Download Clinical and genetic aspects of trigonocephaly: A study of 25 cases

American Journal of Medical Genetics 117A:127– 135 (2003)
Clinical and Genetic Aspects of Trigonocephaly:
A Study of 25 Cases
Cyrus Azimi,1,3 Shelley J. Kennedy,1,2 David Chitayat,1 Pranesh Chakraborty,1 Joe T.R. Clarke,1
Christopher Forrest,2 and Ahmad S. Teebi1,2*
1
Division of Clinical & Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
Division of Plastic Surgery, Centre for Craniofacial Care and Research, The Hospital for Sick Children, Toronto,
Ontario, Canada
3
Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
2
We reviewed 25 patients ascertained through
the finding of trigonocephaly/metopic synostosis as a prominent manifestation. In 16
patients, trigonocephaly/metopic synostosis
was the only significant finding (64%); 2 patients had metopic/sagittal synostosis (8%)
and in 7 patients the trigonocephaly was
part of a syndrome (28%). Among the nonsyndromic cases, 12 were males and 6 were
females and the sex ratio was 2 M:1 F. Only
one patient with isolated trigonocephaly
had an affected parent (5.6%). All nonsyndromic patients had normal psychomotor
development. In 2 patients with isolated
metopic/sagittal synostosis, FGFR2 and
FGFR3 mutations were studied and none
were detected. Among the syndromic cases,
two had Jacobsen syndrome associated with
deletion of chromosome 11q 23 (28.5%). Of the
remaining five syndromic cases, different
conditions were found including Say-Meyer
syndrome, multiple congenital anomalies
and bilateral retinoblastoma with no detectable deletion in chromosome 13q14.2 by
G-banding chromosomal analysis and FISH,
I-cell disease, a new acrocraniofacial dysostosis syndrome, and Opitz C trigonocephaly syndrome. The last two patients were
studied for cryptic chromosomal rearrangements, with SKY and subtelomeric FISH
probes. Also FGFR2 and FGFR3 mutations
were studied in two syndromic cases, but
none were found. This study demonstrates
*Correspondence to: Dr. Ahmad S. Teebi, Division of Clinical
& Metabolic Genetics, The Hospital for Sick Children, 555
University Ave, Toronto, Ontario, M5G 1X8, Canada.
E-mail: [email protected]
Received 14 February 2002; Accepted 31 July 2002
DOI 10.1002/ajmg.a.10021
ß 2003 Wiley-Liss, Inc.
that the majority of cases with nonsyndromic trigonocephaly are sporadic and benign,
apart from the associated cosmetic implications. Syndromic trigonocephaly cases
are causally heterogeneous and associated
with chromosomal as well as single gene
disorders. An investigation to delineate the
underlying cause of trigonocephaly is indicated because of its important implications
on medical management for the patient and
the reproductive plans for the family.
ß 2003 Wiley-Liss, Inc.
KEY WORDS: metopic synostosis; Jacobsen syndrome; I-cell disease;
Say-Meyer syndrome; Opitz
C trigonocephaly syndrome
INTRODUCTION
Trigonocephaly is a frontal bone anomaly often associated with synostosis of the metopic suture. It is
characterized by a triangular appearance of the forehead when viewed from above and is usually associated
with ocular hypotelorism. Some patients with metopic synostosis have additional sutural involvement
[Anderson and Geiger, 1965; Shillito and Matson,
1968; Hunter and Rudd, 1977]. Trigonocephaly can be
syndromic or nonsyndromic. In the more common nonsyndromic form, the trigonocephaly/metopic synostosis
is the only prominent feature. In most cases this form
occurs sporadically, but familial cases with autosomal
dominant mode of inheritance have also been reported
[Hennekam and Van den Boogaard, 1990]. Syndromic
trigonocephaly is causally heterogeneous as metopic
synostosis is found in several delineated syndromes
such as some cases of Saethre-Chotzen syndrome
[Hunter et al., 1976; Cristofori and Filippi, 1992], Opitz
C trigonocephaly syndrome [Opitz et al., 1969; Sargent
et al., 1985; Prager et al., 1991; Omran et al., 1997;
Lindor et al., 2000], Say-Meyer trigonocephaly syndrome [Say and Meyer, 1981], Christian syndrome
[Christian et al., 1977; Dlouhy et al., 1987], and
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Azimi et al.
Floating-Harbor syndrome [Hersh et al., 1998]. It is also
found in some undelineated conditions [Frydman et al.,
1984; Fryns et al., 1990; Teebi, 1991; Sadove et al., 1991;
Schneider et al., 2000; Al-Sannaa et al., 2001]. Trigonocephaly has also been reported in association with
several chromosomal anomalies, including del(3q) and
del(7p) [De Grouchy and Turleau, 1984]; del(13q)
[Cohen and MacLean, 2000]; del(11q) or Jacobsen
syndrome [Lewanda et al., 1995; Pivnick et al., 1996;
Leegte et al., 1999], and del (9p) syndrome [Christ et al.,
1999]. Chu et al. [1994] described a patient with a
severe Opitz C trigonocephaly phenotype and partial
trisomy 13, tetrasomy 13 and a 13;18 translocation.
McGaughran et al. [2000] reported dup(3pter) and 3;5
translocation in a patient with apparent Opitz C trigonocephaly phenotype.
Lajeunie et al. [1998a,b] analyzed a series of 278
patients with trigonocephaly. They estimated the birth
prevalence of metopic synostosis to be 67 per 1,000,000.
The male to female ratio was 3.3:1 and no maternal
or paternal age effects were observed. It is extremely
important to note that metopic synostosis is frequently
misdiagnosed during infancy, as metopic ridging without synostosis is very common and is estimated to occur
in 10–25% of normal infants and young children and
has nothing to do with metopic synostosis [Cohen and
MacLean, 2000]. Therefore, radiographs and CT scans
are essential in diagnosing true metopic synostosis.
Little is known about the pathogenesis and molecular genetics of trigonocephaly/metopic synostosis.
Extrinsic causes include head constraint in utero
[Graham et al., 1979; Graham and Smith, 1980] and
exposure to high levels of thyroxine resulting from
maternal, neonatal or juvenile hyperthyroidism. Intrinsic causes include deficient brain growth, a primary
abnormality of mesenchymal tissues, rickets, and hypercalcemia [Zakarija et al., 1986; Leonard et al., 1987;
Hirano et al., 1995].
Gene mutations for FGFRs, TWIST, and MSX2 have
been extensively summarized by Cohen and MacLean
[2000]. Some of these have had trigonocephaly. Here, we
analyze 25 patients with syndromic and nonsyndromic
trigonocephaly.
MATERIALS AND METHODS
The Clinical Genetics patient database at the Hospital
for Sick Children, Toronto, Ontario, Canada was searched for all entries under trigonocephaly/metopic synostosis or known syndromes with metopic synostosis as a
prominent feature. Study forms to extract clinical data
and a family history questionnaire were designed and
approved by the Hospital for Sick Children’s Research
Ethics Board. Information obtained included the patients’ name, age, sex, growth parameters, birth order
and Apgar scores. The following craniofacial characteristics of the proband were recorded: presence of a central
frontal ridge/trigonocephaly involving metopic suture
with or without additional sutural involvement, details of the radiological records, hypo or hypertelorism,
(confirmed by measurements), abnormal head shape,
hydrocephaly and other craniofacial abnormalities.
Skull radiographs and CT scan or MRI of head were
used to document metopic synostosis in all cases.
Extracranial details collected include the presence of
any limb anomalies, deafness, ocular and visual abnormalities, organomegaly, cardiovascular, renal and
genital abnormalities, hypotonia, and abnormal development. A skeletal survey was performed in all
syndromic cases. Hematological tests, chromosomal
analysis and molecular/cytogenetic investigations were
performed when needed.
The family history questionnaire included information regarding the siblings of the propositus, any
affected family member, maternal and paternal age at
the time of birth, parental birth place and ethnic origin,
maternal and paternal phenotype and health, prenatal
exposure to teratogens, pregnancy complications, mode
of delivery, complications during delivery, and gestational age.
RESULTS
Twenty-five patients were identified and their charts
were reviewed. They were ascertained during the 5-year
period between 1996–2001. Their ages ranged from 1
week to 5 years with a mean of 14 months at the time
of presentation. In 16 patients, the trigonocephaly/
metopic synostosis was the only significant finding
(64%), in 2 patients metopic synostosis was also associated with sagittal synostosis and was considered
nonsyndromic (8%) and in 7 the trigonocephaly was
part of a syndrome (28%). Of the nonsyndromic patients,
12 were males and 6 were females with a sex ratio of
2 M:1 F. Only 1 patient had a clearly affected parent
(5.6%). Physical examination on the 18 nonsyndromic
cases showed trigonocephaly in all, additional scaphocephaly in 2 (11%) hypotelorism in 11 cases (61%) and
bilateral epicanthal folds in 14 cases (78%). There were
4 cases with upward slanting palpebral fissures (22%),
and 1 case with strabismus (5.6%). (Fig. 1a,b) The trigonocephaly was surgically treated in all patients and
all had normal psychomotor development on initial and
repeat assessments. In the 2 patients with metopic/
sagittal synostosis, FGFR2 and FGFR3 mutations were
studied and none were detected.
There were 7 syndromic patients with the following
clinical reports:
Patient 1
She was the first child born to phenotypically normal
nonconsanguineous parents with normal karyotypes.
The delivery was by Caesarean section at 41 weeks of
gestation. Her birth weight was 3,415 g (50th centile),
body length 52 cm (75th centile), OFC 36 cm (98th
centile). She had trigonocephaly, bitemporal narrowing
with wide occipital protuberance. The anterior fontanelle was open and soft. There was nevus flammeus
on the forehead and upper part of the nose. The mouth
was triangular, the uvula was bifid and the chin was
relatively small. The palate was high and narrow. The
nasal bridge was broad with an upturned nose and
bilateral epicanthic folds. Her nipples were inverted and
cardiac examination revealed a faint systolic murmur.
Trigonocephaly
There was bilateral single transverse palmar crease
with adducted thumbs associated with camptodactyly
at the middle interphalangeal joints of other fingers.
The big toes were proximally inserted. Tone and reflexes
were normal. Echocardiography revealed a moderate to
large size atrial septal defect with mild ventricular
dilatation. A CT scan of the head revealed trigonocephaly involving the metopic and coronal sutures, as
well as poor growth of the brain. Skeletal survey was
otherwise normal. Ophthalmological examination and
renal ultrasound were normal. Complete blood cell
count revealed thrombocytopenia which was isoimmune. Chromosome analysis showed a de novo deletion
of the distal segment of the long arm of chromosome 11
(46,XX, del 11q23.3!qter) consistent with Jacobsen
syndrome (Fig. 2).
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quently he developed hypoglycemia, hypocalcemia and
thrombocytopenia. He was noted to have an unusual
appearance with trigonocephaly, a short triangular
forehead and a ridge over the frontal metopic suture,
which was confirmed on a skull X-ray. He had a narrow
bitemporal diameter, ridge above the supraorbital
regions and deep set eyes. The anterior fontanelle measured 2 cm 2 cm. There was upward slanting of the
palpebral fissures and bilateral epicanthal folds. He had
Patient 2
He was the second child born to nonconsanguineous
parents with normal karyotypes. He had a sister and a
stepbrother who were normal. Pregnancy and delivery
were normal. His birth weight was 3,640 g (65th centile).
At 2 years of age, his height was 85 cm (25th centile)
and his OFC was 49.5 cm (55th centile). He had a high
forehead, prominent metopic ridging with trigonocephaly and a flat occiput. He demonstrated a low nuchal
hairline and a short neck. He had ptosis of the eyelids,
a broad nasal root, a flat nasal bridge and tip with
anteverted nares and a square shaped chin. He had
prominent and simple auricles. He had mild pectus
carinatum with widely spaced and inverted nipples.
His upper limbs showed proximally inserted thumbs
with prominent fetal pads and clinodactyly of the fifth
fingers bilaterally. The lower limbs showed bilateral pes
cavus and eczema on both soles, hallux valgus, broad
toes and the second toe was shorter than the third. He
had normal muscle tone with normal deep tendon
reflexes. A CT scan of the head indicated dysgenesis of
the corpus callosum. A renal ultrasound was normal.
Ophthalmological examination showed divergent intermittent strabismus and retinal dystrophy. He had
recurrent epistaxis. Hematological tests revealed
thrombocytopenia. He had significant psychomotor
retardation. Chromosomal analysis indicated a de novo
deletion of the distal segment of the long arm of chromosome 11 (46,XY, del 11q2311q25) consistent with
Jacobsen syndrome.
Patient 3
This boy was born to a 25-year-old mother and a
27-year-old father who are nonconsanguineous. The
pregnancy was uncomplicated except for hypertension
and thrombocytopenia, consistent with HELLP syndrome, which developed around 33 weeks of gestation.
Labour was induced 4 weeks later. Apgar scores were 1
and 6 at 1 and 5 min, respectively. His birth weight was
2,140 g (<3 centile), and OFC was 30.5 cm (<2 centile).
At birth, he developed respiratory distress and needed
supplemental oxygen therapy. He had multiple apneic
spells and seizures treated with Phenobarbital. Subse-
Fig. 1. a: A composite of eight children with nonsyndromic trigonocephaly showing the prominent metopic ridge and typical face. b: A composite
of MRI images of four children with nonsyndromic trigonocephaly.
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Azimi et al.
Fig. 1. (Continued )
a broad nasal root with a small pointed nose, anteverted
nostrils and hypotelorism. He showed hypoplastic malar
area, long philtrum, small mouth and retrognathia.
His cardiac examination was normal. His upper and
lower limbs as well as his abdominal and genital examinations were normal. Tone and reflexes were normal.
He had conductive hearing loss. His vision was normal.
Chest X-ray and echocardiography revealed biventricular cardiac hypertrophy with dilated aorta. A CT scan
of the head showed a left intraventricular bleed filling
the frontal and occipital horns. EEG showed seizure
activity over the left temporal region. Abdominal ultrasonography showed normal right kidney and mild left
hydronephrosis. There was a thrombus in the left portal
vein. Chromosomal analysis was normal The facial
features resemble those of Say-Meyer trigonocephaly
syndrome.
Patient 4
A boy was born to nonconsanguineous parents of
European descent. The mother had strabismus corrected in infancy. She had migraine headaches and
Trigonocephaly
Fig. 2.
131
A composite of patient 1 with Jacobsen syndrome showing the face and feet.
endometriosis as an adult. The pregnancy was uncomplicated and fetal ultrasound revealed no fetal abnormalities. Fetal movements were feeble. Delivery was at
39 weeks gestation by an elective cesarean section. At
birth, he weighed 3,912 g (80th centile) and had no
neonatal complications. On initial physical examination
he was noted to have metopic synostosis which was
operated on at the age of 13 months. At the age of
3 months, he was found to have bilateral retinoblastoma. He underwent left eye enucleation, and the right
eye tumor was treated with chemotherapy combined
with LASER. Apart from the above, he was healthy and
his growth and development were within the normal
range. Hearing assessment was normal.
Family history was non-contributory for retinoblastoma. At the age of 19 months, his weight was 14.3 kg
(95th centile), height 87.5 cm (95th centile) and OFC
50.5 cm (90th centile). He demonstrated a high forehead with mild metopic ridging and scars on both sides
of the forehead. He had left eye prosthesis, right epicanthic fold, a small tipped nose, anteverted nares,
long grooved philtrum, and a wide mouth with thick lips.
His hands and feet were normal. Shawl scrotum was
noted. Abdominal and pelvic ultrasound were normal.
Chromosomal analysis was normal. No mutation was
detected on analysis of the FGFR2 gene. High-resolution chromosomal analysis and FISH analysis using
a probe for RB locus within 13q14.2 revealed no detectable deletion.
Patient 5
He was born to phenotypically normal first-cousin
parents from Pakistan. Pregnancy was uncomplicated
and delivery was at 39 weeks gestation by cesarean
section. His birth weight was 2,647 g (3rd centile) and
his OFC was 33 cm (15th centile). He had trigonocephaly
with prominent metopic suture, bitemporal narrowing,
hypotelorism, prominent eyes and cheek, flat nasal
bridge, short nose, micrognathia, intact palate and
slightly low-set ears. There was webbing between the
thumb and the index finger of the right hand, and
clinodactyly of fourth and fifth fingers bilaterally.
Genitalia were normal. He had mild psychomotor delays
and hearing problems. A CT scan of the head confirmed
metopic and sagittal synostosis and normal brain, with
mildly enlarged subarachnoid space. Chest X-ray revealed pectus carinatum and Morgagni type diaphragmatic hernia. Skeletal survey confirmed widening of
the pubic symphysis, stippled calcification in the region of the coccyx, anterior to the lumbar vertebral
bodies and in the ankles, and 11 pairs of thick ribs.
Cardiology and ophthalmology assessments were normal. Chromosomal analysis was normal. Analysis for
VLCFA and phytanic blood levels was normal. Mutation
analysis of the FGFR2 (Exons IIIa and IIIc) and FGFR 3
(Pro250Arg) was negative.
When reassessed at 18 months of age his facial
features had coarsened, and he had developed gingival
hyperplasia. He had experienced recurrent otitis media,
and had developed obstructive sleep apnea requiring
nocturnal CPAP. His development had slowed in all
spheres, but he did not experience any regression. His
rate of somatic growth had slowed symmetrically. He
had developed contractures of the large joints, and
marked thickening of his skin. A repeat skeletal survey
demonstrated a dysostosis multiplex, as well as shallow
acetabula, ovoid lumbar vertebral bodies and calcaneal
stippling (Fig. 3). A urine MPS screen was positive,
and there was a mild elevation in keratin sulfate on
MPS thin layer chromatography. Plasma hexosaminidase and arylsulfatase activities were markedly
elevated when diminished leukocyte activities were
confirming the diagnosis of mucolipidosis II or I-cell
disease.
Patient 6
He was born to a non-consanguineous couple from
Sri Lanka. Their first pregnancy resulted in a daughter
who is 3-years old and well. His mother had multiple
café-au-lait spots but no other signs consistent with
neurofibromatosis. His parents had no signs of trigonocephaly. After delivery he was noted to have trigonocephaly, microcephaly, severe micrognathia, large ears,
café-au-lait spots, and syndactyly of some fingers and
toes. He is developmentally delayed. The skeletal survey
showed asymmetry of the mandible, 11 pairs of ribs
which were gracile on the right side, and thoracolumbar
Fig. 3.
A composite of patient 5 with I-cell disease showing the face, an MRI image to show trigonocephaly and an X ray of the left foot showing calcaneal stippling.
Trigonocephaly
scoliosis convex to the left side. The pelvis and long
bones were normal. Echocardiogram showed atrioventricular septal defects and a small PDA. Ophthalmologic
evaluation, renal ultrasound and brain CT scan were
normal. Chromosomal analysis including FISH and
SKY for cryptic rearrangements was normal. FISH for
22q11.2 microdeletion was negative. It was concluded
that he represents a new acrocraniofacial dysostosis
syndrome [Al-Sannaa et al., 2001].
Patient 7
The patient was born to a 28-year-old G3P2L0 healthy
mother of Scottish/German descent and a 43-year-old
father of German/Irish descent. The couple’s first pregnancy resulted in a female child who was born with
a diaphragmatic hernia and died after 3 days. Her
karyotype was normal. Pregnancy was uncomplicated
and delivery was normal at term. Apgar scores were 7
and 9 at 1 and 5 min, respectively. At 11 months, her
weight was 7.41 kg (<3rd centile), length 67.5 cm (<3rd
centile), and her OFC 40.1 cm (<2nd centile). She had
trigonocephaly, closed fontanels, bitemporal narrowing,
higharched palate with bifid uvula, thick upper frenulum and mild retrognathia. She had abnormal dentition with large cusps of her upper incisors bilaterally.
Her ears were prominent, simple, and cupped. She had
an extensive capillary malformation of her right face,
which extended onto her right scalp, and thick hair
with seborrheic dermatitis. She had a right transverse
palmar crease and her fingers were tapering with distal
arthrogryposis. She showed apparent edema of her feet.
Neurological examination revealed hypotonia, increased deep tendon reflexes, seizure disorder, and bilateral vocal cord paralysis. She had hypoplastic labia
minora and had several strands of dark thick hair on her
labia majora. She has had occasional GI bleeding.
Ophthalmological examination was normal except for
left strabismus. Brain MRI showed thin corpus callosum, decreased myelination as well as white matter loss,
with a small increase in ventricular size. She had severe
psychomotor delay. Her karyotype was normal. Investigation for a cryptic chromosomal rearrangement using
SKY and FISH was normal.
133
The manifestations were highly suggestive of Opitz C
trigonocephaly syndrome (Fig. 4).
DISCUSSION
In our study population, 72% of the cases with trigonocephaly were nonsyndromic and with a sex ratio of
2 M:1 F; 5.6% of these cases were familial. These figures
are comparable to those of Lajeunie et al. [1998b] who
studied 278 cases of whom 74.8% were nonsyndromic,
with a male to female ratio being 3.3 M:1 F and 6% being
familial.
Patients 1 and 2 were diagnosed with Jacobsen syndrome with the involvement of the critical region 11q24.
Both of them had trigonocephaly and thrombocytopenia.
In Jacobsen syndrome, trigonocephaly is present in 85%
of the cases, broad nasal bridge and upturned nose in
95%, heart anomalies in 65%, camptodactyly and single
palmar creases in 65%, and thrombocytopenia in 50%.
In patient 3, the craniosynostosis involved the metopic and sagittal sutures and was associated with
hypotelorism, developmental delay, and short stature.
In the absence of chromosomal anomalies, his features
were suggestive of Say-Meyer trigonocephaly syndrome,
a rare X-linked recessive disorder.
In patient 4, it is not clear if the patient’s bilateral
retinoblastoma, metopic synostosis and other abnormalities were casually related or separate conditions.
Patients with deletions within or close to 13q14.22
may have trigonocephaly due to metopic synostosis.
Also a small percentage of patients with retinoblastoma
have a deletion in the RB region 13q14. However, it is
interesting that our patient has bilateral retinoblastoma without any chromosome deletion and no family
history of retinoblastoma or metopic synostosis.
In patient 5, multiple suture synostosis, developmental delay, and stippled calcifications in his skeletal
survey were suggestive of a peroxisomal disorder. However, his clinical phenotype evolved, and the diagnosis
of I-cell disease was confirmed by lysosomal enzyme
assays. Of note, metopic synostosis has been previously noted to be a relatively common feature in I-cell
disease, and it is sometimes associated with synostosis
of other sutures as well. Calcaneal stippling is usually
Fig. 4. A composite of patient 7 with Opitz C-trigonocephaly syndrome showing the face with trigonocephaly, the mouth with frenulae and foot with
partial syndactyly of second and third toes.
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Azimi et al.
characteristic of this condition [Taber et al., 1973;
Patriquin et al., 1977; Yamada et al., 1987].
Patient 7 has been diagnosed with Opitz C trigonocephaly syndrome. While trigonocephaly is a prominent
abnormality in this disorder, other manifestations include, thick alveolar ridge with multiple oral frenulae,
forehead capillary malformation, frontal cowlick, upslanting palpebral fissures with prominent epicanthic folds, polysyndactyly and cerebral white matter
changes. Most of these manifestations were present
in this patient. As indicated in the Oxford Medical
Databases, there has been overreporting of this syndrome in patients with trigonocephaly as the only
common manifestations, and this has made the delineation of this syndrome more difficult.
In two of the syndromic cases (patients 4 and 5) the
FGFR2 and FGFR3 genes were studied, but no mutations were detected which is in agreement with the
findings of Tartaglia et al. [1999].
Some authors, including Teebi et al. [1993] and
McGaughran et al. [2000], have emphasized that the
combined application of new molecular and cytogenetic
techniques may permit the characterization of subtle
balanced and unbalanced rearrangements in patients
with unrecognized multiple congenital anomalies/developmental delay/mental retardation.
This study demonstrates that the majority of cases of
nonsyndromic trigonocephaly are sporadic and benign,
apart from cosmetic implications. On the other hand
syndromic cases involving trigonocephaly are causally
heterogeneous and include both chromosomal and single
gene disorders. This study emphasizes the importance of
thoroughly investigating such patients.
ACKNOWLEDGMENTS
The authors thank Professor M. Michael Cohen, Jr.
for his invaluable comments on the manuscript and
Rozmin Visram for her secretarial assistance.
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