Trichothiodystrophy

Trichothiodystrophy

Overview

Trichothiodystrophy (TTD) is a rare inherited, genetic disease characterized by a broad spectrum of abnormalities. Patients with different symptoms are linked together by the common feature of short, dry, brittle, sulfur-deficient hair which has a characteristic “tiger tail” pattern (alternating light and dark bands) under polarizing microscopy. The signs and symptoms vary widely between patients. Typically, patients are born preterm 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. Despite the burning on sun exposure, skin cancer has only very rarely been reported in patients with TTD.

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 healthcare management and do not accurately reflect the multiple features of the condition. TTD is currently described by number (1-9) according to the mutated gene and photosensitivity status of the patient. TTD is generally apparent at birth but can be difficult to diagnose due to the symptom variability and its similarity to other conditions. TTD patients have a reduced life expectancy primarily related to increased risk of infection.

Symptoms

Pregnancy and newborn

The first sign an infant may have TTD can 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 80% of TTD pregnancies. TTD infants often have low birthweight (<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.

Skin, hair, and nails

When the collodion membrane peels off in the newborn period, the skin in many areas of the body may be dry and 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 pruritus.

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 have more hair on the top of their heads and little to no hair on the sides or back. Testing of the hair in research laboratories shows low sulfur content and abnormal levels of the amino acid cystine.

The scalp skin can be dry, itchy, scaly rough and red (ichthyotic), and this can prevent hair growth.

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, or abnormal nails, 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, (spoon nails) a turning upward at the tips of the nails.

Growth and feeding

TTD children have short stature, many have poor weight gain, and will not grow along the standard growth curves. Most children and adults with TTD will be shorter than their peers.

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 and have poor weight gain, resulting in a thinner prematurely aged-looking face.

Neurologic

Most children and adults with TTD have some form of developmental delay and/or intellectual disability. Small head size (microcephaly) is also a common finding. 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 a reduced 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.

Minor infections may lead to prolonged illness with hospitalization, sometimes requiring ICU management. This often leads to regression with decline in functional abilities. When recovered from the infections, the children usually improve and regain most of their abilities. However, repeated infections can interfere with normal development over time. This is different from the progressive degeneration typical of patients with xeroderma pigmentosum (XP), a related disorder with mutations in some of the same genes as TTD (see below). In contrast to TTD, XP neurologic degeneration is slow, progressive, and occurs without repeated infections and hospitalizations. TTD patients without repeated infections and hospitalization may develop slowly but generally do not have the progressive loss of function that occurs with XP neurologic degeneration.

Hematologic and immune

TTD children may also have recurrent infections. The most common infections occur in the gastrointestinal and respiratory tracts. 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.

Eyes

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 (the eyes make repetitive, uncontrolled movements that can affect visual acuity and depth perception). Children with TTD 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 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 macular/retinal degeneration as they age.

Skeletal and dental

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.

Some children with TTD develop debilitating hip degeneration leading to pain, inability to walk and avascular necrosis of the femoral head. The debilitating hip degeneration is seen most commonly in TTD children who also have the combination of osteosclerosis and osteopenia, and mutations in the XPD/ERCC2 gene.

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.

Miscellaneous

Males 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 females, breast tissue may be sparsely developed despite normal development of the nipples. A few TTD females have developed menstruation and pregnancy may be possible.

Causes

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 and skin cancer in a few rare 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 (variants or mutations) in the ERCC2 (XPD) gene are found in the majority of patients with TTD. Mutations in the following genes are also associated with TTD: ERCC3 (XPB), TTDA (GTF2H5), TTDN1 (MPLKIP), TARS, CARS, AARS1, MARS1 and GTF2E2.

There is also evidence suggesting that mutations in the X-linked RNF113A gene may also cause TTD.

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 of having 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.

Affected populations

TTD presents 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.

Disorders with Similar Symptoms

Symptoms of the following disorders may resemble those of trichothiodystrophy. Comparisons may be useful for a differential diagnosis.

Ichthyoses or “disorders of cornification” are general terms describing a group of scaly skin disorders. (See “ichthyosis” in the Rare Disease Database for more information.)

Xeroderma pigmentosum is a disorder in which damage done by ultraviolet light (especially sun light) is not repaired properly leading to dry skin with heavy freckling and development of skin cancer at a young age. Patients may also have progressive neurologic impairment. Xeroderma pigmentosum is also caused by alterations in genes involved in DNA repair. (For more information on this condition, search for “xeroderma pigmentosum” in the Rare Disease Database.)

Diagnosis

An initial evaluation for TTD involves a diagnostic work-up, including obtaining a detailed history of the patient’s prenatal and neonatal history. A thorough physical exam is performed to assess clinical features such as hair abnormalities, short stature, small chin, ichthyosis, intellectual impairment or developmental delay, cataracts, cryptorchidism (in males) and bone and teeth anomalies. Evaluation by a developmental pediatrician or neurologist may determine whether there is any developmental delay or intellectual disability. MRI imaging of the brain to identify abnormal patterns of myelination is often performed. Laboratory testing for immune function, blood count, low red blood cell MCV, elevated hemoglobin A2 level and iron levels can also be performed. TTD is often diagnosed by polarized light microscopy of hair shafts, revealing a tiger-tail pattern. 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 needed to confirm the diagnosis. Some patients with features of TTD will not have mutations in the known genes. They may have mutations in yet to be identified TTD associated genes.

Standard Therapies

Treatment

Many infants with TTD will be discharged from the NICU after several weeks, then require close medical monitoring at home for several months.

TTD patients generally have complex health care needs and benefit from a multidisciplinary approach to their medical management. No formal guidelines for the medical management of TTD exist and management is largely based on symptoms.

Patients who are sensitive to ultraviolent rays must be protected from exposure to the sun and other sources of ultraviolet radiation 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 fluorescent light bulbs and mercury vapor lamps. Photosensitive patients should avoid these types of light sources. Despite the burning on sun exposure, skin cancer has only very rarely been reported in patients with TTD, there are a few very 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.

Management of the ichthyosis and dry skin varies with severity. For some patients it is a minor issue but for others management is a daily process of gently removing thickened scale during bathing and followed immediately 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 to avoid allergic reactions. It can be helpful to include the nails when moisturizing the skin of the hands and palms. Applying oil to the scalp and then washing the hair with a gentle shampoo designed for scaling skin conditions can help loosen the scale.

Some children with TTD have received IgG infusions to help treat the recurrent infections. Anemia and low iron levels can be treated with dietary iron supplementation.

Monitoring is needed for developmental delay and special education services may be required in school. The children should be evaluated for rehabilitation needs. Ongoing physical therapy may be advised for joint stiffness, muscle tightening (contractures), and poor coordination.

Genetic counseling is recommended for families of children with trichothiodystrophy.

Type of Doctor Department : A dermatologist or geneticist