INHERITED ENDOCRINE TUMOUR SYNDROMES
Multiple
endocrine neoplasia type 1
Three
tumour types predominate in MEN-1 (Figure 33.1):
1.
Parathyroid adenomas (90–100%)
2.
Pancreatic neuroendocrine tumours (NETs; 30–75%)
3. Pituitary adenomas (40%).
Genetic
testing
The
presence of two out of these
three main tumours establishes a working diagnosis of MEN-1. It has a
prevalence of roughly 1 in 10 000 and is inherited as an autosomal dominant
trait. The MEN1 gene is located on chromosome 11q13. Genetic testing for
mutations should be considered in an index case with at least two out of the
three main MEN-1 related tumours, and extended to asymptomatic first degree
relatives if positive. Genetic testing should also be considered in patients
with multiple parathyroid tumours at a young age, recurrent
hyperparathyroidism, gastrinoma or multiple islet cell tumours, and in familial
hyperparathyroidism (Chapter 16).
Primary
hyperparathyroidism
Primary
hyperparathyroidism is the presenting feature in most patients, reaching 100%
penetrance by the age of 50. Measurement of PTH and calcium should therefore
commence on an annual basis from age 8 in a known carrier. The treatment is
parathyroid surgery, although the timing and extent of surgery needs to be
considered on an individual basis. Options are near-total parathyroidectomy,
which will ultimately require re-operation because of growth of residual
tissue, or total parathyroidectomy, needing lifelong vitamin D replacement.
Pituitary
tumours
Although
all types of pituitary adenomas can occur in patients with MEN-1, prolactinomas
(60%) and somatotroph adenomas (30%, causing acromegaly) account for the
majority. Measurement of prolactin and IGF-1 should therefore be performed
annually in mutation carriers. Imaging (MRI) and treatment should proceed along
the same lines as for sporadic adenomas.
Pancreatic
NETs
Islet
cell NETs are usually multicentric. Gastrinomas (usually arising in the
duodenal submucosa) are the most common and are managed with high dose proton
pump inhibitors with or without surgery. Other tumour types, including
non-functioning NETs, can
require surgery depending on size and symptoms. Screening with annual fasting
gut hormone profile and MRI every 1–3 years should commence from age 20.
Multiple
endocrine neoplasia type 2
MEN-2,
which occurs because of mutations in the RET gene and is inherited in an
autosomal dominant manner, is characterised by (Figure 33.2):
• Medullary
thyroid carcinoma (MTC; 100%)
• Phaeochromocytoma
(0–50%)
• Parathyroid
adenomas (0–20%).
It
is subdivided along phenotypic lines into MEN-2a (75% cases) and several rare
variants, including familial MTC and MEN-2b (characterised by a Marfanoid body
habitus, intestinal and mucosal ganglioneuromas). In contrast to MEN-1, there
is a strong relationship between genotype and phenotype in MEN-2. This has
important practical implications in relation to the timing of thyroidectomy,
which should be undertaken in the first year, first 5 years, or later depending
on the ‘risk’ group of the RET mutation. Phaeochromocytoma is screened
for annually with measurement of metanephrines and managed as per sporadic
disease. Hyperparathyroidism usually runs a mild course but can be managed with
subtotal parathyroidectomy.
Carney
complex
This
is a rare autosomal dominant condition characterised by spotty skin
pigmentation, cardiac myxomas, peripheral nerve lesions and one or more
endocrine disorders, of which Cushing’s syndrome caused by primary pigmented
adrenal disease is the most common. GH-secreting tumours, testicular, ovarian
and thyroid tumours (benign or malignant) are other recognised manifestations.
McCune–Albright
syndrome
This
syndrome, which arises from a somatic mutation in the GNAS1 gene, is
characterised by the triad of café au lait patches (Figure 33.3),
polyostotic fibrous dysplasia (Figure 33.4) and multiple endocrinopathies:
precocious puberty, gigantism hyperprolactinaemia, thyroid nodules and yperthyroidism, and Cushing’s syndrome.
