Balanced Translocation of 10q and 13q, Including the PTENGene, in a Boy with a Human Chorionic Gonadotropin-Secreting Tumor and the Bannayan-Riley-Ruvalcaba Syndrome
S. Faisal Ahmed,
Debbie J. Marsh,
Stanislawa Weremowicz,
Cynthia C. Morton,
Denise M. Williams and
Charis Eng
Department of Pediatrics (S.F.A., D.M.W.) and the Cancer Research
Campaign Human Cancer Genetics Research Group (C.E.), University of
Cambridge, Cambridge, United Kingdom CB2 2QQ; Clinical Cancer Genetics
and Human Cancer Genetics Programs, Ohio State University Comprehensive
Cancer Center (D.J.M., C.E.), Columbus, Ohio 43210; Charles A.
Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Harvard
Medical School (D.J.M., C.E.), Boston, Massachusetts 02115; and the
Cytogenetics Laboratory, Departments of Pathology and Obstetrics,
Brigham and Womens Hospital and Harvard Medical School (S.W.,
C.C.M.), Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Dr. S. Faisal Ahmed, Department of Pediatrics, University of Cambridge Clinical School, Box 116, Addenbrookes Hospital, Hills Road, Cambridge, United Kingdom CB2 2QQ. E-mail: sfa21{at}cam.ac.uk
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Introduction
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Bannayan-Riley-Ruvalcaba syndrome (BRR) is a
hamartoma syndrome characterized by early-onset macrocephaly,
lipomatosis, hemangiomas, hamartomatous polyps of the gastrointestinal
tract, vascular malformations, pigmented macules of the glans penis
(speckled penis) in males, Hashimotos thyroiditis, and mild
intellectual delay (1, 2, 3). Although an anecdotal case of malignant
tumor has been reported to be associated with BRR (4), malignancy has
yet to be formally accepted as part of this syndromes phenotypic
spectrum. BRR shows both clinical and genetic overlap with another
hamartoma syndrome, Cowden syndrome (CS), characterized by hamartomas
in multiple organ systems including the breast, skin, thyroid, central
nervous system, and gastrointestinal tract (5, 6, 7). Patients with CS may
suffer from malignancies and also have macrocephaly; brain tumors,
especially meningiomas, have also been reported in these patients
(8).
Germline mutations in PTEN, a novel tumor suppressor gene
mapping to 10q23.3, have been found in 1381% of CS patients (9, 10, 11, 12)
and 5760% of BRR cases (12, 13). Two cases of 10q deletion
encompassing PTEN have also been reported in BRR (14, 15).
PTEN encodes a dual specificity phosphatase with homology to
the focal adhesion molecules tensin and auxilin (16, 17, 18, 19). Mutant or
decreased levels of PTEN have been shown to lead to accumulation of the
phospholipid phosphotidylinositol triphosphate, which, in turn,
activates the cell survival factor protein kinase B (PKB)/Akt via the
phosphatidylinositol 3-kinase pathway (20, 21, 22, 23, 24). Thus, PTEN may have a
role in cell growth, apoptosis, and adhesion.
We report a case of a boy with features consistent with BRR with a
novel de novo balanced translocation, 46,XY,
t(10;13)(q23.2;q33), and a malignant intracranial hCG-secreting tumor
resulting in precocious puberty. The pathology of these tumors can
vary, but none of them has been associated with the CS or BRR phenotype
or PTEN mutations to date. Although previous reports have
provided evidence that germline intragenic mutation and gross deletion
of PTEN can lead to BRR, we postulate that a germline
balanced translocation incorporating PTEN can also lead to
the BRR phenotype.
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Materials and Methods
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After obtaining parental consent, peripheral blood lymphocyte
karyotypes were generated for both the proband and his parents, and DNA
was extracted from peripheral leukocytes. Cultured skin fibroblasts
from the proband were grown in DMEM supplemented with 10%
heat-inactivated FCS, 1 x MEM sodium pyruvate solution,
penicillin/streptomycin, 10 mmol/L HEPES buffer solution and 4.4 mmol/L
L-glutamine. DNA was extracted from the fibroblast cell
line and from the probands paraffin-embedded lipoma using the QIAamp
Tissue Kit (QIAGEN, Chatsworth, CA). Fine mapping of the
translocation using fluorescence in situ hybridization
(FISH) was performed, as described previously (25), using a
digoxigenin-labeled probe, BAC46B12 (18), containing the
PTEN gene, and the D10Z1 probe (Oncor, Gaithersburg, MD)
specific to the centromere of chromosome 10. Hybridization signals were
detected using antidigoxigenin-rhodamine supplied in the Oncor Kit
(Oncor). Chromosomes were counterstained with
4,6-diamidino-2-phenylindole-dihydrochloride, and hybridization was
observed using a Carl Zeiss Axiophot fluorescence
microscope (New York, NY).
Denaturing gradient gel electrophoresis (DGGE) was used to examine the
nine PTEN exons and flanking intronic sequences in germline
DNA extracted from peripheral blood leukocytes as well as from
fibroblasts from the proband. Primer sequences and PCR conditions have
been described previously (26, 27, 28). For purposes of haplotype analysis,
exclusion of hemizygosity, and loss of heterozygosity (LOH) analysis,
genotyping across 18cM in 10q2224 was performed using 12 polymorphic
microsatellite markers,
D10S219-D10S551-D10S1644-D10S1744-D10S579-D10S2491-AFMa086wg9-D10S2492/IVS8
+ 32T/G-D10S541-D10S1739-D10S583 (centromeric to telomeric) (29;
see http://www.genome.wi. mit.edu). PCR conditions and analyses for
the microsatellite markers have been described previously (12, 26, 30, 31). LOH studies were also performed to detect a second genetic hit in
the probands lipoma tissue using intragenic PTEN markers
determined to be heterozygous in the proband. Conditions for LOH
studies have also been described previously (31).
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Case Report and Results
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An 8.5-yr-old son of healthy parents presented with precocious
puberty and macrocephaly. After an uneventful pregnancy, he was born at
term weighing 3.86 kg (0.7 SD above the mean) with a head
circumference of 37 cm (1.3 SD above the mean). By 6 weeks
of age, his head circumference at 43 cm was 2.6 SD above
the mean; a computed tomography scan at the age of 6 months did not
reveal any abnormalities. At 5.5 yr, the patient presented with a
swelling in the left groin that revealed a lipoma after excision. At
6.8 yr, he was referred with a few months history of poor weight
gain, reduced appetite, and occasional effortless vomiting. Testicular
enlargement was noted. Thorough investigation for failure to thrive did
not reveal any abnormalities. Magnetic resonance imaging (MRI) scan of
the head failed to reveal any focal lesions or ventricular dilatation
(Fig. 1
). After 6 months of nutritional
supplements, nasogastric feeding, and behavior modification therapy,
the patient started to regain weight and was discharged from follow-up.
During this period, he was noticed to have symptoms of obstructive
sleep apnea that improved after a tonsillectomy. At 8.4 yr, he
presented to his family practitioner with a dry scaly rash that was
diagnosed as eczema. Treatment with topical steroids did not lead to
any improvement. He was, however, noticed to be markedly virilized,
prompting his referral to the pediatric endocrine service. He had
attained his developmental milestones at the appropriate age, and his
educational progress in mainstream school had not been of concern to
the parents or his school. The patients parents were probably
unrelated, although both had been adopted and were not aware of their
own familys histories. They were both healthy and did not have
macrocephaly. The probands mother reached menarche at 10.5 yr. A
younger sibling was generally well.

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Figure 1. MRI scan of the head showing at age 6.8 yr
no intracranial abnormality (A), at age 8.4 yr the presence of two
intracranial tumors (arrows), a smaller hypothalamic
lesion and a larger tumor arising from the base of the fourth ventricle
(B), and at age 9.0 yr resolution of intracranial abnormalities present
6 months previously.
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On examination, the patients height, weight, and head circumference
were 1.1, 1.4, and 4.7 SD above the mean, respectively. His
previous height recordings were between 0.10.5 SD above
the mean. Blood pressure was 110/60 mm Hg. He had marked frontal
bossing and scaphocephaly, and neurological examination showed mild
papilloedema and evidence of left-sided cerebellar dysfunction.
Pubertal status was G5 PH5 AH3, with testicular volumes of 8 mL
bilaterally. He had hyperpigmented, velvety, hyperkeratotic papules
consistent with acanthosis nigricans in a number of areas, but
especially the neck, axillae, upper arms, and thighs. Close examination
of his penis revealed speckling of the glans. His bone age, assessed by
the radius-ulna score, was 13 yr. Details of biochemical investigations
are listed in Table 1
. MRI scan of the
head confirmed the presence of two intracranial tumors: a smaller
hypothalamic lesion and a larger tumor arising from the base of the
fourth ventricle (Fig. 1
). MRI scan of the spine, ultrasound
examination of the abdomen, and a plain x-ray of the chest did not
reveal any abnormalities. The patient was started on an international
germ cell tumor trial consisting of multiagent chemotherapy and
radiotherapy. He developed profound myelosuppression and central
diabetes insipidus. During therapy, he required prolonged artificial
ventilation after central respiratory failure. His treatment was then
changed to a combination of radiotherapy and chemotherapy, consisting
of carboplatin, etoposide, and vincristine, and he is presently in
remission 2 yr after completion of this regimen. Repeat MRI of the head
6 months after treatment showed resolution of the lesions seen earlier
(Fig. 1
). Investigations performed at 2 yr after completion of
treatment showed evidence of GH deficiency and secondary hypothyroidism
(Table 1
). The short Synacthen test at retesting was normal. His
pubertal status was G5 PH1 AH1, with testicular volumes of 3 mL
bilaterally. He still requires nocturnal positive pressure support at
home and suffers from central diabetes insipidus.
Cytogenetic analysis revealed a karyotype of 46,XY,
t(10;13)(q23.2;q33). The karyotypes of both parents were normal. FISH
mapping revealed that hybridization signals for the BAC46B12 probe
specific for PTEN were present on the normal chromosome 10
and on the derivative chromosome 13[der(13)], indicating that the
breakpoint on the chromosome 10 long arm was centromeric to
PTEN. The D10Z1 DNA probe facilitated identification of the
der(10) chromosome, and hybridization signals specific for this probe
were seen, as expected, on the normal copy of chromosome 10 and the
der(10) (Fig. 2
). No residual
hybridization signal specific to PTEN was observed on the
der(10), suggesting that PTEN was not rearranged due to this
translocation.

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Figure 2. FISH mapping of the balanced translocation
46,XY, t(10;13)(q23.2;q33). The PTEN-specific BAC, BAC
46B12, clearly identified two copies of PTEN.
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Analysis of the 12 polymorphic markers within and flanking
PTEN showed that of the four markers intragenic to
PTEN, two, residing at either end of the gene, were
heterozygous (Fig. 3
). Four of the five
centromeric flanking markers and two of the three telomeric flanking
markers were also heterozygous. DGGE-based PTEN analysis in
the proband did not reveal any mutations. Further, loss of
heterozygosity within PTEN was not observed in lipoma tissue
from the proband (data not shown).

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Figure 3. Haplotypes of the proband and his parents.
Heterozygosity is clearly observed at intragenic PTEN
markers as well as at markers in intervals flanking either side of
PTEN in the proband. Parental haplotypes are consistent
with paternity.
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Discussion
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Unlike many other syndromes of overgrowth where considerable
phenotypic overlap exists (32), the BRR phenotype has become more
defined after the identification of PTEN abnormalities in
affected cases (29, 33). It is unlikely that the phenotype of our case
is part of any other overgrowth syndrome, such as Sotos syndrome, a
condition often confused with BRR in the past (33, 34). The
constellation of lipoma, early onset macrocephaly with normal
ventricular size, normal childhood stature, pigmented penile lesions,
absence of marked mental retardation, and the phenomenon of transient
marked wasting associated with a cytogenetic abnormality in the
vicinity of PTEN support the diagnosis of BRR (35, 36).
However, intracranial tumors in BRR seem to be restricted to
meningiomas. To our knowledge, this case is the first report of a
hCG-secreting intracranial tumor in an individual with BRR. Although
tumors of embryonal and nonembryonal origin occur in a number of
overgrowth syndromes (32), hCG-secreting tumors have not been
associated with any overgrowth syndromes, and the only reported
associations seem to be with Down syndrome and Klinefelter syndrome
(37, 38). In our case, signs of puberty were evident well before
radiological changes were evident on MRI scan. It is possible that the
intracranial lesions were metastases from an occult extracranial
primary tumor. However, their location within the brain is unusual for
metastases and more in keeping with the midline sites associated with
germ cell tumors. The presence of two distinct lesions within the brain
emphasizes the invasive nature of the tumor, but could also suggest two
primaries. The latter would support the true association of cranial
germ cell tumors and PTEN-related BRR. Centrally mediated isosexual
precocious puberty in boys is a rare occurrence, and hCG-producing
tumors may account for 420% of these cases of precocious puberty
(39, 40). Postnatally, an elevated hCG concentration indicates the
presence of a germ cell tumor derived from primitive embryonal cells
such as embryonic yolk sac tumors or choriocarcinomas (40, 41). In this
case, the hCG-secreting tumor is probably due to a choriocarcinoma, as
-fetoprotein is often elevated in cases of yolk sac tumors. The
discordance between testicular size and the stage of virilization has
been described before in cases of hCG-mediated precocious puberty and
may be a useful clue in the investigation of precocious puberty. The
selective stimulation of the LH receptor may explain high testosterone
levels with only modest testicular enlargement.
Germline mutation of PTEN, including both intragenic
mutation and gross deletion, has been firmly established as the primary
genetic event in the development of the majority of cases of BRR and CS
(9, 10, 11, 12, 13, 14, 15, 29, 31, 33) and the germline balanced de novo
translocation, 46,XY, t(10;13)(q23.2;q33), in this boy was, therefore,
considered to be a contributory factor in the development of the
phenotype in this case. However, FISH analysis was clearly able to show
the presence of two copies of PTEN in skin fibroblast cells
from this patient with no detectable physical disruption of
PTEN mediated by this translocation. Heterozygosity of
intragenic and flanking microsatellite markers further argued against
any loss of PTEN material as a result of this translocation.
Methylation studies of the lipoma tissue were not attempted because the
specimen had been fixed in paraffin. Lack of detectable biallelic
inactivation is not uncommon for PTEN (31), and as its
promoter is not characterized, methylation studies would probably have
been inconclusive. DGGE analysis did not reveal any germline intragenic
PTEN mutations that are commonly associated with CS or BRR.
We did not proceed to DNA sequencing because, unlike SSCP analysis,
DGGE is virtually 100% sensitive, and an alteration can be detected
even if a mutation is represented in only 10% of the cells; in
contrast, direct sequencing, which is considered the gold standard of
mutation detection, requires the mutation to be present in more than
35% of the cells (42, 43). Although our FISH data suggest that the
translocation breakpoint occurred centromeric to PTEN, it is
possible that if it occurred at the very 5'-end of PTEN, we
would have been unable to detect the signal due to limitations of FISH
sensitivity. Alternatively, the translocation breakpoint may have
occurred upstream of PTEN, causing the physical separation
of important PTEN regulatory elements. Yet another
possibility is that a gene on 13q, when brought proximal to
PTEN, may dysregulate PTEN transcription or
translation, leading to functional haploinsufficiency. One also needs
to consider the possibility that an inactivating mutation in an as yet
unidentified gene may contribute toward the BRR phenotype.
Although malignancy has not been accepted formally as a feature of BRR,
this case represents the second report of a malignant tumor occurring
in conjunction with BRR, and the first occurring in a pure BRR patient.
An anecdotal family comprising individuals with features of BRR and CS
has been reported; the teenage male proband with features of BRR also
had a thyroid insular follicular carcinoma and nodular hyperplasia with
a focus of papillary microcarcinoma. This family was found to have the
germline nonsense point mutation, R130X, in the region encoding the
protein tyrosine phosphatase core motif of PTEN (4). These two cases
provide anecdotal evidence of malignancy in BRR; however, the
possibility that these malignant tumors arise on a background other
than that of a germline PTEN mutation in these individuals
cannot be excluded. Based on genetic and phenotypic evidence, it is
becoming increasingly likely that BRR and CS, previously thought to be
two discrete hamartoma syndromes, may, in fact, represent different
manifestations of a single syndrome (29). If this is true, then BRR
patients should be targeted along with CS individuals with respect to
cancer surveillance.
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Acknowledgments
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Dr Patricia Dahia is thanked for critical review of this
manuscript.
Received April 29, 1999.
Revised July 13, 1999.
Revised August 4, 1999.
Accepted August 13, 1999.
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