RESEARCH ARTICLE
New Clinico-Genetic Classification ofTrichothiodystrophyFanny Morice-Picard,1,2* Muriel Cario-Andr�e,3 Hamid Rezvani,3 Didier Lacombe,2 Alain Sarasin,4
and Alain Ta€ıeb1,3
1Department of Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Pellegrin University Hospitals, Bordeaux, France2Department of Medical Genetics (National Reference Center for Developmental Defects), Pellegrin University Hospitals, Bordeaux, France3INSERM U876, Victor Segalen Bordeaux 2 University, Bordeaux, France4CNRS FRE 2939, University Paris-Sud, Gustave Roussy Institute, Villejuif, France
Received 11 February 2009; Accepted 4 April 2009
Trichothiodystrophy (TTD) is a congenital hair dysplasia with
autosomal recessive transmission. Cross banding pattern under
polarized light plus trichoschisis and a low sulfur content of hair
shafts define the disorder, which is associated with variable and
neuroectodermal symptoms. So-called photosensitive forms of
TTD (with low level of in vitro UV-induced DNA repair, not
constantly associated with marked clinical photosensitivity) are
caused by mutations in genes encoding subunits of the
transcription/repair factor IIH (TFIIH). Ten percentage of non-
photosensitive patients are known to have TTDN1 mutations,
the specific role of which is unknown. We studied nine patients
recruited at our institution and reviewed 79 with molecular
analysis out of 122 TTD patients reported in literature with the
aim to collect systematically the clinical findings in TTD patients
and establish genotype–phenotype correlations. The frequency
of congenital ichthyosis, collodion-baby type, was significantly
higher in the TFIIH mutated group. Hypogonadism was signifi-
cantly more frequent in the non-photosensitive group. There was
no statistical difference regarding osseous anomalies. Mutations
in TFIIH sub-units leading to abnormal expression in genes
involved in epidermal differentiation could explain the particu-
lar dermatological changes seen in photosensitive cases of TTD.
We suggest a new clinico-genetic classification of TTD, which
may help clinicians confused by the current acronyms used
(IBIDS, PIBIDS. . .). Understanding the TTD ichthyotic pheno-
type could lead to therapeutic advances in the management of
TTD and other types of ichthyoses. � 2009 Wiley-Liss, Inc.
Key words: TTD; photosensitivity; DNA repair; transcription
factor THFIIH; ichthyosis
INTRODUCTION
Trichothiodystrophy (TTD) is a rare ectodermal disorder first
described by Pollitt et al. [1968] and named by Price et al.
[1980]. The patients usually present with dry and sparse hair. Hair
shafts break easily with trauma. The name trichothiodystrophy was
proposed to group several phenotypes on the basis of a common
deficiency in sulfur proteins of the hair shaft [Price et al., 1980].
Several neuroectodermal manifestations are variably seen in this
phenotype including mental retardation, ichthyotic skin, reduced
stature, osseous anomalies and hypogonadism but none is a con-
stant trait [Itin and Pittelkow, 1990; Itin et al., 2001].
TTD is inherited as an autosomal recessive trait [Jackson et al.,
1974; Price et al., 1980; Howell et al., 1981]. DNA repair defect is
present in around 50% of patients, which have been referred to as
‘‘photosensitive’’ even without clear-cut evidence of associated
clinical photosensitivity [Nishiwaki et al., 2004]. Mutations in
XPD, XPB, p8 have been subsequently found in ‘‘photosensitive’’
TTD patients [Stefanini et al., 1986; Weeda et al., 1997; Giglia-Mari
et al., 2004]. Mutations in C7Orf11, encoding TTDN1 of unknown
function was found in the group of patients without DNA repair
anomalies [Nakabayashi et al., 2005]. However mutations in this
gene were excluded in some non-photosensitive patients including
those described by Howell et al. [1981] (Sabinas syndrome) and
Pollitt et al. [1968] suggesting further genetic heterogeneity in the
group without DNA repair anomaly [Nakabayashi et al., 2005]. A
genetic classification into three groups can thus be proposed
distinguishing a group with DNA repair anomalies (I), a group
*Correspondence to:
Fanny Morice-Picard, National Reference, Center for Rare Skin Disorders,
Unit�e de Dermatologie P�ediatrique, Hopital Pellegrin-Enfants, 33076
Bordeaux, France. E-mail: [email protected]
Published online 13 August 2009 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.a.32902
How to Cite this Article:Morice-Picard F, Cario-Andr�e M, Rezvani H,
Lacombe D, Sarasin A, Ta€ıeb A. 2009. New
clinico-genetic classification of
trichothiodystrophy.
Am J Med Genet Part A 149A:2020–2030.
� 2009 Wiley-Liss, Inc. 2020
without DNA repair defect and with TTDN1 mutations (II), and a
group without DNA repair defect and without identified genetic
basis (III).
XPD, XPB, and p8 are subunits of the transcription/DNA repair
factor IIH (TFIIH). TFIIH is a complex consisting of 10 proteins
essential for both nucleotide excision-repair (NER) and transcrip-
tion [Schultz et al., 2000; Coin et al., 2006; Laine and Egly, 2006].
Mutations in subunits associated with TTD destabilize the TFIIH
structure and lead to decreased cellular concentrations [Coin et al.,
1998; Vermeulen et al., 2000]. The lower amount of TFIIH found in
individuals with TTD contributes to a limiting level of transcription
of targeted genes and could explain the TTD phenotype including
cutaneous and neurological features [Compe et al., 2007].
TTDN1 is a nuclear protein not involved in DNA repair. It has
been shown that TTDN1 interacts with polo-like kinase 1 (PLK1), a
highly conserved serine-threonine kinase regulating cellular cycle
and mitosis [Zhang et al., 2007]. TTDN1 has several phosphoryla-
tion sites and is a regulator of mitosis. Interactions between cell
cycle regulation and transcription efficiency could explain the TTD
phenotype observed in patients with TTDN1 mutations.
In this article, we review patients seen in our Clinical Department
and those published to compare the phenotypes in photosensitive
and non-photosensitive groups, especially for cutaneous, neuro-
logical, osseous and gonadal aspects with the aim to establish
genotype–phenotype correlations in TTD.
PATIENTS AND METHODS
We analyzed the clinical condition of TTD patients and their genetic
characterization when available, through a literature review. Pa-
tients were included if the characteristic hair anomalies were
present, including a sulfur deficiency of hair and an abnormal
microscopic aspect (trichoschisis and hair-banding under polar-
ized light) allowing a definite diagnosis of TTD. Following a
comprehensive literature review, we selected a series of informative
features of the TTD phenotype to establish a clinical database,
including mental retardation, growth failure, osteosclerosis, go-
nadal dysfunction, cutaneous changes, and clinical photosensitivi-
ty. We looked at the associated genetic status of each patient
published in the literature, generally in consecutive reports. For
the analysis, two groups where distinguished, namely group A with
DNA repair anomalies and group B without DNA repair anomalies
and irrespective of the classification in three genetic groups. We
compared the frequencies of the selected clinical findings in both
groups using the c2 test (a¼ 5%).
RESULTS
Literature ReviewWe reviewed 122 patients with criteria for TTD [Pollitt et al., 1968;
Brown et al., 1970; Tay, 1971; Jackson et al., 1974; Arbisser et al.,
1976; Jorizzo et al., 1980; Price et al., 1980; Howell et al., 1981;
Crovato and Rebora, 1983; Diaz-perez and Vasquez, 1983; Van
Neste and Bore, 1983; Happle and Traupe, 1984; King et al., 1984;
Lucky et al., 1984; De Prost et al., 1986; Rebora et al., 1986; Stefanini
et al., 1986, 1992; Meynadier et al., 1987; Baden and Katz, 1988; Fois
et al., 1988; Lehmann et al., 1988; Motley and Finlay, 1989; Van
Neste et al., 1989; Broughton et al., 1990; Przedborski et al., 1990;
Kousseff, 1991; Savary et al., 1991; Peserico et al., 1992; Rizzo et al.,
1992; Sarasin et al., 1992; Alfandari et al., 1993; Calvieri et al., 1993;
Hersh et al., 1993; McCuaig et al., 1993; Chen et al., 1994; Feier and
Solovan, 1994; Tolmie et al., 1994; Eveno et al., 1995; Lynch et al.,
1995; Bracun et al., 1997; Brusasco and Restano, 1997; Malvehy
et al., 1997; Schepis et al., 1997; Takayama et al., 1997; Botta et al.,
1998, 2002, 2009; Petrin et al., 1998; Foulc et al., 1999; Itin et al.,
2001; Toelle et al., 2001; Vermeulen et al., 2001; Viprakasit et al.,
2001; Mazereeuw-Hautier et al., 2002; Dollfus et al., 2003; Giglia-
Mari et al., 2004; Wakeling et al., 2004; Faghri et al., 2008].
DNA repair analysis data and genetic status was available on 79
patients.
UV-induced DNA repair deficiency was found in 42 (group A).
The genetic status was available on 36 patients in group A, including
30 patients with XPD mutations [Crovato and Rebora, 1983; King
et al., 1984; Stefanini et al., 1986, 1992; Broughton et al., 1990;
Peserico et al., 1992; Chen et al., 1994; Tolmie et al., 1994; Eveno
et al., 1995; Takayama et al., 1997; Botta et al., 1998, 2009; Foulc
et al., 1999; Vermeulen et al., 2000; Boyle et al., 2008], 4 with p8
mutations [Jorizzo et al., 1980; Giglia-Mari et al., 2004] and 2 with
XPB mutations [Sarasin et al., 1992; Weeda et al., 1997]. Six patients
were presenting with abnormal DNA repair without molecular
characterization.
Thirty-seven patients presented with normal DNA repair
(group B). Twenty-eight patients had TTDN1 mutations
[Nakabayashi et al., 2005; Botta et al., 2007]. We obtained clinical
data on 26 of them [Jackson et al., 1974; Diaz-perez and Vasquez,
1983; Fois et al., 1988; Lehmann et al., 1988; Przedborski et al., 1990;
Rizzo et al., 1992; Nakabayashi et al., 2005; Botta et al., 2007].
Normal DNA repair was found in 11 patients, two of them had no
TTDN1 mutations [Nakabayashi et al., 2005]. Molecular analysis
was not performed in the nine remaining patients.
All observations are summarized in Table I.
Summary of the Observations of Our PatientsNine TTD cases were diagnosed at our institution between 1982 and
2007. Only the seven patients on whom DNA repair analysis data are
available are described here.
Patient 1 (TTD1VI). This boy was the first child born at term to
nonconsanguineous healthy parents. Family history was not rele-
vant. Intrauterine growth retardation was noted. Birth weight (BW)
was: 2,740 g (�1.5 SD), length (BL) 44 cm (�2 SD). Ichthyosiform
lesions of lower legs were noted on the 8th day of life. He was first
seen at 8 years for severe psychomotor delay. Neurologic exam
showed axial hypotonia with peripherical hypertonia and general-
ized convulsions. He had large protruding ears and unilateral single
palmar crease. Sparse brittle hair was noted. Magnetic resonance
imaging (MRI) showed pachygyria and ventricular dilatation.
Metabolic investigations including very long chain fatty acid level,
lysosomal enzymatic activities, mucopolysaccharides dosage were
normal. Hair microscopy showed a tiger-tail banding and bio-
chemical exam displayed a low-sulfur-hair content thus confirming
the diagnosis of TTD. UV-induced DNA repair deficiency was
found in vitro at about 30–40% of control. Full complementation
was observed following transfection with wild-type XPD gene. XPD
MORICE-PICARD ET AL. 2021
TAB
LEI.
Sum
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Clin
ical
and
Mol
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ngs
of7
9TT
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ent
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[19
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98
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99
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al.
[19
92
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etal
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al.
[19
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12
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12
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59
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12
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al.
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al.
[19
98
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etal
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18
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al.
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97
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iet
al.
[19
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]�
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mz
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/p1
Bro
ught
onet
al.
[19
90
]B
roug
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etal
.[1
99
0]
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oder
ate
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p.R
72
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.L4
61
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etal
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00
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leet
al.
[20
08
]�
þþ
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.R7
22
W,
p.R
37
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35
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etal
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00
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leet
al.
[20
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31
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ne
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al.
[20
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rosi
sþ
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62
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24
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.[2
00
9]
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taet
al.
[20
09
]�
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cet
al.
[19
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ulc
etal
.[1
99
9]
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iaþ
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ofer
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steo
scle
rosi
s
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al.
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99
9]
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eosc
lero
sis
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open
ia
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Chen
etal
.[1
99
4]
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etal
.[1
99
4]
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htyo
se,
ther
mos
ensi
tive
þ�
�þ
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Chen
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.[1
99
4]
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etal
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99
4]
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sis
trun
k,PP
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al.
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iglia
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al.
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sis,
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oder
ate
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torc
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iaN
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Da
p.A
56
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99
RO
Gig
lia-M
ari
etal
.[2
00
4]
Gig
lia-M
ari
etal
.[2
00
4]
�Ic
hthy
osis
mod
erat
eM
oder
ate
��
þTT
Da
pA5
6X/
p.L2
1P
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13
PVG
iglia
-Mar
iet
al.
[20
04
]G
iglia
-Mar
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al.
[20
04
]�
�M
oder
ate
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Da
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z
2022 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TAB
LEI.
(Con
tin
ued)
Pati
ent
Ref
eren
ces
Der
mat
olog
ical
aspe
cts
Gon
adal
anom
alie
s
Oss
eou
s
anom
alie
s
DN
A
UD
SM
olec
ula
ran
alys
isCl
inic
alre
port
Mut
atio
nre
port
edCo
llodi
onIc
hthy
osis
Phot
osen
siti
vity
TTD
14
PVG
iglia
-Mar
iet
al.
[20
04
]G
iglia
-Mar
iet
al.
[20
04
]�
�M
oder
ate
��
þTT
Da
p.M
1T
hm
z
TTD
6VI
p3Sa
rasi
net
al.
[19
92
]W
eeda
etal
.[1
99
7]
þM
oder
ate
icht
hyos
is
trun
k
Mod
erat
e�
Nor
mal
X-ra
yþ
XPB
p.Y
11
9P
hm
z
TTD
4VI
/p4
Sara
sin
etal
.[1
99
2]
Wee
daet
al.
[19
97
]þ
Mod
erat
eic
hthy
osis
trun
k
Mod
erat
e�
Nor
mal
X-ra
yþ
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p.Y
11
9P
hm
z
Luck
yet
al.
[19
84
]�
þþ
Test
ishy
pop
last
icO
steo
pen
iaþ
nd
Van
Nes
tean
dB
ore
[19
83
]�
þþ
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one
mat
urat
ion
del
ay
þn
d
Mey
nad
ier
etal
.[1
98
7]
þþ
þCr
ypto
rchi
dia
,
hypo
f
�þ
nd
Fort
ina
etal
.[2
00
1]
�Ic
htyo
se,
derm
atit
e
atop
ique
þCr
ypto
rchi
dia
Ost
eosc
lero
sis
þn
d
McC
uaig
etal
.[1
99
3]
�Ic
htyo
sis
trun
k,
PPK
�Te
stis
hypo
pla
stic
Ost
eosc
lero
sis
þn
d
McC
uaig
etal
.[1
99
3]
þIc
htyo
seAD
þCr
ypto
rchi
dia
Axia
l
oste
oscl
eros
is
þn
d
TTD
5PV
Fois
etal
.[1
98
8]
Nak
abay
ashi
etal
.[2
00
5]
�Fo
llicu
lar
kera
tosi
s�
Hyp
ogon
adis
mLo
caliz
ed
oste
oscl
eros
is
�TT
DN
1n
e
TTD
9PV
Riz
zoet
al.
[19
92
]N
akab
ayas
hiet
al.
[20
05
]�
��
�N
orm
alX-
ray
�TT
DN
1d
elex
on1
,2h
mz
TTD
1M
ALe
hman
net
al.
[19
88
]N
akab
ayas
hiet
al.
[20
05
]�
Icht
hyos
istr
unk
��
��
TTD
N1
p.R
77
Gfs
X76
hm
z
Prze
dbor
ski
etal
.[1
99
0]
Nak
abay
ashi
etal
.[2
00
5]
��
�H
ypof
erti
lity
Ost
eop
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MORICE-PICARD ET AL. 2023
gene analysis found two deleterious mutations (First allele:
p.R722W and second allele p.L461V/716-730del) [Takayama
et al., 1997].
Patient 2 (TTD3VI). This boy was born at term after a normal
pregnancy. Family history was uninformative. He was first seen for
chronic alopecia. Clinical examination showed ichthyosis most
prominent on trunk, dry sparse hair with alopecia. Photosensitivity
was noted since age 7 years. A major psychomotor delay was
present. Hair analysis showed a tiger-tail pattern under polarized
light (Fig. 1). Amino-acid dosage shown diminished sulfur hair
content confirming the diagnosis of TTD. Skin histological exami-
nation showed a thin granular layer (Fig. 2). Zonular cataract was
present. UV-induced DNA repair deficiency was confirmed in
vitro. XPD gene analysis found two deleterious mutations (First
allele: p.R658H, and second allele p.L461V and Del p.716-730)
[Takayama et al., 1997].
Patients 3 and 4. The first child of a first-cousin healthy couple
was a boy. He was born at term after an uneventful pregnancy. He
was seen at birth, when he presented with congenital ichthyosis
(collodion baby) progressing to mild ichthyosis on the trunk
(Fig. 3a). Diagnosis of TTD was suspected at age 3 years on the
basis of mild ichthyosis of trunk, scalp, palms and soles (Fig. 3b),
mild photosensitivity noted after sun exposure and hair macro-
scopically normal but coarse and with a tiger-tail pattern under
polarized light. The diagnosis of TTD was confirmed by the analysis
of hair aminoacid content. Minor facial anomalies included broad
nasal bridge, apparently low-set abnormaly modelate ears. Growth
and psychomotor development were normal. Osseous radiogra-
phies were normal. A full blood count was normal. Hemoglobin
electrophoresis was normal. IgE were elevated. A UV-induced DNA
repair anomaly was detected. Complementation analysis showed
for the first time that the DNA repair defect was associated with the
XPB gene [Weeda et al., 1997]. Homozygous deleterious mutations
in the XPB gene were found. He was seen again at age 22. Photo-
sensitivity had disappeared. Ichthyosis of the flanks was more
marked and associated with a palmar hyperkeratosis (Fig. 3c–e).
A sensorineural deafness was recently diagnosed.
The second child was a girl. She was born at term with the same
presentation of congenital ichthyosis with a favorable outcome
(Fig. 4a). The diagnosis of TTD was confirmed by hair microscopy
and biochemical analysis. There was no mental or growth delay. She
was reevaluated at age 18. Ichthyosis was noted on the trunk with
desquamation following sun exposure (Fig. 4b). She had also mild
deafness. The two patients have two homozygous mutations in the
XPB gene (p.Y119P) [Weeda et al., 1997].
FIG. 1. Hair anomalies observed in Patient 2. a: Hypotrichosis with
brittle short hair. b: Trichoschisis with irregular aspect of cuticle. c:
Tiger-tail banding under polarized light (courtesy of Dr. D. Van
Neste).FIG. 2. Histologic examination of skin showing a thin granular layer,
compatible with ichthyosis vulgaris.
2024 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Patient 5. The patient is the first child of a nonconsanguineous
healthy couple. He was examined at 15 years for short, sparse hair
with alopecia associated with a generalized xerosis and keratosis
pilaris. Hair microscopical exam shown trichoschisis associated to a
tiger-tail banding under polarized light. Hypogonadism was asso-
ciated with micropenis and cryptorchidia. He also had leucopenia,
microcytosis, myopia, moderate developmental delay but normal
growth. Bone X-rays were normal. The diagnosis of TTD was
confirmed by hair aminoacid analysis showing a low sulfur hair
content. UV-induced DNA repair analyses were normal.
Patient 6 and 7. The boy (No. 6) was the first child of a non-
consanguineous healthy couple. Toxaemia was noted during preg-
nancy. He was born at 37 weeks (birth weight 2,700 g) and was
found to have a congenital ichthyosis (collodion baby). He was first
seen at age 7 years with his sister who had presented with the same
history of toxemia and collodion baby. Both had sparse, brittle,
hypopigmented hair. Microscopical and biochemical analysis of
hair confirmed a diagnosis of TTD. Hair loss following fever
episodes was noted. The girl (No. 7) had early onset insulin-
dependent diabetes. Other findings included moderate leuconeu-
tropenia, normal growth and developmental delay. DNA repair
studies were normal in both sibs. Both of them had a marked
pigmentary dilution (skin and hair) as compared with their parents.
Phenotype Analysis of 79 TTD PatientsNon-Cutaneous Aspects. The non-cutaneous aspects are sum-
marized in Table II.
Neurological involvement consists mainly in mental retardation,
and more uncommonly in ataxia, spastic paralysis or cerebellar
atrophy. Convulsions have rarely been described. MRI may show
abnormal white matter aspects. The two groups were similar. For
example, mental retardation was observed in 87% of in vitro
photosensitive patients (group A) and in 84% of the non-in vitro
photosensitive patients (group B).
Growth failure was observed in both groups, usually moderate
and rarely severe.
Typical osseous manifestations manifested as axial osteosclerosis
with peripherical osteopenia. Osseous manifestations were more
frequent in group A, but the difference was not significant
(c2 ¼ 2.62). Osseous anomalies can be asymptomatic and are not
often specified in the reports.
Hypoplastic testis, cryptorchidia are observed in males. Hypo-
gonadism has been sometimes substantiated by hormonal dosages
(diminished testosterone, elevated FSH, LH levels). A low fecundity
rate has been observed in the TTDN1-mutated Amish families
suggesting a defect in fertility. This may be the consequence of
gonadal dysfunction. Gonadal anomalies were significantly more
frequent in group B than in group A (65% in group B vs. 24% in
group A; c2¼ 13.69). However the lack of detailed clinical descrip-
tion including gonadal function constitutes a bias in this analysis.
Cutaneous Aspects. The results are summarized in Table III.
Skin anomalies mainly consisting of ichthyosis. An aspect of
collodion baby with a favorable course may precede the develop-
ment of ichthyosis. The descriptions of ichthyosis are often consis-
tent with the vulgaris type with small, white scales of the legs. Other
FIG. 3. Skin aspects of Patient 3. a: Collodion aspect at birth, (b) Moderate ichthyosis aspect of trunk at age 5, (c,d) Ichthyosiform skin changes more
pronounced at 22 years, (e) Moderate palmar keratoderma.
MORICE-PICARD ET AL. 2025
findings include xerosis, palmoplantar keratoderma, atopic der-
matitis, follicular keratosis. Pooled data shows a significantly
elevated frequency of ichthyosis in group A than in group B
(c2¼ 47), and a higher prevalence of neonatal forms (collodion
baby) (c2 ¼ 5.34). Moreover no description of collodion baby
was found in patients with TTDN1 mutations [Nakabayashi
et al., 2005; Botta et al., 2007]. However, two of our patients were
described as mild collodion babies and were subsequently found to
have normal DNA repair. Skin changes in group B are most often
non-specific, consisting of xerosis, follicular keratosis, and atopic
dermatitis.
The frequency of ichthyosis in patients with clinical photosensi-
tivity is higher than the frequency of ichthyosis in the global TTD
population (Table IV) These results highlight the association
between congenital ichthyosis and group A TTD with abnormal
DNA repair.
DISCUSSION
Our main finding is a significantly higher frequency of neonatal
ichthyosis in TFIIH-related TTD (group A) patients, as compared
to the non-TFIIH related group (group B). Ichthyosis in group A
has a mild course and looks like ichthyosis vulgaris. An aspect of
collodion baby can be observed at birth in nearly a third of the
patients. Among the environmental modifications, which could
lead to the more severe cutaneous phenotype in the neonatal period,
temperature might be considered. Cyclic hair loss has been de-
scribed in association with fever in four patients belonging to group
A [Kleijer et al., 1994]. This feature has been associated with the
XPD p.Arg658Cys mutation which gives rise to a thermosensitive
XPD protein. Elevation of temperature would be responsible for a
worsening of DNA repair and transcription anomalies leading
clinically to hair loss and increase of severity of ichthyosis
[Vermeulen et al., 2001].
In TTD cells, abnormal TFIIH needs to be produced quickly
enough to compensate its instability [Botta et al., 2002]. In differ-
entiating TTD cells, de novo synthesis is insufficient and leads
to accumulation of inactive factors and depression of basal
transcription particularly for genes involved in terminal
epidermal differentiation or neuronal myelination and pseudo-
thalassemia. Mutations in epidermal differentiation genes (TGM1
(MIM190195), ALOXE3 (MIM607206), ALOX12B (MIM603741),
ABCA12 (MIM607800), ichthyin (MIM609383), loricrin
(MIM152445)) involved in the congenital ichthyoses manifest also
commonly by a collodion baby phenotype. It could thus be specu-
lated that the clinical and histological aspects of ichthyosis vulgaris
observed in TTD patients could result of the defective expression of
epidermal differentiation complex proteins, most of which are
FIG. 4. Skin aspects of Patient 4. a: Short brittle hair with collodion
changes of the skin at birth. b,c: Ichthyotic skin with palmar
hyperlinearity at age 18.
TABLE II. Frequency of the Main Non-Cutaneous Features in TTD Groups A and B
Group A Group B
n ¼ 42 % n ¼ 37 %Failure to thrive 38 90 27 73Psychomotor delay 37 88 31 84Osseous anomalies 9 21.5 5 13.5Genital/reproductive anomalies 10 24 24 65
2026 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
located in 1q21 including filaggrin and SPRR2. Skin biopsies of
ichthyosis performed in group A patients had similarities with
ichthyosis vulgaris, with diminished keratohyalin expression, a
marker of profilaggrin (Fig. 2). Furthermore, a diminution of
SPRR2 expression has been found in the TTD mouse model
homozygous for the XpdR722W allele [De Boer et al., 1998]. In vitro
reconstruction of TTD human epidermis could allow to study the
modification of the expression of proteins involved in keratinocyte
differentiation and their dependence on temperature.
Instability and dysfunction of TFIIH with mutated sub-units
could account for TTD findings [Schultz et al., 2000; Dubaele et al.,
2003]. It has been shown that TFIIH activates transcription by
phosphorylation of nuclear receptors such as RARa or thyroid
hormone receptor through its CDK subunit [Htun et al., 1996; Liu
et al., 2005]. Mutations in C terminal domain of XPD are directly
responsible for a decrease of phosphorylation of nuclear receptors
and expression of targeted genes [Keriel et al., 2002]. In particular, it
has been shown that the phosphorylation of the N-terminal domain
of the g subunit of the RAR by the CDK7 component of TFIIH leads
to receptor activation through modulation of its interaction with a
coregulator (vinexin b) [Bour et al., 2007].
Hypogonadism, which was initially described in Amish and
Moroccan patients who belong to group B, is also found in group
A. The difference of frequency between the two groups was signifi-
cant but more patients with TTDN1 mutations have to be studied to
make definitive conclusions. TTDN1 mutants responsible for
group II TTD could be involved in the maturation of spermatozoid
sulfur-rich proteins. In the drosophila, spermatogenesis is sensitive
to b2-tubulin level, a protein of the tubula. XPD mutations in
drosophila affect b2-tubulin leading to sterility in males. This
mechanism could explain gonadal immaturity in TTD group A
patients [Raff et al., 1982].
Osseous anomalies were found at a similar frequency in groups I
and II, suggesting that abnormal function of both TFIIH or of
TTDN1 could affect bone formation. The TTD-Xpd mouse model
provides a good clinical reproduction of the disease for bony
anomalies, which indicates a potent modulation of bone minerali-
zation by abnormal TFIIH [De Boer et al., 1998, 2002].
Unlike xeroderma pigmentosum, TTD is not a cancer prone-
disease. The group I cells are unable to repair the major cyclobutane
pyrimidine dimers (CPD) induced by solar UV. However, the TTD
cells mutated on the 50 part of the XPD gene are also defective in the
repair of the second type of UV-induced DNA lesions (pyrimidine
6-4 pyrimidone), while the cells mutated on the 30 part of the same
gene are proficient in this repair [Chigancas et al., 2008]. Never-
theless, none of these TTD patients are cancer-prone and therefore
the cancer-free phenotype in TTD should not be directly related to a
DNA repair defect [Nishiwaki et al., 2004]. On the other hand,
differences in cellular catalase activity between TTD and XP indi-
cate that UV light, directly or indirectly, together with defective
oxidative metabolism may increase the initiation and/or the pro-
gression steps in the XP environment compared to TTD [Vuillaume
et al., 1992]. It has been shown on normal and XP human recon-
structed epidermis that catalase overexpression had a protective
effect against deleterious effects of UV irradiation [Rezvani et al.,
2007, 2008]. This may partly explain the differences in skin tumor
proneness between group A TTD and XP.
In conclusion, TTD regroups recessively inherited affections,
which have in common a specific hair dysplasia. Molecular studies
suggest to classify TTD in three genetic groups. Mutations in the
three genes encoding TFIIH subunits (XPD, XPB, p8) are respon-
sible for the in vitro photosensitive form (group I). The non-
photosensitive group is genetically heterogeneous including
TTDN1 mutated patients (group II) and a third group without
known molecular basis. Our phenotype/genotype correlation study
showed a highly significant association between ichthyosis and
group I, and the collodion baby phenotype gives an early diagnostic
orientation for this group, without being completely specific. This
classification is presented with its genetic and clinical correlations in
Table V.
TABLE III. Frequency of Cutaneous Anomalies in TTD Groups A and B
Group A Group B
n ¼ 42 % n ¼ 37 %Ichthyosis 38 90 5 13.5Collodion baby 14 33.5 4 11
TABLE IV. Frequency of Ichthyosis in Patients With Clinical Photosensitivity and in Global TTD Population
Clinical photosensitivity Total TTD population
N¼ 39 % N¼ 122 %Ichthyosis 31 79 55 44
MORICE-PICARD ET AL. 2027
ACKNOWLEDGMENTS
Dr. Peter Itin and Dr. Mark Pittelkow for their help with literature
review. This study was supported by the GENESKIN 6th PCRD
programme 512117.
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TABLE V. Classification of TTD
Group A(in vitro photosensitivity)
Group B(no in vitro photosensitivity)
TTD-TFIIH/TTDP Group I TTD-non-TFIIH/TTDN-1 Group II Not classified Group IIIOMIM 601675 234050 275550, 211390Locus 19q 13.2–q 13.3 (XP-D)
6p25.3 (TTD-a/p8) 2q21(XP-B)
7p14 (C7Orf11) Unknown
Function DNA repair-transcription Unknown UnknownClinical subtype
of TTDTay; IBIDS (TTD-A) ABHS; BIDS Pollitt; Sabinas; other
TTD subtypes
IBIDS: ichthyosis, brittle hair, intellectual impairment, decrease fertility, short stature; BIDS: brittle hair, intellectual impairment, decrease fertility, short stature; ABHS: Amish brittle hair syndrome.
2028 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
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