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SHORT COMMUNICATION
A complex endocrine conundrum
G. Bano • V. Siedel • N. Beharry • P. Wilson •
T. Cranston • S. Hodgson
Published online: 15 December 2012
� Springer Science+Business Media Dordrecht 2012
Abstract We describe a case of recurrent primary hyper-
parathyroidism, manifested as 3 metachronous parathyroid
adenomata, in a 50 year-old woman who also had Hashimoto
hypothyroidism, gastric gastrointestinal stromal tumour
(GIST), cysts in liver and kidneys, 5 intestinal polyps (one of
these a villous adenoma), diverticulitis and telangiectasia of
lips. She did not have medullary thyroid carcinoma (MTC).
Genetic analysis of the CDC73 gene [for Hyperparathy-
roidism—jaw tumor (HPT-JT)], MEN1 for Multiple Endo-
crine Neoplasia Type1, CDKN1B for MEN4, SDHB and
SDHD for Paraganglioma/Pheochromocytoma susceptibil-
ity, VHL for von Hippel-Lindau Syndrome, BMPR1A and
SMAD4 for Juvenile Polyposis Syndrome (JPS) (sequencing
and MLPA), karyotype and array CGH (44 K) were all
normal. She was found to be homozygous for a synonomous
germline variant in exon 14 (p. Ser836Ser) of the RET
oncogene. This RET variant is of unclear clinical signifi-
cance, and has been previously reported both in normal
individuals and in individuals with MTC. It is unlikely that
homozygosity for the RET variant has been casual in the
multiple pathologies that our patient has developed.
Keywords Hyperparathyroidism � GIST � MTC �RET proto oncogene
Case report
This patient is the child of non-consanguineous Caucasian
parents and has one older sister aged 59. Her mother had
thyroidectomy for goitre at age 45 and she died aged 53
from lung cancer. Her father died in his seventies from
ischaemic heart disease, and had been diagnosed with
schizophrenia. There are no known endocrine problems or
cancers in close relatives (to second degree). The patient
has one daughter, who has learning difficulties and hearing
problems since childhood.
Her past medical history included congenital left hip
subluxation and a unilateral benign ovarian cyst, which was
removed at 30 years of age. She has 3-yearly colonoscopies
by the Gastroenterologist since the age of 45 when she pre-
sented with diarrhoea, abdominal pain and rectal bleeding.
A colonic villous adenoma was found and removed. At age 46
she complained of urinary incontinence and detrusor insta-
bility was diagnosed. She was diagnosed with Hashimoto
thyroiditis and was prescribed thyroxine at age 47. Six
months later the patient had a total hip replacement, and
hypercalcemia was detected on routine pre-operative tests.
G. Bano
Cellular and Molecular Medicine, St. George’s University
of London, London SW17 ORE, UK
G. Bano (&)
Thomas Addison Unit, St. George’s Hospital, Blackshaw Road,
London SW17 ORE, UK
e-mail: gbano@sgul.ac.uk
V. Siedel � S. Hodgson
Department of Clinical Genetics, St. George’s Healthcare
NHS Trust, London SW17 ORE, UK
N. Beharry
Department of Radiology, St. George’s Healthcare NHS Trust,
London SW17 ORE, UK
P. Wilson
Department of Cellular Pathology, St. George’s Healthcare
NHS Trust, London SW17 ORE, UK
T. Cranston
Oxford Medical Genetics Laboratories, Oxford University
Hospitals NHS Trust, The Churchill Hospital,
Oxford OX3 7LE, UK
123
Familial Cancer (2013) 12:577–580
DOI 10.1007/s10689-012-9594-7
Further investigations to find the cause of hypercalcemia
revealed paraproteinemia. Electrophoresis showed high
IgA kappa, and Bence-Jones protein was absent. Bone
marrow aspiration demonstrated no malignancy. Diagnosis
of Monoclonal Gammopathy of Unknown Significance
(MGUS) was made and the levels of her paraprotein have
remained stable at 6–7 g/l. Her hypercalcemia was due to
primary hyperparathyroidism as she had a high serum cal-
cium of 2.85 (2.15–2.55 mmol/l), low phosphate 0.69
(0.75–1.50 mmol/l), with high Parathyroid hormone of 7.1
(1.1–6.9 pmol/l). The patient was symptomatic with poly-
uria and polydipsia. Imaging of the neck showed an enlarged
right inferior parathyroid gland and this was removed. His-
tology confirmed it to be a parathyroid adenoma. Her
symptoms resolved and calcium and phosphate levels nor-
malized after the operation. However, 3 weeks after her
parathyroid surgery the tests showed that patient was again
hypercalcemic. Over the following 5� years her serum
calcium ranged between 2.67 and 2.88 mmol/l with PTH of
11–12 (1.1–6.9 pmol/l).
During this time patient was diagnosed with bilateral
sensorineural deafness and provided with hearing aids. At
the age of 53, she had a total hysterectomy with left sal-
pingo-oophrectomy for benign fibroleiomyomas, adeno-
myosis. A benign serous cyst was found attached to left
Fallopian tube.
The persistence of hypercalcaemia prompted further
investigations. Her parathyroid venous sampling was sug-
gestive of left inferior parathyroid adenoma. Sestamibi scan
showed some tracer uptake in region of lower pole of thy-
roid, which corresponded to the 1.5 cm lesion suggesting
parathyroid adenoma on the ultrasound scan. MRI neck did
not detected parathyroid adenoma but showed somewhat
dilated oesophagus. The patient had a second parathyroid
surgery with removal of left inferior parathyroid adenoma at
age 55 years. The pathology described it as an encapsulated
nodule of parathyroid tissue showing no evidence of sup-
pression, measuring 10 9 6 9 3 mm and weighing 25 mg.
However, the patient’s hypercalcaemia and high levels of
PTH persisted (Calcium 2.62; PTH 13.1 1 month post-
surgery). The patient also complained of generalized mus-
cle aches, bone pain and tiredness. Biphosphonate therapy
with alendronic acid was tried for 3 months with no change
in her symptoms. A sestamibi scan performed 2 years after
the second parathyroidectomy showed increased uptake of
the tracer localising to the upper pole of the left lobe of the
thyroid gland and a third parathyroid surgery was under-
taken (at 58 years). Left superior parathyroid gland and left
thyroid lobe were removed Fig. 1. Subsequently her cal-
cium and PTH levels have remained stable in the normal
range. She also had a renal USS scan which showed bilat-
eral renal cysts: a 6.6 cm cyst in the lower pole and 1 cm
cyst in middle third of the right kidney and a 1 cm cyst in
left kidney. The patient was seen in the combined endocrine
genetics clinic, and was noticed to have telengiectasia of the
lips and a high arched palate Fig. 2. The differential diag-
nosis at this stage included the Hyperparathyroidism—Jaw
Tumor (HPT-JT) Syndrome because of hyperparathyroid-
ism and renal cysts, and MEN 1. Genetic tests for germline
mutations in the CDC73 gene and MEN 1 were negative but
the RET gene showed that she was homozygous for c.2508
C [ T in exon 14. Analysis of the RET gene was targeted to
the characterised mutation hotspots and was undertaken by
PCR using standard conditions and sequencing analysis of
exons 8, 10, 11, 13, 14, 15 and 16. Primer sequences and
PCR conditions are available on request. Fluorescent San-
ger Sequencing was undertaken using ABI Big Dye version
3.1 and an ABI 3730.
This RET variant is of unclear clinical significance, and
has been detected both in normal individuals and in
Fig. 1 Parathyroid adenoma. HE 910. Parathyroid to the left; rim of
suppressed parathyroid tissue to the right
Fig. 2 Telengactesia of lips
578 G. Bano et al.
123
individuals with MTC. The patient was extensively inves-
tigated for medullary thyroid carcinoma and other features
of MEN2. Her pentagastrin-stimulated calcitonin level was
normal. Her 24 h urinary metanephrines excretion, over-
night dexamethasone suppression test and MRI of the pitu-
itary gland were also normal. Her abdominal CT scan
showed an intraluminal mass in the stomach, nephrocalci-
nosis of the right kidney, a 1.5 cm calcified mesenteric
nodule, 3 small subpleural lung nodules, and bone islands in
L5 vertebra and iliac wing. Gastroscospy confirmed the
submucosal location of the mass in her stomach. It was a
large 3.7 cm polyp on the lesser curve of the stomach. In
addition to this two other duodenal polyps were detected.
These were removed endoscopically and reported to be
Brunner gland hyperplasia/adenoma. The patient had
laparascopic excision of the gastric polyp with Nissen fun-
doplication for the hiatus hernia and grade III oesophagitis.
She was also prescribed the proton pump. The pathology
confirmed it to be gastric intestinal stromal tumour (GIST)
with no mucosal or lymphovascular invasion Figs. 3 and 4.
The tumour was less than 5 cm and had B6 mitosis per high
power field (hpf). One year later she had complete GI tract
assessment including barium swallow, gastroscopy and
colonoscopy and these were normal. The patient is currently
well and is under regular surveillance.
Genetic tests performed on the patient:
• RET exons 10, 11, 13, 14, 15 and 16 (sequencing)
normal except homozygosity for exon 14 variant
• MEN 1 (ex 2–10 sequencing and MPLA) for MEN1:
normal
• CDKNIB for MEN4: normal
• Karyotype: 46, XX
• Array CGH (44 K): normal
• SDHB and SDHD sequencing (Succinate Dehydroge-
nase subunits) for paraganglioma/Pheochromocytoma:
negative/SDHB, C, D MPLA: normal
• VHL sequencing (Von Hippel Lindau) anf MPLA:
normal
• BMPRIA and SMAD4 for juvenile Polyposis Syn-
drome (JPS) sequencing and MPLA (for BMPRIA and
SMAD4) normal
Discussion
This patient has an unusual constellation of pathology, notably
endocrine abnormalities affecting the parathyroid glands,
gastrointestinal stromal tumor (GIST), intestinal polyps, renal
cysts and telangiectasia. The endocrine abnormality does not
conform to any pattern of abnormalities associated with
established genetic endocrine disorders. No germline patho-
genic changes were identified in any of the genes considered
as potentially responsible for the clinical spectrum. This
included the coding region of MEN1, CDKN1B, CDC73,
SDHB, SDHD, VHL, BMPR1A and SMAD4 and targeted
analysis RET. The patient was found to be homozygous for a
c.2508C [ T; Ser836 Ser variant in RET. This is not consid-
ered a high risk, high penetrance, pathogenic mutation;
however the literature is highly contradictory as to whether it
has any clinical implications or modifying effects.
Fig. 3 HE 94. Spindle cells tumour located in the gastric submu-
cosa. The elongated spindle cells arranged in interlacing fasciles. Less
than 6 mitoses are seen per 50 high power fields and the tumour is less
than 5 cm in size, in keeping with a low grade tumour (using the NIH
risk table (Fletcher et al. 2002)
Fig. 4 GIST immunostained for CD117 (characteristically positive)
A complex endocrine conundrum 579
123
Some reports in the literature suggest that heterozygous
carriers of this variant have a three to fourfold risk of sporadic
MTC [1], but others report no effect [2, 3]. Most of these
papers have relatively small patient cohorts or there is limited
matched control data. Baumgartner-Parzer reported on 158
alleles and found Ser836Ser in 5.7 % of normal controls,
4.5 % FMTC cases and 4.4 % cases of sporadic MTC [4].
Costa et al. [5] tested 50 normal individuals and 50 MTC
patients (total 200 alleles). They found S836S to have allele
frequencies of 6 % and 5 % in MTC and normal cohorts
respectively. They report 1in 50 individuals from each cohort
to be homozygous for the variant. They also conducted a meta-
analysis of studies published by that date and including their
data. From the 6 reports this gave a total of 928 alleles from an
MTC affected cohort and 1306 alleles from a normal cohort,
again they found no statistical difference between normal and
MTC cohorts (*6 and 5 % again) [5].
The variant is also listed on the Single Nucleotide
Polymorphism database (SNP database), and data from the
1,000 genomes project reported the allele frequencies to be
C = 0.942 T = 0.058 based on 120 ‘normal’ chromo-
somes. This would suggest a homozygote gene frequency
(q2) of *1/275.
In 2010 Siqueira et al. [6] reported that the S836S allele
frequency was higher in sporadic MTC patients than in
controls. Individuals harbouring the S836S variant were
younger and showed a higher percentage of lymph node
and distant metastases. Pai et al. [7] also reported similar
results suggesting that the S836S variant is associated with
earlier onset and increased risk for metastatic disease in
patients with hereditary or sporadic MTC. Other individ-
uals homozygous for this variant have not been affected in
the same way as our case. Our patient did not have med-
ullary thyroid carcinoma, and so far no association has
been reported between multiple parathyroid adenomas,
GIST, telangiectasia in individuals carrying this variant. It
is therefore unlikely that homozygosity for the RET variant
has been casual in the multiple pathologies that our patient
has developed. We have not exhaustively sequenced all
known candidate genes for endocrine problems of this
nature but we feel that it is probable that the molecular
findings may be significant. A further advance in molecular
genetics may provide an explanation.
In summary, we present a case of multiple parathyroid
adenomas with gastric GIST, recurrent intestinal polyps,
renal and liver cysts with labial telangiectasia and no
clearly identified causative mutation. This combination
could represent a new syndrome.
References
1. Ruiz A, Antinolo G, Fernandez RM, Eng C, Marcos I, Borrego S
(2001) Germline sequence variant S836S in the RET proto-
oncogene is associated with low level predisposition to sporadic
medullary thyroid carcinoma in the Spanish population. Clin
Endocrinol 55:399–402
2. Machens A, Spitschak A, Lorenz K, Putzer BM, Dralle H (2011)
Germline RET sequence variation I852M and occult medullary
thyroid cancer: harmless polymorphism or causative mutation?
Clin Endocrinol 75:801–805
3. Machens A, Frank-Raue K, Lorenz K, Rondot S, Raue F, Dralle H
(2012) Clinical relevance of RET variants G691S, L769L, S836S
and S904S to sporadic medullary thyroid cancer. Clin Endocrinol
76:691–697
4. Baumgartner-Parzer SM, Lang R, Wagner L, Heinze G, Niederle
B, Kaserer K, Waldhausl W, Vierhapper H (2005) Polymorphisms
in exon 13 and intron 14 of the RET protooncogene: genetic
modifiers of medullary thyroid carcinoma? J Clin Endocrinol
Metabol 90:6232–6236
5. Costa P, Domingues R, Sobrinho LG, Bugalho MJ (2005) RET
polymorphisms and sporadic medullary thyroid carcinoma in a
Portuguese population. Endocrine 27:239–243
6. Siqueira DR, Romitti M, da Rocha AP, Ceolin L, Meotti C,
Estivalet A, Punales MK, Maia AL (2010) The RET polymorphic
allele S836S is associated with early metastatic disease in patients
with hereditary or sporadic medullary thyroid carcinoma. Endocr
Relat Cancer 17:953–963
7. Pai R, Arun Nehru G, Samuel P, Paul MJ, Thomas N, Premkumar
JA, Hephzibah J, Shanthyl N, Oommen R, Nair A, Seshadri MS,
Rajaratnam S (2011) Mutational analysis of RET proto-oncogene
among patients with medullary thyroid carcinoma and ‘at risk’
carriers from India. Clinical Endocrinol 75:571–572
580 G. Bano et al.
123
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