Pediatric and Developmental Pathology 10, 142-148, 2007

DOl: 10.2350/06-06-0111.1
© 2007 Society for Pediatric Pathology

A Severely Affected Female Infant with

X-Linked Dominant Chondrodysplasia
Punctata: A Case Report and a Brief
Review of the Literature
DiNESH RAKHEJA/'^ CHARLES P. READ,^ DAVID H U L L / RICHARD L. BORIACK,^ AND
CHARLES F. TIMMONS^'^
^Department of Pathology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard,
Dallas, TX 75390-9073, USA
^Department of Pathology, Children's Medical Center, Dallas, TX, USA
^Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center,
5323 Harry Hines Boulevard, Dallas, TX 75390-9073, USA

Received June 18. 2006: accepted August 12. 2006; published online March 7, 2007.

ABSTRACT multisystem dysmorphogenesis. The most com-

We recently performed an autopsy on a premature female
newbom with rhizomesoacromelic limb shortening of the
upper and lower extremities, eraniofacial dysmorphism,
and chondrodysplasia punctata. A diagnosis of Conradi-
Huncrmann-Happle syndrome or X-linked dominant
chondrodysplasia punctata was made based on elevated
cholest-8(9)-ene-3/?-ol in serum and tissues. Molecular
analysis of EBP. mutations of which are responsible for
this malformation syndrome, revealed a monoallelic
missense mutation, c.328 G>A (Rl lOQ). We present this
case as an illustration of an unusually severe manifestation
of this disorder in a female, with additional unusual
features including lack of skin tnanifestations and apparent
bilateral symmetry of the skeletal findings.
Key words: Conradi-Hunermann-Happle syndrome,
emopamil-binding protein, 3P-hydroxysteroid A^, A^-
isomerase, X-linked dominant chondrodysplasia punctata
INTRODUCTION
Disorders of postsqualene cholesterol biosynthesis
are single-gene metabolic defects that lead to
* Corresponding author, c-raail: drakheja@hotmail.coni
tnon of these disorders is the Smith-Lemli-Opitz
syndrome (SLOS, OMIM # 270400), which occurs
at a frequency of 1 in 60 000 to 70 000 live births
in the USA, Canada, and the UIC, hut at higher
frequencies in Central Europe, with an incidence of
1 in 15 000 to 20 000 in Slovakia [1-^]. Smith-
Lemli-Opitz sytidrome is caused by a deficiency of
3p-hydroxystero!d A^-reductase or 7-dehydrocho-
lesterol reductase (EC 1.3.1.21), which catalyzes
the reduction of 7-dehydrochoIestcroI, the final
step in the biosynthesis of cholesterol [5-7].
Besides SLOS, 6 other disorders of postsqualene
cholesterol biosynthesis have been identified as the
etiologies for tnal format ion syndromes (Table 1)
[8-13].
Conradi-Hunennann-Happle syndrome (Hap-
ple syndrome) or X-linked dotninant chondrodys-
plasia punctata (CDPX2, OMIM # 302960) is an
uncommon disorder of postsqualene cholesterol
biosynthesis, caused by a deficiency ofthe enzyme
3p-hydroxysteroid A^, A^-isomerase (EC 5.3.3.5),
which catalyzes the isomerization of choIest-8(9)-
ene-3P-ol to lathosterol (Fig. 1) [10, 14-17]. The
gene, Emopamil Binding Protein (EBP), which
Table 1. Known disorders of post-squalene cholesterol biosynthetic pathway
Disorder
1 Antley-Bixler syndrome
4 HEM skeletal dysplasia
5 CHILD syndrome
6 CDPX2
7 Lathosterolosis
8 SLOS
9 Desraosterolosis
HEM skeletal dysplasia indicates hydrops-eclopic calcification-moth eaten skeletal dysplasia: CHILD syndrome. congenital hemidyspla.sia with iehthyosiibrm
eryilirodemia and limb defects; CDPX2. X-linked dominant chondrodysplasia punctata (Conradi-t-lunermann-Happle syndrome); SLOS, Smith-Lemli-Opitz
syndrome.
ol [Cholert-gfffl-me-3B-on
[jiilniriH-nliaiol(at-7(B1-iiie-3B-Qll
8-dht [ChiilBit-if61,8f9)-dicnc-3p-oll
7-dhc |Ctiolnt-5t61.7fm-diaw;.3B-oll
Choleatgol
Figure 1. The final steps of cholesterol biosynthesis involv-
ing the conversion of cholest-8(9)-ene-3p-ol to cholesterol
are shown. The conversion of cholest-8(9)-ene-3|Vol to
lathosterol is deficient in patients with X-linked dominant
chondrodysplasia punctata. tn these patients, there Is a
diagnostic accumulation of cholest-8(9)-ene-3p-ol in blood
and tissues, which can be detected by gas chromatography/
mass spectrometry. An accumulation of 8-dehydrochoies-
terol is also seen in these patients; this may represent
oxidation of the excess cholest-8(9)-ene-3p-ol (dotted
arrow). In patients with Smith-Lemli-Opitz syndrome,
accumulation of 8-dehydrocholesterol is thought to result
from isomerization of excess 7-dehydrocholesterol (dashed
arrow).
Enzvme Gene
Lanosterol 14o(-deinethylase CYP51AI on7q21.2-q2L3
3P-hydroxysteroid A'"*-reductase LBRan Iq42.1
Sterol-4-demethylase NSDHL on Xq2S
3p-hydroxysteroid A**, A^-isomerase EBPoT\ Xp! 1.23-pl 1.22
3 P-hydroxysteroid A" -desaturase SC5DL on Ilq23.3
3p-hydroxysteroid A^-reductase DHCR7 on Ilql2-ql3
3 p-hydroxysteroid A^'*-reductase DHCR24 on Ip33-31.1
encodes 3p-hydroxysteroid A**, A^-isomerase, re-
sides on chromosome region Xpl 1.23-pl 1.22. A
loss-of-function mutation in EBP, leading to the
deficiency of 3j3~hydroxysteroid A**, A^-isomerase,
produces widespread anotnalies and in utero
demise of the hemizygous male fetuses. In
heterozygous affected females, signs and symp-
toms of the disorder are milder but variable,
presumably because ofthe random inactivation of
either allele. This random lyonization may also
account for the bilaterally asymmetric findings in
females with CDPX2. The clinical features of
CDPX2 include punctate calcifications in epiphy-
seal cartilages or chondrodysplasia punctata,
scoliosis, hemivertebrae, rhizomesomelic limb
shortening, patellar dislocation, club feet, ichthy-
osiform erythroderma, follicular atrophoderma,
patchy alopecia with sparse eyebrows and eyelash-
es, hypoplastic malar eminences, nasal hypoplasia,
frontal bossing, abnormal ears with hearing loss,
down-slanting palpebral fissures, microphthalmos,
cataracts, glaucoma, nystagmus, short neck, tra-
cheal stenosis, Dandy-Walker malformation, men-
tal retardation, hydronephrosis, growth retardation,
failure to thrive, fetal hydrops, and polyhydramnios
[18]. We recently diagnosed, at autopsy, a severely
affected female infant with CDPX2 who had
bilaterally symmetric skeletal findings and did
not have any skin lesions. Here, we describe the
morphologic, biochemical, and genetic findings
that led to the diagnosis of CDPX2 in this child.
CASE REPORT
The proposita, a 28-week gestation female infant,
was bom by spontaneous vaginal delivery to a 22-
year-old primigravida. An initial fetal sonogram
performed at 12 weeks of gestation had confirmed
CDPX2 143
the gestational age estimated by the mother's last
menstrual period. There was no history of fever in
the mother or any suspected teratogen intake by the
mother during the pregnaney. Excessive flindal
growth prompted another ultrasound examination
at 27 weeks of gestation. At this examination, the
ratio of femur length to abdominal circumference
was noted to be <0.16, which was interpreted as
being highly indicative of the presence of a lethal
skeletal dysplasia [19]. The thoracic circumference
was <3rd percentile, and there was exaggerated
lumbar lordosis and polyhydramnios. At birth, the
infant had Apgar scores of 3 and 6 at 1 and 5
minutes, respectively. The child had poor respira-
toi-y effort and was intubated for mechanical
ventilation. Adequate ventilation proved difficult,
which was attributed to suspected pulmonary
hypoplasia. The care was redirected and the infant
died 2 hours after birth.
At autopsy, the infant weighed 890 g. The
child had obvious shortening of all limbs (Fig. 2).
The upper and lower extremities were bilaterally
symmetrically shortened. In each limb, hypoplasia Figure 2. Tbe external malformations seen in our patient
of all segments contributed to the shortening; that with X-linked dominant chondrodysplasia punctata includ-
is, the limb shortening was rhizomesoacromelic. In ed ocular bypertelorism, hypoplastic nose, short upper and
lower extremities, and bilateral talipes equinovarus.
addition, the middle fingers of both hands were
also short (brachyphalangy). Other dysmorphic able. In summary, the infant had chondrodysplasia
features included brachycephaly, a depressed nasal punctata with craniofacial dysmorphism and hy-
bridge with nasal hypoplasia, hypertelorism, bilat- poplastic lungs. The diagnostic considerations
eral talipes equinovams, and a posteriorly dis- included disorders of peroxisomal and cholesterol
placed anus. The external genitalia were of a metabolism.
normal female and postmortem cytogenetic analy-
sis confirmed a nonnal female karyotype of
46,XX. No skin lesions or cataracts were noted. Laboratory workup for peroxisomal disorders
A whole-body roentgenogram showed punctate Transmission electron microscopy, performed on
calcifications involving epiphyseal cartilages of the glutaraldehyde-fixed liver and kidney samples,
long bones of all limbs, the short bones of the revealed structurally and numerically normal
hands and feet, the ribs, and the pelvis (Fig. 3). peroxisomes. Fibrobiast cultures established from
Calcifications were also seen in trachea! cartilages a postmortem skin sample were submitted to the
and soft tissues of the neck. Internal examination Kennedy Krieger Institute in Baltimore, MD, USA
revealed a normal situs. The normally lobated for analysis of peroxisomal metabolism. No
lungs were markedly hypoplastic, with the right peroxisomal metabolic defect was identified.
lung weighing 4.2 g and the left lung weighing 4.3
g (expected combined weight, 23.7 ± 10.0 g). Laboratory workup for cholesterol
Histologic examination confinned the calcifica- biosynthetic disorders
tions in tracheal cartilage, epiphyseal eartilages of Samples of the infant's liver, rib cartilage, brain,
femur and tibia, and soft tissues of the neck (Fig. and serum were analyzed for the postsqualene
3). Histologic examination of the grossly unre- cholesterol biosynthetic pathway by gas chroma-
markable brain revealed scattered ischemic neu- tography/mass spectrometry in the Metabolic
rons, consistent with terminal hypoxia. All other Laboratory of the Department of Pathology at
organs were grossly and histologically unremark- Children's Medical Center. All samples revealed
144 D. RAKHEJA ET AL.
 Figure 3. Whole body
roentgenogram of the fetus
shows stippling of the
epiphyses of ribs, pelvis,
long bones of upper and
lower extremities, and
bones of hands and feet. A
section from the knee joint
shows caicifications (corre-
sponding to the stippling in
the X-ray) in the distal fem-
oral epiphysis (hematoxylin
and eosin, magnification
xlOO).

Table 2. Sterols identified in liver samples from deficiency of the enzyme 3p-hydroxysteroid A^,
CDPX2 patient and two controls A^-isomerase, which converts cholest-8(9)-ene-3p-
CDPX2 Control Control ol to lathosterol (Fig. 1), and is diagnostic for
patient 1 2 CDPX2 [10].
Choiesferol 7.760 10.339 7.I4I
Dihydrociiolesterol nd 0.008 0,006
Molecular analysis of EBP
8-dhc 0.026 nd nd
8(9)-cholestenol 0.270 nd nd Ail 5 exons and intron-exon boundaries of EBP, the
Lathosterol 0,077 0.025 0.007 gene that encodes 3j3-hydroxysteroid A , A -
The stcro! values are expressed in ng of sterol per jng of liver tissue. The
isomerase, were sequenced per Bravennan and
CDPX2 palieni was a 28-week-gestation fetus. The control values were colleagues [17] at the Advanced Diagnostic
obtained from liver samples of fciuses not aU'ecled by any eholesierol
biosynlhetic disorder. Control I was a 35-week-gestation fetus and Control 2
Laboratory of the Department of Pathology at
was a 25-week-gestation feius, CDPX2 indicates X-linked dominant Children's Medical Center and the Gene Sequenc-
chondrodysplasia punclata (Conradi-Hunermann-Happle syndrome); 8-dhc,
8-dehydrocholestcrol: nd, not detected.
ing Core Facility at the University of Texas
Southwestern Medical Center. A mono-allelic
missense mutation, c.329G>A, was found in exon
abnormal accumulations of the sterol pathway 3 (Fig. 5). This mutation would lead to the amino
intermediates, cholest-8(9)-ene-3p-ol, lathosterol, acid change R11OQ, wherein arginine is replaced
and 8-dehydrocholesterol (Figs. 1,4). Quantitatioti by gltitamine at amino acid position 110.
of the sterols in the liver sample showed 95.42%
cholesterol, 3.32% cholest-8(9)-ene-3p-ol, 0.94%
lathosterol, and 0.32% 8-dehydrocholesterol (Table DISCUSSION
2). Accumulation of cholest-8(9)-ene-3p-ol (also Conradi-Hunermann-Happle syndrome is 1 of 7
called 8(9)-cholesteno! or zymostenol) indicates a postsqualene cholesterol biosynthetic pathway
CDPX2 145
 im*it

Control Patient
MCOOOD
B B
MOOOOO

Moneo

UCDOOO

NMOOD
IMOOOO-

1400000

tilOOOOO

tTDOOOD

D
-A-

Figure 4. The patient's liver tissue was analyzed for sterols by gas chromatography/mass spectrometry. Gas chromatogram
of tbe control sample on the left shows a large peak of cholesterol (B), and trace amounts of dihydrocbolesterol (C) and
lathosterol (D). The patient's sterol profile shows elevated lathosterol (D) and abnormal peaks of 8-dehydrocholesterol (E),
and cholest-8(9)-ene-3li-ol (F), the pattern being diagnostic for X-linked dominant chondrodysplasia punctata. The peak
labeled (A) represents epicoprostanol (internal standard).

C Control abnormalities that are asymmetrically distributed in

Figure 5. Sequencing of EBP, the gene that encodes 3|3-
hydroxysteroid A^ A^ isomerase, revealed a mono-allelJc
missense mutation, c.329G>A, in exon 3. This mutation
would lead to substitution of arginine by glutamine at
amino acid position IIO(RIIOQ).
disorders that are currently known to cause
multiple malformation syndromes with often
devastating consequences for the developing fetus.
Conradi-Hunermann-Happie syndrome is caused
by a deficiency of 3p-hydroxysteroid A^, A^-
isomerase and is characterized by male fetal
lethality and by skeletal, craniofacial, and skin
beterozygously affected females. The gene that
encodes 3 p-hydroxysteroid A^, A^-isomerase, EBP
{Emopamil Binding Protein, so named because it
binds to the anti-ischemic calcium antagonist,
emopamil), resides on chromosome X p l l . 2 3 -
pll.22, explaining the severe manifestations with
early lethality in hemizygous males and the usually
milder manifestations in heterozygous females.
The random inactivation of X chromosome genes
(iyonization) is thought to explain the variable and
bilaterally asymmetrical clinical findings in affect-
ed females. In the present case of a female infant,
the severity of the disorder with early lethality and
the symmetrical skeletal features are unusual,
probably representing an unusually high percent-
age of the nonnal allele being inactivated [20].
Another unusual feature is the absence of obvious
skin lesions that characterize CDPX2. It is possible
that the characteristic skin lesions and skeletal
asymmetry develop later during fetal development
and were not manifest in this infant, who was bom
at 28 weeks of gestational age. This case highlights
the importance of considering the diagnosis of

146 D. RAKHEJA ETAL.

CDPX2 in severely affected females with chon-
drodysplasia punctata.
The lack of skin and hair changes in a patient
with chondrodysplasia punctata, limb shortening,
and craniofacial dysmorphism including nasal
hypoplasia raises the possibility of embryopathy
caused by warfarin or other antagonists of vitamin
K [21 ]. It is therefore important to find out whether
the mother was being administered any such
teratogen during pregnancy; in the present case,
the mother was not taking any such drugs. It is also
of note that the limb shortening in our patient was
not limited to hypoplasia of the proximal segments
(rhizomelic), which would be characteristic for
rhizomelic chondrodysplasia punctata syndromes
that are caused by peroxisomal defects [22]. We
did not find any abnormality in peroxisomal
metabolism in the present case. The rhizomeso-
melic limb shortening in CDPX2 was first
emphasized by Kelley and colleagues [10]; how-
ever, the authors did not state whether or not there
was acromelic shortening and brachyphalangy in
their reported cases. Conradi-Hunermann-Happle
syndrome should also be distinguished from the
brachytelephalangic chondrodysplasia punctata,
which is apparently inherited in an autosomal
fashion [23], and the X-linked recessive brachyte-
lephalangic chondrodysplasia punctata caused by
mutation in the arylsulfatase E gene [24].
The missense mutation, c.329G>A (RI lOQ),
identified in the present case, has been described
previously by Derry and colleagues [16]. who
showed that the amino acid arginine at position 110
is conserved through evolution. However, there is a
misprint in their article: although the amino acid
change R > Q is correctly identified, the base
change is incorrectly identified as G > T Of note,
no codon for the amino acid glutamine (Q) has
thymine (T) in it. The 2 codons for glutamine are
GAA and GAG. In all. 55 mutations of EBP have
now been described and include missense, non-
sense, deletions, insertions, and splice-site muta-
tions [25-26]. No obvious genotype-phenotype
correlation has been noted in the affected females,
presumably because of the random nature of
lyonization. Conversely, Ikegawa and colleagues
[27] have suggested that EBP mutations that
produce truncated proteins result in typical
CDPX2. On the other hand, the phenotypes
resulting from missense mutations, as seen in our
case, may result in atypical features. We were
unable to perform biochemical or genetic investi-
gations on the mother, who at least clinically
appeared to be unaffected. If indeed the mother
does not carry the mutated EBP allele in her
somatic cells, then either gonadal mosaicism or a
new mutation would explain the disease in this
case [28]. This is important to know because the
probability of the next offspring's being affected
would be different in each of these situations.
The pathophysiologic basis for the severe
malfonnations caused by defects in postsqualene
cholesterol biosynthesis is being actively investi-
gated. It is known that sterols are precursors for
biologically active compounds. For example,
cholesterol is a precursor for bile acids, oxysterols,
and steroids; 7-dehydrochoIesterol is a precursor of
vitamiti D3; and lanosterol forms meiosis-activat-
ing sterols found in gemi cells. However, lack of
these compounds probably does not explain the
widespread malformations. It is now well estab-
lished that cholesterol plays a role in autocleavage
and activation of the hedgehog proteins, which are
secreted morphogens involved in body patterning
and organogenesis. It is currently believed that a
block in the hedgehog signaling pathway accounts
for the maldevelopment of the growing fetus in
cholesterol biosynthetic disorders [29-30]. It is
interesting to note that in the present case, the
absolute amount of cholesterol in the liver was not
markedly reduced (Table 2) and should have been
sufficient to activate the hedgehog signaling
pathway; yet the infant suffered from a fatal
malformation syndrome. Cholesterol is a ubiqui-
tous component of all biomembranes, and plays a
special role in stabilization of lipid rafts, the liquid-
ordered membrane microdomains of restricted
fluidity. Lipid rafts house biologically important
membrane proteins atid are involved in cellular
ftinctions like signaling, endocytosis, and mem-
brane trafticking [31]. We have previously shown
that SLOS lymphobiasts, cultured in cholesterol-
free medium, accumulate 7-dehydrocholesterol in
their lipid rafts, thereby altering the sterol envi-
ronment and likely the protein composition of the
rafts [32]. We believe that the identification of such
membrane lipid raft alterations will shed further
light on the pathophysiology of cholesterol bio-
synthetic disorders.
In summary, we have described morphologic,
biochemical, and molecular findings in a new
severe case of CDPX2 occurring in a female infant.
CDPX2 147
ACKNOWLEDGMENTS
The authors thank Dr Richard Keiley for confirm-
ing the mass spectrum of choIest-8(9)-ene-3p-ol,
and Midori Mitui and Nora Leos for the mutational
analysis.
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Pediatric and Developmental Pathology 10, 149-152, 2007
DOI: 10.2350/06-06-0103.1
ic) 2007 Society for Pediatric Pathology
Atypical Fibroxanthoma and Squamous Cell
Carcinoma of the Conjunctiva in Xeroderma
Pigmentosum
LEI S H A O / * BRANDON NEWELL/ AND NORMA QUINTANILLA^
'Department of Pathology, Children's Mercy Hospitals and Clinics, 2401 Gillham Road,
Kansas City, MO 64108, USA
•^Section of Dermatology, Children's Mercy Hospitals and Clinics, 2401 Gillham Road,
Kansas City, MO 64108, USA
Received June 9, 2006; accepted August 12. 2006; published online March 7, 2007.
ABSTRACT
Patients with xeroderma pigmentosum (XP) have defective
DNA repair and a high predisposition to developing
abnormalities and neoplasia in the sun-exposed areas of
the skin and mucous membranes. The most cotnmon
tumors reported in patients with XP are squamous cell
carcinomas, basal cell carcinomas, and melanomas.
Atypical fibroxanthoma (AFX) is a pleomorphic tumor
that arises predominantly in the sun-damaged skin of the
head and neck regions of the elderly. We describe a unique
ease of a 6-year-old African American boy with XP who
developed an atypical fibroxatithoma and 2 squamous cell
carcinomas in the conjunctiva. The clinical and histopath-
ologic findings of AFX are discussed.
Key words: atypical fibroxanthoma, squamous cell car-
cinoma, xeroderma pigmentosum
INTRODUCTION
Xerodenna pigmetitosum (XP) is an inherited
autosomal recessive disorder associated with a
germline nucleotide excision repair defect [1]. It is
characterized by increased sensitivity to ultraviolet
(UV)-induced cellular injury. Some patients also
have progressive neurologic degeneration [2,3]-
Xeroderma pigmentosum occurs in all races with
an incidence of 1:250 000 and a gene frequency of
'Corresponding author, e-mail:
1:200. Most patients develop severe sunburns and
variable skin freckling before 1 year of age. These
initial symptoms and signs are followed by
progressive hyperpigmentation of the skin, cutane-
ous atrophy, telangiectasia, and tumorigenesis.
Patients with XP have a 1000-fold increased risk
for developing cutaneous tumors before the age of
20 years. The median age of the 1st nonmelanoma
skin cancer among patients with XP is 8 years [2].
It is very common for patients with XP to develop
multiple skin and mucosal tumors. Eye involve-
ment includes the eyelids, conjunctiva, and cornea.
The iris, the lens, and the posterior segment are
spared. The ocular changes include severe photo-
phobia, conjunctivitis, corneal opacity, conjuncti-
val nevi, pterygium, epibulbar neoplasm, and lid
neoplasm [2,4,5]. The most common cutaneous
and ocular tumor reported was squamous cell
carcinoma, followed by basal cell carcinoma and
melanoma [2]. Soft tissue tumors are extremely
rare. Three cases of atypical fibroxanthoma (AFX)
have been reported in the facial skin and lower lip
of patients with XP [6-8]. We report the clinico-
pathologic findings of a 6-year-old African Amer-
ican boy with XP. He presented with AFX and 2
squamous cell carcinomas in the conjunctiva. To
our knowledge, this is the 1st report of a child with
XP presenting with multifocal synchronous con-
junctival tumors that included AFX.