The Turkish Journal of Pediatrics
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Bilateral Pheochromocytoma as First Manifestation of von Hippel-Lindau Disease: A Case Report
Gönül Çatlı1, Ayhan Abacı1, H. C. Hartmut Neumann2, Ayça Altıncık1, Korcan Demir1,
1Division of Pediatric Endocrinology, Department of Pediatrics, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey,
and 2Section for Preventive Medicine, Department of Nephrology, Albert-Ludwigs University, University Medical Center,
Freiburg, Germany. E-mail: firstname.lastname@example.org
|Von Hippel-Lindau syndrome is an autosomal dominant disorder that includes
susceptibility to hemangioblastomas of the eyes and central nervous system,
renal clear cell carcinoma, multiple pancreatic cysts, serous cystadenomas and
pancreatic neuroendocrine tumors, pheochromocytoma, endolymphatic sac
tumors, and cystadenomas of the epididymis and broad ligament.
We present a 16-year-old male who had been followed for having bilateral
adrenal, and in addition, extraadrenal multifocal pheochromocytoma for six
years. At the age of 16, he presented with bilateral retinal hemangioblastomas,
which led to the diagnosis of von Hippel-Lindau disease type 2A confirmed
by genetic analysis. The patient’s mother also had bilateral adrenal
pheochromocytoma with no other von Hippel Lindau-associated tumor. In
children, pheochromocytoma may be the only and/or initial manifestation
of the disease with delayed manifestations of the syndrome in other organs.
Von Hippel-Lindau disease is a complex multidisciplinary disorder that
requires well-coordinated medical care. Surveillance of these patients and
asymptomatic relatives may prevent morbidity and mortality and improve
long- term prognosis. Molecular analysis of the von Hippel-Lindau gene is
useful for early diagnosis of the disease in individuals who do not yet fulfill
the clinical diagnostic criteria and is instrumental in the management and
follow-up of the affected family.
von Hippel-Lindau syndrome, pheochromocytoma, retinal hemangioblastoma.
|Von Hippel-Lindau (VHL) disease is an
autosomal dominantly inherited neoplastic
syndrome characterized by hemangioblastomas
of the retina, brain and spinal cord, renal clear
cell carcinoma, pheochromocytoma, pancreatic
neuroendocrine tumors, and endolymphatic
sac tumors,. Incidence of VHL syndrome is
approximately 1 in 36,000 live births and its
penetrance is over 90% by the age of 65.
According to the diagnostic criteria, a diagnosis
of VHL disease can be made by finding only
a single VHL tumor, provided that a family
history of VHL disease is present. On the
other hand, approximately 20% of VHL
disease cases are sporadic, and if there is no
family history, presence of two VHL tumors
is needed to diagnose the disease. VHL
disease displays complex genotype-phenotype
correlations and can be classified according
to the absence (type 1) or presence (type 2)
of pheochromocytoma. VHL type 2 is further
divided into types 2A, 2B and 2C (5). Type
2A families manifest hemangioblastomas and
pheochromocytoma with a lower risk of renal
cell carcinoma (RCC) and families with type
2B manifest hemangioblastomas, RCC and
pheochromocytoma, whereas families with
specific VHL missense mutations in which
pheochromocytoma is the only feature are
designated as type 2C VHL disease . The
VHL gene is localized on the short arm of
chromosome 3 with three exons coding for
two isoforms of the protein. A wide variety of
mutations have been described in more than 900 kindreds . The type of the mutation differs
between subtypes of the disease. Missense
mutations usually confer better prognosis and
are almost always responsible for VHL type 2,
whereas deletions and nonsense mutations may
be present as well as missense mutations in
type 1 patients . Molecular analysis of the VHL
gene in patients and at-risk relatives allows
early diagnosis of the disease and prevents
morbidity and mortality. On the other hand,
the identification of VHL gene mutations may
also change the management and follow-up of
the affected family.
We present a patient who was initially diagnosed
as bilateral familial pheochromocytoma. During
the follow-up, the emergence of retinal
hemangioblastomas led to a diagnosis of
VHL disease. We report this case to point out
the importance of genetic analysis and careful
follow-up of patients who are diagnosed with
familial or bilateral pheochromocytoma.
|Case Presentation |
|A 10-year-old boy was admitted to our hospital
with complaints of headache and diplopia. On
physical examination, he weighed 40 kg (75-
90p), with a height of 142 cm (50-75p). His
brachial blood pressure was 150/120 mmHg
(95th percentile 123/81 mmHg). His mother had
been operated for bilateral pheochromocytoma
at the age of 23 and had not been under medical
follow-up since then. Laboratory tests showed
elevated 24-hour (h) urinary vanillylmandelic
acid (VMA) (40 mg/day; normal value 1-11)
and normetanephrine (>2000 μg/day), but
normal metanephrine levels (143 μg/day).
Abdominal magnetic resonance imaging (MRI)
indicated the presence of multiple lesions in
perivascular areas neighboring both adrenal
glands. An iodine 123 metaiodobenzylguanidine
(MIBG) scan revealed multiple focal areas
of increased uptake near the adrenal glands.
After the preparation for operation, bilateral
subtotal adrenalectomy including removal of
the masses was performed. The diagnosis of
bilateral pheochromocytoma was confirmed
histologically and immunohistochemically.
The patient remained asymptomatic with
no laboratory or radiologic abnormalities
for six years of follow-up. At the age of 16,
the patient was referred to our clinic with
visual defect in the left eye. Ophthalmologic
examination led to the diagnosis of bilateral
retinal hemangiomas, and he underwent laser
photocoagulation. Positive family history
with bilateral pheochromocytoma and retinal
hemangioma revealed the diagnosis of VHL
disease. Cerebral, spinal MRI and abdominal
computed tomography (CT) were normal.
DNA extraction, polymerase chain reaction and
direct sequencing of exons 1 to 3 revealed a
mutation in exon 3 of the VHL gene (c.695
G>A), both in the patient and his mother,
which resulted in the amino acid change
The patient’s mother was evaluated by
ophthalmologic examination and no
abnormalities were found. She underwent
cerebral and spinal MRI and abdominal CT to
investigate any possible VHL tumors, and no
tumor was detected.
|Pheochromocytoma is a rare tumor, with an
incidence of 2-8 cases per million per year.
Approximately 10-20% of cases are diagnosed
during childhood at an average age of 11.
The prevalence of pheochromocytoma is 1%
among hypertensive adolescents. In comparison
with adults, childhood pheochromocytoma is
associated with sustained hypertension rather
than hypertensive attacks with the classical triad
of palpitation, headache and excess sweatiness.
Although most pheochromocytomas are
sporadic, up to 25% of cases are associated
with familial cancer syndromes such as
neurofibromatosis type 1 (NF1 gene), multiple
endocrine neoplasia type 2 (MEN2) (RET gene),
VHL syndrome (VHL gene) and paraganglioma
syndrome types 1, 3 and 4 (SDHD, SDHC,
SDHB genes) . Recently, two new susceptibility
genes, the TMEM127 gene and MAX gene,
without homology to other functional classes,
have been described ,.
Familial pheochromocytomas are often
multifocal and frequently bilateral. Finding
of multicentric tumors is highly suggestive
of familial disease and is more common in
childhood presentations. The patient in the
current report was a 10-year-old boy who was
initially diagnosed as familial, bilateral and
multicentric pheochromocytoma presenting
with intractable hypertension. At follow-up,
the emergence of bilateral retinal hemangiomas led to the diagnosis of VHL disease.
Von Hippel-Lindau (VHL) disease is
propounded to account for about 50% of
patients with apparently isolated familial
pheochromocytoma. In childhood and
adolescence, pheochromocytoma may be the only
initial manifestation of VHL disease with delayed
manifestations of the syndrome in the eye,
central nervous system (CNS) or other organs.
Patients with VHL type 1 are characterized
with retinal and CNS hemangioblastomas and
RCC but not pheochromocytoma. They usually
have truncating mutations and large deletions
exceeding an exon. Pheochromocytomas are
the hallmark of VHL type 2, and nearly all
mutations associated with pheochromocytoma
are of missense type. VHL type 2 can be
classified as 2A, 2B and 2C. VHL type 2A
has a lower risk of RCC, while VHL type 2B
manifests RCC more commonly (70%). Patients
with pheochromocytoma alone are classified as
VHL type 2C . In our patient, the presence
of pheochromocytoma, negative family history
for RCC and the result of mutation analysis
suggested VHL type 2A. The patient’s mother
was investigated for additional VHL tumors,
but no tumors other than the known bilateral
adrenal pheochromocytoma were detected.
She was thus considered as having VHL type
2C. Since the same mutation may cause two
different subtypes, it may be suggested that
the classification of VHL disease is most
helpful for research studies and is less useful
for clinical management. Langrehr et al. 
reported a 12-year-old girl with c.605 G>A
mutation in exon 3 of the VHL gene resulting
in neuroendocrine tumor of the pancreas
and bilateral adrenal pheochromocytomas.
According to an unpublished registry data
from Neumann (n.d.), of the 10 cases with
the identical mutation in exon 3 of the VHL
gene (c.695 G>A, amino acid p.R161Q), all
had pheochromocytoma, four had CNS tumors,
four had pancreatic neuroendocrine tumors,
three had retinal angiomas, and one had renal
carcinoma. No endolymphatic sac tumor or
epididymal/broad ligament tumor was detected.
Pheochromocytomas associated with VHL
syndrome exhibit a clearly and constantly
noradrenergic pattern, with the concentrations
of 98% norepinephrine and 1.5% epinephrine of
the total catecholamine content . The patient
in the present report was diagnosed upon the
elevated 24-h urinary normetanephrine and
VMA levels. His 24-h urinary metanephrine
level was normal, compatible with the literature.
Several demographic and clinical features have
been associated with a germ-line mutation in
patients with pheochromocytoma. According to
a recent algorithm for the genetic diagnosis of
patients with pheochromocytoma, patients of
young age, with multifocal disease, extraadrenal
location, and malignancy should be genetically
tested. Identifying a VHL mutation may
provide early diagnosis of other manifestations
and may facilitate definition of the disease risk
in other family members.
In conclusion, VHL disease should be considered
in children and adolescents with familial,
bilateral and multifocal pheochromocytoma,
even in individuals who do not yet satisfy the
clinical diagnostic criteria. Surveillance of VHL
patients and asymptomatic relatives facilitates
the prevention of morbidity and mortality and
may improve long-term prognosis. Thus, all
patients with VHL disease and at-risk relatives
should be included in routine screening
programs beginning from childhood.
1. Maher ER, Yates JR, Harries R, et al. Clinical features
and natural history of von Hippel-Lindau disease. Quart
J Med 1990; 77: 1151–1163.
2. Richard S, Graff J, Lindau J, Resche F. Von Hippel-
Lindau disease. Lancet 2004; 363: 1231–1234.
3. Kim JJ, Rini BI, Hansel DE. Von Hippel Lindau
syndrome. Adv Exp Med Biol 2010; 685: 228-249.
4. Maher ER, Neumann HP, Richard S. Von Hippel-Lindau
disease: a clinical and scientific review. Eur J Hum
Genet 2011; 19: 617-623.
5. Zbar B, Kishida T, Chen F, et al. Germline mutations in
the Von Hippel-Lindau disease (VHL) gene in families
from North America, Europe, and Japan. Hum Mutat
1996; 8: 348-357.
6. Barontini M, Dahia PL. VHL disease. Best Pract Res
Clin Endocrinol Metab 2010; 24: 401-413.
7. Erlic Z, Neumann HP. Familial pheochromocytoma.
Hormones 2009; 8: 29-38.
8. Bissada NK, Safwat AS, Seyam RM, et al.
Pheochromocytoma in children and adolescents: a
clinical spectrum. J Pediatr Surg 2008; 43: 540-543.
9. Neumann HP, Sullivan M, Winter A, et al. Germline
mutations of the TMEM127 gene in patients with
paraganglioma of head and neck and extraadrenal
abdominal sites. J Clin Endocrinol Metab 2011; 96:
10. Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, et
al. Exome sequencing identifies MAX mutations as
a cause of hereditary pheochromocytoma. Nat Genet
2011; 43: 663-667.
11. Waguespack SG, Rich T, Grubbs E, et al. A current
review of the etiology, diagnosis, and treatment of
pediatric pheochromocytoma and paraganglioma. J
Clin Endocrinol Metab 2010; 95: 2023-2037.
12. Neumann HP, Bausch B, McWhinney SR, et al. Germline
mutations in nonsyndromic phaeochromocytoma.
N Engl J Med 2002; 346: 1459–1466.
13. Langrehr JM, Bahra M, Kristiansen G, et al.
Neuroendocrine tumor of the pancreas and bilateral
adrenal pheochromocytomas. A rare manifestation of
von Hippel-Lindau disease in childhood. J Pediatr Surg
2007; 42: 1291-1294.
14. Eisenhofer G, Walther MM, Huynh TT, et al.
Pheochromocytomas in von Hippel-Lindau syndrome
and multiple endocrine neoplasia type 2 display distinct
biochemical and clinical phenotypes. J Clin Endocrinol
Metab 2001; 86: 1999–2008.
15. Erlic Z, Rybicki L, Peczkowska M, et al. European-
American Pheochromocytoma Study Group. Clinical
predictors and algorithm for the genetic diagnosis of
pheochromocytoma patients. Clin Cancer Res 2009;
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