Annals of Diagnostic Paediatric Pathology

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types were diagnosed in participating patients. A medullary
thyroid carcinoma was present in one patient with MEN 2B
syndrome. Renal cell carcinoma (RCC) occurred in two patients
– in SDHB mutation carrier and in patient with von
Hippel – Lindau disease. Pancreatic islet tumors and haemangioblastoma
of IV brain ventricle were found in patient
with VHL. In the cohort presented here, there were also two
reports of multiple head and neck paraganglioma in SDHD
gene mutation carriers [Table 4].
Table 4
Clinical characteristic of patients with hereditary syndromes
of pheochromocytoma
Characteristics of pheochromocytoma patients with
hereditary syndromes under 20 years of age
Multiple tumors – 12 patients (80%)
Extra – adrenal tumors – 7 patients (47%)
Bilateral adrenal tumors – 6 patients (40%)
Thoracic localization of tumors – 2 patients (13%) – only in
SDHD gene mutations
Recurrence of the disease – 5 patients (33%)
Malignant – 0
Associated tumors:
! Renal cell carcinoma – 2 patients: VHL and SDHB
! Pancreatic islet tumors – 1 patient – VHL
! haemangioblastoma of IV brain ventricle
! Multiple head and neck paraganglioma – 2 patients –
SDHD
! Medullary thyroid carcinoma – 1 patient – MEN 2B
Multiple or extraadrenal or bilateral adrenal pheochromocytoma
– 13 patients (87%)
Discussion
Our clinical and molecular evaluation of 136 unrelated
patients who presented with pheochromocytoma revealed
that 34 patients (24,8%) had a hereditary predisposition
to von Hippel–Lindau disease, MEN-2, neurofibromatosis
type 1, or the syndromes associated with pheochromocytoma
and paraganglioma. Among the 34 patients with mutations,
32% had mutations of RET, 18% had germ-line mutations
of VHL, 12 percent had clinical signs of NF1 syndrome,
and 18 and 21% had mutations of two newly
identified genes, SDHD and SDHB. Patients with hereditary
syndromes were younger that those with sporadic disease
and multiple and extra- adrenal tumors were more frequent
in this group. Our results are consistent with other population-based
studies [2, 4, 7, 8, 9]. In our registry almost one
half of patients with hereditary pheochromocytoma was under
20 years of age. We can state that 87% of all multifocal
(including bilateral tumors) and extra – adrenal tumors in
patients with onset of the disease at the age of 20 years or
younger were found to be hereditary. All these findings po-
inted out, that extra – adrenal and/or multiple pheochromocytomas
as well as young age at presentation may be striking
features of hereditary disease [9]. Interestingly, 91% of
probands found to have hereditary disease with the use of
molecular testing had no associated signs and symptoms at
presentation. Only three (9%) of them had positive family
history at presentation. A partial explanation for the high
frequency of hereditary pheochromocytoma without family
history of disease might include spontaneous mutation in
one of the susceptibility genes, decreased penetrance, and
maternal imprinting [9]. In our registry, spontaneous mutations
in one of four susceptibility genes occurred in two patients
with hereditary von Hippel–Lindau disease, one with
MEN 2B syndrome, one with SDHD gene mutation and one
with SDHB mutation (Table 5).
Today, more than 200 different VHL mutations have
been identified which appear to be equally distributed throughout
the gene. De novo mutations at hypermutable sequences
result in most of the recurrent mutations. In large German
registry of von Hippel–Lindau disease, frequency of
spontaneous mutation in VHL is thirteen percent of all cases
[9, 10]. In MEN 2B syndrome, which is the most distinct and
aggressive of the MEN 2 variants, de novo mutations are very
often and reach fifty percent [12]. A little is known about
spontaneous mutations in SDHD and SDHB genes because
they are newly identified genes.
Penetrance is known to be relatively high (approximately
70 percent by the age of 70) among patients with MEN-
2 and von Hippel–Lindau disease, overall [9, 10]. Benn et al.
reported a statistically significant age-related penetrance difference
for SDHB and SDHD mutation carriers. By age 30
yr, 29% of SDHB mutation carriers and 48% of SDHD mutation
carriers were diagnosed with paraganglioma; by age
40 yr, 45% of SDHB mutation carriers and 73% of SDHD
mutation carriers were diagnosed with paraganglioma [3,
13]. As discussed by authors, SDHD and SDHB mutations
have an age-related penetrance, and the lifetime risk of developing
paraganglioma (s)/pheochromocytoma (s) approaches
100% by age 70 yr [3, 13].
In patients with SDHD mutations, penetrance depends
on whether the individual inherited the mutation from
the mother or the father [11, 13]. The disease is not manifested
when the mutation is inherited from the mother, but is
highly penetrant when inherited from the father. This phenomenon
is known as maternal imprinting.
Overall, therefore, pheochromocytomas in patients
without family histories are due to spontaneous mutations,
decreased penetrance, or maternal imprinting, although other
causes such as gene–gene interactions and gene–environment
interactions may be possible. Genetic testing can be
a powerful aid to the identification of a syndrome in such cases.
Since disease is likely to develop in virtually all patients
with a family specific mutation, it seems reasonable to subject
such patients to lifelong surveillance.
This report highlights the value of genetic testing for
affected patients and at-risk asymptomatic family members.
Genetic testing should be considered in all patients with pa-