tricho-hepato-enteric syndrome

Tricho-hepato-enteric syndrome is one particular form of intractable diarrhea of infancy, presenting typically in the first month of life. These babies are usually born small for their age and continue to experience failure to thrive, usually with a final short stature. Typical facial features include prominent forehead and cheeks, a broad nasal root and widely spaced eyes (hypertelorism). Their hairs are woolly, easily removed and poorly pigmented. Liver disease is mainly present as cirrhosis or fibrosis, and staining might reveal high iron content of the liver cells (consistent with hemochromatosis).{{cite journal |vauthors=Verloes A, Lombet J, Lambert Y, etal |title=Tricho-hepato-enteric syndrome: further delineation of a distinct syndrome with neonatal hemochromatosis phenotype, intractable diarrhea, and hair anomalies |journal=Am. J. Med. Genet. |volume=68 |issue=4 |pages=391–5 |date=February 1997 |pmid=9021008|doi=10.1002/(SICI)1096-8628(19970211)68:4<391::AID-AJMG3>3.0.CO;2-P}} Most evaluated patients had some degree of decrease in intelligence.{{cn|date=November 2020}}

The syndrome appears to be due to mutations in the gene tetratricopeptide repeat domain 37 (TTC37), which encodes the protein Thespin or the SKIV2L gene.{{cite journal | vauthors = Fabre A, Martinez-Vinson C, Roquelaure B, Missirian C, André N, Breton A, Lachaux A, Odul E, Colomb V, Lemale J, Cézard JP, Goulet O, Sarles J, Levy N, Badens C | year = 2011 | title = Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome | url = https://hal.archives-ouvertes.fr/hal-00614846/file/PEER_stage2_10.1002%252Fhumu.21420.pdf| journal = Hum Mutat | volume = 32 | issue = 3| pages = 277–281 | doi = 10.1002/humu.21420 | pmid = 21120949 | s2cid = 22834121 }}{{cite journal | vauthors = Vardi I, Barel O, Sperber M, Schvimer M, Nunberg M, Field M, Ouahed J, Marek-Yagel D, Werner L, Haberman Y, Lahad A, Anikster Y, Rechavi G, Barshack I, McElwee JJ, Maranville J, Somech R, Snapper SB, Weiss B, Shouval DS | date = May 2018 | title = Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome | journal = Dig Dis Sci | volume = 63 | issue = 5| pages = 1192–1199 | doi = 10.1007/s10620-018-4983-x | pmid = 29484573 | pmc = 6167312 }} This gene is expressed in the adrenal gland, amniotic fluid, bladder, blood, bones, bone marrow, brain, cervix, uterus and ovaries (in females), testis, epididymis and prostate (in males), connective tissue, ears, eyes, heart, intestines, kidneys, liver, lungs, lymph nodes, mammary glands (in females), mouth, muscles, nerves, oesophagus, pancreas, pharynx, placenta, pituitary gland, salivary glands, thyroid gland, tonsils, thymus, trachea, skin, spleen, spinal cord, stomach and vascular tissue. It is also expressed in ascites and various embryonic tissues. It is expressed at high level in the intestines, lungs, lymph nodes, pituitary and vascular tissues. This gene is also known as KIAA0372, MGC32587 and TPR repeat protein 37.{{cn|date=November 2020}}

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 kilodaltons 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 frog (Xenopus tropicalis), the mouse (Mus musculus) and the rat (Rattus norvegicus). In the mouse, this gene is located on chromosome 13.{{cn|date=November 2020}}

Image:Tricho-hepato-enteric syndrome (1).jpg) and longitudinal breaks.]]

Image:Tricho-hepato-enteric syndrome (3).jpg biopsy of a patient with THE syndrome showing severe villous atrophy with intense mononuclear cell infiltration in the lamina propria. (Courtesy of Prof. Michel Peuchmaur, Hôpital Robert Debré, Paris, France)]]

The typical facial features are low-set ears, prominent eyes with hypertelorism, broad flat nose, prominent forehead and large mouth.{{cn|date=November 2020}}

There may be fibrosis with bile duct proliferation, occasional giant cells and regenerative parenchymal nodules. Siderosis is common.{{cn|date=November 2020}}

Microscopic examination of a biopsy of the small bowel in these patients shows villous atrophy with low or no mononuclear cell infiltration of the lamina propria nor specific abnormalities involving the epithelium. The amount of villous atrophy does not explain the severity of the diarrhea.{{cn|date=November 2020}}

Studies of enterocyte brush-border ion transporter proteins (sodium-hydrogen exchanger 2, sodium-hydrogen exchanger 3, aquaporin 7, sodium-iodide symporter and hydrogen potassium ATPase) showed reduced expression or mislocalization in all patients with different profiles for each.{{cite journal | vauthors = Hartley JL, Zachos NC, Dawood B, Donowitz M, Forman J, Pollitt RJ, Morgan NV, Tee L, Gissen P, Kahr WH, Knisely AS, Watson S, Chitayat D, Booth IW, Protheroe S, Murphy S, de Vries E, Kelly DA, Maher ER | year = 2010 | title = Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy) | journal = Gastroenterology | volume = 138 | issue = 7| pages = 2388–2398 | doi = 10.1053/j.gastro.2010.02.010 | pmid = 20176027 | pmc = 3166659 }}

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). Scanning electron microscopy might reveal hair budding (trichorrhexis blastysis). Biochemical analysis may reveal sulfur-deficient, brittle hair (trichothiodystrophy; note that disulfide bonds determine hair waviness).{{cn|date=November 2020}}

Platelets 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 platelets. Despite these abnormalities there is no increased tendency to bleed in this syndrome.{{cn|date=November 2020}}

More than 90% of patients present immune defects. Low immunoglobulin level, a defect in antibody production after vaccination, monoclonal hyper IgA, and low lymphocyte count have been reported. In these cases, some patients may need immunoglobulin supplementation.Fabre, A., Martinez-Vinson, C., Goulet, O. et al. Syndromic diarrhea/Tricho-hepato-enteric syndrome. Orphanet J Rare Dis 8, 5 (2013). https://doi.org/10.1186/1750-1172-8-5

No specific treatment or cure exists. Affected children usually need total parenteral nutrition through a central venous catheter. Further worsening of liver damage should, however, be avoided if possible. Diarrhea will likely continue even though food stops passing through the gastrointestinal system.{{cite journal |vauthors=Girault D, Goulet O, Le Deist F, etal |title=Intractable infant diarrhea associated with phenotypic abnormalities and immunodeficiency |journal=J. Pediatr. |volume=125 |issue=1 |pages=36–42 |date=July 1994 |pmid=8021782 |doi= 10.1016/S0022-3476(94)70118-0}} They can subsequently be managed with tube feeding, and some may be weaned from nutritional support during adolescence.{{cn|date=November 2020}}

Tricho-hepato-enteric syndrome is estimated to affect 1 in 300,000 to 400,000 live births in Western Europe. This syndrome was first reported in 1982 with a report on 2 siblings,{{cite journal |vauthors=Stankler L, Lloyd D, Pollitt RJ, Gray ES, Thom H, Russell G |title=Unexplained diarrhoea and failure to thrive in 2 siblings with unusual facies and abnormal scalp hair shafts: a new syndrome |journal=Arch. Dis. Child. |volume=57 |issue=3 |pages=212–6 |date=March 1982 |pmid=7073301 |pmc=1627586 |doi= 10.1136/adc.57.3.212}} 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.{{cn|date=November 2020}}

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Category:Rare syndromes

Category:Syndromes with short stature

Category:Syndromes with craniofacial abnormalities

Category:Syndromes affecting the hepatobiliary system

Category:Syndromes affecting the gastrointestinal tract