Uncoupling of Secretion From Growth in Some Hormone Secretory Tissues

Abstract

Context:

Most syndromes with benign primary excess of a hormone show positive coupling of hormone secretion to size or proliferation in the affected hormone secretory tissue. Syndromes that lack this coupling seem rare and have not been examined for unifying features among each other.

Evidence Acquisition:

Selected clinical and basic features were analyzed from original reports and reviews. We examined indices of excess secretion of a hormone and indices of size of secretory tissue within the following three syndromes, each suggestive of uncoupling between these two indices: familial hypocalciuric hypercalcemia, congenital diazoxide-resistant hyperinsulinism, and congenital primary hyperaldosteronism type III (with G151E mutation of the KCNJ5 gene).

Evidence Synthesis:

Some unifying features among the three syndromes were different from features present among common tumors secreting the same hormone. The unifying and distinguishing features included: 1) expression of hormone excess as early as the first days of life; 2) normal size of tissue that oversecretes a hormone; 3) diffuse histologic expression in the hormonal tissue; 4) resistance to treatment by subtotal ablation of the hormone-secreting tissue; 5) causation by a germline mutation; 6) low potential of the same mutation to cause a tumor by somatic mutation; and 7) expression of the mutated molecule in a pathway between sensing of a serum metabolite and secretion of hormone regulating that metabolite.

Conclusion:

Some shared clinical and basic features of uncoupling of secretion from size in a hormonal tissue characterize three uncommon states of hormone excess. These features differ importantly from features of common hormonal neoplasm of that tissue.

Coupling of Secretion and Size in Hormonal Tissue

Secretion is positively and tightly coupled to size in most hormone-secretory tissues (1, 2). This has obvious long-term value to sustain raises of hormone secretion rates. Several mechanisms might underlie this coupling. For example, stimulation by cAMP may contribute to both activation of secretion and activation of growth in the thyrocyte or in the adrenal cortex (3–5). Rarely, secretion is weakly coupled or not coupled to the size of a secretory tissue. This is usual in the parathyroids of familial hypocalciuric hypercalcemia (FHH) (6–8). However, deficient coupling has rarely been mentioned, even for FHH (9). I compare aspects of this coupling in FHH to the coupling in two other syndromes to recognize uncoupling and to recognize shared features related to the uncoupling (Table 1).

Table 1.

Expressions of Three Hereditary States With Uncoupling of Secretion From Size in the Hormone Secretory Tissues

Syndrome	Earliest Onset, y	Main Expression	Other Expression	Hormone in Excess	Histology of Hormone-Secreting Tissue
Familial hypocalciuric hypercalcemia	0	High serum calcium	Relative hypocalciuria	PTH	Normal; few with mild hyperplasia
Congenital diazoxide-resistant hyperinsulinism	0	Low serum glucose	Macrosomia	Insulin	Some β-cell nuclei enlarged without β-cell hyperplasia
Congenital hyperaldosteronism type III (with germline KCNJ5 G151E)	0	Hypertension	Low serum potassium	Aldosterone	CAT scans normal in each of 6 carriers. Histology normal in 1 case

Abbreviation: CAT, computerized axial tomography.

Evidence Acquisition

Useful indices of this uncoupling are: 1) hormone level in blood; and 2) size of secretory tissue. Related indices include: 1) hormone secretion rate, and hormone immune histochemistry; and 2) hormonal cell growth, division, proliferation, and Ki67 index. I focus mainly upon blood level of hormone and on size of secretory tissue because the most data were available for these. I include only states of primary excess of hormone and such states wherein the entire secretory tissue is affected (ie, a diffuse process). States of cancerous or secondary excess of hormone were excluded. I examined both clinical and basic features at baseline and during hormone excess; thus, each syndrome with uncoupled hormone excess had its own normal control. Data for each syndrome were analyzed from a patient group, and outlier cases were not cited.

Three Syndromes of Primary Benign Excess of a Hormone With Uncoupling of Secretion and Size in Hormonal Tissue

Familial hypocalciuric hypercalcemia

Clinical expressions

FHH expresses early onset of asymptomatic hypercalcemia that is compatible with a long lifespan of persistent hypercalcemia (7, 8). Asymptomatic hypercalcemia in FHH has been recognized at the earliest ages, and it probably is present in most carriers from the first week of life (10, 11). Urine calcium is typically normal and thus relatively low, considering the hypercalcemia.

Treatments

Efforts to treat with subtotal parathyroidectomy in FHH almost always lead to persistent postoperative hypercalcemia or rarely to chronic hypoparathyroidism (7, 12). Most cases of FHH are followed without any intervention. Calcimimetic drugs are allosteric activators of the calcium-sensing receptor (CaSR) (13); recently, a calcimimetic has decreased serum calcium in FHH (14, 15).

Size of the parathyroids in FHH

On average, the parathyroid gland in FHH is normal-sized. Analyses have been based on surgical specimens, which reflect the bias toward removal and analysis of larger glands. In one series, 55 parathyroids from operations for FHH were analyzed from 18 patients between ages 0 and 59 years. Thirty-five of the 55 (64%) were normal-sized (16). Histological appearance varied between normal and mildly hyperplastic cellularity and correlated roughly with gland size. Another series reported 23 glands from 23 patients ages 20–67 years (17); 19 of the 28 (83%) had a normal weight. Histology showed a spectrum but an average parenchymal area below normal (62 vs 71%). Marked enlargement (interpreted as adenoma) of one or several parathyroids rarely arises in FHH (16–22). Genetic analyses including tests for monoclonality have not been reported on these rare adenomatous glands.

Secretion-related aspects in the parathyroids of FHH

Serum calcium acts through the CaSR as the main inhibitor of PTH secretion by the parathyroid cell (Supplemental Figure 1) (23). The CaSR is a G protein-coupled serpentine receptor. It couples in the parathyroid to signaling pathways through Ga11, Gaq, and perhaps other G proteins (24, 25).

PTH blood levels in FHH are normal or occasionally elevated mildly (26). These normal PTH levels in the face of lifelong hypercalcemia reflect a parathyroid tissue with a pathological failure of secretory suppression by blood calcium.

Law (8) reported 14 cases of FHH that underwent parathyroidectomy and close follow-up. By day 7 postoperatively, they showed persistent hypercalcemia. One can infer that, after subtotal parathyroidectomy, a small remnant of parathyroid tissue was sufficient to sustain their hypercalcemia. This course must reflect short-term dysregulation of PTH secretion and not dysregulation of parathyroid size. Such a course contrasts sharply to that after subtotal parathyroidectomy for other parathyroid tumor, such as in multiple endocrine neoplasia (MEN) type 1; there parathyroid tissue in a small postoperative remnant enlarges slowly, sustains eucalcemia, and may not cause recurrence of hyperparathyroidism until 10 or more years after surgery (27).

Mutated molecules

The CASR gene encodes the CaSR. The CaSR has a large extracellular domain of 612 amino acids, modeled to assume a Venus flytrap configuration. Binding of serum calcium is believed to be mainly in the cleft of the Venus flytrap domain (28). Heterozygous germline inactivating mutation of the CASR is the main cause of FHH (29, 30); 70% of those mutations are clustered in the Venus flytrap cleft.

The CASR mutations of some FHH cases alter the sigmoidal curve for suppression of PTH secretion by calcium (31). In particular, most inactivating mutations in FHH shift the curve to the right (ie, toward higher Ca++ set-point values). There is modest clustering of the degree of hypercalcemia by family or by mutated codon of CASR (8, 32). FHH-causing mutation of GA11 or AP2S1 also shifts the calcium suppression curve of the CaSR to the right, suggesting that each of these two molecules can interact with the CaSR in calcium sensing (33, 34) (Supplemental Figure 1).

Genetics of FHH

The inheritance of FHH is autosomal dominant with nearly 100% penetrance for hypercalcemia at all ages. FHH can be caused by heterozygous loss-of-function mutation in at least three genes (CASR, GA11, AP2S1), most frequently in the CASR (29, 33, 34). The FHH phenotype from mutation in each of these three genes seems similar or identical.

In contrast, two other phenotypes from inactivation of the CASR do not show uncoupling in parathyroid tumors. Neonatal severe primary hyperparathyroidism is a syndrome with severe and early enlargement of all parathyroid glands. It is a syndrome distinct from FHH and usually caused by biallelic inactivation of the CASR (29). Similarly, one family with an unusual location of CASR mutation expressed a unique syndrome of hypercalcemia, hypercalciuria, and parathyroid adenomas responsive to resection (35, 36).

Relations of FHH to common parathyroid tumor

Cells from sporadic parathyroid tumor often show variably decreased affinity for extracellular calcium (37); 70% show decreased expression of the CaSR (38). Most but not all sporadic parathyroid adenomas are believed to be monoclonal (39, 40). However, somatic CASR mutation has not been identified in sporadic parathyroid adenoma (41). This is notable because the CASR has features of a growth suppressor gene that might cause tumor via biallelic inactivation. In particular, germline biallelic inactivation of the CASRs causes striking enlargement of all four parathyroids in the neonate (see Genetics of FHH) (42). The main mutation in common parathyroid adenoma is MEN1 inactivation (43, 44).

Congenital diazoxide-resistant hyperinsulinism

Clinical expressions

Congenital hyperinsulinism (CI) was previously termed neonatal nesidioblastosis or persistent hyperinsulinemic hypoglycemia of infancy. This is the commonest cause of persistent hypoglycemia in infants and children. Serum insulin is inappropriately high and is the cause of hypoglycemia (45). There is a wide variation in presentations, reflecting in part origin from mutation in one among nine nonsyndromal genes, 11 syndromal genes, and as yet unidentified genes (46, 47).

The nonsyndromal variants are divided into those resistant to diazoxide and those responsive to diazoxide. About half of all cases of CI are diazoxide resistant. Diazoxide-resistant CI (DRCI) cases are the most severely affected. The severest hypoglycemia is usually recognizable in the neonatal period and otherwise usually before age 12 months. I focus on this severe form as a well-studied candidate for uncoupling of secretion and size in β-cells.

Treatments

In the most frequent, early-onset DRCI cases, glucose is initially infused at a high rate. Glucagon can be given for initial emergency care. Patients with severe hypoglycemia resistant to medications are considered for pancreatic surgery. Efforts to treat with subtotal pancreatic surgery lead to a high likelihood of persistent hypoglycemia or insulin insufficiency (48).

Size of the pancreatic β-cells

Proliferation rate in mature β-cells of man is extremely low, and its regulation is poorly understood (49). Early claims about enlargement and budding of islets from ducts (nesidioblastosis) in DRCI were eventually recognized as resulting from islet features of the normal neonate (50).

Histology has been examined in many cases of DRCI treated with pancreatic surgery. I focus upon most cases with biallelic mutation of a K+ channel subunit. The total volume of β-cells in the pancreas of DCRI is not increased (50–53). Histologically, an abnormality of β-cell morphology is subtle and represents irregularity in cell shape and increase in size of a minority of nuclei. This β-cell abnormality is diffuse throughout the islets. Similarly Sur 1^−/− (knockout) mice show transient neonatal hypoglycemia and islet histology that also is nearly normal (54). Such histological features in mouse and man have indicated that insulin oversecretion in DCRI results mainly from a severe defect in secretory function of the β-cells (51). Nodularity of β-cells in DCRI has not been reported from either of the genes of DCRI (53).

Secretion-related aspects in the islet β-cell

Normal insulin secretion from the β-cell is stimulated by the rise of serum glucose; this causes a rise of ATP, and then ATP-related closure of the plasma membrane K⁺ channels. These channels are composed of two subunits (a sulfonylurea binding subunit [SUR1], and a potassium channel subunit [Kir6.2]). In vivo and in vitro, islets with K+ channel inactivating mutations show increased basal secretion of insulin but a lack of the normal K+ channel response to tolbutamide. In DRCI, there is a blunted insulin maximal response to most secretagogues in vitro and to glucose in vivo (55, 56). There is a failure to suppress insulin secretion at the lowest blood sugar concentrations (55, 56). Residual β-cells, years after pancreatic surgery for DCRI, show persistent hyperfunction as measured by failed C-peptide suppression by glucose (48).

Mutated molecules

Most inactivating mutations of the K+ channel cause a lack of expression of the channel at the cell surface (57). The two principal genes that are mutated in DRCI are ABCC8 that encodes SUR1 and KCNJ11 that encodes Kir6.2. Most other genes for CI encode proteins in other steps of the β-cell, at steps between glucose sensing through to insulin secretion (Supplemental Figure 2) (58, 59).

Genetics of DCRI

DRCI from K+ channel loss is a recessive mutation. Most other causes of CI have dominant transmission and reflect activation of an enzyme (Supplemental Figure 2).

Congenital focal hyperinsulinism is not a syndrome of this discussion because its β-cell defect does not meet the criterion of diffuse distribution in the pancreas. The focal lesions have a maternally derived germline mutation of ABCC8 or KCNJ5 and somatic loss of the paternal allele in the zone about this locus (isodisomy 11p15) (60).

Relations of DCRI to common insulinoma

None of the genes implicated in CI have been implicated in sporadic insulinoma. Rather, YY1 is mutated in 30% of common insulinoma, and MEN1 is mutated in 1% (61).

Hyperaldosteronism (HA) type III with KCNJ5 G155E mutation

Clinical expressions

Currently, familial HA is classified into three variants. High aldosterone levels in serum are central in each. HA-I is a rare variant caused by germline fusion between the 11B-hydroxylase and aldosterone synthase genes. HA-II is the category for all kindreds not classified as type I or type III; HA-II is by far the most frequent of the three categories and presents diverse clinical features of sporadic HA in a family, often with only two affected members.

HA-III (62–66) has been identified recently in nine families by the currently essential criterion of germline mutation in KCNJ5 (62–66). The cases with HA-III present with early onset of hypertension, hypokalemia, and high serum aldosterone. Hypertension has presented as early as age 3 months (63). Among HA-III, the cases with KCNJ5 G151E mutation show uncoupling of aldosterone secretion and size in the adrenal cortex (65, 66).

Treatments

In HA-III, there is resistance to spironolactone in affected members of most kindreds (64). Cases in kindreds resistant to spironolactone have also not benefitted from subtotal adrenalectomy. Treatment has succeeded with total adrenalectomy. However, cases with KCNJ5 G151E mutation are very responsive to spironolactone; thus, they usually do not need adrenalectomy.

Size of the adrenal cortical tissue in HA-III

In HA-III with germline KCNJ5 G151E mutation, there is evidence of normal adrenocortical size (65, 66). This phenotype is so far based on only nine affected cases in three families with that same mutation. Adrenal size was normal by computerized axial tomography scan in six of these cases, including as late as age 37 years. The one case with 90% adrenalectomy at age 11 (before availability of spironolactone) showed normal adrenal histology. In contrast, there is bilateral adrenocortical hyperplasia with or without nodularity in cases with KCNJ5 G151R, a different mutation of the same codon. The normal adrenal size with KCNJ5 G151E has been attributed to a paradoxically more severe KCNJ5 mutation, causing accelerated apoptosis in the adrenal cortex (65). These have been suggested as two distinct variants of HA-III from two distinct mutations of the same codon.

Secretion-related aspects of aldosterone

Normally, little aldosterone is stored in the adrenal cortex, and secretory vesicles are absent. Serum levels of aldosterone are mainly regulated via aldosterone synthesis in mitochondria, with regulation occurring at the levels of transcription and post-transcription (67). The main extracellular regulators of aldosterone secretion are angiotensin II and potassium; normally, there is less control by ACTH (via cAMP) (Supplemental Figure 3).

The initial adrenal contacts for signaling by serum potassium are potassium channels. Normally, the plasma membrane of the glomerulosa cell is activated by a rise of serum K+ (68). The first step in this response is potassium inflow that decreases the normal membrane hyperpolarization and thereby increases influx of calcium through calcium channels of the plasma membrane. Some 80 genes for subunits of mammalian potassium channels have been cloned. Their detailed relevance to the adrenal cortex is poorly understood (67, 69).

Mutated molecule

Several K+ channels in the 2-pore family (K2P) are expressed on glomerulosa cells (including TREK1, TASK1, TASK3). Knockout of TASK1 can cause HA in mice (70). KCNJ5 encodes Kir3.4 (or GIRK4) one of four G protein-coupled inward rectifying K⁺ channels (71, 72); they may interact directly with a G protein such as Ga or RGS. A role for GIRK4 in normal aldosterone secretion became apparent after its mutations in sporadic aldosteronoma and HA-III were discovered (63). Each of the mutated codons of KCNJ5 in HA is highly conserved and has been modeled (with crystal structure of chicken KCNJ12) as being close to the selectivity filter of an inward-rectifying potassium channel (of the adrenal glomerulosa). KCNJ5 is normally expressed in the adrenal glomerulosa, but surprisingly, the glomerulosa is atrophic in HA-III. Expression of missense mutants of Kir3.4 in 293T cells resulted in the decrease of K+ ion selectivity (63).

Genetics of HA-III

One kindred with HA-III showed a KCNJ5 germline heterozygous T158A mutation (62, 63). Several other families have shown heterozygous G151R or G151E (65, 66).

Relations of HA-III with G151E to common aldosteronoma

KCNJ5 G151E has not been found in sporadic aldosteronoma. However, G151R (but not G151E) or L168R mutations of KCNJ5 are present in 40% of sporadic aldosteronomas and account for 99% of the mutations so far found there; KCNJ5 E145Q or del 157 was found in fewer than 1%. Several other plasma membrane ion transporter molecules are somatically mutated in a few sporadic aldosteronomas and less frequently in the germline among familial cases; these are ATP1A1 in 5% (Na,K-ATPase) and ATP2B3 in 2%, and CACNA1D (Ca-transporting ATPase) (73–75).

Discussion

Some shared clinical features among three syndromes

Contrasts from common syndromes

Each of the three uncommon hormone excess states herein has a set of contrasts to features of the more common sporadic excess of that hormone (Table 2).

Table 2.

Shared Features Among Three States

Syndrome	Earliest Onset Age Below 1 y	Resist Subtotal Ablation of Hormone-Secreting Tissue	Secretory Histology Diffusely Normal	No Nodules in Secretory Tissue	No Cancer in Secretory Tissue	Mutation Sequence for Diffuse Excess Rarely Causes Tumor by Somatic Mutation, %	Mutated Gene Is in Sensor/ Secretor Pathway
Familial hypocalciuric hypercalcemia	+	+	+	+	+	0	+
Congenital diazoxide-resistant hyperinsulinism	+	+	+	+	+	0	+
Congenital hyperaldosteronism type III (with KCNJ5 G151E)	+	+	+	+	+	0	+

Each of these features suggests or is consistent with hyperfunction in the hormone secretory tissue, but is different from the features in common endocrine tumors.

Young age at onset of expression of hormone excess

For each of the three syndromes herein, hormone excess has been expressed as early as during the first year of life, and for many cases it has been expressed in the first days of life. Such an early onset requires that the hormone-secreting tissue during these young ages be sufficient in size, differentiation, and secretory activation. In the more common states, any hormone excess is typically asymptomatic during infancy and presents after a decade or more of increasingly abnormal size of hormone-secretory tissues.

Process affecting all hormone-secretory cells of the disturbed tissue

All of the hormone-secretory cells of one target tissue seem to be dysregulated by the germline mutation discussed here, typically termed a diffuse process throughout the gland. There is no normal rim, normal segment, or even a portion of concentrated admixture with unaffected secretory tissue. Such a diffuse expression could also account for persistent oversecretion when a small remnant of secretory tissue remains after surgery. The combination of a germline mutation and a diffuse process in all secretory cells of a tissue suggests polyclonality of hormone secretory tissue (9). Definitive proof of polyclonality is not available. Primary excess of a hormone usually results from a hormone-secreting monoclonal neoplasm and usually with tight coupling of secretion and size. There are exceptions (2); for example, sporadic excess of cortisol is often heterozygous, suggesting polyclonality (76).

Normal size of secretory tissue

Preoperatively, the size of secretory tissue is nearly normal. This was a principal criterion for selection of the three states for examination herein. Normal size is not sufficient to explain uncoupled dysregulation of secretion. Normal size can also occur with normal tissue or with evolving hyperplasia.

Hormone excess persists after subtotal resection of the secretory tissue

Therapy of a sporadic cause of hormonal excess may achieve durable remission via complete or incomplete ablation of tumors by surgery or by drugs. In contrast, subtotal treatment is usually followed by persistence or rapid recurrence of hormone excess in FHH, DRCI, or HA-III with KCNJ5 G155E. The rapid persistence of hormone excess despite only a small secretory remnant is another indication of a strong secretory drive and of disproportion of this drive to the size of secretory tissue. As was illustrated in FHH, this suggests mainly a secretory abnormality that can sustain hormonal excess, even after subtotal removal of hormonal tissue (8).

Rarity of hormonal neoplasia in that syndrome

Neoplasms, including cancers, have not been identified from the mutations of the three syndromes discussed herein. In contrast, most of the more frequent hereditary syndromes of hormone-secreting neoplasia with normal coupling have high penetrance for tumors and occasional malignancy in their main hormonal tissue or in other tissues.

Frequent misdiagnosis and frequent mistreatment

Because each case herein represents a small fraction of cases with excess of that hormone while mimicking most cases, it is often misdiagnosed and mistreated.

Shared mechanisms about uncoupling

Germline mutation as cause

Cause by a germline mutation is a central reason why the presumably uncoupled disorder seems to be expressed mainly as oversecretion in all of the hormone-secretory cells of the target tissue. It can also help explain why a secretory dysfunction can be strongly expressed near birth.

Specific DNA sequence of germline mutation that causes each uncoupled syndrome has low likelihood to cause a sporadic neoplasm in the same tissue

All of the genes discussed here can express mutation from the germline in all or most target cells of a hormonal tissue. The same mutation sequences that can cause uncoupled expression have not been identified to cause progression to monoclonal tumor in germline or somatic tissue.

Mutation in sensor, transducer, or secretor molecules

Uncoupling, by itself, should not account for early age of onset or for diffuse dysregulation of hormone secretion. There must also be a specific dysregulation of hormone secretion. The germline mutations discussed herein almost certainly contribute centrally to that other disturbance. I speculate that a mutation that can increase hormone secretion without a detectable increase in size of secretory tissue could account for early onset of hormone excess and for a lack of a role for that gene in tumorigenesis by mutation in somatic tissues. Such a mutation could be the initiating feature for the entire syndrome.

Tabulating the mutated genes by function suggests that several of the mutations are in pathways from sensing to secretion (Table 3). The CASR functions as a calcium sensor in secretory regulation. GA11 is the most clear to be in the transduction category, based on studies of its biology (24, 32, 77). Several other mutations may be centered in the hormone secretion process. None of these mutations are in molecules known to be in the vesicle exocytosis machinery; however, very little is known about the molecules involved in exocytosis of hormonal secretory granules (78).

Table 3.

Functions of Genes Whose Germline Mutation Is Expressed as Uncoupled Secretory Excess in Hormonal Tissues

Syndrome	Serum Metabolite	Hormone	Mutated Gene by Likely Function
			Sensor of Serum Metabolite	Transducer of Serum Metabolite	Secretor of Hormone
Familial hypocalciuric	Calcium	PTH	CASR	GA11, AP2S1
Congenital diazoxide-resistant hyperinsulinemic hypoglycemia	Glucose	Insulin			ABCC8, KCNJ11
Congenital hyperaldosteronism type III (with KCNJ5 G151E)	Potassium	Aldosterone	KCNJ5 G151E

There are limits to this specific functional classification of the genes. Other mutations of the same genes need not cause uncoupling. For example, there is tight coupling expressed by a CASR mutation with rare location in the cytoplasmic tail of the CaSR (35, 36). And a KCNJ5 G155R mutation causes coupled tumor via the same codon that can cause uncoupling via G155E (65). Furthermore, other mutation in these paths can cause a tumor with typical coupling, for example, TSHR in thyroid (3, 4)—just as mutation outside of these pathways might cause an uncoupled excess not yet recognized.

The specific pathways of these gene functions contrast with pathways of other genes whose mutation causes coupled secretion and size in a hormonal tumor; some are in growth pathways (RET or PTEN), whereas most are in unknown pathways likely to involve growth (eg, MEN1, VHL, BRAF).

Some gaps in our knowledge

Deficiencies in certain types of data

These are rare syndromes, and some aspects have not been reported or are based on few observations. For example, testing for mutation of some of the genes implicated in DRCI has not been reported in sporadic tumors.

Meaning of a normal-sized secretory tissue in a state of hormone excess

Maintenance of high hormone in serum generally requires increased secretion rate or decreased clearance rate of hormone as compared to normal. Neither has been measured in these three states. Regarding increased secretion, it would be of interest to measure this or to investigate ultrastructure of the secretory apparatus. The decreased renal clearance of calcium in FHH (12) could mean that a lesser secretion of PTH than in common hyperparathyroidism could sustain hypercalcemia.

Other states with uncharacterized uncoupling of secretion and size in a hormonal tissue

Because of the few cases or insufficient histological data, some other states with uncoupling cannot currently be assigned to an uncoupled status. This may apply to some mutations in selected other states, such as some variants of CI. In particular glucokinase is believed to act as the main glucose sensor in the pancreatic islet, and its activating mutation is a cause of CI (79, 80). However, the associated islet histology is insufficiently known.

Two patients with a syndrome resembling HA-III had sporadic congenital HA and severe neurological defects. In one, computed tomography of the adrenals at age 9 years showed no abnormality. They had germline mutation of CACNA1D (73). CACNA1D is the calcium channel gene most highly expressed on the adrenocortical cell (64). Lastly, secretion by outwardly normal-appearing osteoblasts and osteocytes can give several syndromes with high levels of hormonal FGF23 or mutated FGF23, resulting in hypophosphatemia, low serum 1,25(OH)2D, and osteomalacia (81).

Unidentified genes

Mutation of a main gene and sometimes other genes has been identified as a germline cause for each of these three syndromes. However, 10–20% of families with FHH or with DRCI do not have a germline mutation identified. Some will prove to have occult mutation in one of its already identified genes. Other families may have mutation in as yet unidentified genes. The present analysis suggests that most of these unidentified genes are in the sensor/transducer/secretor pathway.