Trichothiodystrophy

Trichothiodystrophy (syn. Tay syndrome)

A recessive hereditary disease (the faulty gene is carried by both parents) characterised by sulphur-deficient brittle hair.
It was first described by Dr. Tay Chong Hai in 1971.

The hair deformity may exist with or without other symptoms which may include:

• skin resembling fish scales (ichthyosiform erythroderma).
• light sensitivity (photosensitivity) in 75%+ of reported cases.
• abnormalities of finger-nails and toe-nails onchodystrophy.
• premature aging (progeria-like).
• low level weight gain.

The hair-shaft is brittle – it fractures and severs on emergence from its host follicle. The overall appearance being of short, sparse hair.
Eyebrows and eyelashes may be inculcated. There is currently no treatment for TrichoThioDystrophy.

Examination of the hair reveals that its cross sectional shape is oval. There are also irregularities in its diameter and pigmentation. Its cuticle may present with abnormalities or may be absent.

Where TTD is confirmed, hair samples tested will usually indicate a reduction of approximately 50% of normal levels of sulphur and cysteine.

TRICHOTHIODYSTROPHY

Dr Svitlana Soroka  MB BS LTTS

21/06/2025

INTRODUCTION

Trichothiodystrophy (TTD) is a rare, autosomal recessive genetic disorder characterized by brittle, sulphur-deficient hair and a spectrum of systemic abnormalities affecting multiple organ systems. The term "trichothiodystrophy" is derived from Greek: "tricho" (hair), "thio" (sulphur), "dys" (faulty), and "trophy" (nourishment), reflecting the hallmark feature of sulphur-deficient hair. ​

Sulphur plays a crucial role in hair formation, primarily through its inclusion into keratin, the structural protein that constitutes the hair shaft. Keratin is rich in the sulphur-containing amino acid cysteine, which forms disulfide bonds that provide strength and resilience to the hair fiber. In TTD, mutations in genes involved in DNA repair and transcription, such as ERCC2 (XPD), ERCC3 (XPB), and GTF2H5 (TTDA), lead to defective synthesis of high-sulphur matrix proteins, resulting in hair that is brittle and prone to breakage (Itin, 2001).

HISTORY

The term "trichothiodystrophy" was first introduced by Vera H. Price in 1979 in the book Haar und Haarkrankheiten and further elaborated in a 1980 publication, where she described patients exhibiting a range of clinical features linked by the common finding of low sulphur (cystine) content in hair (Liang et al, 2006). This deficiency was associated with the distinctive "tiger tail" banding pattern observed under polarized light microscopy, establishing a unifying marker for this neuroectodermal symptom complex.​

Prior to Price's formalization of the condition, earlier reports had documented similar clinical presentations. In 1968, Pollitt, Jenner, and Davies described a family exhibiting mental and physical retardation alongside hair abnormalities termed "trichorrhexis nodosa," noting an abnormal amino acid composition of the hair . Additionally, in 1971, Dr. Chong Hai Tay reported a recessive disorder characterized by ichthyosiform erythroderma, hair shaft abnormalities, and mental and growth retardation, a condition that would later be recognized as a variant of TTD.​

These early observations laid the groundwork for the identification and classification of TTD as a distinct clinical entity. The recognition of sulphur-deficient brittle hair as a hallmark feature has been instrumental in diagnosing the disorder and understanding its underlying genetic and biochemical mechanisms.

AETIOLOGY

Trichothiodystrophy (TTD) arises from mutations in genes involved in DNA repair and transcription processes, leading to the diverse clinical manifestations observed in affected individuals (Stefanini et al, 2010), (Itin, 2001).​

Genetic Causes

TTD is genetically heterogeneous, with mutations identified in several genes:​

ERCC2 (XPD): Mutations in this gene are the most common cause of the photosensitive form of TTD. ERCC2 encodes a helicase involved in nucleotide excision repair (NER) and transcription initiation. ​

ERCC3 (XPB): This gene encodes another helicase component of the transcription factor IIH (TFIIH) complex, essential for NER and transcription. ​

GTF2H5 (TTDA): Mutations here affect a small subunit of TFIIH, disrupting its stability and function. ​

MPLKIP (TTDN1): Associated with non-photosensitive TTD, the exact function of this gene remains unclear, but it's believed to play a role in cell cycle regulation. ​

Aminoacyl-tRNA Synthetase Genes: Mutations in genes like CARS1, TARS1, AARS1, and MARS1 have been linked to non-photosensitive TTD. These genes are crucial for protein synthesis, and their disruption can affect hair and skin integrity. ​

RNF113A: An X-linked gene implicated in some TTD cases, though its exact role in the disease pathogenesis is still being studied. ​

Pathophysiological Mechanisms

The mutations in these genes disrupt the normal function of the TFIIH complex, leading to impaired DNA repair and transcription. This impairment affects the synthesis of sulfur-rich proteins, particularly in hair, resulting in the characteristic brittle hair seen in TTD. Additionally, the defective DNA repair mechanisms contribute to the systemic features of the disease, including developmental delays, photosensitivity, and neurological abnormalities.​

Inheritance Pattern

TTD follows an autosomal recessive inheritance pattern, meaning that an individual must inherit two copies of the mutated gene (one from each parent) to manifest the disease. Carriers, with only one copy of the mutation, typically do not exhibit symptoms. ​

Understanding the genetic and molecular basis of TTD is crucial for accurate diagnosis, enetic counseling, and exploring potential therapeutic avenues.

CLASSIFICATION

Classification of TTD is primarily based on the presence or absence of photosensitivity and associated genetic mutations (6).​

1. Photosensitive TTD (TTD-P)

Approximately 50% of TTD cases exhibit photosensitivity, characterized by an abnormal response to ultraviolet (UV) light. This form is associated with defects in the nucleotide excision repair (NER) pathway due to mutations in genes encoding subunits of the transcription factor IIH (TFIIH) complex:​

ERCC2 (XPD)

ERCC3 (XPB)

GTF2H5 (TTDA)

These genes are integral to DNA repair and transcription processes. Mutations lead to impaired DNA repair mechanisms, resulting in clinical manifestations such as photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature. This constellation of symptoms is often referred to by the acronym PIBIDS (Photosensitivity, Ichthyosis, Brittle hair, Intellectual impairment, Decreased fertility, and Short stature).

2. Non-Photosensitive TTD

The non-photosensitive form of TTD lacks the UV sensitivity seen in TTD-P and is associated with mutations in different genes:​

MPLKIP (TTDN1)

RNF113A (X-linked)

AARS1 (Alanyl-tRNA synthetase)

CARS1 (Cysteinyl-tRNA synthetase)

TARS1 (Threonyl-tRNA synthetase)

MARS1 (Methionyl-tRNA synthetase)

GTF2E2 (General transcription factor IIE subunit 2)

These genes are involved in various cellular processes, including protein synthesis and transcription regulation. Clinical features in non-photosensitive TTD can include brittle hair, intellectual impairment, ichthyosis, and other systemic abnormalities, but without the photosensitivity component .​

3. Syndromic Subtypes

TTD can also be categorized into specific syndromic subtypes based on clinical features:​

IBIDS: Ichthyosis, Brittle hair, Intellectual impairment, Decreased fertility, and Short stature.

BIDS: Brittle hair, Intellectual impairment, Decreased fertility, and Short stature.

PIBIDS: Photosensitivity, Ichthyosis, Brittle hair, Intellectual impairment, Decreased fertility, and Short stature.

PBIDS: Photosensitivity, Brittle hair, Intellectual impairment, Decreased fertility, and Short stature.​

These acronyms help in identifying the constellation of symptoms present in individual patients and can guide clinical management.

CLINICAL FEATURES​

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by a spectrum of clinical manifestations affecting multiple systems. The hallmark of TTD is brittle, sulphur-deficient hair, but the condition encompasses a wide range of additional features (Itin, 2001).​

• Hair and Nail Abnormalities

Brittle, sulphur-deficient hair: Hair that is fragile and prone to breakage, often displaying a characteristic "tiger tail" pattern—alternating light and dark bands—under polarized light microscopy. ​

Sparse or absent eyebrows and eyelashes: In some cases, individuals may have reduced or missing eyebrows and eyelashes.​

Nail abnormalities: Brittle nails or other nail deformities may be present. ​

• Skin Manifestations

Ichthyosis: Dry, scaly skin resembling fish scales. ​

Photosensitivity: Sensitivity to sunlight, leading to skin reactions upon exposure. ​

Erythroderma and eczema: Widespread redness of the skin and inflammatory skin conditions.​

• Neurological and Developmental Features

Intellectual impairment: Ranging from mild learning difficulties to severe cognitive deficits. ​

Developmental delays: Delayed milestones in motor and cognitive development.​

Neurological dysfunctions: Including spasticity, ataxia, tremors, and impaired motor control. ​

• Growth and Skeletal Abnormalities

Short stature: Below-average height for age.​

Skeletal anomalies: Such as scoliosis, kyphosis, and limb deformities. ​

• Facial and Craniofacial Features

Microcephaly: A smaller than average head size.​

Distinctive facial features: Including a receding chin, protruding ears, and a thin, beaked nose. ​

• Ocular and Auditory Issues

Cataracts: Clouding of the eye's lens, leading to vision impairment.​

Conjunctivitis: Inflammation of the eye's conjunctiva.​

• Other Systemic Features

Recurrent infections: Due to immune system abnormalities.​

Growth retardation: Delayed physical growth.​

Impaired sexual development: Delayed or absent puberty.​

Dental abnormalities: Including dental caries and other tooth defects. ​

The severity and combination of these features can vary widely among individuals with TTD. Some may exhibit only mild symptoms, while others experience significant multisystem involvement. Early diagnosis and multidisciplinary management are crucial for addressing the diverse clinical manifestations of TTD.

DIAGNOSTIC

Diagnosing TTD involves a combination of clinical evaluation, specialized hair analysis, and genetic testing (Hashimoto, 2009).​

1. Clinical Evaluation

The diagnostic process begins with a thorough clinical assessment:​

Medical History and Physical Examination: Clinicians assess for hallmark features such as brittle, sulphur-deficient hair, intellectual impairment, ichthyosis, short stature, and photosensitivity. ​

Family History: Given its autosomal recessive inheritance, a detailed family history can provide insights into potential genetic predispositions.​

2. Hair Analysis

Hair examination is pivotal in TTD diagnosis:​

Polarized Light Microscopy: Reveals the characteristic "tiger-tail" pattern—alternating light and dark bands along the hair shaft. ​

Scanning Electron Microscopy (SEM): Identifies structural abnormalities such as trichoschisis (clean transverse fractures) and trichorrhexis nodosa-like fraying. ​

Sulfur Content Analysis: Biochemical assays demonstrate reduced sulfur levels in hair, a hallmark of TTD. ​

3. Genetic Testing

Confirmatory diagnosis often involves identifying mutations in genes associated with TTD:​

Photosensitive TTD: Mutations commonly found in ERCC2 (XPD), ERCC3 (XPB), and GTF2H5 (TTDA) genes. ​

Non-Photosensitive TTD: Associated with mutations in MPLKIP (TTDN1) and other genes involved in protein synthesis. ​

Genetic testing methods include targeted gene sequencing and whole-exome sequencing to identify pathogenic variants.​

4. Prenatal Diagnosis

In families with a known history of TTD, prenatal diagnostic options are available:​

Fetal Hair Biopsy: Allows for early detection of hair abnormalities indicative of TTD. ​

Molecular Genetic Testing: Enables identification of known familial mutations during pregnancy.​

Early and accurate diagnosis of TTD is crucial for managing the condition and providing appropriate genetic counselling. A multidisciplinary approach, involving dermatologists, geneticists, and other specialists, ensures comprehensive care for affected individuals.

Differential Diagnoses of Trichothiodystrophy

• Cockayne Syndrome (CS)

Similarities: Photosensitivity, growth retardation, neurological deficits, and developmental delays.

Distinguishing Features: CS typically lacks the characteristic brittle hair with "tiger-tail" banding seen in TTD. Additionally, CS patients often exhibit progressive neurodegeneration and early-onset hearing loss. ​

• Xeroderma Pigmentosum (XP)

Similarities: Photosensitivity and defects in nucleotide excision repair pathways.

Distinguishing Features: XP is marked by a significantly increased risk of UV-induced skin cancers, which is not characteristic of TTD. Furthermore, XP patients may present with pigmentary changes and ocular abnormalities. ​

• Menkes Disease

Similarities: Brittle, kinky hair and neurodevelopmental delays.

Distinguishing Features: Menkes disease is an X-linked disorder caused by copper transport defects, leading to systemic copper deficiency. It often presents with seizures, hypotonia, and connective tissue abnormalities. ​

• Netherton Syndrome

Similarities: Ichthyosis and hair shaft abnormalities.

Distinguishing Features: Netherton syndrome is characterized by trichorrhexis invaginata ("bamboo hair"), atopic dermatitis, and a predisposition to allergies. Unlike TTD, it does not involve sulphur-deficient hair. ​

• Monilethrix

Similarities: Brittle hair with a beaded appearance.

Distinguishing Features: Monilethrix presents with periodic narrowing of the hair shaft, leading to fragility. It typically lacks the systemic features seen in TTD. ​

• Sabinas Brittle Hair Syndrome

Similarities: Brittle hair and intellectual impairment.

Distinguishing Features: This condition is characterized by low sulfur content in hair, similar to TTD, but is distinguished by its unique biochemical profile, including increased copper/zinc ratios and the presence of argininosuccinic acid in blood and urine. ​

Diagnostic Approach

Accurate differentiation of TTD from these conditions involves:​

Hair Shaft Analysis: Polarized light microscopy revealing "tiger-tail" banding is indicative of TTD.​

Genetic Testing: Identifying mutations in genes such as ERCC2, ERCC3, or GTF2H5 supports a TTD diagnosis.​

Clinical Evaluation: Assessing for systemic features like photosensitivity, intellectual impairment, and growth abnormalities aids in distinguishing TTD from other disorders.​

A multidisciplinary approach, incorporating dermatological, neurological, and genetic assessments, is essential for accurate diagnosis and management.

TREATMENT

Currently, there is no definitive cure for TTD; therefore, management focuses on symptom alleviation and improving quality of life.​

For individuals with photosensitive TTD, rigorous protection against ultraviolet (UV) radiation is essential. This includes the use of broad-spectrum sunscreens, wearing protective clothing, and minimizing sun exposure to prevent UV-induced skin damage. ​

In some cases, dietary supplementation with cytosine has been recommended. Cytosine is a nitrogenous base integral to the structure of DNA and RNA, playing a crucial role in genetic information encoding and protein synthesis. ​

Overall, management of TTD requires a multidisciplinary approach tailored to the individual's specific symptoms and needs (5).

PROGNOSIS

The prognosis for TTD varies depending on the severity of systemic involvement. While some individuals may have a relatively mild course, others experience significant complications (4):​

Growth and Development: Many patients exhibit growth retardation and developmental delays. ​

Neurological Issues: Intellectual disability and neurological abnormalities, such as impaired myelination, are common. ​

Infections: Recurrent respiratory and other infections are a major concern and can be life-threatening, contributing to increased mortality rates. ​

Life Expectancy: Severe cases, especially those with significant systemic involvement, may result in reduced life expectancy. ​

Early diagnosis and comprehensive management are critical to improving outcomes and quality of life for individuals with TTD.

REFERENCES

• https://escholarship.org/content/qt2s37g91n/qt2s37g91n_noSplash_290b6c46145ad41e67d9b1b0c5b797e4.pdf (accessed 12/06/2025)
• https://www.researchgate.net/figure/Distinctive-features-of-trichothiodystrophy-TTD-and-xeroderma-pigmentosum_fig1_51681590(accessed 12/06/2025)
• http://www.forgottendiseases.org/assets/Trichothiodystrophy.html (accessed 13/06/2025)
• https://pubmed.ncbi.nlm.nih.gov/24918982/ (accessed 16/06/2025)
• https://www.orpha.net/en/disease/detail/33364?utm_source (accessed 16/06/2025)
• https://dermnetnz.org/topics/trichothiodystrophy?utm (accessed 13/06/2025)

Itin PH, Sarasin A, Pittelkow MR. (2001) Trichothiodystrophy: update on the sulfur-deficient brittle hair syndromes. J Am Acad Dermatol ; 44: 891–920

Hashimoto S, Egly JM. (2009) Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH. Hum Mol Genet; 18: R224–30. DOI: 10.1093/hmg/ddp390

Liang C, Morris A, Schlucker S, et al. (2006) Structural and molecular hair abnormalities in trichothiodystrophy. J Invest Dermatol; 126: 2210–16

Stefanini M, Botta E, Lanzafame M, Orioli D. (2010) Trichothiodystrophy: from basic mechanisms to clinical implications. DNA Repair (Amst).; 9: 2–10. DOI: 10.1016/j.dnarep.2009.10.005.

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Trichothiodystrophy

by Tolani Ojebuovboh LTTS

Trichothiodystrophy (TTD) also called Amish brittle hair syndrome is a rare autosomal recessive inherited disorder that affects many parts of the body. The Greek compound word trichothiodystrophy is derived from 3 other words: ‘tricho’ (hair), ‘thio’ (sulphur) and ‘dystrophy’ (wasting away). It is characterised by brittle, sparse and easily broken hairs, caused by a deficiency in sulphur, required for the strength of hair. Sulphur is an essential component of proteins and biologic compounds. Mild cases may involve only the hair while more severe cases involve damage to the structure of hair, intellectual disability, recurrent infections, delayed development and some patients might even die at early childhood.

It is such an extremely rare disease with only an estimated incidence of about 1 in 1 million newborns in the US and Europe. Only about 100 affected individuals have been reported worldwide.

 

History

In 1971, Tay described the distinct characteristics of TTD. The term trichothiodystrophy was introduced by Price et al in 1980, he noted some symptoms of the condition such as sulphur deficient brittle hair.

 

Symptoms/Signs

Signs that a woman might be pregnant with a child that has TTD include:

o         preeclampsia, high blood pressure and excess protein in the urine after 20 weeks of pregnancy

o         HELLP syndrome, a life threatening liver disorder thought to be a type of severe preeclampsia

o         premature birth

The symptoms of TTD include:

o         low birth weight and poor weight gain

o         slow growth

o         short stature compared with other kids in the same age range

o        delayed development

o   brain abnormalities

o   intellectual disabilities

o   ichthyosis (a congenital skin condition that causes the epidermis to become dry and rough like fish scales)

o   congenital cataracts clouding the lens in both eyes from birth, leading to a decrease in vision

o   recurrent infections especially those of the respiratory system

o   poor coordination

o   abnormalities of the toe and finger nails

o   skeletal abnormalities

o   premature aging of facial features, osteoporosis (a disease that thins and weakens the bones to the point that they become fragile and break easily) and hearing loss

o   abnormal brittle, fragile and sparse hairs

o   dental abnormalities

o   sensitivity to ultraviolet rays from the sun in patients with the photosensitive type

Classification

TTD can be sub classified into 4 syndromes: BIDS, PBIDS, IBIDS and PIBIDS.

      i.               BIDS Syndrome

BIDS syndrome is an acronym for brittle hair-ichthyosis-decreased fertility-short stature syndrome. It is also called Amish brittle hair syndrome and hair brain syndrome. It is an autosomal recessive inherited disease characterised by brittle hair, ichthyosis, decreased fertility and short stature. Patients with BIDS syndrome are not photosensitive.

     ii.              PBIDS Syndrome

PBIDS syndrome is an acronym for photosensitivity-brittle hair-ichthyosis-decreased fertility-short stature syndrome. The letters of the acronym PBIDS represent its characteristics. It is basically a photosensitive form of BIDS syndrome.

   iii.           IBIDS Syndrome

IBIDS syndrome is an acronym for intellectual impairment-brittle hair-ichthyosis-decreased fertility-short stature syndrome. It is also called Tay syndrome because it was first described by D-Tay in 1971 and sulphur-deficient brittle hair syndrome. It is an autosomal recessive congenital disease, characterised by intellectual impairment, brittle hair, ichthyosis, decreased fertility, short stature and non photosensitivity.

   iv.               PIBIDS syndrome is the photosensitive form of IBIDS syndrome.

 Causes

TTD is inherited in an autosomal recessive pattern, both copies of the gene in each cell have mutations and both parents carry one copy of the mutated gene but do not show any signs or symptoms of the condition. The parents are just carriers of the abnormal gene in which they pass on to their children. In some forms of TTD the genetic cause is unknown. The XPB or ERCC3, XPD or ERCC2, GTF2H5 and MPLKIP or TTDN1 genes have been identified for their role in the development of TTD.

DNA or deoxyribonucleic acid is a complex molecule that encodes the genetic instructions used in the development and functioning of an organism, it contains all the information necessary to build and maintain an organism. DNA can be modified or damaged from endogenous sources such as reactive oxidative species (chemically reactive molecules containing oxygen) and exogenous sources such as ultraviolet (UV) ionizing radiation (UV light with radiation composed of particles that carry enough kinetic energy to liberate an electron from an atom or molecule, converting it to an ion) which will increase reactive oxidative specie levels dramatically damaging cell structures. This causes defects in successive DNA replication and errors in genetic information within the DNA. If damaged DNA is not repaired it can lead to a range of disorders with neurological abnormalities (abnormalities relating to the nervous system), developmental defects, photosensitivity, accelerated age process and cancer. NER (nucleotide excision repair) is the most important DNA repair system or pathway in the cells that detects and removes specific types of DNA lesions especially those induced by drugs used to fight against tumours and UV radiation, to maintain the integrity of the genetic information contained within the DNA. Defects in NER have been associated with some rare autosomal recessive diseases like TTD, Cockayn syndrome (CS) and xerodermal pigmentosum (XP). Cockayn syndrome is a genetic disease that results from an inability to repair damage to DNA. Xerodermal pigmentosum is an inherited condition characterized by an extreme sensitivity to ultraviolet rays from the sun.

The products of 11 genes participate in NER and their mutations have been associated with TTD, XP and CS. Three genes (XPB, XPD and GTF2H5) out of the 11 are involved in the basal transcription repair factor TFIIH. The proteins produced from genes XPB, XPD and GTF2H5 work together as part of a group of proteins called general transcription factor IIH (TFIIH) complex. These genes encode subunits of the transcription factor IIH (TFIIH) complex which initiates the NER when DNA is damaged and plays an active role in gene transcription, the first step in protein production. Gene transcription is needed for normal development of a child and studies have shown this may be responsible for other forms of TTD.

PIBIDS and PBIDS syndrome have defects in the NER systems. Mutations in the subunits of DNA TFIIH disturb regulatory activity and or the ability to act as catalyst (a substance that causes a chemical reaction to happen more quickly) of the 2 XPB, XPD helicase (an enzyme that unwinds double strand DNA to single DNA strands) or ATpases (a class of enzymes that is used to speed up the chemical process of decomposing adenosine triphosphate, a substance that provides energy for many metabolic processes, to form adenosine diphosphate, a lower energy form of adenosine triphosphate). This results in a defective DNA repair and transcription system and disturbs the architecture of the TFIIH complex and its ability to transactivate certain nuclear receptor responsive genes. The photosensitive form of TTD, results from mutations in any of XPB, XPD and GTF2H5 genes which reduces the amount of the complex in cells therefore impairing DNA repair and gene transcription. An inability of the body to repair DNA causes patients with TTD to get sunburns easily when exposed to UV light.

The NER defect is not present in non photosensitive TTD. In less than 20% of cases of non-photosensitive TTD, mutations in MPLKIP gene have been reported to be the cause. Unfortunately, very little is known of the MPLKIP gene, the protein it produces, its function or how its mutations cause the various characteristics of TTD.

Clinical Features

Babies with TTD are born with shiny transparent skin known as collodion baby. The clinical features of TTD are photosensitivity, ichthyosis, brittle hair, decreased fertility, intellectual impairment and short stature.

a.       Photosensitivity

The defects in NER pathway which results in inefficient removal of DNA lesions caused by UV damage make a majority of TTD patients photosensitive. Patients show strong sensitivity to ultraviolet A and B light. Patients must not stay in the sun or stand the risk of sunburn. Despite the link between photosensitivity and reduced capacity of DNA repairs, no association with cancer and pigmentory abnormalities have been identified. Patients do not develop other sun related problems like freckling of the skin, skin cancer or even sweat. It has been reported that the severity of photosensitivity declines with age.

b.       Ichthyosis

Ichthyosis characterised by dry crackled skin covered with thin adherent scales (Fig. 2) is often experienced by patients with TTD.

It has been reported in many cases of TTD, that follicular keratosis (a cutaneous condition characterized by a horny growth) may be a sign of ichthyosis (PFOND, 2012).

c.     Brittle hair

Patients have abnormally brittle, sparse, dry and fragile hair (Fig. 2) caused by the decrease in the production of sulphur matrix proteins (a member of the family of keratins) reducing effective cyteine (a sulphur containing amino acids) content. A microscope might reveal a pattern of alternating light and dark bands on the hair shaft, trichoschisis and the absence of or a defective cuticle.

d.       Decreased fertility

    Spermatogenesis, the process of male gamete (a mature sexual reproductive cell as a sperm or egg) formation requires the production of sulphur containing proteins. Gonadial (a sex gland in which gametes are produced, an ovary and testis) defects and decreased fertility due to sulphur deficiency is a common feature. Absent breast tissue, oligomenorrhea (infrequent or very light menstruation) and delayed menarche (first menstrual period) have been reported in female patients with under developed genitalia. In male patients with PIBIDS, testicular failure has been reported.

e.       Intellectual impairment

Mental retardation with low IQ, delayed physical maturation, defects in the development of the nervous system, lethargy (a lowered level of consciousness, with drowsiness, listlessness and apathy), irritability and unusual social behaviours, have been reported in patients with TTD. In severe cases, patients may have very poor mental and motor performance. However, despite these intellectual impairments, they are social, friendly, outgoing and engaging.

f.        Short stature

In patients with TTD, growth retardation and abnormal body proportions in the form of dwarfism, microcephalia (an abnormal smallness of the head), delayed puberty and skeletal malformations such as an unusual bird like facial appearance, are common features.

Diagnosis

TTD can be diagnosed by physical examination of the hair, light microscopy and amino acid analysis.

Physical examination of a patient’s hair shows brittle, fragile, sparse and short hairs, the end product of hairs becoming exposed to the environment. Most patients also have sparse eyebrows and eyelashes (Fig. 1).

Light microscopy test of hair shafts reveal trichoschisis (broken or split hairs), and irregular and flattened hair shafts like trichorrhexis nodosa. Polarizing microscopy shows alternating light and dark bands, a tiger tail pattern.

An amino acid analysis is a tool for determining protein quantities and getting information on relative amino acid composition and free amino acids. An amino acid analysis that quantifies sulphur inversely correlates with the percentage of hairs showing abnormalities. It is the most dependable diagnostic test for TTD. It will show a decreased high sulphur matrix protein. High sulphur matrix protein is a member of the family of keratins, it is one of the rigid matrix proteins in which microfibrils of hair (a keratin protein) are embedded.  Reduced hair robustness is caused by the increased proportion of unstable disulfide conformers. Disulfide bonds are single covalent bonds (a bond formed by the sharing of one or more electrons especially pairs of electrons between atoms) between the sulphur atoms to two amino acids called cysteine. These disulfide bonds make up the cortex of the hair and its shape determines hair texture. Patients with xerodermal pigmentosum (XP) and Cockayn syndrome (CS) do not have sulphur deficient brittle hair phenotypes (a set of observable characteristics of an individual resulting from the interaction of its genotype with the environment).

Treatment

Unfortunately, there is no cure for TTD. Prevention from sun induced skin damage especially for patients with photosensitive TTD is important. Dietary cytosine supplementation is sometimes recommended. Cytosine is a single-ringed, crystalline organic base that codes genetic information in the polynucleotide chain of DNA or RNA. Ribonucleic acid of RNA is used to translate instructions from DNA to make proteins in the body.

 References

 

1.     Blume-Peytavi, U., Tosti, A., Whiting, D.A & Trub R.M. (2008). Hair growth and disorders, Germany: Graphics LLC.

2    Journal of Medical Genetics (2014). Trichothiodystrophy, photosensitive. Retrieved from: http://www.gfmer.ch/genetic_diseases_v2/genetics_detail_list.php?cat3=1426.

3.       Trichothiodystrophy (May 2010). Retrieved from: http://ghr.nlm.nih.gov/condition/trichothiodystrophy.

      Trichothiodystrophy (Oct. 2014). Retrieve from: http://en.m.wikipedia.org/wiki/Trichothiodystrophy.

5.      Trichothiodystrophy syndrome (Aug. 2012). Retrieved from: http://pfond.cmmt.ubc.ca/trichothiodystrophy/about/overview/.

      Trichothiodystrophy Syndromes (n.d). Retrieved from: http://www.lookfordiagnosis.com/mesh_info.php?term=Trichothiodystrophy+Syndromes.