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Trichothiodystrophy
— A Case Report —
Pei-Lun Sun
Yang-Chih Lin
Hsin-Yi Su
Shuan-Pei Lin 1
Trichothiodystrophy is a rare hair disorder inherited in an autosomal recessive pattern. It is a disease complex which is usually associated with other neuroectodermal abnormalities and photosensitivity. The hair shows trichoschisis, trichorrhexis nodosa under light microscopy, absent or damaged hair
cuticles under scanning electron microscopy, and alternating light and dark bands under polarized
microscopy. The sulfur content of the hair is low. We report a patient with hair changes and developmental delay. (Dermatol Sinica 21 : 52-57, 2003)
Key words: Trichothiodystrophy, Sulfur
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( ̚රϩᄫ 21 : 52 - 57, 2003 )
Introduction
Trichothiodystrophy ( TTD ) is a heterogeneous group of disorders characterized by short,
brittle hair with low sulfur content and distinctive light and electron microscopic findings. It is
inherited in an autosomal recessive pattern.
Though cases with isolated TTD have been
reported,1,2 it is usually associated with neuroectodermal abnormalities. We report a patient with
TTD with physical developmental delay and
briefly review the literature.
From the Departments of Dermatology and Pediatrics1, Mackay Memorial Hospital-Taipei
Accepted for publication: July, 11, 2002
Reprint requests: Pei-Lun Sun, M.D., Department of Dermatology, Mackay Memorial Hospital - No. 92, Sec. 2, Chung-Shan N Rd.,
10499. Taipei, Taiwan, R.O.C. TEL: +886-2-2543-3535 ext. 2556 FAX: +886-2-2543-3642 E-mail: [email protected]
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Fig. 1
Fig. 3
Sparse, brittle hair is noted all over the scalp of this
2-year-2-month-old girl.
Alternating light and dark bands of the hair shaft on
polarized microscopy.
Case Report
A 2-year-2-month-old girl was admitted
to our Pediatric Department with watery diarrhea, vomiting, and fever. She was born to a
G5P2 mother via NSD at a gestational age of 36
weeks and was small for gestational age (birth
weight: 1696 gm [ < 10 th percentile ], head circumference: 29cm [ < 10 th percentile ] ). She had
been admitted to hospital several times for
intractable diarrhea. Developmental history
revealed that she was incapable of scribbling,
running, or hopping. There was no history of
seizures, eye problems, intellectual impairment
or skin photosensitivity. Her parents reported
that her hair had been dry and sparse since
birth. Both parents and her elder sister were
healthy. On physical examination, her height
was 70.8 cm ( < 3 rd percentile) and weight 6214
gm ( < 3 rd percentile ). Her face was otherwise
normal. Her skin was dry but not ichthyotic.
Our Dermatology Department was consulted
and found the hair to be thin, brittle, and sparse
over the entire scalp ( Fig.1 ). On light
microscopy, trichorrhexis nodosa was noted on
nearly every hair sampled ( Fig.2A ). No trichoschisis was seen. Polarized microscopy
A
B
Fig. 2
Trichorrhexis nodosa on light microscopy (A) and scanning electron microscopy (B). The absence of normal
cuticular scales on the hair shaft can be noted.
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revealed alternating light and dark bands of the
hair ( Fig. 3 ). The " tiger- tail " pattern was not
clearly demonstrated. Scanning electron
microscopy revealed the absence of normal
cuticular scales on the hair shaft (Fig. 2B). The
sulfur content of hair was decreased by more
than 50% compared to a normal control specimen, using energy dispersive x - ray spectroscopy (Noran VANTAGE A4105). The plasma zinc was slightly elevated (1382 µg / L, reference range: 800-1200 µg / L), but copper was
in the normal range. Plasma ammonia was normal. A chromosome study showed a normal
female 46,XX karyotype. Urine organic acid
analysis and plasma amino acid quantitative
analysis were both normal. The complete blood
count was grossly normal. The diagnosis of trichothiodystrophy was made. The patient was
seen again 1.5 years later, at which time the hair
abnormality and developmental delay persisted,
with primarily gross motor delay, as evaluated
by the Denver Developmental Screening Tests
(DDST). She had just learned to hop and to go
upstairs with assistance, milestones of a 3 year - old child. No other neuroectodermal
abnormalities were noted.
Discussion
The term 'trichothiodystrophy' (TTD) was
first proposed by Price in 1980 to describe a
disease complex characterized by brittle hair
with a low sulfur content and neuroectodermal
abnormalities.3 It is inherited as an autosomal
recessive trait with a wide spectrum of clinical
presentations. Patients with brittle nails, mental
retardation, growth retardation, impaired sexual
development, photosensitivity, ichthyosis,
cataracts, recurrent infections, and ataxia have
all been reported. Many eponyms and acronyms
have been used to describe these subgroups of
TTD (Table I).4,5 Our patient does not clearly fit
any of the subgroups. Her disorder included
only hair abnormality, growth retardation, and
physical developmental delay.
Hair dysplasia is the most important and
common feature of TTD. Examination usually
Table I. TTD subtype classification 4
Type Findings
A
Hair +/-nails
B
Hair +/-nails + mental retardation
C
Hair +/-nails + mental retardation + folliculitis + retarded bone
Eponym / Acronym
OMIM
Sabinas
Pollitt
211390
275550
age +/-caries
Brittle hair +/-nails + intellectual impairment + decreased
BIDS
234050
fertility + short stature*
E
Ichthyosis + BIDS. Hair +/-nails + mental retardation + short
Tay + BIDS
242170
stature +/-decreased gonadal function +/-lenticular opacities/
cataracts + failure to thrive/"progeria" + microcephaly +/-ataxia
+/-calcifications of the basal ganglia + erythroderma and scale
F
Photosensitivity + IBIDS
PIBIDS
278730
G
TTD with immune defects. Hair +/-mental retardation + chronic
neutropenia or immunoglobulin deficiency
Itin
258360
H
Trichothiodystrophy with severe intrauterine growth retardation
(IUGR). Hair + severe IUGR and failure to thrive +
developmental delay + recurrent infections + cataracts + hepatic
angioendotheliomas
*The original description "Brittle hair +/-nails + infertility + developmental delay + short stature" in the reference is corrected here according to OMIM.5
D
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reveals sparse, brittle hair, with or without
involvement of the eyelashes and eyebrows.
Trichoschisis and trichorrhexis nodosa can be
seen with light microscopy. Under polarized
microscopy, affected hair shows alternating
light and dark bands resulting in a "tiger-tail"
or " zigzag " pattern. Scanning electron
microscopy shows damage or loss of cuticle
scales and longitudinal grooving. Lack of the
exocuticle and thinning of the cysteine - rich
cuticular A layer can also be detected on a
cross-section of the cuticle.4 Usually the sulfur
or cysteine content of the hair is less than 50%
of normal. However, urine and serum levels of
these amino acid constituents are generally normal.4
Normal hair is made up of two structural
proteins: intermediate keratin filaments ( low
sulfur proteins ), and matrix proteins, which
includes cysteine-rich proteins ( high - sulfur
proteins ) and glycine - and tyrosine-rich proteins. The reduction of high - sulfur proteins in
late stage keratinocytes in TTD patients likely
causes a decreased number of multiple covalent
disulfide bonds between the intermediate keratin proteins. This results in the reported ultrastructural changes of the hair cuticle and cortex
and clinically in sparse, brittle hair.6
Alternating light and dark bands of the
hair are a distinctive, though not diagnostic,
feature of TTD. These can also be detected in
patients with argininosuccinic acidouria, acrodermatitis enteropathica, methionine deficiency,
and in normal infants. Argininosuccinic acidouria is an autosomal recessive metabolic disorder due to deficiency of argininosuccinate
lyase. Hyperammonemia and markedly increased plasma argininosuccinic acid are noted.
It is characterized clinically by mental retardation and dry, brittle hair, which in a few cases
has alternating light and dark bands of the hair
shaft. This condition can be reversed by reducing the protein load and giving arginine supplements.7 Acrodermatitis enteropathica is a disease due to zinc deficiency. Alternating light
and dark bands can be detected occasionally.
This condition can be reversed by zinc supple55
ments.8 In 1996, Goerz et al. reported an 8 year-old girl with brittle and sparse hair in her
early childhood. Alternating dark and bright
bands of hair was noted on polarized
microscopy. Hair amino acid analysis showed
increased cysteine content and completely
devoid of methionine. Hair growth improved at
puberty and returned to normal during pregnancy.9 A "tiger-tail" pattern of the hair on polarized microscopic examination is also a relatively common finding in healthy infants.10 Sulfur
amino acid analysis of the hair is the definitive
test for TTD, which will distinguish it from
these other disorders.
A low sulfur content in hair can be detected in other diseases such as kwashiorkor,
ichthyosis and Clouston's syndrome ( hidrotic
ectodermal dysplasia).11-13 However, these disorders have characteristic clinical presentations
and don't have the typical electron microscopic
findings of TTD. Cold - wave lotions, depilatories, bleaching solutions, and synthetic-organic
dyes also decrease the low sulfur content in
hair.14
For our patient, with congenital trichorrhexis nodosa, the differential diagnosis included argininosuccinic acidouria, citrullinemia,
Menkes syndrome, and TTD.15 Normal arginine
and citrulline levels excluded the two former
disorders. Menkes syndrome is a disorder of
defective copper metabolism with low plasma
copper and ceruloplasmin. Our patient has normal plasma copper. Hair examination by light
microscopy, polarized microscopy and electron
microscopy all showed findings of TTD. We
used energy dispersive x - ray spectroscopy to
determine the sulfur content of the hair, a useful
method for identifying specific elemental components of hair by their x-ray emission spectrum following electron bombardment.16
Photosensitivity is noted in nearly 50% of
patients with TTD. This phenomenon is due to
nucleotide excision DNA repair defects like
those in the xeroderma pigmentosum or
Cockayne syndromes. Mutations within the
XPD, XPB or TTD - A gene ( as yet unidentified ) have been noted in affected persons. 6
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Nucleotide excision repair is an important
mechanism for repairing damaged DNA in
order to reduce the chance of developing a
malignancy. Surprisingly, TTD patients with
nucleotide excision repair defects don't have an
increased risk of malignancy as do patients with
xeroderma pigmentosa. There may be several
reasons for this, including hyperkeratosis of the
epidermis which blocks UV light, preservation
of cellular catalase activity, and different molecular characteristics of the mutation after UV
irradiation.6 Recently, it has been suggested that
TTD is a transcription disease with depressed
RNA synthesis, which may account for the clinical features of growth retardation, neurologic
abnormalities, and brittle hair and nails.4
Currently, there is no known effective
treatment for TTD. Food rich in cysteine is of
little help because affected persons are not cysteine deficient; they can't utilize the cysteine
they have due to a genetic error. The most
important recommendation that can be made is
to reduce physical stress ( frequent washing,
brushing, wearing of hats, and UV exposure) or
chemical trauma to the hair.2
In conclusion, trichothiodystrophy is a rare
disease complex. When sparse, brittle hair is
noted, direct hair sampling for light microscopic examination is of great help for diagnosis.
Typical microscopic and electron microscopic
findings and low sulfur content of the hair make
the diagnosis. Thorough examination for other
possible associated neuroectodermal abnormalities is also necessary.
Acknowledgement
We thank the Department of Medical
Research of Mackay Memorial Hospital for
energy dispersive x-ray spectroscopy ( EDS )
microanalysis.
References
1. Alfandari S, Delaporte E, van Neste D, et
al.: A new case of isolated trichothiodystrophy. Dermatology 186: 197-200, 1993.
2. Peter C, Tomczok J, Hoting E, et al.:
Trichothiodystrophy without associated
neuroectodermal defects. Br J Dermatol
139: 137-140, 1998.
3. Price VH, Odom RB, Ward WH, et al.:
Trichothiodystrophy: sulfur-deficient brittle
hair as a marker for a neuroectodermal
symptom complex. Arch Dermatol 116:
1375-1384, 1980.
4. Itin PH, Sarasin A, Pittelkow MR:
Trichothiodystrophy: update on the sulfurdeficient brittle hair syndromes. J Am Acad
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5. OMIM (Online Mendelian Inheritance in
Man): Available at: http://www.ncbi.nlm.nih
.gov/omin. Accessed March 2002.
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of keratin: Clouston's ectodermal dysplasia.
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57
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