2989 Multiple Endocrine Neoplasia Syndromes CHAPTER 388

TABLE 388-4 Recommendations for Tests and Surgery in MEN 2 and MEN 3a

RECOMMENDED AGE (YEARS) FOR TEST/INTERVENTION

RET MUTATION, EXON (EX)

LOCATION, AND CODON

INVOLVED RISKb

RET MUTATIONAL

ANALYSIS

FIRST SERUM

CALCITONIN AND

NECK ULTRASOUND

PROPHYLACTIC

THYROIDECTOMY

SCREENING FOR

PHEOCHROMOCYTOMA

SCREENING FOR

PHPT

Ex8 (533)c

; Ex10 (609, 611, 618,

620)c

; Ex11 (630, 631, 666)c

; Ex13

(768, 790)c

; Ex14 (804)c

; Ex15

(891)c

; EX16 (912)c

+ <3–5 5 <5d 16e 16

Ex11 (634)c

; Ex15 (883)c ++ <3 <3 <5f 11e 11

Ex15 (883)g

; Ex16 (918)g +++ ASAP and by <1 ASAP and by <0.5–1 ASAP and by <1 11e —h

a

Data from American Thyroid Association Guidelines Task Force, RT Kloos et al: Medullary thyroid cancer: management guidelines of the American Thyroid Association.

Thyroid 19:565, 2009 and revised from SA Wells Jr et al: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid

25:567, 2015. b

Risk for early development of metastasis and aggressive growth of medullary thyroid cancer: +++, highest; ++, high; and + moderate. c

Mutations associated

with MEN 2A (or medullary thyroid carcinoma only). d

Timing of surgery to be based on elevation of serum calcitonin and/or joint discussion with pediatrician, surgeon,

and parent/family. Later surgery may be appropriate if serum calcitonin and neck ultrasound are normal. e

Presence of pheochromocytoma must be excluded prior to

any surgical intervention, and also in women with RET mutation who are planning pregnancy or are pregnant. f

Surgery earlier than 5 years based on elevation of serum

calcitonin. Optimal timing of surgery should be decided by the surgeon and pediatrician, in consultation with the child’s parent. g

Mutations associated with MEN 2B (MEN 3). h

Not required because PHPT is not a feature of MEN 2B (MEN 3).

Abbreviations: ASAP, as soon as possible; MEN, multiple endocrine neoplasia; PHPT, primary hyperparathyroidism.

FDG avid adrenal

pheochromocytoma

Metastatic

MTC in

liver

FDG avid MTC

in neck

[H]

[F]

FIGURE 388-2 Fluorodeoxyglucose (FDG) positron emission tomography scan

in a patient with multiple endocrine neoplasia type 2A, showing medullary

thyroid cancer (MTC) with hepatic and skeletal (left arm) metastasis and a left

adrenal pheochromocytoma. Note the presence of excreted FDG compound

in the bladder. (Reproduced with permission from A Naziat et al: Confusing

genes: A patient with MEN2A and Cushing’s disease. Clin Endocrinol (Oxf)

78:966, 2013.)

extracellular domain, with mutations of codon 634 accounting for

~85% of MEN 2A mutations; FMTC patients also have mutations of

the cysteine-rich extracellular domain, with most mutations occurring

in codon 618. In contrast, ~95% of MEN 2B/MEN 3 patients have

mutations of codon 918 of the intracellular tyrosine kinase domain

(Table 388-1 and Table 388-4).

Medullary Thyroid Carcinoma MTC is the most common

feature of MEN 2A and MEN 2B and occurs in almost all affected

individuals. MTC represents 5–10% of all thyroid gland carcinomas,

and 20% of MTC patients have a family history of the disorder. The

use of RET mutational analysis to identify family members at risk for

hereditary forms of MTC has altered the presentation of MTC from that

of symptomatic tumors to a preclinical disease for which prophylactic

thyroidectomy (Table 388-4) is undertaken to improve the prognosis

and ideally result in cure. However, in patients who do not have a known

family history of MEN 2A, FMTC, or MEN 2B, and therefore have not

had RET mutational analysis, MTC may present as a palpable mass in

the neck, which may be asymptomatic or associated with symptoms of

pressure or dysphagia in >15% of patients. Diarrhea occurs in 30% of

patients and is associated either with elevated circulating concentrations

of calcitonin or tumor-related secretion of serotonin and prostaglandins.

Some patients may also experience flushing. In addition, ectopic ACTH

production by MTC may cause Cushing’s syndrome. The diagnosis of

MTC relies on the demonstration of hypercalcitoninemia (>90 pg/mL in

the basal state); stimulation tests using IV pentagastrin (0.5 mg/kg) and

or calcium infusion (2 mg/kg) are rarely used now, reflecting improvements in the assay for calcitonin. Neck ultrasonography with fine-needle

aspiration of the nodules can confirm the diagnosis. Radionucleotide

thyroid scans may reveal MTC tumors as “cold” nodules. Radiography

may reveal dense irregular calcification within the involved portions of

the thyroid gland and in lymph nodes involved with metastases. Positron emission tomography (PET) may help to identify the MTC and

metastases (Fig. 388-2). Metastases of MTC usually occur to the cervical lymph nodes in the early stages and to the mediastinal nodes, lung,

liver, trachea, adrenal, esophagus, and bone in later stages. Elevations

in serum calcitonin concentrations are often the first sign of recurrence

or persistent disease, and the serum calcitonin doubling time is useful

for determining prognosis. MTC can have an aggressive clinical course,

with early metastases and death in ~10% of patients. A family history of

aggressive MTC or MEN 2B may be elicited.

TREATMENT

Medullary Thyroid Carcinoma

Individuals with RET mutations who do not have clinical manifestations of MTC should be offered prophylactic surgery between

the ages of <1 and 5 years. The timing of surgery will depend on

the type of RET mutation and its associated risk for early development, metastasis, and aggressive growth of MTC (Table 388-4).

Such patients should have a total thyroidectomy with a systematic

central neck dissection to remove occult nodal metastasis, although

the value of undertaking a central neck dissection has been subject to debate. Prophylactic thyroidectomy, with lifelong thyroxine

replacement, has dramatically improved outcomes in patients with

MEN 2 and MEN 3, such that ~90% of young patients with RET

mutations who had a prophylactic thyroidectomy have no evidence

2990 PART 12 Endocrinology and Metabolism

of persistent or recurrent MTC at 7 years after surgery. In patients

with clinically evident MTC, a total thyroidectomy with bilateral

central resection is recommended, and an ipsilateral lateral neck

dissection should be undertaken if the primary tumor is >1 cm in

size or there is evidence of nodal metastasis in the central neck.

Surgery is the only curative therapy for MTC. The 10-year survival

in patients with metastatic MTC is ~20%. For inoperable MTC or

metastatic disease, TKR inhibitors (e.g., vandetanib, cabozantinib,

selpercatinib) have improved the progression-free survival times.

PRRT with 177Lu-DOTATATE has been reported to be beneficial for

metastatic MTCs that were found by SRS to express somatostatin

receptors. Other types of chemotherapy are of limited efficacy, but

radiotherapy may help to palliate local disease.

Pheochromocytoma (See also Chap. 387) These noradrenalineand adrenaline-secreting tumors occur in >50% of patients with MEN

2A and MEN 2B and are a major cause of morbidity and mortality.

Patients may have symptoms and signs of catecholamine secretion

(e.g., headaches, palpitations, sweating, poorly controlled hypertension), or they may be asymptomatic with detection through biochemical screening based on a history of familial MEN 2A, MEN 2B, or

MTC. Pheochromocytomas in patients with MEN 2A and MEN 2B

differ significantly in distribution when compared with patients without MEN 2A and MEN 2B. Extra-adrenal pheochromocytomas, which

occur in 10% of patients without MEN 2A and MEN 2B, are observed

rarely in patients with MEN 2A and MEN 2B. Malignant pheochromocytomas are much less common in patients with MEN 2A and MEN

2B. The biochemical and radiologic investigation of pheochromocytoma in patients with MEN 2A and MEN 2B is similar to that in non–

MEN 2 patients and includes the measurement of plasma (obtained

from supine patients) and urinary free fractionated metanephrines

(e.g., normetanephrine and metanephrines measured separately),

CT or MRI scanning, radionuclide scanning with meta-iodo-(123I or 131I)-benzyl guanidine (MIBG), and PET using (18F)-fluorodopamine

or (18F)-fluoro-2-dexoxy-d-glucose (Fig. 388-2).

TREATMENT

Pheochromocytoma

Surgical removal of pheochromocytoma, using α and β adrenoreceptor blockade before and during the operation, is the recommended treatment. Other antihypertensive agents, including

calcium channel blockers, are sometimes required for adequate

blood pressure control. Endoscopic adrenal-sparing surgery, which

decreases postoperative morbidity, hospital stay, and expense, as

opposed to open surgery, has become the method of choice.

Parathyroid Tumors (See also Chap. 410) Parathyroid tumors

occur in 10–25% of patients with MEN 2A. However, >50% of these

patients do not have hypercalcemia. The presence of abnormally

enlarged parathyroids, which are unusually hyperplastic, is often seen

in the normocalcemic patient undergoing thyroidectomy for MTC.

The biochemical investigation and treatment of hypercalcemic patients

with MEN 2A is similar to that of patients with MEN 1.

Genetics and Screening To date, ~50 different RET mutations have been reported, and these are located in exons 5, 8, 10,

11, 13, 14, 15, and 16. RET germline mutations are detected in

>95% of MEN 2A, FMTC, and MEN 2B families, with Cys634Arg

being most common in MEN 2A, Cys618Arg being most common in

FMTC, and Met918Thr being most common in MEN 2B (Tables 388-1

and 388-4). Between 5 and 10% of patients with MTC or MEN 2A–

associated tumors have de novo RET germline mutations, and ~50% of

patients with MEN 2B have de novo RET germline mutations. These de

novo RET germline mutations always occur on the paternal allele.

Approximately 5% of patients with sporadic pheochromocytoma have

a germline RET mutation, but such germline RET mutations do not

appear to be associated with sporadic primary hyperparathyroidism.

Thus, RET mutational analysis should be performed in (1) all patients

with MTC who have a family history of tumors associated with MEN

2, FMTC, or MEN 3, such that the diagnosis can be confirmed and

genetic testing offered to asymptomatic relatives; (2) all patients with

MTC and pheochromocytoma without a known family history of MEN

2 or MEN 3; (3) all patients with MTC, but without a family history of

MEN 2, FMTC, or MEN 3, because these patients may have a de novo

germline RET mutations; (4) all patients with bilateral pheochromocytoma; and (5) patients with unilateral pheochromocytoma, particularly

if this occurs with increased calcitonin levels.

Screening for MEN 2/MEN 3–associated tumors in patients with

RET germline mutations should be undertaken annually and include

serum calcitonin measurements, a neck ultrasound for MTC, plasma

(or 24-h urinary) fractionated metanephrines for pheochromocytoma,

and albumin-corrected serum calcium or ionized calcium with PTH

for primary hyperparathyroidism. In patients with MEN 2–associated

RET mutations, screening for MTC should begin by 1–5 years, for

pheochromocytoma by 11–16 years, and for primary hyperparathyroidism by 11–16 years of age (Table 388-4).

■ MULTIPLE ENDOCRINE NEOPLASIA TYPE 4

Clinical Manifestations Patients with MEN 1–associated tumors,

such as parathyroid adenomas, pituitary adenomas, and pancreatic

NETs, occurring in association with gonadal, adrenal, renal, and thyroid tumors have been reported to have mutations of the gene encoding the 196–amino acid cyclin-dependent kinase inhibitor (CK1) p27

kip1 (CDKN1B). Such families with MEN 1–associated tumors and

CDKN1B mutations are designated to have MEN 4 (Table 388-1). The

investigations and treatments for the MEN 4–associated tumors are

similar to those for MEN 1 and non–MEN 1 tumors.

Genetics and Screening To date, 50 MEN patients (from

<20 kindreds) with mutations of CDKN1B, which is located on

chromosome 12p13, have been reported, and all of these are predicted to result in a loss of function. These MEN 4 patients may represent ~3% of the 5–10% of patients with MEN 1 who do not have

mutations of the MEN1 gene. Germline CDKN1B mutations may rarely

be found in patients with sporadic (i.e., nonfamilial) forms of primary

hyperparathyroidism.

■ HYPERPARATHYROIDISM-JAW TUMOR

SYNDROME (SEE ALSO CHAP. 410)

Clinical Manifestations Hyperparathyroidism-jaw tumor

(HPT-JT) syndrome is an autosomal dominant disorder characterized by the development of parathyroid tumors (15% are carcinomas)

and fibro-osseous jaw tumors. In addition, some patients may also

develop Wilms’ tumors, renal cysts, renal hamartomas, renal cortical

adenomas, renal cell carcinoma (RCC), pancreatic adenocarcinomas,

uterine tumors, testicular mixed germ cell tumors with a major seminoma component, and Hürthle cell thyroid adenomas. The parathyroid

tumors may occur in isolation and without any evidence of jaw tumors,

and this may cause confusion with other hereditary hypercalcemic

disorders, such as MEN 1. However, genetic testing to identify the causative mutation will help to establish the correct diagnosis. The investigation and treatment for HPT-JT–associated tumors are similar to

those in non-HPT-JT patients, except that early parathyroidectomy is

advisable because of the increased frequency of parathyroid carcinoma.

Genetics and Screening The gene that causes HPT-JT is

located on chromosome 1q31.2 and encodes a 531–amino acid

protein, parafibromin (Table 388-2). Parafibromin is also referred

to as cell division cycle protein 73 (CDC73) and has a role in transcription. Genetic testing in families helps to identify mutation carriers who

should be periodically screened for the development of tumors

(Table 388-5).

■ VON HIPPEL–LINDAU DISEASE

(SEE ALSO CHAP. 387)

Clinical Manifestations von Hippel–Lindau (VHL) disease is an

autosomal dominant disorder characterized by hemangioblastomas

2991 Multiple Endocrine Neoplasia Syndromes CHAPTER 388

of the retina and CNS; cysts involving the kidneys, pancreas, and epididymis; RCC; pheochromocytomas; and pancreatic islet cell tumors.

The retinal and CNS hemangioblastomas are benign vascular tumors

that may be multiple; those in the CNS may cause symptoms by compressing adjacent structures and/or increasing intracranial pressure.

In the CNS, the cerebellum and spinal cord are the most frequently

involved sites. The renal abnormalities consist of cysts and carcinomas,

and the lifetime risk of RCC in VHL is 70%. The endocrine tumors in

VHL consist of pheochromocytomas and pancreatic islet cell tumors.

The clinical presentation of pheochromocytoma in VHL disease is similar to that in sporadic cases, except that there is a higher frequency of

bilateral or multiple tumors, which may involve extra-adrenal sites in

VHL disease. The most frequent pancreatic lesions in VHL are multiple

cyst-adenomas, which rarely cause clinical disease. However, nonsecreting pancreatic islet cell tumors occur in <10% of VHL patients,

who are usually asymptomatic. The pancreatic tumors in these patients

are often detected by regular screening using abdominal imaging.

Pheochromocytomas should be investigated and treated as described

earlier for MEN 2. The pancreatic islet cell tumors frequently become

malignant, and early surgery is recommended.

Genetics and Screening The VHL gene, which is located on

chromosome 3p26-p25, is widely expressed in human tissues and

encodes a 213–amino acid protein (pVHL) (Table 388-2). A wide

variety of germline VHL mutations have been identified. VHL acts as a

tumor-suppressor gene. A correlation between the type of mutation

and the clinical phenotype has been reported; large deletions and

protein-truncating mutations are associated with a low incidence of

pheochromocytomas, whereas some missense mutations in VHL

patients are associated with pheochromocytoma (referred to as VHL

type 2C). Other missense mutations may be associated with hemangioblastomas and RCC but not pheochromocytoma (referred to as

VHL type 1), whereas distinct missense mutations are associated with

hemangioblastomas, RCC, and pheochromocytoma (VHL type 2B).

VHL type 2A, which refers to the occurrence of hemangioblastomas

and pheochromocytoma without RCC, is associated with rare missense

mutations. The basis for these complex genotype-phenotype relationships remains to be elucidated. One major function of pVHL, which is

also referred to as elongin, is to downregulate the expression of vascular endothelial growth factor (VEGF) and other hypoxia-inducible

mRNAs. Thus, pVHL, in complex with other proteins, regulates the

expression of hypoxia-inducible factors (HIF-1 and HIF-2) such that

loss of functional pVHL leads to a stabilization of the HIF protein

complexes, resulting in VEGF overexpression and tumor angiogenesis.

Screening for the development of pheochromocytomas and pancreatic

islet cell tumors is as described earlier for MEN 2 and MEN 1, respectively (Tables 388-3 and 388-4).

■ NEUROFIBROMATOSIS

Clinical Manifestations Neurofibromatosis type 1 (NF1), which

is also referred to as von Recklinghausen’s disease, is an autosomal

dominant disorder characterized by the following manifestations:

neurologic (e.g., peripheral and spinal neurofibromas); ophthalmologic (e.g., optic gliomas and iris hamartomas such as Lisch nodules);

dermatologic (e.g., café au lait macules); skeletal (e.g., scoliosis, macrocephaly, short stature, pseudoarthrosis); vascular (e.g., stenoses of renal

and intracranial arteries); and endocrine (e.g., pheochromocytoma,

carcinoid tumors, precocious puberty). Neurofibromatosis type  2

(NF2) is also an autosomal dominant disorder but is characterized by

the development of bilateral vestibular schwannomas (acoustic neuromas) that lead to deafness, tinnitus, or vertigo. Some patients with

NF2 also develop meningiomas, spinal schwannomas, peripheral nerve

neurofibromas, and café au lait macules. Endocrine abnormalities are

not found in NF2 and are associated solely with NF1. Pheochromocytomas, carcinoid tumors, and precocious puberty occur in ~1%

of patients with NF1, and growth hormone deficiency has also been

reported. The features of pheochromocytomas in NF1 are similar to

those in non-NF1 patients, with 90% of tumors being located within

the adrenal medulla and the remaining 10% at an extra-adrenal location, which often involves the para-aortic region. Primary carcinoid

tumors are often periampullary and may also occur in the ileum

but rarely in the pancreas, thyroid, or lungs. Hepatic metastases are

associated with symptoms of the carcinoid syndrome, which include

flushing, diarrhea, bronchoconstriction, and tricuspid valve disease.

Precocious puberty is usually associated with the extension of an

optic glioma into the hypothalamus with resultant early activation of

gonadotropin-releasing hormone secretion. Growth hormone deficiency has also been observed in some NF1 patients, who may or

may not have optic chiasmal gliomas, but it is important to note that

short stature is frequent in the absence of growth hormone deficiency

in patients with NF1. The investigation and treatment for tumors are

similar to those undertaken for each respective tumor type in non-NF1

patients.

Genetics and Screening The NF1 gene, which is located on

chromosome 17q11.2 and acts as a tumor suppressor, consists of

60 exons that span >350 kb of genomic DNA (Table 388-2). Mutations in NF1 are of diverse types and are scattered throughout the

exons. The NF1 gene product is the protein neurofibromin, which has

homologies to the p120GAP (GTPase activating protein) and acts on

p21ras by converting the active GTP bound form to its inactive GDP

form. Mutations of NF1 impair this downregulation of the p21ras signaling pathways, which in turn results in abnormal cell proliferation.

Screening for the development of pheochromocytomas and carcinoid

tumors is as described earlier for MEN 2 and MEN 1, respectively

(Tables 388-3 and 388-4).

■ CARNEY COMPLEX

Clinical Manifestations Carney complex (CNC) is an autosomal

dominant disorder characterized by spotty skin pigmentation (usually

of the face, labia, and conjunctiva), myxomas (usually of the eyelids

and heart, but also the tongue, palate, breast, and skin), psammomatous melanotic schwannomas (usually of the sympathetic nerve chain

and upper gastrointestinal tract), and endocrine tumors that involve

the adrenals, Sertoli cells, somatotropes, thyroid, and ovary. Cushing’s

syndrome, the result of primary pigmented nodular adrenal disease

(PPNAD), is the most common endocrine manifestation of CNC and

may occur in one-third of patients. Patients with CNC and Cushing’s

syndrome often have an atypical appearance by being thin (as opposed

to having truncal obesity). In addition, they may have short stature,

muscle and skin wasting, and osteoporosis. These patients often

have levels of urinary free cortisol that are normal or increased only

marginally. Cortisol production may fluctuate periodically with days

or weeks of hypercortisolism; this pattern is referred to as “periodic

Cushing’s syndrome.” Patients with Cushing’s syndrome usually have

loss of the circadian rhythm of cortisol production. Acromegaly, the

TABLE 388-5 HPT-JT Screening Guidelines

TUMORa TEST FREQUENCYb

Parathyroid Serum Ca, PTH 6–12 months

Ossifying jaw fibroma Panoramic jaw x-ray with neck

shieldingc

5 years

Renal Abdominal MRIc,d 5 years

Uterine Ultrasound (transvaginal or

transabdominal) and additional

imaging ± D&C if indicatede

Annual

a

Screening for most common HPT-JT–associated tumors is considered. Assessment

for other reported tumor types may be indicated (e.g., pancreatic, thyroid, testicular

tumors). b

Frequency of repeating test after baseline tests performed. c

X-rays

and imaging involving ionizing radiation should ideally be avoided to minimize

risk of generating subsequent mutations. d

Ultrasound scan recommended if MRI

unavailable. e

Such selective pelvic imaging should be considered after obtaining a

detailed menstrual history.

Abbreviations: Ca, calcium; D&C, dilation and curettage; HPT-JT,

hyperparathyroidism-jaw tumor syndrome; MRI, magnetic resonance imaging; PTH,

parathyroid hormone.

Source: Reproduced with permission from PJ Newey et al: Cell division cycle

protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumor

syndrome (HPT-JT) and parathyroid tumors. Hum Mutat 31:295, 2010.

2992 PART 12 Endocrinology and Metabolism

result of a somatotrope tumor, affects ~10% of patients with CNC.

Testicular tumors may also occur in one-third of patients with CNC.

These may either be large-cell calcifying Sertoli cell tumors, adrenocortical rests, or Leydig cell tumors. The Sertoli cell tumors occasionally

may be estrogen-secreting and lead to precocious puberty or gynecomastia. Some patients with CNC have been reported to develop thyroid

follicular tumors, ovarian cysts, or breast duct adenomas.

Genetics and Screening CNC type 1 (CNC1) is due to

mutations of the protein kinase A (PKA) regulatory subunit 1 α

(R1α) (PRAKAR1A), a tumor suppressor, whose gene is located

on chromosome 17q.24.2 (Table 388-2). The gene causing CNC type 2

(CNC2) is located on chromosome 2p16 and has not yet been identified. It is interesting to note, however, that some tumors do not show

LOH of 2p16 but instead show genomic instability, suggesting that this

CNC gene may not be a tumor suppressor. Screening and treatment of

these endocrine tumors are similar to those described earlier for

patients with MEN 1 and MEN 2 (Tables 388-3 and 388-4).

■ COWDEN’S SYNDROME

Clinical Manifestations Multiple hamartomatous lesions, especially of the skin, mucous membranes (e.g., buccal, intestinal, colonic),

breast, and thyroid, are characteristic of Cowden’s syndrome (CWS),

which is an autosomal dominant disorder. Thyroid abnormalities

occur in two-thirds of patients with CWS, and these usually consist of

multinodular goiters or benign adenomas, although <10% of patients

may have a follicular thyroid carcinoma. Breast abnormalities occur in

>75% of patients and consist of either fibrocystic disease or adenocarcinomas. The investigation and treatment for CWS tumors are similar

to those undertaken for non-CWS patients.

Genetics and Screening CWS is genetically heterogenous,

and seven types (CWS1–7) are recognized (Table 388-2). CWS1 is

due to mutations of the phosphate and tensin homologue deleted

on chromosome 10 (PTEN) gene, located on chromosome 10q23.31.

CWS2 is caused by mutations of the succinate dehydrogenase subunit

B (SDHB) gene, located on chromosome 1p36.13; and CWS3 is caused

by mutations of the SDHD gene, located on chromosome 11q13.1.

SDHB and SDHD mutations are also associated with pheochromocytoma. CWS4 is caused by hypermethylation of the Killin (KLLN) gene,

the promoter of which shares the same transcription site as PTEN on

chromosome 10q23.31. CWS5 is caused by mutations of the phosphatidylinositol 3-kinase catalytic alpha (PIK3CA) gene on chromosome

3q26.32. CWS6 is caused by mutations of the V-Akt murine thymoma

viral oncogene homolog 1 (AKT1) gene on chromosome 14q32.33, and

CWS7 is caused by mutations of the saccharomyces cerevisiae homology of B (SEC23B) gene on chromosome 20p11.23. Screening for thyroid abnormalities entails neck ultrasonography and fine-needle

aspiration with analysis of cell cytology.

■ MCCUNE-ALBRIGHT SYNDROME

(SEE ALSO CHAP. 412)

Clinical Manifestations McCune-Albright syndrome (MAS) is

characterized by the triad of polyostotic fibrous dysplasia, which

may be associated with hypophosphatemic rickets; café au lait skin

pigmentation; and peripheral precocious puberty. Other endocrine

abnormalities include thyrotoxicosis, which may be associated with

a multinodular goiter, somatotrope tumors, and Cushing’s syndrome

(due to adrenal tumors). Investigation and treatment for each endocrinopathy are similar to those used in patients without MAS.

Genetics and Screening MAS is a disorder of mosaicism

that results from postzygotic somatic cell mutations of the G protein α-stimulating subunit (Gs

α), encoded by the GNAS1 gene,

located on chromosome 20q13.32 (Table 388-2). The Gs

α mutations,

which include Arg201Cys, Arg201His, Glu227Arg, or Glu227His, are

activating and are found only in cells of the abnormal tissues. Screening

for hyperfunction of relevant endocrine glands and development of

hypophosphatemia, which may be associated with elevated serum

fibroblast growth factor 23 (FGF23) concentrations, is undertaken in

MAS patients.

Acknowledgment

The author is grateful to the National Institute of Health Research

(NIHR) Oxford Biomedical Research Centre Programme for support and

to Mrs. Tracey Walker for typing the manuscript.

■ FURTHER READING

Brandi ML et al: Multiple endocrine neoplasia type 1: Latest insights.

Endocr Rev 42:133, 2021.

Cardoso L et al: Molecular genetics of syndromic and non-syndromic

forms of parathyroid carcinoma. Hum Mutat 38:1621, 2017.

Frederiksen A et al: Clinical features of multiple endocrine neoplasia

type 4: Novel pathogenic variant and review of published cases. J Clin

Endocrinol Metab 1:3637, 2019.

Frost M et al: Current and emerging therapies for PNETs in patients

with or without MEN1. Nat Rev Endocrinol 14:216, 2018.

Hannan FM et al: The calcium-sensing receptor in physiology and in

calcitropic and noncalcitropic diseases. Nat Rev Endocrinol 15:33,

2018.

Parghane RV et al: Clinical utility of 177 Lu-DOTATATE PRRT in

somatostatin receptor-positive metastatic medullary carcinoma of

thyroid patients with assessment of efficacy, survival analysis, prognostic variables, and toxicity. Head Neck 4:401, 2020.

Salpea P, Stratakis CA: Carney complex and McCune Albright syndrome: An overview of clinical manifestations and human molecular

genetics. Mol Cell Endocrinol 386:85, 2014.

Thakker RV et al: Clinical practice guidelines for multiple endocrine

neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97:2990, 2012.

Wells SA Jr et al: Revised American Thyroid Association guidelines

for the management of medullary thyroid carcinoma. Thyroid

25:567, 2015.

Wirth LJ et al: Efficacy of selpercatinib in RET-altered thyroid cancers.

N Engl J Med 383:825, 2020.

Polyglandular deficiency syndromes have been given many different

names, reflecting the wide spectrum of disorders that have been associated with these syndromes and the heterogeneity of their clinical

presentations. The name used in this chapter for this group of disorders is autoimmune polyendocrine syndrome (APS). In general, these

disorders are divided into two major categories, APS type 1 (APS-1)

and APS type 2 (APS-2). Some groups have further subdivided APS-2

into APS type 3 (APS-3) and APS type 4 (APS-4) depending on the

type of autoimmunity involved. For the most part, this additional classification does not clarify our understanding of disease pathogenesis

or prevention of complications in individual patients. Importantly,

there are many nonendocrine disease associations included in these

syndromes, suggesting that although the underlying autoimmune disorder predominantly involves endocrine targets, it does not exclude

other tissues. The disease associations found in APS-1 and APS-2

are summarized in Table 389-1. Understanding these syndromes and

their disease manifestations can lead to early diagnosis and treatment

of additional disorders in patients and their family members.

■ APS-1

APS-1 (Online Mendelian Inheritance in Man [OMIM] 240300) has also

been called autoimmune polyendocrinopathy–candidiasis–ectodermal

389 Autoimmune

Polyendocrine Syndromes

Peter A. Gottlieb, Aaron W. Michels

2993Autoimmune Polyendocrine Syndromes CHAPTER 389

Clinical Manifestations Classical APS-1 develops very early in

life, often in infancy (Table 389-2). Chronic mucocutaneous candidiasis without signs of systemic disease is often the first manifestation.

It affects the mouth and nails more frequently than the skin and

esophagus. Chronic oral candidiasis can result in atrophic disease

with areas suggestive of leukoplakia, which can pose a risk for future

carcinoma. The etiology is associated with anticytokine autoantibodies

(anti-interleukin [IL] 17A, IL-17F, and IL-22) related to T helper (TH)

17 T cells and depressed production of these cytokines by peripheral

blood mononuclear cells. Hypoparathyroidism usually develops next,

followed by adrenal insufficiency. The time from development of one

component of the disorder to the next can be many years, and the order

of disease appearance is variable.

Chronic candidiasis is nearly always present and is not very responsive to treatment. Hypoparathyroidism is found in >85% of cases, and

Addison’s disease is found in nearly 80%. Gonadal failure appears to

affect women more than men (70 vs 25%, respectively), and hypoplasia

of the dental enamel also occurs frequently (77% of patients). Other

endocrine disorders that occur less frequently include type 1 diabetes (23%) and autoimmune thyroid disease (18%). Nonendocrine

manifestations that present less frequently include alopecia (40%),

vitiligo (26%), intestinal malabsorption (18%), pernicious anemia

(31%), chronic active hepatitis (17%), and nail dystrophy. An unusual

and debilitating manifestation of the disorder is the development of

refractory diarrhea/obstipation that may be related to autoantibodymediated destruction of enterochromaffin or enterochromaffin-like

cells. The incidence rates for many of these disorders peak in the first or

second decade of life, but the individual disease components continue

to emerge over time. Therefore, prevalence rates may be higher than

originally reported.

Diagnosis The diagnosis of APS-1 is usually made clinically when

two of the three major component disorders are found in an individual patient. Siblings of individuals with APS-1 should be considered

affected even if only one component disorder has been detected due to

the known inheritance of the syndrome. Genetic analysis of the AIRE

gene should be undertaken to identify mutations. Detection of anti–

interferon α and anti–interferon ω antibodies can identify nearly 100%

of cases with APS-1. The autoantibody arises independent of the type of

AIRE gene mutation and is not found in other autoimmune disorders.

Diagnosis of each underlying disorder should be done based on their

typical clinical presentations (Table 389-3). Mucocutaneous candidiasis may present throughout the gastrointestinal tract, and it may be

detected in the oral mucosa or from stool samples. Evaluation by a gastroenterologist to examine the esophagus for candidiasis or secondary

stricture may be merited based on symptoms. Other gastrointestinal

TABLE 389-1 Disease Associations with Autoimmune Polyendocrine

Syndromes

AUTOIMMUNE

POLYENDOCRINE

SYNDROME TYPE 1

AUTOIMMUNE

POLYENDOCRINE

SYNDROME TYPE 2

OTHER AUTOIMMUNE

POLYENDOCRINE

DISORDERS

Endocrine Endocrine IPEX (immune dysfunction

polyendocrinopathy

X-linked)

Addison’s disease Addison’s disease Thymic tumors

Hypoparathyroidism Type 1 diabetes Anti-insulin receptor

antibodies

Hypogonadism Graves’ disease or

autoimmune thyroiditis

POEMS syndrome

 Graves’ disease or

autoimmune thyroiditis

Hypogonadism Insulin autoimmune

syndrome (Hirata’s

syndrome)

Type 1 diabetes Adult combined pituitary

hormone deficiency

(CPHD) with anti-Pit1

autoantibodies

Kearns-Sayre syndrome

DIDMOAD syndrome

Nonendocrine Nonendocrine Congenital rubella

associated with thyroiditis

and/or diabetes

 Mucocutaneous

candidiasis

Celiac disease,

dermatitis

herpetiformis

 Chronic active

hepatitis

Pernicious anemia

Pernicious anemia Vitiligo

Vitiligo Alopecia

Asplenism Myasthenia gravis

Ectodermal dysplasia IgA deficiency

Alopecia Parkinson’s disease

 Malabsorption

syndromes

Idiopathic

thrombocytopenia

IgA deficiency

Abbreviations: DIDMOAD, diabetes insipidus, diabetes mellitus, progressive

bilateral optic atrophy, and sensorineural deafness; POEMS, polyneuropathy,

organomegaly, endocrinopathy, M-protein, and skin changes.

Note: Italics denote less common disorders.

TABLE 389-2 Comparison of APS-1 and APS-2

APS-1 APS-2

Early onset: infancy Later onset

Siblings often affected and at risk Multigenerational

Equivalent sex distribution Females > males affected

Monogenic: AIRE gene, chromosome

21, autosomal recessive

Polygenic: HLA, MICA, PTNP22, CTLA4

Not HLA associated for entire

syndrome, some specific component

risk

DR3/DR4 associated; other HLA

class III gene associations noted

Autoantibodies to type 1 interferons

and IL-17 and IL-22

No autoantibodies to cytokines

Autoantibodies to specific target

organs

Autoantibodies to specific target

organs

Asplenism No defined immunodeficiency

Mucocutaneous candidiasis Association with other nonendocrine

immunologic disorders like myasthenia

gravis and idiopathic thrombocytopenic

purpura

Abbreviations: APS, autoimmune polyendocrine syndrome; HLA, human leukocyte

antigen; IL, interleukin.

dystrophy (APECED). Mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease form the three major components of this

disorder. However, as summarized in Table 389-1, many other organ

systems can be involved over time. APS-1 is rare, with <500 cases

reported in the literature.

The classical form of APS-1 is an autosomal recessive disorder

caused by mutations in the AIRE gene (autoimmune regulator gene)

found on chromosome 21. This gene is most highly expressed in thymic medullary epithelial cells (mTECs) where it controls the expression

of tissue-specific self-antigens (e.g., insulin). Deletion of this regulator

leads to decreased expression of tissue-specific self-antigens and is

hypothesized to allow autoreactive T cells to avoid central deletion,

which normally occurs during T-cell maturation in the thymus. The

AIRE gene is also expressed in epithelial cells found in peripheral

lymphoid organs, but its role in these extrathymic cells remains controversial. To date, >100 mutations have been described in this gene,

and there is a higher frequency within certain ethnic groups including Iranian Jews, Sardinians, Finns, Norwegians, and Irish. Recently,

several autosomal dominant mutations have been identified and are

localized primarily in the PHD1 domain of the AIRE gene, rather than

the CARD region, where the autosomal recessive mutations have been

found. Individuals with this nonclassical form of APS-1 may have a

later onset of symptoms and less aggressive disease, without the full

spectrum of autoimmune components being expressed.

2994 PART 12 Endocrinology and Metabolism

manifestations of APS-1, including malabsorption and obstipation, may

also bring these young patients to the attention of gastroenterologists for

first evaluation. Specific physical examination findings of hyperpigmentation, vitiligo, alopecia, tetany, and signs of hyper- or hypothyroidism

should be considered as signs of development of component disorders.

The development of disease-specific autoantibody assays can help

confirm disease and also detect risk for future disease. For example,

where possible, detection of anticytokine antibodies to IL-17 and IL-22

would confirm the diagnosis of mucocutaneous candidiasis due to APS-1.

The presence of anti-21-hydroxylase antibody or anti-17-hydroxylase

antibody (which may be found more commonly in adrenal insufficiency associated with APS-1) would confirm the presence or risk for

Addison’s disease. Other autoantibodies found in type 1 diabetes (e.g.,

anti-GAD65), pernicious anemia, and other component conditions

should be screened for on a regular basis (6- to 12-month intervals

depending on the age of the subject).

Laboratory tests, including a complete metabolic panel, phosphorous

and magnesium, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH; morning), hemoglobin A1c, plasma vitamin B12

level, and complete blood count with peripheral smear looking for

Howell-Jolly bodies (asplenism), should also be performed at these

time points. Detection of abnormal physical findings or test results

should prompt subsequent examinations of the relevant organ system

(e.g., presence of Howell-Jolly bodies indicates need for ultrasound of

spleen).

TREATMENT

APS-1

Therapy of individual disease components is carried out as outlined

in other relevant chapters. Replacement of deficient hormones

(e.g., adrenal, pancreas, ovaries/testes) will treat most of the endocrinopathies noted. Several unique issues merit special emphasis.

Adrenal insufficiency can be masked by primary hypothyroidism

by prolonging the half-life of cortisol. The caveat therefore is that

replacement therapy with thyroid hormone can precipitate an

adrenal crisis in an undiagnosed individual. Hence, all patients

with hypothyroidism and the possibility of APS should be screened

for adrenal insufficiency to allow treatment with glucocorticoids

prior to the initiation of thyroid hormone replacement. Treatment of

mucocutaneous candidiasis with ketoconazole in an individual with

subclinical adrenal insufficiency may also precipitate adrenal crisis.

Furthermore, mucocutaneous candidiasis may be difficult to eradicate entirely. Severe cases of disease involvement may require systemic immunomodulatory therapy, but this is not commonly needed.

■ APS-2

APS-2 (OMIM 269200) is more common than APS-1, with a prevalence of 1–2 in 100,000. It has a gender bias and occurs more often in

female patients, with a ratio of at least 3:1 compared to male patients.

In contrast to APS-1, APS-2 often has its onset in adulthood, with a

peak incidence between 20 and 60 years of age. It shows a familial,

multigenerational heritage (Table 389-2). The presence of two or more

of the following endocrine deficiencies in the same patient defines

the presence of APS-2: primary adrenal insufficiency (Addison’s disease; 50–70%), Graves’ disease or autoimmune thyroiditis (15–69%),

type 1 diabetes mellitus (T1D; 40–50%), and primary hypogonadism.

Frequently associated autoimmune conditions include celiac disease

(3–15%), myasthenia gravis, vitiligo, alopecia, serositis, and pernicious

anemia. These conditions occur with increased frequency in affected

patients but are also are found in their family members (Table 389-3).

Genetic Considerations The overwhelming risk factor for

APS-2 has been localized to the genes in the human lymphocyte

antigen (HLA) complex on chromosome 6. Primary adrenal insufficiency in APS-2, but not APS-1, is strongly associated with both

HLA-DR3 and HLA-DR4. Other class I and class II genes and alleles,

such as HLA-B8, HLA-DQ2 and HLA-DQ8, and HLA-DR subtypes

such as DRB1*

04:04, appear to contribute to organ-specific disease susceptibility (Table 389-4). HLA-B8- and HLA-DR3-associated illnesses

include selective IgA deficiency, juvenile dermatomyositis, dermatitis

herpetiformis, alopecia, scleroderma, autoimmune thrombocytopenia

purpura, hypophysitis, metaphyseal osteopenia, and serositis.

Several other immune genes have been proposed to be associated

with Addison’s disease and therefore with APS-2 (Table 389-3). The

“5.1” allele of a major histocompatibility complex (MHC) gene is an

atypical class I HLA molecule MIC-A. The MIC-A5.1 allele has a very

strong association with Addison’s disease that is not accounted for

by linkage disequilibrium with DR3 or DR4. Its role is complicated

because certain HLA class I genes can offset this effect. PTPN22 codes

for a polymorphism in a protein tyrosine phosphatase, which acts on

TABLE 389-3 Clinical Features and Recommended Follow-Up for

APS-1 and APS-2

COMPONENT DISEASE RECOMMENDED EVALUATION

APS-1

Addison’s disease Sodium, potassium, ACTH, cortisol, 21- and

17-hydroxylase autoantibodies

Diarrhea History

Ectodermal dysplasia Physical examination

Hypoparathyroidism Serum calcium, phosphate, PTH

Hepatitis Liver function tests

Hypothyroidism/Graves’

disease

TSH; thyroid peroxidase and/or thyroglobulin

autoantibodies and anti-TSH receptor Ab

Male hypogonadism FSH/LH, testosterone

Malabsorption Physical examination, anti-IL-17 and anti-IL-22

autoantibodies

Mucocutaneous candidiasis Physical examination, mucosal swab, stool

samples

Obstipation History

Ovarian failure FSH/LH, estradiol

Pernicious anemia CBC, vitamin B12 levels

Splenic atrophy Blood smear for Howell-Jolly bodies; platelet

count; ultrasound if positive

Type 1 diabetes Glucose, hemoglobin A1c, diabetes-associated

autoantibodies (insulin, GAD65, IA-2, ZnT8)

APS-2

Addison’s disease 21-Hydroxylase autoantibodies, ACTH

stimulation testing if positive

Alopecia Physical examination

Autoimmune hyper- or

hypothyroidism

TSH; thyroid peroxidase and/or thyroglobulin

autoantibodies, anti-TSH receptor Ab

Celiac disease Transglutaminase autoantibodies; small

intestine biopsy if positive

Cerebellar ataxia Dictated by signs and symptoms of disease

Chronic inflammatory

demyelinating polyneuropathy

Dictated by signs and symptoms of disease

Hypophysitis Dictated by signs and symptoms of disease,

anti-Pit1 autoantibody

Idiopathic heart block Dictated by signs and symptoms of disease

IgA deficiency IgA level

Myasthenia gravis Dictated by signs and symptoms of disease,

antiacetylcholinesterase Ab

Myocarditis Dictated by signs and symptoms of disease

Pernicious anemia Anti–parietal cell autoantibodies

CBC, vitamin B12 levels if positive

Serositis Dictated by signs and symptoms of disease

Stiff man syndrome Dictated by signs and symptoms of disease

Vitiligo Physical examination, NALP-1 polymorphism

Abbreviations: Ab, antibody; ACTH, adrenocorticotropic hormone; APS, autoimmune

polyendocrine syndrome; CBC, complete blood count; FSH, follicle-stimulating

hormone; IL, interleukin; LH, luteinizing hormone; PTH, parathyroid hormone; TSH,

thyroid-stimulating hormone.

2995Autoimmune Polyendocrine Syndromes CHAPTER 389

TABLE 389-4 APS-2 and Other Polyendocrine Disorder Associations

DISEASE HLA ASSOCIATION INITIATING FACTOR MECHANISM AUTOANTIGEN

Graves’ disease DR3 Iodine

Anti-CD52

Antibody TSH receptor

Myasthenia gravis DR3, DR7 Thymoma

Penicillamine

Antibody Acetylcholine receptor

Anti-insulin receptor ? SLE or other

autoimmune disease

Antibody Insulin receptor

Hypoparathyroidism ? ? Antibody Cell surface inhibitor

Insulin autoimmune

syndrome

DR4, DRB1*

0406 Methimazole

Sulfhydryl-containing

drugs

Antibody Insulin

Celiac disease DQ2/DQ8 Gluten diet T cell Transglutaminase

Type 1 diabetes DR3/DR4

DQ2/DQ8

?

Congenital rubella

T cell Insulin, GAD65, IA-2,

ZnT8, IGRP

Addison’s disease DR3/DR4

DRB1*

0404

Unknown T cell 21-Hydroxylase

P450-5cc

Thyroiditis DR3/DQB1*

0201

DQA1*

0301

Iodine

Interferon α

T cell Thyroglobulin

Thyroid peroxidase

Pernicious anemia ? ? T cell Intrinsic factor

H+/K+ ATPase

Vitiligo ? Melanoma

Antigen Immunization

? Melanocyte

Chromosome

dysgenesis–trisomy 21

and Turner’s syndrome

DQA1*

0301 ? ? Thyroid, islet,

transglutaminase

Hypophysitis ? Pit-1, TDRD6 ? Pituitary, Pit-1

Abbreviations: APS, autoimmune polyendocrine syndrome; SLE, systemic lupus erythematosus; TSH, thyroidstimulating hormone.

intracellular signaling pathways in both T and B lymphocytes. It has

been implicated in T1D, Addison’s disease, and other autoimmune conditions. CTLA4 is a receptor on the T-cell surface that modulates the

activation state of the cell as part of the signal 2 pathway (i.e., binding

to CD80/86 on antigen presenting cells). Polymorphisms of this gene

appear to cause downregulation of the cell surface expression of the

receptor, leading to decreased T-cell activation and proliferation. This

appears to contribute to Addison’s disease and potentially other components of APS-2. Allelic variants of the IL-2Rα are linked to development of T1D and autoimmune thyroid disease and could contribute to

the phenotype of APS-2 in certain individuals.

Diagnosis When one of the component disorders is present, a

second associated disorder occurs more commonly than in the general

population (Table 389-3). There is controversy as to which tests to use

and how often to screen individuals for disease. A strong family history

of autoimmunity should raise suspicion in an individual with an initial

component diagnosis. The development of a rarer form of autoimmunity, such as Addison’s disease, should prompt more extensive screening for other linked disorders, as ~50% of Addison’s disease patients

develop another autoimmune disease during their lifetime.

Circulating autoantibodies, as previously discussed, can precede

the development of clinical disease by many years but would allow

the clinician to follow the patient and identify the disease onset at its

earliest time point (Tables 389-3 and 389-4). For each of the endocrine components of the disorder, appropriate autoantibody assays are

listed and, if positive, should prompt physiologic testing to diagnose

clinical or subclinical disease. For Addison’s disease, antibodies to

21-hydroxylase antibodies are highly diagnostic for risk of adrenal

insufficiency. However, individuals may take many years to develop

overt symptoms of hypoadrenalism. Screening of 21-hydroxylase antibody–positive patients can be performed measuring morning ACTH

and cortisol on a yearly basis. Rising ACTH values over time or low

morning cortisol in association with signs or symptoms of adrenal

insufficiency should prompt testing via the cosyntropin stimulation

test (Chap. 386). T1D can be screened for by measuring autoantibodies

directed against insulin, GAD65, IA-2,

and ZnT8. Risk for progression to disease

is based on the number of antibodies (≥2

islet autoantibodies with normal glucose

tolerance is now defined as stage 1 of

T1D as the lifetime risk for developing

clinical symptoms is nearly 100%) and

metabolic factors (impaired oral glucose

tolerance test). Many efforts are ongoing

and underway to screen relatives of T1D

patients and those in the general population for islet autoantibodies to identify

prediabetic individuals who may qualify for intervention trials to change the

course of the disease prior to clinical

onset.

Screening tests for thyroid disease can

include anti–thyroid peroxidase (TPO)

or anti-thyroglobulin autoantibodies or

anti-TSH receptor antibodies for Graves’

disease. Yearly measurements of TSH can

then be used to follow these individuals. Celiac disease can be screened for

using the anti–tissue transglutaminase

(tTg) antibody test. For those <20 years

of age, testing every 1–2 years should be

performed, whereas less frequent testing

is indicated after the age of 20 because

the majority of individuals who develop

celiac disease have the antibody earlier

in life. Positive tTg antibody test results

should be confirmed on repeat testing,

followed by small-bowel biopsy to document pathologic changes of celiac disease. Many patients have asymptomatic celiac disease that is nevertheless associated with osteopenia

and impaired growth. If left untreated, symptomatic celiac disease has

been reported to be associated with an increased risk of gastrointestinal

malignancy, especially lymphoma, and osteoporosis later in life.

The knowledge of the particular disease associations should guide

other autoantibody or laboratory testing. A complete history and physical examination should be performed every 1–3 years including CBC,

metabolic panel, TSH, and vitamin B12 levels to screen for most of the

possible abnormalities. More specific tests should be based on specific

findings from the history and physical examination.

TREATMENT

APS-2

With the exception of Graves’ disease, the management of each

endocrine component of APS-2 involves hormone replacement and

is covered in detail in the chapters on adrenal (Chap. 386), thyroid

(Chap. 382), gonadal (Chaps. 391 and 392), and parathyroid diseases (Chap. 410). As noted for APS-1, adrenal insufficiency can be

masked by primary hypothyroidism and should be considered and

treated as discussed above. In patients with T1D, decreasing insulin

requirements or hypoglycemia, without obvious secondary causes,

may indicate the emergence of adrenal insufficiency. Hypocalcemia

in APS-2 patients is more likely due to malabsorption, potentially

from undiagnosed celiac disease, than hypoparathyroidism.

Immunotherapy for autoimmune endocrine disease has been

reserved for T1D, for the most part, reflecting the lifetime burden of

the disease for the individual patient and society. Although several

immunotherapies (e.g., modified anti-CD3, rituximab, abatacept,

alefacept, low-dose antithymocyte globulin) can prolong the honeymoon phase of T1D, none has achieved long-term success. The

anti-CD3 monoclonal antibody (teplizumab) does delay the onset

of clinical diabetes by an average of 2 years when administered to

individuals with stage 2 T1D (e.g., those with autoantibodies and