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