CLINICAL REVIEW 109: Contrasting Paradigms for Hereditary Hyperfunction of Endocrine Cells
Stephen J. Marx
Genetics and Endocrinology Section, National Institute of Diabetes
and Digestive and Kidney Diseases, Bethesda, Maryland 20892
Address correspondence and requests for reprints to: Stephen J. Marx, M.D., Bld 10, Room 9C-101, National Institutes of Health, Bethesda, Maryland 20892-1802; E-mail: StephenM{at}INTRA.NIDDK.NIH.GOV
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Hereditary Endocrine HyperfunctionCategories, Syndromes, and
Mutated Genes
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Hereditary endocrine hyperfunction is
categorized here as neoplastic or not neoplastic. The disorders and
their mutated genes are subdivided further by hyperfunctional hormone
secretory tissue (Table 1
). For example,
the parathyroids hyperfunction in at least three hereditary neoplastic
syndromes [multiple endocrine neoplasia type 1 (MEN1), multiple
endocrine neoplasia type 2a (MEN2a), and hyperparathyroidism-jaw tumor
syndrome (HPT-JT)], each associated with one distinct gene (1, 2) or
locus (3, 4, 5). Alternately, the parathyroids can be overactive in two
hereditary non-neoplastic syndromesfamilial hypocalciuric
hypercalcemia (FHH) or neonatal severe primary hyperparathyroidism
(NSHPT). Either is usually caused by mutations of the CaSR
gene (6, 7, 8, 9); two other undiscovered genes account for FHH in a few
families (10, 11). A similar classification dichotomy applies to
hereditary hyperfunction of pancreatic islet ß cells (1, 12, 13, 14, 15, 16, 17), of
thyrocytes (18, 19, 20, 21, 22, 23), or of Leydig cells (19, 24, 25, 26) (Table 1
).1
For didactic purposes, this analysis omits endocrine tissue without
separate hereditary disorders in each of the two categories. For
example, hereditary pheochromocytoma may arise from neoplasia with
germline mutation of VHL (12), RET (2), or
NF1, but apparently not from non-neoplastic processes. This
analysis also excludes dysfunctions outside the hyperfunctional
endocrine tissue (for example, hereditary hyperandrogenism can be
caused by activation of the CRF/ACTH axis secondary to defective
cortisol synthesis).
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Molecules, Pathways, and Crosstalk
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Germline mutations predisposing to neoplasia of hormone-secreting
cells
The mutations predisposing to neoplasia of hormone-secreting cells
are gene inactivation (MEN1, VHL, PTEN), gene activation
(RET)2, or unknown gene change
(genes for HPT-JT or Carney complex (28) not yet identified). With a
neoplastic process, gene inactivation reflects a tumor supressor gene,
and gene activation reflects a tumor-promotor gene or oncogene.
Though some of the genes associated with hereditary endocrine neoplasia
have been cloned, their pathophysiology is still poorly understood.
Their proteins can normally be in the plasma membrane
[RET-encoded tyrosine kinase (2)], the cytoplasm and
nucleus [VHLencoded protein (29)], the nucleus
[MEN1-encoded menin (30)], or undetermined compartment(s)
(PTEN). This heterogeneous subcellular distribution is
analogous to that of the proteins disturbed in all hereditary neoplasia
syndromes (31). Assignment of subcellular compartment and molecular
interactions (32) are steps towards understanding the pathophysiology
of any gene. Mutations in genes predisposing to neoplasia have been
implicated in highly diverse physiologic processes including cell
birth, cell death, genome integrity, and cell differentiated functions
(31).
Germline mutation causing non-neoplastic hyperfunction of
hormone-secreting cells
As with neoplasia-associated mutations, the mutations causing
endocrine hyperfunction without neoplasia disrupt through gene
inactivation (CaSR, SUR1, Kir6.2), gene activation
(TSHR, LHR, GK, GLUD1), or untested gene change (2 unknown
genes for FHH (10, 11)).
All the proteins known to cause hereditary non-neoplastic endocrine
hyperfunction disrupt directly hormone exocytosis or cell-sensing of an
extracellular regulator of hormone exocytosis (Fig. 1
).

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Figure 1. Pathways and mutations in
non-neoplastic endocrine hyperfunction (numbered 17).
Left side of cell shows main pathways regulating insulin
secretion in pancreatic ß cells. Glucokinase (GK) and glutamate
dehydrogenase (GLUD1) are in cytoplasm and mitochondria respectively.
Adenine nucleotides interact with the sulfonyluria-binding component
(SUR1) of the inward rectifying potassium channel, which includes
channel subunits (Kir6.2). Diazoxide increases the open time of the
potassium channel. Potassium channel closure depolarizes the plasma
membrane, opening plasma membrane voltage-gated calcium channels.
Increased cytosolic calcium promotes exocytosis of insulin. Right side
of cell shows hormones with secretion regulated mainly by G-protein
regulated pathways. A serpentine plasma membrane receptor (shown as
TSHR, LHR, or CaSR gene) activates Gs or other
heterotrimeric G proteins (G?). Gs activates
adenylyl cyclase; the cAMP produced activates protein kinase A (PK-A).
PK-A stimulates synthesis and secretion (iodothyronines and
testosterone) of hormones. PK-A also activates/phosphorylates CREB
(cAMP response element binding protein) for its transcriptional
actions. The CaSR is believed to regulate an unknown G-protein
(G?) with uncertain distal messengers.
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Three of the proteins (calcium-sensing receptor (CaSR), thyrotrophin
receptor (TSHR), and luteinizing hormone receptor (LHR)) belong to the
serpentine receptor family of G-protein coupled receptors (33); another
(glucokinase) is a cytoplasmic enzyme that functions as a sensor of
extracellular glucose (34, 35). The frequent implication of
G-protein-coupled receptors in hereditary non-neoplastic endocrine
disorders reflects G-protein centrality in coupling of extracellular
factors (such as ionized calcium, TSH, and LH) to rapid activation of
intracellular signals (33), and consequently, to secretion of
hormones.
Among the other three encoded proteins, two are subunits
(pancreatic islet specific sulfonylurea receptor (from SUR1
gene) and ATP-binding pancreatic islet subunit (from Kir6.2
gene)) of the inward rectifying potassium channel; one is a
mitochondrial enzyme (glutamate dehydrogenase from GLUT1
gene) that helps determine the cytoplasmic ATP/ADP ratio. All three
regulate insulin exocytosis (36, 37).
Crosstalk of pathways
Neoplastic and non-neoplastic hyperfunctions have certain shared
expressions, partly because intracellular information flows
simultaneously down and across many pathways (Fig. 2
).

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Figure 2. Flow diagram to illustrate that one
hormone-mediated clinical outcome can result from hyperfunction through
two different categories of cellular mechanism.
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If the normal negative feedbacks are intact, neoplasia of
hormone-secreting cells need not be accompanied by over-release of
hormone. For example, many islet cell tumors in MEN1 synthesize
hormones without oversecreting them (38, 39). Alternately, a normally
incompletely suppressible endocrine gland might release too much
hormone as a simple mechanical consequence of the overwhelming rise in
cell numbers (40). Another mechanism for neoplasia to cause
oversecretion is with secondarily disordered hormone secretory control.
When bovine parathyroid cells are incubated in culture media, they lose
75% of messenger RNA for the CaSR within 24 h (41). A similar
process may explain the lowered concentrations of CaSR protein in
parathyroid tumors (42). This, in turn, could account for a shift of
the extracellular Ca++-PTH secretion curve, depicting
increased PTH release (43).
A primary non-neoplastic defect of hormone secretory feedback can be
associated with increased secretory cell accumulation, although such
cell accumulation rarely becomes neoplastic. For example, the
impressive parathyroid gland enlargement from inactivation of both
copies of the CaSR in NSHPT of man (44, 45, 46) or mouse (47) seems to
reflect such a process. Cyclic AMP, in some cells, can stimulate both
hormone secretion and cell accumulation (48, 49, 50, 51). For example,
hereditary activation of the TSHR or the LHR is accompanied by diffuse
proliferation of their cells. Though these germline mutations have not
yet been tied to hereditary neoplasia, the same or similar mutations in
somatic tissues have sometimes caused somatic or nonhereditary
neoplasia (52, 53).
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Pathology: Comparisons Between Two Categories of Hereditary
Endocrine Hyperfunction
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Clonality as a feature with neoplasia
Clonality means that the accumulated cells had a common precursor
cell, descendents of which accumulated in preference to neighboring
cells. Clonal endocrine tumor cells divide far more frequently than
their polyclonal cell relatives (54). Disproportionate accumulation of
one or several clones is a feature of benign or malignant neoplasms. In
fact, it is often used as a criterion for defining a process as
neoplastic. There are several tests for clonality, including X
chromosome inactivation analysis in females, loss of heterozygosity
(LOH) at discrete chromosomal loci, and comparative genome
hybridization (55, 56).
Parathyroid cell hyperfunction
The parathyroid tumors in MEN1 are mono- or oligoclonal,
based on the criterion that, compared to germline, a DNA pattern
change, 11q13 LOH, is identifiable in most (Table 2
) (57). The parathyroid tumors in MEN1
also show LOH at other chromosomal loci (58), as well as evidence for
clonal-type gene rearrangements when analyzed by comparative genome
hybridization (59). Only one case of parathyroid cancer in familial
MEN1 was reported (60), but subsequently was determined not to be
cancer (JJ Shepherd, personal communication). At the time of
parathyroid exploration, a MEN1 patient typically has enlargement
of most parathyroid glands, with four gland mass enlarged by
10-fold. Also, size is variable, with an average ratio of 9:1
between the largest and smallest tumor (61).
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Table 2. Three features of hereditary neoplastic versus
nonneoplastic hyperfunction disorders, by type of hyperfunctioning
tissue
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Fewer parathyroid glands are enlarged in the hyperparathyroidism of
MEN2a than of MEN1 (62, 63). Clonality has not been tested in MEN2a
parathyroids, but the assymmetry of the process and the clonality of
other MEN2a tumors (2) suggest clonality of parathyroid tumors also.
Parathyroid cancer is rare in MEN2a (64).
Parathyroid tumors in HPT-JT often present asynchronously. Frequently
the parathyroids have many small or large cysts (5, 65) as do the
kidneys in this syndrome (3, 4). Parathyroid cancer occurs in 8% of
cases with HPT-JT; this high parathyroid cancer prevalence contrasts
with less than 1% in MEN1, MEN2a, or sporadic hyperparathyroidism.
Parathyroid tumor clonality in HPT-JT has been suggested by three
features: 1q LOH has been identified in some parathyroid tumors
(adenoma and cancer) from this syndrome (4, 5); cancer is a clonal
process; and polycystic disease, as seen in the kidneys or liver of
hereditary polycystic kidney disease syndrome, can be clonal (66).
The parathyroids in MEN1, MEN2a, or HPT-JT may not pass through a stage
of polycellular hyperplasia before a clonal tumor develops. A
circulating factor that could stimulate parathyroid cell accumulation
in vitro was found in MEN1, but no in vivo role
has been proved (67).
The parathyroids in FHH generally appear histologically normal.
However, mild enlargement occurs in most parathyroid glands (68).
Clonality has not been analyzed in the parathyroid of FHH, but the
symmetry of gland size and generally normal histologic appearance
suggest polyclonality (Table 2
). In vivo testing has
suggested that the FHH parathyroid cell set-point for suppression of
PTH release by extracellular calcium is shifted (by 15%) to mildly
higher calcium values (1.5 mM Ca++; normal, 1.3) sufficient
to account for that same degree of hypercal-cemia in vivo(69). Expression of several CaSR mutations in vitro has
paralleled the defect of calcium-sensing in vivo (70).
The parathyroids in NSHPT show a diffuse, symmetric, and marked
enlargement of all glands (44, 45, 46). Clonality has not been tested but
the diffuse and symmetric features suggest underlying polyclonal
hyperfunction. The set-point for calcium suppression of PTH has been
tested in vitro in only two glands; there was no suppression
in one (46), and in the other, the set-point was increased uniquely (by
150%) (i.e. set-point 2.5 mM Ca++; normal, 1.0)
(71). Other islet tumors in MEN1 are more often malignant.
Pancreatic islet ß-cells hyperfunction
Nesidioblastosis is the postnatal development of new islets by
budding from pancreatic ducts. This is uncommon in and not specific for
MEN1 (72). Similarly, diffuse islet hyperplasia is not found in MEN1.
Most adults with MEN1 have several pancreatic islet macroscopic tumors
(37, 38) and several microscopic tumors (69, 70). Immunostaining for
peptide hormones in MEN1 islet tumors shows that approximately 30% of
tumors are principally ß-cell in content, with a similar predominance
of
-cell (glucagon) tumors (38, 39). Symptomatic insulinoma in MEN1
is usually benign. Its clonality has been supported by 11q13 LOH
(75).
Pancreatic islet tumors in von Hippel-Lindau disease (VHL) are
clonal [allelic loss at 3p, the VHL locus (76)], although
this has not been documented in a VHL insulinoma. Approximately 10% of
the VHL islet tumors are malignant (76). The VHL islet tumors stain for
neuroendocrine markers; this includes insulin in about one tenth of
tumors (76).
The pancreatic islets in non-neoplastic persistent
hyperinsulinemic hypoglycemia of infancy (PHHI) show a diffuse but
subtle ß-cell abnormality with enlarged ß-cell nuclei but normal
ß-cell mitotic indices (77, 78). No histology has been specific for
any of the four mutated genes in PHHI (Table 1
).
Malignant tumors
Malignancy is a principal or associated component of all
hereditary neoplastic syndromes characterized herein. On the other
hand, not all tissues affected in these syndromes express malignancy as
exemplified by the parathyroids in MEN1 or MEN2a (see above).
By definition, malignancy is rarely if ever an expression of the
non-neoplastic hyperfunction disorders. A partial explanation for this
contrast in the two categories is that multiple stepwise cell
accumulation-favoring mutations must accrue for malignancy to develop
(79). This seems inherent in the benign and malignant tumors of the
neoplastic endocrine syndromes, and it is the basis for the two-hit
hypothesis of neoplasia (80) (see below). In contrast, the hereditary
non-neoplastic endocrine hyperfunctions are expressed in all secretory
cells of a tissue and are expressed without cells acquiring secondary
mutations and favored clones.
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Penetrance and Onset Age: Comparisons Between Two Categories of
Hereditary Endocrine Hyperfunction
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Penetrance of parathyroid hyperfunction
Hyperparathyroidism shows increasing penetrance with age in MEN1,
reaching nearly 100% by age 50 (81, 82). In MEN2a, hyperparathyroidism
reaches 80% penetrance by age 70 (62). Hyperparathyroidism in HPT-JT
reaches about 85% penetrance by age 40.
Hyperparathyroidism has near 100% penetrance in FHH (6). However,
there is variation among families. In one large family expressing very
mild hypercalcemia, the trait could not be recognized biochemically
without repeated testing in many members (9). In NSHPT, the penetrance
of hyperparathyroidism is 100%.
Penetrance in pancreatic islet ß-cells
Insulinoma syndrome is expressed in 2030% of MEN1 cases (82)
and in 0% of VHL cases. Thus, although islet tumors store insulin in a
small fraction (about 2%) of VHL cases, they do not oversecrete
insulin.
Hyperinsulinism is expressed in virtually 100% of carriers with
mutations for PHHI. However, there has been variable severity within a
single family (15).
Earliest and average onset age of hyperparathyroidism
Hyperparathyroidism in MEN1 shows earliest and average onset ages
as 8 yr and 25 yr (81) (Table 2
). In MEN2a the earliest onset age is 10
yr, possibly as low as 2 [anecdotal (62)], with typical onset at 33
yr; in HPT-JT these are 10 and 30 yr.
In contrast, expression of hyperparathyroidism in FHH begins at birth
(6). Because it causes no symptoms, the hypercalcemia in FHH may not be
recognized until adulthood. In cases of NSHPT under study, the
parathyroid overfunction was so severe that parathyroid enlargement and
PTH oversecretion clearly had developed in some cases before birth
(44, 45, 46).
Earliest and average onset age for ß-cell hyperfunction
For insulinoma syndrome in MEN1, the earliest onset age is 6 yr
(83), with an average age of 34 yr (82). Asymptomatic insulinoma was
discovered in two cases of VHL at ages 18 and 23 yr (76).
In contrast, in PHHI the onset age is generally 0 yr, but some variants
present later (15).
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Treatments: Comparisons Between Two Categories of Hereditary
Endocrine Hyperfunction
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Parathyroid cell hyperfunction
While there are subtle differences among the approaches to
hyperparathyroidism among the parathyroid neoplasia syndromes, the
similarities are greater. In all three hereditary neoplasia syndromes
with hyperparathyroidism, all but a normal-sized parathyroid remnant
are removed (Table 2
). The residual tissue may function normally, but
has caused recurrent hyperparathyroidism on the average 812 yr
postoperatively in MEN1 (84). In MEN2a, many surgeons remove only the
enlarged parathyroid glands; even so, postoperative recurrence has been
less common than in MEN1 (63). Hyperparathyroidism in HPT-JT, when not
malignant, has been managed similarly to that in MEN2a.
Subtotal parathyroidectomy in FHH has resulted in persistent
hyperparathyroidism in virtually all cases (6). For this reason and
because of its generally benign course, most cases of FHH are now
managed without parathyroid surgery. In NSHPT total parathyroidectomy
is necessary during the neonatal period.
Pancreatic islet ß-cells hyperfunction
Insulinoma syndrome in MEN1 is generally curable by removal of
only one insulin over-secreting tumor (85, 86).
In contrast, PHHI has usually been difficult to treat. Subtotal
pancreatectomy has virtually always been unsuccessful (78); near total
pancreatectomy is often successful but carries higher morbidity,
including the possibility of diabetes mellitus. Diazoxide and/or
octreotide have given partial control of symptoms and have been used
with surgery (87). Most cases with neonatal onset have been
unresponsive to diazoxide, presumably reflecting inactivation of the
ß-cell potassium channel that is the target for this drug (Fig. 1
)
(13, 37, 87). Diazoxide has been effective in a minority of PHHI cases,
in particular those with mutation of glucokinase or of glutamate
dehydrogenase (15, 16). Approximately one third of neonates with PHHI
have focal adenomatous hyperplasia, a distinctive nonfamilial process
that can be cured by partial pancreatectomy (88) (see below).\.
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Unifying Patterns Within and Contrasting Patterns Between Two
Categories of Hereditary Endocrine Hyperfunction
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Hereditary endocrine neoplasia as a two-hit process
Clear patterns emerge among all the hereditary neoplastic
disorders in selected indices (Table 2
) and in assembled data (Table 3
).
In the neoplastic disorders, the tissue process is mono- or
oligo-clonal. This feature is almost trivial as it is a criterion for
the neoplasia category. The tumors discussed herein are often multiple
within one tissue. The neoplastic lesions are asynchronous and unequal
in size. Some of the tumors in the endocrine neoplasia syndromes have
high potential for malignancy. Penetrance is zero at birth and rises
with age, but is usually below 80% for any one tissue. Though they
become evident years, even decades, after birth, they still present at
earlier ages than would the same tumors in a nonhereditary setting. The
differences in onset age are particularly large for
hyperparathyroidism: age 2533 yr for hyperparathyroidism in MEN1,
MEN2a, or HPT-JT, vs. age 55 for sporadic parathyroid
adenoma (89). For some neoplasia-related lesions, removal of one or
several tumors (for example, parathyroid tumor or in-sulinoma
in MEN1) may leave behind an apparently normally-functioning
tissue.
Similar epidemiologic features have been grouped under the
so-called two-hit hypothesis of neoplasia (80). The fundamentals of the
hypothesis are that hereditary or sporadic neoplasms develop similarly
after two or more discrete (mutational) events give one cell an
accumulation advantage. For hereditary neoplasms, the first event is
germline inheritance of a mutation in all cells. As a consequence, one
or several cells with germline mutation are likely to acquire a second
event (a somatic mutation) at an earlier age and in more locations than
if a first hit had to occur in a somatic cell. The first event
generally causes neither neoplasia nor any tissue phenotype, but the
second and perhaps subsequent events initiate neoplasia.
On occasion, the first of such two hits can have a phenotype, usually
subclinical. For example, C-cell cancer caused by RET
mutation has a multifocal precursor stage considered hyperplastic (90, 91). And Cowden syndrome can be expressed as diffuse enlargement of the
brain, also termed Bannayan-Riley-Ruvalcaba syndrome (92, 93) (C. Eng,
personal communication).
The two-hit hypothesis does not require that the gene be a tumor
suppressor (like MEN1), with tumors arising after sequential
inactivation of both copies. The RET mutation, in
particular, predisposes to mono- or oligoclonal tumors (95, 96), in
which the first hit is gene activation; a presumed second hit in MEN2
is still not identified. There may be an analogy of second-hit
mechanisms between the RET and the MET genes.
RET and MET are structurally homologous.
MET mutation predisposes to hereditary papillary cancer of
the kidney (12); the second hit in MET-mediated cancers
likely is amplification of the already mutated MET allele
(97).
Hereditary endocrine hyperfunction without neoplasia as a
one-hit process
In the hereditary non-neoplastic endocrine hyperfunction
disorders, the tissue process has been hyperplastic and diffuse (Table 2
and Table 3
). This has suggested a polyclonal process, but
polyclonality of hyperfunctional endocrine tissue has not been examined
rigorously in any of these syndromes. Because some polyclonal processes
can be overgrown by mono- or oligoclonal components (98), this needs
examination. These considerations diminish the certainty of the
non-neoplastic categorization herein. However, the consistent patterns
strongly support the overall validity of the categories. Among the
non-neoplastic hereditary hyperfunction syndromes, there is no
associated malignancy. The penetrance has approached 100% with onset
at birth, sometimes in utero. Postnatal increase of
endocrine cell accumulation may occur, but it is generally not required
for the expression of hormone hypersecretion. The clinical disorder
persists after incomplete excision of the endocrine tissue. Effective
treatments generally involve surgical or medical strategies to ablate
hormone secretion from the entire tissue (9, 26, 52, 87).
This complex of features can be related to the functional properties of
the mutant protein. When the mutation is clearly within a metabolite
sensor, mutation can affect the functional affinity of that sensor
(CaSR, GK) (15, 69), with the result that each affected cell
has an inherent drive to regulate the metabolite inappropriately. Other
mutations in the exocytosis pathway (SUR1, Kir6.2) might
have similar consequences for control, such as causing a largely
unregulated increase in hormone output.
A germline mutational process causing non-neoplastic hyperfunction in
endocrine cells is all-or-none (conceptually, one-hit). Whether it is
inherited as a heterozygous (ex: FHH as CaSR wt/-) or as a
homozygous (ex: NSHPT as CaSR -/-) mutation (7, 9), it is
expressed in all of the target cells as a phenotype (gene dosage
effect) near parturition.
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Apparent Exceptions to the Classification Dichotomy
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The McCune-Albright syndrome (MAS) has features for and against the
neoplastic category
MAS causes hyperfunction in many tissues, including the thyroid
and Leydig cells (48). MAS is from activating mutation of
GNAS1, which encodes Gs
, the plasma membrane-bound
-subunit of the stimulatory G-protein heterotrimer (Fig. 1
). Gs
can interact with several signaling pathways; the most relevant one is
adenylyl cyclase-cyclic-AMP
Activating mutation of GNAS1 is usually lethal in the germline (48, 99)
but can arise and persist in the blastocyst, leading to dispersed
mosaicism (48), which has similarities to monoclonality. Fibrous
dysplasia mutant cells from MAS could not survive without co-cultured
nonmutant cells in vivo in mice (100). The tissue and
clinical features of MAS are intermediate between the neoplastic and
non-neoplastic categories. Because of its mosaic nature and its
intermediate cellular and clinical features, MAS has not been entered
into a category in this essay.
Persistent hyperinsulinemic hypoglycemia of infancy
caused by a hereditary neoplastic process
Most cases of PHHI are sporadic and have diffuse, mild
pancreatic ß-cell hyperplasia, like hereditary cases; however a third
have focal adenomatous ß-cell hyperplasia (76, 78, 88). Two genetic
disturbances are found together in this subgroup, germline heterozygous
inactivating mutation of paternal SUR1 (101) in a third of cases and,
in the ß-cell lesion of most, acquired loss of the surrounding
alleles at 11p15 (102). The DNA patterns of the second hit and the
histologic features imply a clonal process. Tumor mechanism could thus
be by inactivation of both alleles of SUR1 or both alleles of a nearby
11p15 gene, such as Kir6.2 (101). Other clonal tumor mechanisms are
possible (101, 102). With regard to treatment, this subgroup adheres to
the neoplastic paradigm herein with cure usually by focal removal of
tumor.
In the present context, these cases have at least two unusual features.
First, germline mutation in a so-called non-neoplastic gene (SUR1) is a
precursor to clonal neoplasia. Second, though expressed through a
two-hit or neoplastic process, the syndrome onset is in the neonatal
period.
Congenital thyrotoxicosis caused by somatic mutation in utero
A hot thyroid nodule in a neonate showed an activating
mutation of the TSHR (103). While the vast majority of somatic TSHR
mutations cause single or multiple nodules in adulthood (52), this case
showed that somatic mutation of this gene could cause neoplastic
disease at a very early age.
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A Classification Scheme That Is Particularly Useful for Endocrine
Disorders
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This dichotomy of categories is uniquely meaningful for hormone
secreting tissues. Analogous hereditary hyperfunction processes are
difficult to recognize in hormone nonsecreting tissues (Table 4
). Such a dichotomy is less meaningful
clinically in the absence of a shared distal expression pathway (such
as high circulating hormone level). Still, it retains the common
feature of excessive activation of a signalling pathway in
non-neoplastic hyperfunctions.
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Table 4. Examples of hereditary hyperfunction of tissues
other than hormone secretory tissues, with categorization as neoplastic
or nonneoplastic1
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In hormone-secreting tissue, either neoplastic or non-neoplastic
hereditary hyperfunction can have a common biochemical outcome, excess
of the same circulating hormone (Fig. 2
). The disturbed underlying
process has major implications for disease expression and for disease
management. It seems likely that other endocrine hyperfunction
disorders will come under this schema, including other disorders in the
tissues discussed, disorders in other tissues, and non-hereditary
disorders.
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Acknowledgments
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I thank Francis S. Collins M.D., Ph.D. and Alfred Knudson M.D.
for their helpful suggestions.
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Footnotes
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1 Hereditary disorders with neoplastic or non-neoplastic
hyperfunction of thyrocytes or of Leydig cells are covered in the
Tables. For brevity, their clinical features and detailed literature
citations are not covered in the text. 
2 RET inactivating mutation is one
cause of Hirschsprung disease or aganglionosis of the intestines (a
cell deficiency process) (27 ). 
Received March 23, 1999.
Revised June 14, 1999.
Accepted June 21, 1999.
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