Carney triad versus Carney Stratakis syndrome: two cases whichillustrate the difficulty in distinguishing between these conditionsin individual patients

Ismail Alrashdi • Gul Bano • Eamonn R. Maher •

Shirley V. Hodgson

Published online: 30 January 2010

� Springer Science+Business Media B.V. 2010

Abstract Carney triad is a usually sporadic association of

pulmonary chondroma, gastrointestinal stromal tumours,

and paraganglioma. The majority of patients have two of

these tumours, the gastric and pulmonary tumours being

the most common combination. Carney Stratakis syndrome

is an association of familial paraganglioma and gastric

stromal sarcoma and it is considered to be a distinct con-

dition from Carney triad as it is dominantly inherited and

not associated with pulmonary chondroma. We report two

unrelated patients each with two components of Carney

triad. A pathological mutation in succinate dehydrogenase

subunit B gene was identified in one and a variant in the

same gene was identified in the other. This report dem-

onstrates the difficulty in distinguishing between Carney

triad and Carney Stratakis syndrome due to the rarity of the

individual components. The fact that most patients with

Carney triad have only two components of the Triad, and

the long interval often seen between the occurrence of the

first and the second component makes it difficult to dif-

ferentiate confidently between the two conditions. Molec-

ular information should improve the diagnosis of Carney

triad.

Keywords Carney triad � Carney Stratakis syndrome �Gastric epithelioid leiomyosarcoma � Paraganglioma �Phaeochromocytoma � Pulmonary chondroma

Abbreviations

CD34 Cluster of differentiation, molecule CD34

CT Computerized tomography

DNA Deoxyribonucleic acid

KIT c-Kit

MEN2A Mutliple endocrine neoplasia type 2A

MIBG Meta-iodobenzylguanidine scintiscan

MLPA Multiplex ligation dependent probe

amplification

MRI Magnetic resonance image

PDGFRA Platelet-derived growth factor receptor A

RNA Ribonucleic acid

SDHA Succinate dehydrogenase subunit A

SDHB Succinate dehydrogenase subunit B

SDHC Succinate dehydrogenase subunit C

SDHD Succinate dehydrogenase subunit D

VHL Von Hippel Lindau

Introduction

Carney triad (MIM number 604287) is an association of

pulmonary chondroma, gastrointestinal stromal tumours

and functioning paraganglioma (extra-adrenal phaeo-

chromocytoma). The first description by Carney et al. [1]

reported two young women with three components and five

other unrelated patients with two of the three components

of the triad. Subsequently Carney [2] reviewed the findings

in 24 sporadic affected patients, 22 women and only two

I. Alrashdi � S. V. Hodgson (&)

Department of Medical Genetics, St George’s Hospital Medical

School, Cranmer Terrace, London SW17 0RE, UK

e-mail: shodgson@sgul.ac.uk

G. Bano

Department of Endocrinology, St George’s Hospital,

Blackshaw Road, London SW17 0QT, UK

E. R. Maher

Department of Medical and Molecular Genetics, Institute of

Biomedical Research, University of Birmingham, Edgbaston,

Birmingham B15 2TT, UK

123

Familial Cancer (2010) 9:443–447

DOI 10.1007/s10689-010-9323-z

men, (including some cases reported previously [1]). Only

6 of the 24 patients had all three components of the triad,

whilst the majority manifested only two of the tumour

types. As the coincidental occurrence of these three rare

tumours in more than one patient (in addition to the

observed early age at diagnosis and multicentricity of the

tumours), is unlikely, the author concluded that this unu-

sual association of tumours constitutes a specific genetic

entity.

A review of 79 patients, including 48 patients recog-

nized since 1983, provided an insight into the natural his-

tory of the triad [3]. The majority of reported patients had

two tumours, gastric and pulmonary tumours being the

most common combination. Only 17 (22%) patients had all

the three components. Out of 79 patients reviewed, only

two had a family history, a sibling of each had bilateral

carotid body paraganglioma. The interval between the

diagnosis of the first and second component of the triad

was as long as 26 years. Adrenocortical adenoma,

oesophageal, duodenal and pancreatic islet cell tumours

were also identified to occur in these patients.

Carney Stratakis syndrome is an autosomal dominantly

inherited association of familial paraganglioma and gastric

stromal sarcoma. It was recently described by Carney and

Stratakis [4]. The familial predisposition to multicentric

paragangliomas and rare and multifocal gastric stromal

sarcoma suggested that Carney Stratakis syndrome was a

condition distinct from Carney triad. The dominant pattern

of inheritance and absence of pulmonary chondroma are

differentiating features from Carney triad. Some of the

cases with family history of paraganglioma and gastroin-

testinal stromal tumours described in the original cohort of

Carney triad were included in their description of Carney

Stratakis syndrome. In contrast to Carney Stratakis syn-

drome, most of the patients with Carney triad reported so

far had two tumours, gastric and pulmonary tumours being

the most common combination, and almost all the patients

reviewed by Carney [3] had no family history of the

condition.

Pasini et al. [5] reported germline mutations in SDHB,

SDHC or SDHD in 8 of 11 patients from seven unrelated

families, (including the patients reported in the first

description of Carney Stratakis syndrome [4]) with para-

ganglioma and gastric stromal sarcoma.

In contrast to Carney Stratakis syndrome, the genetics of

Carney triad remained unclear. No mutation was identified

in 37 patients with Carney triad and/or 41 tumours in these

patients by DNA analysis for the coding sequence of

SDHB, SDHC, SDHD, KIT and PDGFRA genes, which

have been shown to be involved in the pathogenesis of

paraganglioma [6]. Comparative genomic hybridization

(CGH) was performed on the tumours from these patients.

The most common alterations found in sporadic

gastrointestinal stromal tumours were 14q, 22q and 1p

losses. In the Carney triad stromal tumours and paragan-

gliomas 1q loss was by far the most frequent genetic

alteration, and it was also found in a single adrenal tumour

and in one of three pulmonary chondromas from Carney

triad patients [6]. It is interesting to note that the SDHB

gene is located on chromosome 1p36.1-p35, and SDHC in

1q21-q23.3, so that one could speculate that the losses in

the tumours represented loss of the second allele where an

undetected germline mutation was present on the other

allele. It is worth mentioning that the absence of familial

cases of Carney Triad hampered positional cloning to

reveal the genetic aetiology of this rare syndrome.

We report the identification of germline SDHB variants

in two unrelated patients with only two components of

Carney triad. A pathogenic mutation was identified in one

patient, and a variant of unknown pathogenicity in the

other. This report aims to increase awareness of the exis-

tence of these two rare syndromes and their overlapping

features. It demonstrates the difficulty in distinguishing

between the Carney triad and Carney Stratakis in isolated

cases on a clinical basis, and emphasizes the need to

identify the genetic aetiology of Carney triad.

Clinical report

Patient 1

This man has been reported previously by Bladen et al. [7]

as a case of Carney Triad. He was referred to our genetic

service after being diagnosed with phaeochromocytoma at

the age of 46. He initially presented with headache, fati-

gability and lethargy and was found to have high blood

pressure. His 24 h urinary catecholamines and their

metabolites were extremely high. A calcified lesion in the

left upper zone consistent with pulmonary chondroma had

been detected by chest radiography. More detailed history

revealed that this lesion was incidentally discovered fol-

lowing investigations for road traffic accident when he was

in his 20’s. At that time he declined further evaluation. He

then remained well until the age of 46.

A computerized tomography (CT) scan of his abdomen

showed a 7.5 cm para-aortic mass consistent with an extra

adrenal paraganglioma. He then underwent attempted

tumour resection. Subsequent histological examination

confirmed malignant phaeochromocytoma and sadly post

operative assessment revealed that the residual tumour was

not amenable to further surgical intervention.

He has two sons and six brothers and sisters, all of

whom are healthy. His father who was a heavy smoker died

of lung cancer in his 50’s. His mother is alive and healthy

in her 70’s.

444 I. Alrashdi et al.

123

On physical examination, he had a number of moles

scattered over his trunk but otherwise there were no other

remarkable findings on systemic examination. Endoscopic

screening for gastric stromal tumours was normal.

Molecular genetic analysis by direct DNA sequencing

identified a heterozygous missense mutation (c.600G[T) in

exon 6 of the succinate dehydrogenase subunit B (SDHB)

gene. This mutation has been reported previously in

patients with inherited paraganglioma [7, 8], and is

believed to be pathogenic. His two healthy sons both tested

negative for this mutation by sequencing exon 6 of SDHB

gene. Other family members have declined testing.

Patient 2

This lady was well until the age of 35 when she developed

Hashimoto thyroiditis and was treated with thyroxine. She

had symptoms of episodic profuse sweating, difficulty in

breathing and later on at the age of 36 she developed

hypertension. The investigations and imaging revealed

4 cm left adrenal phaeochromocytoma which was later

confirmed by histological examination. She successfully

underwent left adrenalectomy. A small lump on her chest,

which she had developed that year was also excised at the

time of adrenalectomy, and subsequently confirmed to be a

basal cell carcinoma.

At the age of 40 she presented with vomiting after

meals, pain in the abdomen and urinary hesitancy.

Abdominal ultrasound and then magnetic resonance image

(MRI) detected a mass arising from the smooth muscle of

the stomach, large enough to cause pressure symptoms of

the bladder. It was subsequently removed and found to be

benign low grade stromal tumour (stained positive for

CD34) from the smooth muscles with low grade malignant

potential. Although chest radiography did not reveal any

lung abnormality, a diagnosis of Carney triad was

suspected.

Meta-iodobenzylguanidine scintiscan (MIBG) and MRI

of the adrenal and retroperitoneal region were both normal.

She is under regular surveillance by annual 24 h urinary

catecholamines and MRI every 2 years for paragangliomas

or phaeochromocytoma and endoscopic ultrasound every

6 months for gastric tumours.

At the age of 43, surveillance endoscopy revealed a

1.5 cm submucous lesion at the oesophagogastric junction

and numerous tiny polyps on the stomach wall. These were

biopsied and found to be benign fundic gland polyps of

specialized gastric mucosa, some with dilated cysts. There

was no evidence of inflammation, dysplasia or malignancy.

At the age of 48 she was found to have uterine leio-

myomatosis following evaluation for menorrhagia. She

subsequently underwent hysterectomy and bilateral sal-

pingo-oophorectomy.

She has two healthy children (aged 9 and 17 years) and

her parents had no history of having developed any

tumours. Her mother, who is 73 years old, is healthy, and

her father, who is 85 years old, only has hypertension. He

has normal 24 h urinary catecholamines.

Molecular genetic analysis for multiple endocrine neo-

plasia type 2A (MEN2A) (sequencing of the RET gene)

and Von Hippel Lindau (VHL) disease (sequence analysis

of exons 1,2 and 3 of the VHL gene and multiplex ligation

dependent probe amplification (MLPA) analysis) demon-

strated no abnormality. Sequence analysis of SDHD and

SDHC demonstrated no evidence of an intragenic muta-

tion, but analysis of SDHB revealed a six base pair intronic

duplication (c.424-19-14dupttcttc) in intron 4. This variant

is apparently novel and has not been previously reported in

the literature. Ribonucleic acid (RNA) studies indicated

that this intronic variant did not appear to affect splicing.

This variant was also detected (by sequencing intron 4 and

exon 5 of SDHB gene) in the proband’s father and a

paternal aunt who died in her 80’s of a chest infection.

Discussion

Although the first report of Carney triad by Carney et al.

[1] described the association of gastric ‘leiomyosarcoma

(later recognized to be a stromal tumours), pulmonary

chondroma and functioning extra adrenal paraganglioma,

in a study of 79 patients [3] 78% of the patients had only

two components of the triad. At the time of the first

diagnosis of a component tumour only 1 of 79 (\2%)

patients had all three tumour types. In view of the indi-

vidual rarity of the three components of the triad, the

presence of two components has been considered suffi-

cient to make the diagnosis of Carney triad. As with the

first patient in our report, almost all patients who had a

chondroma were asymptomatic [3]. In about half of Car-

ney’s patients [3], the chondroma lesion was calcified. The

tumour in our first patient was first detected incidentally

as a calcified tumour following routine radiological

investigation after a road traffic accident. In Carney’s

review [3], 79% of the patients had a pulmonary chon-

droma, a quarter of which had been diagnosed radiologi-

cally only. The mean age of detection of chondroma was

23.7 years, and the median age was 21 years. Our patient

had an apparent pulmonary chondroma detected at his

20’s. Carney [3] indicated that the pulmonary chondromas

in the patients reviewed were generally asymptomatic and

not deleterious, and only 68% of them were removed

surgically. Some of the patients described by Carney [3]

had pulmonary chondroma which were left in situ and

observed for up to 40 years, and remained asymptomatic

and non-deleterious.

Carney triad versus Carney Stratakis syndrome 445

123

Our first patient remained well until he developed par-

aganglioma about 20 years later. Germline mutations in the

SDHB gene have been identified in patients with para-

gangliomas [8, 9]. The mutation detected in our first patient

has been previously reported by Trimmers et al. [8] in a

60 year old man with a paraganglioma. Variable pheno-

typic expression is a frequent feature of germline SDHB

mutations, and there is a possibility that the patient

reported by Timmers et al. [8] has Carney triad, but has, to

date, only developed one component tumour. Therefore,

the diagnosis of Carney triad in our first patient remains

possible, despite the fact that confirming pulmonary

chondroma is impossible as the patient declined further

investigations. However, it is still also possible that this

patient has familial paraganglioma (with confirmed SDHB

mutation) and a co incident pulmonary calcified lesion,

clearly demonstrating the difficulty in distinguishing the

two conditions, since pulmonary chondroma was asymp-

tomatic in all but one of the patients reported so far [3], and

the fact that the interval between the occurrence of the first

and subsequent components of the triad can be as long as

up to 26 years. In about 15% of Carney triad patients, the

pulmonary lesion (which can be asymptomatic and detec-

ted incidentally) is the presenting feature, and only 10%

present with paragangliomas [10].

Patient 2 in this report developed an adrenal phaeo-

chromocytoma at the age of 36 and gastric stromal tumour

from smooth muscle at the age of 40. Gastric stromal

sarcoma, a very uncommon tumour, is the most common

component of Carney triad from its first description [1],

and more than two-thirds of the patients reviewed subse-

quently by Carney [3] had it. Importantly, Carney also

reported that only 17 (22%) patients out of 79 reviewed [3]

had all three components of the triad. This raises the pos-

sibility that some patients with Carney triad might be

diagnosed as Carney Stratakis syndrome if they presented

with two components, gastric and paraganglioma before

they develop pulmonary chondroma, particularly because

of the partial penetrance of the Triad.

Carney in his review of the 79 patients [3] found that the

latest age at detection of pulmonary chondroma was

49 years, including a 48 year old patient with a calcified

lung nodule who had normal radiographic findings at the

age of 45 years. The rarity of a diagnosis of pulmonary

chondromas may be due to misinterpretation of the lesion

as metastatic stromal tumours (in about 25% of cases),

hamartomas or granulomas (in 20%) and other benign

lesions (in about 11% of cases) [11, 12].

The gastric tumour in our patient was large enough to

cause pressure symptoms of the bladder at diagnosis,

although the histological appearance was interpreted as

those of a gastrointestinal stromal tumour, which appeared

to be of low malignant potential. This is in keeping with the

finding in Carney’s review [3] that the gastric tumours in

Carney triad are usually large at diagnosis and are slow to

grow and metastasize.

There was no family history of gastric, or pulmonary

tumours, or paragangliomas, in the two patients we report.

Review of previously reported cases [1–3] of Carney triad

reveals that the great majority do not have a family history

of the condition. This of course does not exclude the pos-

sibility of Carney Stratakis syndrome despite the fact that

the previously reported cases clearly demonstrated familial

occurrence.

Pasini et al. reported germline mutations in SDHB,

SDHC or SDHD in eight of 11 patients from seven unre-

lated families diagnosed with Carney Stratakis syndrome

(none of these patients had pulmonary chondroma) [4, 5].

No mutations or large deletions were identified in the

coding regions of the SDHA, SDHB, SDHC and SDHD

genes of three patients. They are from two unrelated

families were 15, 19 and 20 years old at the time of the

report. Our second patient only had a germline variant in

the SDHB gene and the pathogenicity of this variant is

debatable. The other individuals with the variant had no

signs of the relevant tumours, which is evidence against the

pathogenicity of the variant.

Is the distinction between Carney Triad and Carney

Stratakis syndrome an arbitrary one? The presence of

pathogenic mutations in the succinate dehydrogenase sub-

unit genes clearly delineates Carney Stratakis syndrome

from Carney Triad. The long interval between the occur-

rence of the rare components of Carney Triad and the

reduced penetrance and asymptomatic nature of some

lesions may contribute to underestimation of its existence.

The prevalence of both conditions is still unknown.

Acknowledgments We thank the patients and their families for

their cooperation and for giving us their consents for publishing this

report. We also thank Fiona Macdonald from West Midlands Genetics

Laboratory for her help and support.

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