibroblastic” or “fibromatous” is used to describe tumors of the fibrous connective tissue. When the term fibroma is used without modifier, it is usually considered benign, with the term fibrosarcoma reserved for malignant tumors.

The hard fibroma (fibroma durum) consists of many fibres and few cells, e.g. in skin it is called dermatofibroma (fibroma simplex or nodulus cutaneous). A special form is the keloid, which derives from hyperplastic growth of scars.

The soft fibroma (fibroma molle) or fibroma with a shaft (acrochordon, skin tag, fibroma pendulans) consist of many loosely connected cells and less fibroid tissue. It mostly appears at the neck, armpits or groins. The photo shows a soft fibroma of the eyelid.

The fibroma cavernosum or angiofibroma, consists of many often dilated vessels, it is a vasoactive tumor occurring almost exclusively in adolescent males.

The cystic fibroma (fibroma cysticum) has central softening or dilated lymphatic vessels.

The myxofibroma (fibroma myxomatodes) is produced by liquefaction of the underlying soft tissue.

The cemento-ossifying fibroma is hard and fibrous, most frequently seen in the jaw or mouth, sometimes in connection with a fracture or another type of injury.

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Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds. The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi.[1][2] It should not be confused with Fanconi syndrome, a kidney disorder also named after Fanconi.

FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C.

FA is primarily an autosomal recessive genetic disorder. There are at least 13 genes of which mutations are known to cause FA: FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM and FANCN. FANCB is the one exception to FA being autosomal recessive, as this gene is on the X chromosome. For an autosomal recessive disorder, both parents must be carriers in order for a child to inherit the condition. If both parents are carriers, there is a 25% risk with each pregnancy for the mother to have an affected child. Approximately 1,000 persons worldwide currently suffer from the disease. The carrier frequency in the Ashkenazi Jewish population is about 1/90.[3] Genetic counseling and genetic testing is recommended for families that may be carriers of Fanconi anemia.

Because of the failure of hemotologic components to develop – leukocytes, red blood cells and platelets – the body’s capabilities to fight infection, deliver oxygen, and form clots are all diminished. Bone marrow transplantation is the accepted treatment to repair the hematological problems associated with FA. However, even with a bone marrow transplant, patients face an increased risk of acquiring cancer and other serious health problems throughout their lifetime.

Many patients eventually develop acute myelogenous leukemia (AML). Older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers. Patients who have had a successful bone marrow transplant and, thus, are cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer. Many patients do not reach adulthood.

The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells. In addition, Fanconi patients normally are born with a variety of birth defects. For instance, 90% of the Jewish children born with Fanconi’s have no thumbs. A good number of Fanconi patients have kidney problems, trouble with their eyes, developmental retardation and other serious defects, such as microcephaly (small head).

Good care is available for treating Fanconi anemia. Since research is on-going, there is hope that as knowledge gained through clinical trials and research grows, a cure may be developed.

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Familial dysautonomia (FD, sometimes called Riley-Day syndrome[1]) is a disorder of the autonomic nervous system which affects the development and survival of sensory, sympathetic and some parasympathetic neurons in the autonomic and sensory nervous system resulting in variable symptoms including: insensitivity to pain, inability to produce tears, poor growth, and labile blood pressure (episodic hypertension and postural hypotension). People with FD have frequent vomiting crises, pneumonia, problems with speech and movement, difficulty swallowing, inappropriate perception of heat, pain, and taste, as well as unstable blood pressure and gastrointestinal dysmotility. FD does not affect intelligence. Originally reported by Riley, et al. in 1949,[2] FD is one example of a group of disorders known as hereditary sensory and autonomic neuropathies HSAN.[3] All HSAN are characterized by widespread sensory dysfunction and variable autonomic dysfunction caused by incomplete development of sensory and autonomic neurons. The disorders are believed to be genetically distinct from each other.

FD is seen almost exclusively in Ashkenazi Jews and is inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. The carrier frequency in Jewish individuals of Eastern European (Ashkenazi) ancestry is about 1/30, while the carrier frequency in non-Jewish individuals is about 1/3000. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of familial dysautonomia.

There have been 590 cases in total. Currently there are 350 people living with this condition worldwide.

Familial Dysautonomia, is the result of mutations in IKBKAP gene on chromosome 9, which encodes for the IKAP protein (IkB kinase complex associated protein). There have been three mutations in IKBKAP identified in individuals with FD. The most common FD-causing mutation occurs in intron 20 of the donor gene. Conversion of T–>C in intron 20 of the donor gene resulted in shift splicing that generates an IKAP transcript lacking exon 20. Translation of this mRNA results in a truncated protein lacking all of the amino acids encoded in exons 20-37. Another less common mutation is a G–>C conversion resulting in one amino acid mutation in 696, where Proline substitutes normal Arginine. The decreased amount of functional IKAP protein in cells causes Familial Dysautonomia.

Symptoms displayed by a baby with FD might include:

Symptoms in an older child with FD might include:

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Familial adenomatous polyposis (FAP) is an inherited condition in which numerous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when not treated.

From early adolescence and onwards, patients with this condition develop hundreds to thousands of polyps. These may bleed, leading to blood in the stool. If the blood is not visible, it is still possible for the patient to develop anemia due to gradually developing iron deficiency. If malignancy develops, this may present with weight loss, altered bowel habit, or even metastasis to the liver or elsewhere.

The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g. of the duodenum and stomach. Other signs that may point at FAP are pigmented lesions of the retina (“CHRPE – congenital hypertrophy of the retinal pigment epithelium”), jaw cysts, sebaceous cysts, and osteomata (benign bone tumors). The combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner’s syndrome (with or without abnormal scarring).[1]

Making the diagnosis of FAP before the development of colon cancer is important not just for the individual, but also for the sake of other family members who may be affected. Colonoscopy is considered the diagnostic test of choice as it can provide not only a quantification of polyps throughout the colon but also a histologic diagnosis. Barium enema and virtual colonoscopy can suggest the diagnosis of FAP.

Once the diagnosis of FAP is made, close colonoscopic surveillance with polypectomy is required. Prophylactic colectomy is indicated if more than a hundred polyps are present, there are severely dysplastic polyps, or multiple polyps larger than 1 cm are present. When partial colectomy is performed, colonoscopic surveillance of the remaining colon is necessary as the individual still carries significant risk of developing colon cancer.

Ultrasound of the abdomen and blood tests evaluating liver function are often performed to rule out metastasis to the liver.

Genetic testing provides the ultimate diagnosis in 95%; genetic counseling is usually needed in families where FAP has been diagnosed. Testing may also aid in the diagnosis of borderline cases in families that are otherwise known to have the FAP mutation.

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