Tricho-hepato-enteric syndrome (THE), also known as syndromic or phenotypic diarrhea, is an extremely rare congenital bowel disorder which manifests itself as intractable diarrhea

Diarrhea

Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

 in infants with intrauterine growth retardation, hair

Hair disease

Hair diseases are disorders primarily associated with the follicles of the hair.An example is hypertrichosis.Many hair diseases can be associated with distinct underlying disorders.Piedra are fungal diseases.-External links:...

 and facial abnormalities

Dysmorphic feature

Dysmorphic feature is a medical term referring to a difference of body structure that is suggestive of a congenital disorder, genetic syndrome, or birth defect. A dysmorphic feature can be a minor and isolated birth defect...

. Many also have liver disease

Liver disease

Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...

 and abnormalities of the immune system

Immune system

An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

. The associated malabsorption

Malabsorption

Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...

 leads to malnutrition

Malnutrition

Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....

 and failure to thrive

Failure to thrive

Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....

.

It is thought to be a genetic disorder

Genetic disorder

A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

 with an autosomal recessive inheritance pattern, although responsible gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s have not been found and the exact cause remains unknown

Idiopathic

Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...

. Prognosis is poor; many patients die before the age of 5 (mainly from infection

Infection

An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

s or cirrhosis

Cirrhosis

Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...

), although most patients nowadays survive with intravenous feeding (parenteral nutrition).

Synonyms

It is now recognized that the following conditions constitute one and the same disease: intractable diarrhea of infancy with facial dysmorphism, trichorrhexis nodosa and cirrhosis, neonatal hemochromatosis phenotype with intractable diarrhea and hair abnormalities, and intractable infant diarrhea associated with phenotypic abnormalities and immune deficiency.

Genetics

The syndrome appears to be due to mutations in the gene tetratricopeptide repeat domain 37 (TTC37) which encodes the protein Thespin. This gene is expressed is in the adrenal gland

Adrenal gland

In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...

, amniotic fluid

Amniotic fluid

Amniotic fluid or liquor amnii is the nourishing and protecting liquid contained by the amniotic sac of a pregnant woman.- Development of amniotic fluid :...

, bladder

Bladder

Bladder usually refers to an anatomical hollow organBladder may also refer to:-Biology:* Urinary bladder in humans** Urinary bladder ** Bladder control; see Urinary incontinence** Artificial urinary bladder, in humans...

, blood

Blood

Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

, bone

Bone

Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...

, bone marrow

Bone marrow

Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...

, brain

Brain

The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

, cervix

Cervix

The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...

, connective tissue

Connective tissue

"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...

, ear

Ear

The ear is the organ that detects sound. It not only receives sound, but also aids in balance and body position. The ear is part of the auditory system....

, epididymis

Epididymis

The epididymis is part of the male reproductive system and is present in all male amniotes. It is a narrow, tightly-coiled tube connecting the efferent ducts from the rear of each testicle to its vas deferens. A similar, but probably non-homologous, structure is found in cartilaginous...

, eye

Eye

Eyes are organs that detect light and convert it into electro-chemical impulses in neurons. The simplest photoreceptors in conscious vision connect light to movement...

, heart

Heart

The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...

, intestine

Intestine

In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...

, kidney

Kidney

The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

, liver

Liver

The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, lung

Lung

The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...

, lymph node

Lymph node

A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...

s, mammary gland

Mammary gland

A mammary gland is an organ in mammals that produces milk to feed young offspring. Mammals get their name from the word "mammary". In ruminants such as cows, goats, and deer, the mammary glands are contained in their udders...

s, mouth

Mouth

The mouth is the first portion of the alimentary canal that receives food andsaliva. The oral mucosa is the mucous membrane epithelium lining the inside of the mouth....

, muscle

Muscle

Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

, nerve

Nerve

A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...

, oesophagus, ovary

Ovary

The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...

, pancreas

Pancreas

The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...

, pharynx

Pharynx

The human pharynx is the part of the throat situated immediately posterior to the mouth and nasal cavity, and anterior to the esophagus and larynx. The human pharynx is conventionally divided into three sections: the nasopharynx , the oropharynx , and the laryngopharynx...

, placenta

Placenta

The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

, prostate

Prostate

The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....

, pituitary gland

Pituitary gland

In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...

, salivary gland

Salivary gland

The salivary glands in mammals are exocrine glands, glands with ducts, that produce saliva. They also secrete amylase, an enzyme that breaks down starch into maltose...

, testis, thyroid

Thyroid

The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...

, tonsil

Tonsil

Palatine tonsils, occasionally called the faucial tonsils, are the tonsils that can be seen on the left and right sides at the back of the throat....

, thymus

Thymus

The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....

, trachea

Trachea

Trachea may refer to:* Vertebrate trachea, or windpipe, in terrestrial vertebrates, such as birds and mammals* Invertebrate trachea, in terrestrial invertebrates, such as insects and crustaceans* Vessel elements in plants...

, skin

Skin

-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...

, uterus

Uterus

The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...

, spleen

Spleen

The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...

, spinal cord

Spinal cord

The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

, stomach

Stomach

The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...

 and vascular tissue. It is also expressed in ascites

Ascites

Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...

 and various embryonic tissues. It is expressed at high level in the intestine, lung, lymph nodes, pituitary and vascular tissues. This gene is also known as KIAA0372, MGC32587 and TPR repeat protein 37.

This gene is located on the Crick (minus) strand of the long arm of chromosome 5 (5q15). The gene is 91,113 bases in length and encodes a protein of 1564 amino acid residues with twenty tetratricopeptide repeats. It has 43 exons of which exons 1, 2 and 3 are non coding. The predicted molecular weight of the protein is 175.486 kiloDalton

Dalton

Dalton may refer to:-In Canada:* Dalton, Algoma District, Ontario* Dalton Armoury, a Canadian Forces facility primarily used by the Queen's Own Rifles of Canada- In the United Kingdom :* Dalton, Cumbria, England* Dalton, Dumfries and Galloway, Scotland...

s and its predicted pI is 7.47. Its function is unknown but it may have adenylate cyclase activity and calcium- and calmodulin-responsive adenylate cyclase activity. A homolog has been identified in the the frog (Xenopus tropicalis), the mouse (Mus musculus) and the rat (Rattus norvegicus). In the mouse this gene is located on chromosome 13.

Symptoms

Tricho-hepato-enteric syndrome is one particular form of intractable diarrhea of infancy, presenting typically in the first month of life. These babies were usually born small for their age

Small for gestational age

Small for gestational age babies are those who are smaller in size than normal for the baby's sex and gestational age, most commonly defined as a weight below the 10th percentile for the gestational age.-Terminology:...

 and continue to experience failure to thrive

Failure to thrive

Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....

, usually with a final short stature

Short stature

Short stature refers to a height of a human being which is below expected. Shortness is a vague term without a precise definition and with significant relativity to context...

. Typical facial features include prominent forehead and cheeks, a broad nasal root and widely spaces eyes (hypertelorism

Hypertelorism

Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits . In this condition the distance between the inner eye corners as well as the distance between the pupils is greater than normal...

). Their hairs are woolly, easily removed and poorly pigmented. Liver disease is mainly present as cirrhosis

Cirrhosis

Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...

 or fibrosis

Fibrosis

Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...

, and staining might reveal high iron content of the liver cells

Hepatocyte

A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...

 (consistent with hemochromatosis). Most evaluated patients had some degree of decrease in intelligence

Intelligence

Intelligence has been defined in different ways, including the abilities for abstract thought, understanding, communication, reasoning, learning, planning, emotional intelligence and problem solving....

.

Diagnosis

Facial features

The typical facial features are low-set ears, prominent eyes with hypertelorism, broad flat nose, prominent forehead and large mouth.

Liver

There may be fibrosis with bile duct proliferation, occasional giant cells and regenerative parenchymal nodules. Siderosis is common.

Small bowel

Microscopic examination

Histopathology

Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...

 of a biopsy of the small bowel in these patients shows villous atrophy with low or no mononuclear cell infiltration of the lamina propria

Lamina propria

The lamina propria is a constituent of the moist linings known as mucous membranes or mucosa, which line various tubes in the body ....

 nor specific abnormalities involving the epithelium

Epithelium

Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...

. The amount of villous atrophy does not explain the severity of the diarrhea.

Studies of enterocyte brush-border ion transporter proteins (sodium hydrogen exchanger 2, sodium hydrogen exchanger 3, aquaporin

Aquaporin

Aquaporins are proteins embedded in the cell membrane that regulate the flow of water.Aquaporins are integral membrane proteins from a larger family of major intrinsic proteins that form pores in the membrane of biological cells....

 7, sodium iodide symporter and hydrogen potassium adenosine triphosphatase) showed reduced expression or mislocalization in all patients with different profiles for each.

Hair

Microscopic analysis of the hair shows twisted hairs of unequal size and different shapes (pili torti, aniso- and poikilotrichosis), longitudinal breaks and breaks located at nodes (trichorrhexis nodosa

Trichorrhexis nodosa

Trichorrhexis nodosa is a defect in the hair shaft characterized by thickening or weak points that cause the hair to break off easily. This group of conditions contributes to the appearance of hair loss, lack of growth, and damaged-looking hair....

). Scanning electron microscopy might reveal hair budding (trichorrhexis blastysis). Biochemical analysis may reveal sulfur-deficient brittle hair (trichothiodystrophy; note that disulfide bond

Disulfide bond

In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

s determine hair waviness).

Platlets

Platelet

Platelet

Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

s may be enlarged. The membrane surface connected canalicular system is disrupted with prominent tubules and small membranous vesicles. Alpha granules may be missing from the platlets. Despite these abnormalities there is no increased tendency to bleed in this syndrome.

Other

Immunodeficiency is a consistent feature with low serum concentrations of immunoglobulins which may improve with age and a poor immunological response to childhood vaccination. T cell

T cell

T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

 dysfunction and abnormal antibody

Antibody

An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 generation have been reported.

Treatment

No specific treatment or cure exists. Affected children usually need total parenteral nutrition

Total parenteral nutrition

Parenteral nutrition is feeding a person intravenously, bypassing the usual process of eating and digestion. The person receives nutritional formulae that contain nutrients such as glucose, amino acids, lipids and added vitamins and dietary minerals...

 through a central venous catheter

Central venous catheter

In medicine, a central venous catheter is a catheter placed into a large vein in the neck , chest or groin...

. Further worsening of liver damage should however be avoided if possible. Diarrhea will likely continue even though food stops passing through the gastrointestinal system. They can subsequently be managed with tube feeding, and some may be weaned from nutritional support during adolescence.

Epidemiology

Tricho-hepato-enteric syndrome is estimated to affect 1 in 300,000 to 400,000 live births in Western Europe

Western Europe

Western Europe is a loose term for the collection of countries in the western most region of the European continents, though this definition is context-dependent and carries cultural and political connotations. One definition describes Western Europe as a geographic entity—the region lying in the...

. This syndrome was first reported in 1982 with a report on 2 siblings, and as of 2008 there were around 25 published cases in medical journals. There seem to be no racial differences in its occurrence. It might be more common, as many genetic diseases, in areas with high levels of consanguinity

Consanguinity

Consanguinity refers to the property of being from the same kinship as another person. In that respect, consanguinity is the quality of being descended from the same ancestor as another person...

.