NORD gratefully acknowledges Rachel Hicks, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program, Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, Debby Tamura MS, RN, APNG, and John J. DiGiovanna, MD, Senior Research Physician, DNA Repair Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, for assistance in the preparation of this report.
Trichothiodystrophy (TTD) is a rare inherited, genetic disease characterized a broad spectrum of abnormalities. Patients with different manifestations are linked together by the common feature of short, dry, brittle, sulfur-deficient hair which has a characteristic tiger tail pattern under polarizing microscopy. The signs and symptoms vary widely between patients. Typically, patients are born pre-term and with low birth weight. Maternal pregnancy complications are common. Infants may be born with a shiny parchment-like covering on the skin that peels off over several days to weeks (collodion membrane). Through childhood they may have developmental delay or intellectual disability, short stature with poor weight gain, dry, scaly skin (ichthyosis), eye abnormalities (the most common being congenital cataracts), recurrent infections and bone abnormalities. Nearly half (42%) of patients with TTD have extreme sensitivity to ultraviolet radiation (UV) called photosensitivity, and develop blistering burns on minimal exposure to UV. The population prevalence in the United States is estimated at 1 in 1,000,000 with males and females equally affected. TTD is generally apparent at birth but can be difficult to diagnose due to the symptom variability and its similarity to other conditions. Treatment is based on managing symptoms, including moisturizers to moisten dry skin, surgery to correct cataracts, nutritional support and physical, occupational and speech therapies. Sunscreen and other sun protective measures are recommended for photosensitive patients. Care is best managed through a multidisciplinary approach involving various clinical specialists.
TTD is a serious genetic condition characterized by brittle or fragile hair along with multiple systemic symptoms which vary between patients. In the past, several names and acronyms such as PIBS, BIBS or IBIBS have been used to describe TTD, however they are not useful for patient health care management and do not accurately reflect the multiple features of the condition.
The defining clinical feature of TTD is short, dry, brittle hair that has abnormal sulfur bonds; these bonds normally give hair its strength and flexibility. When examined with a polarized light microscope TTD hair shafts demonstrate a characteristic light and dark banding pattern, commonly referred to as ‘tiger-tail banding’. In addition, the hair shafts appear ‘weathered’ having frayed ends and multiple fractures throughout the length of the shaft. The hair shafts easily break and some TTD patients rarely need haircuts.
Approximately half of TTD patients also demonstrate a marked sensitivity to UV in sun light and other UV emitting sources; they can develop blistering burns on exposed skin after minimal exposure. A significant number of TTD patients have abnormalities of the immune system and develop recurrent infections, including pneumonia and gastroenteritis. These infections can be difficult to manage leading to prolonged hospitalizations. Due to the infections and complex nature of the condition, TTD patients have a 20-fold increased risk of death before age 10 years.
Pregnancy and Newborn Symptoms
The first sign an infant may have TTD may be before birth. Maternal complications during pregnancy such as pre-eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, premature labor and placental abnormalities occur in approximately 81% of TTD pregnancies. The TTD infants often are low birth weight (<2500 grams) and are born with a collodion membrane on the skin. The low birth weight and collodion membrane are serious complications, and many TTD infants are admitted to the neonatal intensive care unit (NICU). In addition to the skin abnormalities, TTD infants may have feeding difficulties and experience gastrointestinal reflux with aspiration and require nasogastric feeding tubes for the first several weeks of life. Many TTD infants will be discharged from the NICU after several weeks, then require close medical monitoring at home for several months; they often qualify for state early childhood intervention programs. Skin, Hair and Nail Symptoms
When the collodion membrane peels off in the newborn period, the skin in many areas of the body may be covered with fine scale called ichthyosis. The scale over time can thicken and darken especially at the waist and flanks; due to the scaly dry nature of their skin, TTD patients can have issues with chronic itching (pruritis). In addition, some children with TTD may not sweat very much and may have issues with hyperthermia in warmer climates. The skin on the palms and soles of the feet is often thickened and dry; painful fissures in flexural areas such as over the knuckles of the hands and instep of the foot can occur. Hyperlinear palms and soles can also be seen in many TTD children and adults. Eczema occurs in a small percentage of patients and increases the problems with the pruritis. Symptomatic management of the ichthyosis and dry skin is a daily process of gently removing thickened scale during bathing and followed by moisturizing the skin. Moisturizers or emollient creams and lotions are designed to make the external layers of the skin (epidermis) softer and more pliable. They also increase the skin’s hydration (water content) by reducing evaporation. The moisturizers ideally are fragrance and dye free.
For the TTD patients who are photosensitive, UV protection is important to prevent severe burns. Patients should avoid being outside for prolonged periods without protection. They should wear hats, sunglasses and clothing to cover their skin, such as long sleeves and long pants. When going outside during the day, they should have sunscreen applied to uncovered skin such as face, neck, ears and hands. UV can come from other artificial light sources such as halogen and florescent light bulbs and mercury vapor lamps. Photosensitive patients should avoid these types of light sources. Most TTD patients are not at an increased risk for skin cancer, however there are a few rare patients who exhibit symptoms of both xeroderma pigmentosum (XP) and TTD (the XP/TTD syndrome) and may develop skin cancers after UV exposure. These patients require more stringent UV protection.
The scalp hair is brittle and can be sparse; it breaks easily and, in some patients, will fall out during fever (febrile) illnesses. The hair may be ‘fine’ and feel soft or it may feel more course and dry. It can be fragile and break off after a slight amount of ‘trauma’ such as combing, and for some affected people, hair breaks so easily that there are broken hairs on the pillow after sleeping. TTD patients may not need many haircuts; however, they can have more hair on the top of their heads and little to no hair on the sides or back. Testing of the hair in a specialty laboratory shows low sulfur content and abnormal levels of the amino acid cystine.
The scalp skin can be icthyotic, and some TTD patients have such thick adherent scale in the scalp that it further impedes hair growth. Applying oil to the scalp and then washing the hair with a gentle shampoo designed for scaling skin conditions can help loosen the scale.
The eyebrows are also sparse and brittle and the hair of the eyebrows may break off as well. In many patients, the eyelashes may be nearly normal. TTD children often have a smaller receding chin, and larger appearing ears.
Onychodystrophy, an alteration of nail development, is a common finding in TTD. The nails may be abnormally short, broad and ridged, and may be soft and split easily. They may also be thick, brittle and slow growing. The nails may demonstrate koilynichia, a turning upward at the tips of the nails. Another term to describe this nail abnormality is ‘spooned’. It can be helpful to include the nails when moisturizing the skin of the hands and palms.
Growth and Feeding Effects
TTD children have short stature, many have poor weight gain, and often will not grow along the standard growth curves. However, they do grow at their own rate and should be followed with growth curves. Most children and adults with TTD will be shorter than their peers. It appears that growth hormone treatment is not helpful to increase overall height.
People with TTD can have problems with chronic gastroesophageal reflux disease and may need medications and feeding modifications to manage the symptoms. Due to feeding problems and poor weight gain, some TTD children will have feeding tubes (either gastrostomy or nasogastric tubes) placed to augment oral feeding. As TTD children age, they may lose subcutaneous fat associated with the poor weight gain, resulting in a thinner prematurely aged-looking face.
Hematologic and Immune Effects
TTD children may also have recurrent infections. The most common infections occur in the gastrointestinal and respiratory tracts and these infections can be life threatening. The children may have low levels of neutrophils, a type of white blood cell important in fighting infections. They may also have lower levels of immunoglobins especially immunoglobin G (IgG) in the blood. This blood protein is also important in fighting infections and some TTD children have received IgG infusions to help treat the recurrent infections. Anemia and low iron levels are also seen in TTD children; they can be treated with dietary iron supplementation.
Ocular (Eye) Effects
TTD patients have a wide variety of ocular abnormalities and ophthalmologic care is an important part of their health monitoring. In some patients, ocular abnormalities are present at birth; however other patients may not develop ocular problems until later in childhood. The most common findings in the newborn period are congenital cataracts and nystagmus (an eye finding where the eyes make repetitive, uncontrolled movements that can affect visual acuity and depth perception). TTD children can also develop cataracts at later ages, and identification and surgical removal of the cataracts as soon as they become visually significant is important to preserve eyesight. Other ocular abnormalities seen in TTD children include small corneas (microcornea) and small eyeballs (microphthalmia) with decreased best corrected vision. As patients with TTD become older, they can develop dry eyes, leading to corneal surface abnormalities. Normally dry eye is a condition seen in older adults, and this TTD complication is often not identified until the child becomes symptomatic. A few TTD patients may develop a macular/retinal degeneration as they age.
Skeletal and Dental Effects
Skeletal and dental abnormalities may also be present. TTD patients have been found to have unusual skeletal findings. They have thick dense bones (osteosclerosis) in the central skeleton including the skull, spine and pelvis. They also have thinner bone (osteopenia) in the peripheral bones of the lower arms, hands and feet. The bone symptoms can vary between people with the condition.
TTD patients often have poorly developed teeth. The tooth enamel is often thin and hypoplastic, leading to recurrent cavities (caries). TTD children may need extensive dental care including extractions and tooth caps.
Most children and adults with TTD have some form of developmental delay. Small head size (microcephaly) is also a common finding in TTD children and adults. Often, these children do not walk or talk at the usual ages. Many children with TTD will have MRI scans of the brain for evaluation of the developmental delay. Most TTD children are found to have an abnormal amount of myelin (white matter) in the brain and central nervous system. The myelin acts as an ‘insulator’ around nerve sheaths, helping to speed up nerve transmission. In addition, TTD children can have tremors and difficulty coordinating fine and gross muscle coordination. A few patients have developed seizures. Hearing loss can also be seen but it is generally due to recurrent ear infections and not nerve deafness. Despite the developmental delays, individuals with TTD are outgoing and highly social.
Boys with TTD may have cryptorchidism, a condition where the testes fail to descend into the scrotum. They generally require surgery to correct the condition. In women, breast tissue may be sparsely developed in spite of normal development of the nipples. A few TTD females have developed menstruation.
TTD is a genetic disorder that can be passed down through families in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Parents who are close blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, which increases the risk to have children with a recessive genetic disorder.
TTD is a genetically heterogenous condition. This means that mutations in several different genes may be responsible for the syndrome. Many patients with TTD have abnormalities in genes involved in the nucleotide excision repair pathway which is responsible for repairing DNA damage caused by ultraviolet radiation. The inability to repair DNA damage can lead to excessive sunburn in some patients. These DNA repair genes also play a role in gene transcription, which is the first step in the process of creating proteins that tell the body how to function.
Changes (mutations) in the ERCC2 (XPD) gene are found in the majority of patients with TTD. Mutations in the following genes are also associated with TDD: ERCC3 (XPB), TTDA (GTF2H5), TTDN1 (MPLKIP) and GTF2E2.
There is also evidence suggesting that mutations in the RNF113A gene may also cause TTD. Unlike the other genes discussed previously in this report, the RNF113A gene is transmitted in an X-linked dominant pattern. X-linked dominant disorders are caused by a non-working gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the non-working gene for a particular disease. Males with a non-working gene for an X-linked dominant disorder are more severely affected than females and often do not survive.
TTD is present at birth. Males and females are affected in equal numbers. The estimated incidence is about 1 in 1,000,000 newborns in the United States and Europe. Over 100 patients have been reported worldwide. TTD has been reported in all ethnic groups.
An initial evaluation for TTD involves a diagnostic work-up, including obtaining a detailed history of the patient’s prenatal and neonatal history. A detailed physical exam is performed to assess clinical features such as hair abnormalities, short stature, small chin, ichthyosis, intellectual impairment or developmental delay, and bone and teeth anomalies. Evaluation by a developmental pediatrician or neurologist may determine whether there is any developmental delay or intellectual impairment. MRI imaging of the brain to identify abnormal patterns of myelination is often performed. Laboratory testing for immune function, blood count and iron levels can also be performed. TTD is typically diagnosed by polarized light microscopy of hair shafts, revealing a tiger-tail pattern, and at times by measurement of reduced sulfur content in patient’s hair. The classical tiger-tail pattern alone usually is enough to diagnose TTD. However, there are other conditions with similar hair shaft abnormalities and often genetic testing is ordered to confirm the diagnosis. However, there are a few patients with features of TTD who will not have mutations in the known genes. They may have mutations in yet to be identified TTD associated genes.
TTD patients generally have complex health care needs and benefit from a multidisciplinary approach to their medical management. Patients who are sensitive to ultraviolent rays must be protected from exposure to the sun and other sources of ultraviolet radiation. Monitoring for developmental delay with special education services may be required in school and the children should be evaluated for rehabilitation needs. Ongoing physical therapy may be advised for joint stiffness, muscle tightening (contractures), and poor coordination. Specialized health care providers may be involved in medical management depending on symptoms (i.e. neurologists for seizures, dermatologists for skin symptoms, endocrinologists for growth issues). Skin symptoms of dry skin (ichthyosis) are treated by applying skin softening emollients and products containing alpha-hydroxy acids which help break down skin buildup (keratolytics).This can be particularly effective after bathing while the skin is still moist. Individuals with frequent infections may benefit from prophylactic antibiotics and in some patients, administration of IgG. No formal guidelines for the medical management of TTD exist and management is largely based on symptoms and clinical manifestations.
Genetic counseling is recommended for families of children with trichothiodystrophy.
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