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Trichothiodystrophy 3, photosensitive(TTD3)

MedGen UID:
865608
Concept ID:
C4017171
Disease or Syndrome
Synonyms: Trichothiodystrophy, complementation group A; TTD3
 
Gene (location): GTF2H5 (6q25.3)
 
Monarch Initiative: MONDO:0014619
OMIM®: 616395

Definition

Trichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. Patients with TTD have not been reported to have a predisposition to cancer (summary by Faghri et al., 2008). For a discussion of genetic heterogeneity of TTD, see 601675. [from OMIM]

Additional description

From MedlinePlus Genetics
Trichothiodystrophy, commonly called TTD, is a rare inherited condition that affects many parts of the body. The hallmark of this condition is hair that is sparse and easily broken. 

In people with trichothiodystrophy, tests show that the hair is lacking sulfur-containing proteins that normally gives hair its strength. A cross section of a cut hair shows alternating light and dark banding that has been described as a "tiger tail."

The signs and symptoms of trichothiodystrophy vary widely. Mild cases may involve only the hair. More severe cases also cause delayed development, significant intellectual disability, and recurrent infections; severely affected individuals may survive only into infancy or early childhood.

Mothers of children with trichothiodystrophy may experience problems during pregnancy including pregnancy-induced high blood pressure (preeclampsia) and a related condition called HELLP syndrome that can damage the liver. Babies with trichothiodystrophy are at increased risk of premature birth, low birth weight, and slow growth. Most children with trichothiodystrophy have short stature compared to others their age. 

Intellectual disability and delayed development are common in people with trichothiodystrophy, although most affected individuals are highly social with an outgoing and engaging personality. Some people with trichothiodystrophy have brain abnormalities that can be seen with imaging tests. A common neurological feature of this disorder is impaired myelin production (dysmyelination). Myelin is a fatty substance that insulates nerve cells and promotes the rapid transmission of nerve impulses.

About half of all people with trichothiodystrophy have a photosensitive form of the disorder, which causes them to be extremely sensitive to ultraviolet (UV) rays from sunlight. They develop a severe sunburn after spending just a few minutes in the sun. However, for reasons that are unclear, they do not develop other sun-related problems such as excessive freckling of the skin or an increased risk of skin cancer. Many people with trichothiodystrophy report that they do not sweat.

Trichothiodystrophy is also associated with recurrent infections, particularly respiratory infections, which can be life-threatening. People with trichothiodystrophy may have abnormal red blood cells, including red blood cells that are smaller than normal. They may also have elevated levels of a type of hemoglobin called A2, which is a protein found in red blood cells. Other features of trichothiodystrophy can include dry, scaly skin (ichthyosis); abnormalities of the fingernails and toenails; clouding of the lens in both eyes from birth (congenital cataracts); poor coordination; and skeletal abnormalities including degeneration of both hips at an early age.  https://medlineplus.gov/genetics/condition/trichothiodystrophy

Clinical features

From HPO
Neoplasm of the skin
MedGen UID:
19993
Concept ID:
C0037286
Neoplastic Process
A tumor (abnormal growth of tissue) of the skin.
Bilateral cryptorchidism
MedGen UID:
96568
Concept ID:
C0431663
Congenital Abnormality
Absence of both testes from the scrotum owing to failure of the testis or testes to descend through the inguinal canal to the scrotum.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Meckel diverticulum
MedGen UID:
9917
Concept ID:
C0025037
Congenital Abnormality
Meckel's diverticulum is a congenital diverticulum located in the distal ileum.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Abdominal adhesions
MedGen UID:
1708320
Concept ID:
C0549357
Acquired Abnormality
Fibrous bands (i.e., bands of scar-like tissue) that span two or more intra-abdominal organs and/or the inner abdominal wall (i.e. peritoneal membrane).
Congenital hypertrophic pyloric stenosis
MedGen UID:
196010
Concept ID:
C0700639
Congenital Abnormality
Pyloric stenosis, also known as infantile hypertrophic pyloric stenosis, is an uncommon condition in infants characterized by abnormal thickening of the pylorus muscles in the stomach leading to gastric outlet obstruction. Clinically infants are well at birth. Then, at 3 to 6 weeks of age, the infants present with projectile vomiting, potentially leading to dehydration and weight loss.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Trigonocephaly
MedGen UID:
82713
Concept ID:
C0265535
Congenital Abnormality
Wedge-shaped, or triangular head, with the apex of the triangle at the midline of the forehead and the base of the triangle at the occiput.
Lymphopenia
MedGen UID:
7418
Concept ID:
C0024312
Disease or Syndrome
A reduced number of lymphocytes in the blood.
Increased circulating IgA level
MedGen UID:
66800
Concept ID:
C0239984
Finding
An abnormally increased level of immunoglobulin A in blood.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Carious teeth
MedGen UID:
8288
Concept ID:
C0011334
Disease or Syndrome
Caries is a multifactorial bacterial infection affecting the structure of the tooth. This term has been used to describe the presence of more than expected dental caries.
Ectropion
MedGen UID:
4448
Concept ID:
C0013592
Disease or Syndrome
An outward turning (eversion) or rotation of the eyelid margin.
Natal tooth
MedGen UID:
10268
Concept ID:
C0027443
Finding
A tooth present at birth or erupting within the first month of life.
Eclabion
MedGen UID:
763344
Concept ID:
C3550430
Finding
A turning outward of the lip or lips, that is, eversion of the lips.
Ichthyosis
MedGen UID:
7002
Concept ID:
C0020757
Disease or Syndrome
An abnormality of the skin characterized the presence of excessive amounts of dry surface scales on the skin resulting from an abnormality of keratinization.
Congenital nonbullous ichthyosiform erythroderma
MedGen UID:
38180
Concept ID:
C0079154
Disease or Syndrome
The term collodion baby applies to newborns who appear to have an extra layer of skin (known as a collodion membrane) that has a collodion-like quality. It is a descriptive term, not a specific diagnosis or disorder (as such, it is a syndrome). Affected babies are born in a collodion membrane, a shiny waxy outer layer to the skin. This is shed 10-14 days after birth, revealing the main symptom of the disease, extensive scaling of the skin caused by hyperkeratosis. With increasing age, the scaling tends to be concentrated around joints in areas such as the groin, the armpits, the inside of the elbow and the neck. The scales often tile the skin and may resemble fish scales.
Congenital ichthyosiform erythroderma
MedGen UID:
86936
Concept ID:
C0079583
Disease or Syndrome
An ichthyosiform abnormality of the skin with congenital onset.
Trichorrhexis nodosa
MedGen UID:
82668
Concept ID:
C0263485
Disease or Syndrome
Trichorrhexis nodosa is the formation of nodes along the hair shaft through which breakage readily occurs. It is thus a focal defect in the hair fiber that is characterized by thickening or weak points (nodes) that cause the hair to break off easily. The result is defective, abnormally fragile hair.
Brittle hair
MedGen UID:
120480
Concept ID:
C0263490
Disease or Syndrome
Fragile, easily breakable hair, i.e., with reduced tensile strength.
Cutaneous photosensitivity
MedGen UID:
87601
Concept ID:
C0349506
Pathologic Function
An increased sensitivity of the skin to light. Photosensitivity may result in a rash upon exposure to the sun (which is known as photodermatosis). Photosensitivity can be diagnosed by phototests in which light is shone on small areas of skin.
Tiger tail banding
MedGen UID:
892884
Concept ID:
C4073178
Finding
An abnormal appearance of hair under polarizing microscopy (using crossed polarizers), whereby hair shafts show striking alternating bright and dark bands, often referred to as tiger tail banding.
Developmental cataract
MedGen UID:
3202
Concept ID:
C0009691
Congenital Abnormality
A cataract that occurs congenitally as the result of a developmental defect, in contrast to the majority of cataracts that occur in adulthood as the result of degenerative changes of the lens.
Microphthalmia
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.\n\nPeople with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.\n\nPeople with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.\n\nBetween one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Hypotelorism
MedGen UID:
96107
Concept ID:
C0424711
Finding
Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).

Professional guidelines

PubMed

Kleijer WJ, van der Sterre ML, Garritsen VH, Raams A, Jaspers NG
Prenat Diagn 2007 Dec;27(12):1133-7. doi: 10.1002/pd.1849. PMID: 17880036
Botta E, Offman J, Nardo T, Ricotti R, Zambruno G, Sansone D, Balestri P, Raams A, Kleijer WJ, Jaspers NG, Sarasin A, Lehmann AR, Stefanini M
Hum Mutat 2007 Jan;28(1):92-6. doi: 10.1002/humu.20419. PMID: 16977596
Kobayashi T, Uchiyama M, Fukuro S, Tanaka K
Am J Med Genet 2002 Jul 1;110(3):248-52. doi: 10.1002/ajmg.10465. PMID: 12116233

Recent clinical studies

Etiology

Ferri D, Orioli D, Botta E
Clin Genet 2020 Jan;97(1):12-24. Epub 2019 Apr 22 doi: 10.1111/cge.13545. PMID: 30919937
Abagge KT, Haupenthal F, Felber GY, Raskin S
BMJ Case Rep 2018 Dec 22;11(1) doi: 10.1136/bcr-2017-223744. PMID: 30580289Free PMC Article
Tuteja N, Tuteja R
Crit Rev Biochem Mol Biol 2001;36(3):261-90. doi: 10.1080/20014091074192. PMID: 11450971
Itin PH, Sarasin A, Pittelkow MR
J Am Acad Dermatol 2001 Jun;44(6):891-920; quiz 921-4. doi: 10.1067/mjd.2001.114294. PMID: 11369901
Bergmann E, Egly JM
Trends Genet 2001 May;17(5):279-86. doi: 10.1016/s0168-9525(01)02280-6. PMID: 11335038

Diagnosis

Ferri D, Orioli D, Botta E
Clin Genet 2020 Jan;97(1):12-24. Epub 2019 Apr 22 doi: 10.1111/cge.13545. PMID: 30919937
Jambhekar SD, Dhongade AR
Indian J Pediatr 2008 Mar;75(3):288-90. doi: 10.1007/s12098-008-0062-1. PMID: 18376101
Leibeling D, Laspe P, Emmert S
J Mol Histol 2006 Sep;37(5-7):225-38. Epub 2006 Jul 20 doi: 10.1007/s10735-006-9041-x. PMID: 16855787
Itin PH, Sarasin A, Pittelkow MR
J Am Acad Dermatol 2001 Jun;44(6):891-920; quiz 921-4. doi: 10.1067/mjd.2001.114294. PMID: 11369901
de Boer J, Hoeijmakers JH
Carcinogenesis 2000 Mar;21(3):453-60. doi: 10.1093/carcin/21.3.453. PMID: 10688865

Therapy

Brooks BP, Thompson AH, Bishop RJ, Clayton JA, Chan CC, Tsilou ET, Zein WM, Tamura D, Khan SG, Ueda T, Boyle J, Oh KS, Imoto K, Inui H, Moriwaki S, Emmert S, Iliff NT, Bradford P, Digiovanna JJ, Kraemer KH
Ophthalmology 2013 Jul;120(7):1324-36. Epub 2013 Apr 16 doi: 10.1016/j.ophtha.2012.12.044. PMID: 23601806Free PMC Article
Emmert S, Ueda T, Zumsteg U, Weber P, Khan SG, Oh KS, Boyle J, Laspe P, Zachmann K, Boeckmann L, Kuschal C, Bircher A, Kraemer KH
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Botta E, Offman J, Nardo T, Ricotti R, Zambruno G, Sansone D, Balestri P, Raams A, Kleijer WJ, Jaspers NG, Sarasin A, Lehmann AR, Stefanini M
Hum Mutat 2007 Jan;28(1):92-6. doi: 10.1002/humu.20419. PMID: 16977596
Itin PH, Sarasin A, Pittelkow MR
J Am Acad Dermatol 2001 Jun;44(6):891-920; quiz 921-4. doi: 10.1067/mjd.2001.114294. PMID: 11369901
Cleaver JE
J Dermatol Sci 2000 May;23(1):1-11. doi: 10.1016/s0923-1811(99)00088-2. PMID: 10699759

Prognosis

Brooks BP, Thompson AH, Bishop RJ, Clayton JA, Chan CC, Tsilou ET, Zein WM, Tamura D, Khan SG, Ueda T, Boyle J, Oh KS, Imoto K, Inui H, Moriwaki S, Emmert S, Iliff NT, Bradford P, Digiovanna JJ, Kraemer KH
Ophthalmology 2013 Jul;120(7):1324-36. Epub 2013 Apr 16 doi: 10.1016/j.ophtha.2012.12.044. PMID: 23601806Free PMC Article
Kleijer WJ, Laugel V, Berneburg M, Nardo T, Fawcett H, Gratchev A, Jaspers NG, Sarasin A, Stefanini M, Lehmann AR
DNA Repair (Amst) 2008 May 3;7(5):744-50. Epub 2008 Mar 10 doi: 10.1016/j.dnarep.2008.01.014. PMID: 18329345
Jaspers NG, Raams A, Silengo MC, Wijgers N, Niedernhofer LJ, Robinson AR, Giglia-Mari G, Hoogstraten D, Kleijer WJ, Hoeijmakers JH, Vermeulen W
Am J Hum Genet 2007 Mar;80(3):457-66. Epub 2007 Jan 29 doi: 10.1086/512486. PMID: 17273966Free PMC Article
Arlett CF, Harcourt SA, Cole J, Green MH, Anstey AV
Mutat Res 1992 Mar;273(2):127-35. doi: 10.1016/0921-8777(92)90074-d. PMID: 1372096

Clinical prediction guides

Hashimoto S, Takanari H, Compe E, Egly JM
J Dermatol Sci 2020 Mar;97(3):201-207. Epub 2020 Jan 24 doi: 10.1016/j.jdermsci.2020.01.012. PMID: 32037099
Singh A, Compe E, Le May N, Egly JM
Am J Hum Genet 2015 Feb 5;96(2):194-207. Epub 2015 Jan 22 doi: 10.1016/j.ajhg.2014.12.012. PMID: 25620205Free PMC Article
Brooks BP, Thompson AH, Bishop RJ, Clayton JA, Chan CC, Tsilou ET, Zein WM, Tamura D, Khan SG, Ueda T, Boyle J, Oh KS, Imoto K, Inui H, Moriwaki S, Emmert S, Iliff NT, Bradford P, Digiovanna JJ, Kraemer KH
Ophthalmology 2013 Jul;120(7):1324-36. Epub 2013 Apr 16 doi: 10.1016/j.ophtha.2012.12.044. PMID: 23601806Free PMC Article
Nakabayashi K, Amann D, Ren Y, Saarialho-Kere U, Avidan N, Gentles S, MacDonald JR, Puffenberger EG, Christiano AM, Martinez-Mir A, Salas-Alanis JC, Rizzo R, Vamos E, Raams A, Les C, Seboun E, Jaspers NG, Beckmann JS, Jackson CE, Scherer SW
Am J Hum Genet 2005 Mar;76(3):510-6. Epub 2005 Jan 11 doi: 10.1086/428141. PMID: 15645389Free PMC Article
Itin PH, Sarasin A, Pittelkow MR
J Am Acad Dermatol 2001 Jun;44(6):891-920; quiz 921-4. doi: 10.1067/mjd.2001.114294. PMID: 11369901

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