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 hyperfunction is categorized here as neoplastic or not neoplastic. The disorders and their mutated genes are subdivided further by hyperfunctional hormone secretory tissue (Table 1Go). 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 syndromes–familial 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 1Go).1


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Table 1. Summary of hereditary disorders according to whether the disturbance in hormone-secreting tissue is neoplastic or not neoplastic (1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 )

 
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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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 [VHL–encoded 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. 1Go).



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Figure 1. Pathways and mutations in non-neoplastic endocrine hyperfunction (numbered 1–7). 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.

 
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. 2Go).



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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.

 
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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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 2Go) (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

 
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 2Go). 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 {alpha}-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 1Go).

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 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 20–30% 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 2Go). 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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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 2Go). The residual tissue may function normally, but has caused recurrent hyperparathyroidism on the average 8–12 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. 1Go) (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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Hereditary endocrine neoplasia as a two-hit process

Clear patterns emerge among all the hereditary neoplastic disorders in selected indices (Table 2Go) and in assembled data (Table 3Go).


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Table 3. Overview of clinical differences between two categories of endocrine cell hyperfunction

 
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 25–33 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 2Go and Table 3Go). 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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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{alpha}, the plasma membrane-bound {alpha}-subunit of the stimulatory G-protein heterotrimer (Fig. 1Go). Gs{alpha} 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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This dichotomy of categories is uniquely meaningful for hormone secreting tissues. Analogous hereditary hyperfunction processes are difficult to recognize in hormone nonsecreting tissues (Table 4Go). 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

 
In hormone-secreting tissue, either neoplastic or non-neoplastic hereditary hyperfunction can have a common biochemical outcome, excess of the same circulating hormone (Fig. 2Go). 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.


    Acknowledgments
 
I thank Francis S. Collins M.D., Ph.D. and Alfred Knudson M.D. for their helpful suggestions.


    Footnotes
 
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. Back

2 RET inactivating mutation is one cause of Hirschsprung disease or aganglionosis of the intestines (a cell deficiency process) (27 ). Back

Received March 23, 1999.

Revised June 14, 1999.

Accepted June 21, 1999.


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