2996 PART 12 Endocrinology and Metabolism

impaired glucose tolerance). Active basic and clinical research

using new approaches and combination therapy may change the

treatment of this disease or other autoimmune conditions that share

similar pathways.

■ IMMUNE CHECKPOINT INHIBITOR–INDUCED

ENDOCRINE AUTOIMMUNITY

Therapies that block immune checkpoints, such as programmed

cell death protein 1 (PD-1), its ligand (PD-L1), or CTLA-4, are beneficial immunotherapies for many advanced-stage cancers. These

immune checkpoint inhibitors (ICIs) block negative immune regulation, thereby allowing for an immune response directed against tumor

cells. However, immune-related adverse events also occur, especially

autoimmunity directed toward self-tissues. ICI-induced T1D, thyroid

disease, hypophysitis, and adrenal insufficiency have all been reported

with these therapies. Hypothyroidism occurs in ~8% and T1D in 1%

of those receiving monoclonal antibodies directed against PD-1 or

PD-L1, and hypophysitis and adrenal insufficiency occur in <1% of

treated patients. These autoimmune side effects can develop during

or after therapy, mostly within a few weeks to months following the

start of therapy. ICI-induced T1D has a very rapid onset, presents with

diabetic ketoacidosis, is permanent, and requires lifelong exogenous

insulin therapy for treatment. There is a genetic association with

HLA-DR4 and islet autoantibodies in ~40–50% of patients at diagnosis.

The pathogenesis is immune mediated as T lymphocyte infiltration

has been documented in the pancreatic islets of an ICI-T1D patient.

Determining the mechanisms of autoimmune disease development

following ICI therapies and developing biomarkers to stratify risk for

autoimmune side effects prior to therapy are active areas of research.

■ IPEX

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked

disease (IPEX; OMIM 304790) is a rare X-linked recessive disorder. The disease onset is in infancy and is characterized by severe

enteropathy, T1D, and skin disease, as well as variable association

with several other autoimmune disorders. Many infants die within

the first days of life, but the course is variable, with some children surviving for 12–15 years. Early onset of T1D, often at birth,

is highly suggestive of the diagnosis because nearly 80% of IPEX

patients develop T1D. Although treatment of the individual disorders

can temporarily improve the situation, treatment of the underlying

immune deficiency is required and includes immunosuppressive

therapy generally followed by hematopoietic stem cell transplantation.

Transplantation is the only life-saving form of therapy and can be fully

curative by normalizing the imbalanced immune system found in this

disorder.

IPEX is caused by mutations in the FOXP3 gene, which is also

mutated in the Scurfy mouse, an animal model that shares much of

the same phenotype of IPEX patients. The FOXP3 transcription factor

is expressed in regulatory T cells designated CD4+CD25+FOXP3+

(Treg). Lack of this factor causes a profound deficiency of this Treg

population and results in rampant autoimmunity due to the lack of

peripheral tolerance normally provided by these cells. Certain mutations may lead to varying forms of expression of the full syndrome,

and there are rare cases where the FOXP3 gene is intact but other genes

involved in this pathway (e.g., CD25, IL-2Rα) may be causative. Future

therapy with autologous CD4+ T cells transfected with a functioning

FOXP3 gene may offer a better long-term outcome than has been seen

in those treated with stem cell transplantation.

■ THYMIC TUMORS

Thymomas and thymic hyperplasia are associated with several autoimmune diseases, with the most common being myasthenia gravis

(44%) and red cell aplasia (20%). Graves’ disease, T1D, and Addison’s

disease may also be associated with thymic tumors. Patients with

myasthenia gravis and thymoma may have unique anti–acetylcholine

receptor autoantibodies. Most thymomas lack AIRE expression within

the thymoma, and this could be a potential factor in the development

of autoimmunity. In support of this concept, thymoma is the one

other disease with “frequent” development of anticytokine antibodies

and mucocutaneous candidiasis in adults. The majority of tumors are

malignant, and temporary remissions of the autoimmune condition

can occur with resection of the tumor.

■ ANTI-INSULIN RECEPTOR ANTIBODIES

This is a very rare disorder where severe insulin resistance (type B) is

caused by the presence of anti-insulin receptor antibodies. It is associated with acanthosis nigricans, which can also be associated with other

forms of less severe insulin resistance. About one-third of patients

have an associated autoimmune illness such as systemic lupus erythematosus or Sjögren’s syndrome. Therefore, the presence of antinuclear

antibodies, elevated erythrocyte sedimentation rate, hyperglobulinemia, leukopenia, and hypocomplementemia may accompany the presentation. The presence of anti-insulin receptor autoantibodies leads

to marked insulin resistance, requiring >100,000 units of insulin to be

given daily with only partial control of hyperglycemia. Patients can also

have severe hypoglycemia due to partial activation of the insulin receptor by the antibody. The course of the disease is variable, and several

patients have had spontaneous remissions. A therapeutic approach that

targets B lymphocytes, including rituximab, cyclophosphamide, and

pulse steroids, has been validated in follow-on case reports to induce

remission of the disease.

■ INSULIN AUTOIMMUNE SYNDROME

(HIRATA’S SYNDROME)

The insulin autoimmune syndrome, associated with Graves’ disease and

methimazole therapy (or other sulfhydryl-containing medications), is

of particular interest due to a remarkably strong association with a specific HLA haplotype. Such patients with elevated titers of anti-insulin

antibodies frequently present with hypoglycemia. In Japan, the disease

is restricted to HLA-DR4-positive individuals with DRB1*

04:06, while

Caucasian patients predominantly have DRB1*

04:03 (which is related

to DRB1*

04:06). In Hirata’s syndrome, the anti-insulin antibodies are

often polyclonal. Discontinuation of the medication generally leads

to resolution of the syndrome over time. There are very rare cases of

insulin autoimmune syndrome not associated with sulfhydryl-containing

medications that result in profound, life-threatening hypoglycemia.

Treatment involves treating the underlying condition that causes antiinsulin antibodies, such as a B lymphocyte lymphoma (tend to have

monoclonal insulin antibodies) or systemic lupus erythematosus. As

hypoglycemia is profound when elevated titers of high affinity insulin

antibodies bind secreted insulin and then release it into circulation,

treatment that begins with high-dose glucocorticoids and rituximab to

target B lymphocytes has been shown to be effective.

■ POEMS SYNDROME

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein,

and skin changes; also known as Crow-Fukase syndrome; OMIM

192240) patients usually present with a progressive sensorimotor

polyneuropathy, diabetes mellitus (50%), primary gonadal failure

(70%), and a plasma cell dyscrasia with sclerotic bony lesions. Associated findings can be hepatosplenomegaly, lymphadenopathy, and

hyperpigmentation. Patients often present in the fifth to sixth decade

of life and have a median survival after diagnosis of <3 years. The

syndrome is assumed to be secondary to circulating immunoglobulins, but patients have excess vascular endothelial growth factor as

well as elevated levels of other inflammatory cytokines such as IL1-β,

IL-6, and tumor necrosis factor α. Patients have been treated with

thalidomide, and more recently lenalidomide, leading to a decrease in

vascular endothelial growth factor. Hyperglycemia responds to small,

subcutaneous doses of insulin. The hypogonadism is due to primary

gonadal disease with elevated plasma levels of follicle-stimulating hormone and luteinizing hormone. Temporary resolution of the features

of POEMS, including normalization of blood glucose, may occur after

radiotherapy for localized plasma cell lesions of bone or after chemotherapy, lenalidomide and dexamethasone, or autologous stem cell

transplantation.

2997 Sex Development CHAPTER 390

■ OTHER DISORDERS

Other diseases can exhibit polyendocrine deficiencies, including

Kearns-Sayre syndrome, DIDMOAD syndrome (diabetes insipidus,

diabetes mellitus, progressive bilateral optic atrophy, and sensorineural

deafness; also termed Wolfram’s syndrome), Down’s syndrome or trisomy 21 (OMIM 190685), Turner’s syndrome (monosomy X, 45,X0),

and congenital rubella.

Kearns-Sayre syndrome (OMIM 530000) is a rare mitochondrial

DNA disorder characterized by myopathic abnormalities leading to

ophthalmoplegia and progressive weakness in association with several endocrine abnormalities, including hypoparathyroidism, primary

gonadal failure, diabetes mellitus, and hypopituitarism. Crystalline

mitochondrial inclusions are found in muscle biopsy specimens, and

such inclusions have also been observed in the cerebellum. Antiparathyroid antibodies have not been described; however, antibodies to the

anterior pituitary gland and striated muscle have been identified, and

the disease may have autoimmune components. These mitochondrial

DNA mutations occur sporadically and do not appear to be associated

with a familial syndrome.

Wolfram’s syndrome (OMIM 222300, chromosome 4; OMIM

598500, mitochondrial) is a rare autosomal recessive disease that is

also called DIDMOAD. Neurologic and psychiatric disturbances are

prominent in most patients and can cause severe disability. The disease

is caused by defects in the Wolfram syndrome 1 (WFS1) gene, which

encodes a 100-kDa transmembrane protein that has been localized to

the endoplasmic reticulum and is found in neuronal and neuroendocrine tissue. Its expression induces ion channel activity with a resultant

increase in intracellular calcium and may play an important role in

intracellular calcium homeostasis. Wolfram’s syndrome appears to be

a slowly progressive neurodegenerative process, and there is nonautoimmune selective destruction of the pancreatic beta cells. Diabetes

mellitus with an onset in childhood is usually the first manifestation.

Diabetes mellitus and optic atrophy are present in all reported cases,

but expression of the other features is variable. Treatments targeting

endoplasmic reticulum dysfunction are being tested and may be a

bridge until gene therapy can be developed to treat the most severely

affected cases.

Down’s syndrome, or trisomy 21 (OMIM 190685), is associated with

the development of T1D, thyroiditis, and celiac disease. Patients with

Turner’s syndrome also appear to be at increased risk for the development of thyroid disease and celiac disease. It is recommended to

screen patients with trisomy 21 and Turner’s syndrome for associated

autoimmune diseases on a regular basis.

■ GLOBAL CONSIDERATIONS

Identification of these syndromes requires access to central laboratories with the ability to detect unique autoantibodies and to sequence

the specific genes that may underlie these disorders. Early recognition

of the clinical features of these disorders and timely referral and/or

consultation with tertiary care centers to confirm the diagnosis and

initiate therapy are important to improving outcomes. The AIRE

recessive gene mutations found in APS-1 were originally described in

high frequency in several populations including Finns, Iranian Jews,

Sardinians, Norwegians, and Irish. Although individuals from many

other countries have now been found to have these mutations and the

newly identified dominant AIRE gene mutations, understanding the

frequency in the background population may raise the clinician’s level

of suspicion for these rare disorders. Hirata’s syndrome was originally

reported in Japanese populations but also may be found in other populations, as noted.

■ FURTHER READING

Anderson MS, Su MA: AIRE expands: New roles in immune tolerance and beyond. Nat Rev Immunol 16:247, 2016.

Husebye ES et al: Autoimmune polyendocrine syndromes. N Engl J

Med 378:1132, 2018.

Postow MA et al: Immune-related adverse events associated with

immune checkpoint blockade. N Engl J Med 378:158, 2018.

Section 2 Sex- and Gender-Based

Medicine

390 Sex Development

Courtney Finlayson, J. Larry Jameson,

John C. Achermann

Sex development begins in utero but continues into young adulthood

with the achievement of sexual maturity and reproductive capability.

The major determinants of sex development can be divided into three

components: chromosomal sex, gonadal sex (sex determination), and

phenotypic sex (sex differentiation) (Fig. 390-1). Variations at each

of these stages can result in differences (or disorders) of sex development (DSDs) (Table 390-1). In the newborn period, ~1 in 5000 babies

undergo investigation because of atypical or ambiguous genitalia.

Urgent assessment is indicated, because some causes such as congenital adrenal hyperplasia (CAH) can be associated with life-threatening

adrenal crises. An experienced multidisciplinary team is important for

counseling, planning appropriate investigations, discussing long-term

well-being, supporting parents, and providing clear communication

about the diagnosis and management options. DSDs can also present at

other ages and to a range of health professionals (Table 390-2). Subtler

forms of gonadal dysfunction (e.g., Klinefelter syndrome [KS], Turner

syndrome [TS]) often are diagnosed later in life by internists. Because

DSDs are associated with a variety of psychological, reproductive, and

potential medical consequences, an open dialogue must be established

between the patient and health care providers to ensure continuity

and attention to these issues across the life span. Gender variance and

gender dysphoria are more common among some individuals with

DSD than in the general population. Thus, attention to and comfort

discussing gender identity is important. Support groups also have a

valuable role to play for many patients and families.

Care of individuals with DSDs has evolved from primarily focusing

on medical and surgical intervention to “genitalia” to a more holistic

approach involving medical, surgical, and psychosocial care, acknowledging that the best way to care for individuals with DSD is not always

clear and should be individualized. This includes many controversies,

particularly concerning whether genitoplasty or prophylactic gonadectomy in selected conditions should be performed for infants and young

children prior to the age of consent. Accepted nomenclature is also

controversial. Previous terms such as intersex and hermaphrodite were

Testis-determining

genes

Gonadal steroids

& peptides

(T, DHT, AMH/MIS)

Gonadal steroids

(E2)

Ovary-determining

genes

XX

Chromosomal Sex

Gonadal Sex

Phenotypic Sex

XY

FIGURE 390-1 Sex development can be divided into three major components:

chromosomal sex, gonadal sex, and phenotypic sex. AMH, anti-müllerian hormone

also known as Müllerian-inhibiting substance, MIS; DHT, dihydrotestosterone;

T, testosterone.

2998 PART 12 Endocrinology and Metabolism

changed by the 2006 Consensus Statement to disorder of sex development

and ovotesticular DSD, but these terms are not universally accepted.

SEX DEVELOPMENT

Chromosomal sex, defined by a karyotype, describes the X and/or Y

chromosome complement (46,XY; 46,XX) established at the time of

fertilization. The presence of a normal Y chromosome determines

TABLE 390-1 Classification of Disorders of Sex Development (DSDs)a

SEX CHROMOSOME DSD 46,XY DSD (SEE TABLE 390-3) 46,XX DSD (SEE TABLE 390-4)

47,XXY (Klinefelter syndrome and

variants)

45,X (Turner syndrome and

variants)

45,X/46,XY mosaicism (mixed

gonadal dysgenesis)

46,XX/46,XY (chimerism/

mosaicism)

Disorders of gonadal (testis) development

Complete or partial gonadal dysgenesis (e.g., SRY, SOX9, SF1, WT1,

DMRT1, DHH, GATA4, ZFPM2, MAP3K1, ESR2, ZNRF3, SOX8, DHX37)

Impaired fetal Leydig cell function (e.g., SF1/NR5A1, CXorf6/

MAMLD1, HHAT, SAMD9)

Ovotesticular DSD

Testis regression

Disorders in androgen synthesis or action

Disorders of androgen biosynthesis

LH receptor (LHCGR)

Smith-Lemli-Opitz syndrome (DHCR7)

Steroidogenic acute regulatory (StAR) protein

Cholesterol side-chain cleavage (CYP11A1)

3β-Hydroxysteroid dehydrogenase II (HSD3B2)

17α-Hydroxylase/17,20-lyase (CYP17A1)

P450 oxidoreductase (POR)

Cytochrome b5 (CYB5A)

17β-Hydroxysteroid dehydrogenase III (HSD17B3)

5α-Reductase II (SRD5A2)

Aldo-keto reductase 1C2 (AKR1C2)

Disorders of androgen action

Androgen insensitivity syndrome

Drugs and environmental modulators

Other

Syndromic associations of male genital development

Associated with fetal growth restriction

Persistent müllerian duct syndrome

Vanishing testis syndrome

Isolated hypospadias

Congenital hypogonadotropic hypogonadism

Cryptorchidism

Environmental influences

Disorders of gonadal (ovary) development

Gonadal dysgenesis

Ovotesticular DSD

Testicular DSD (e.g., SRY+, dup SOX9, RSPO1, SF1/NR5A1,

NR2F2, WT1)

Androgen excess

Fetal

3β-Hydroxysteroid dehydrogenase II (HSD3b2)

21-Hydroxylase (CYP21A2)

P450 oxidoreductase (POR)

11β-Hydroxylase (CYP11B1)

Fetoplacental

Aromatase deficiency (CYP19)

Oxidoreductase deficiency (POR)

Maternal

Maternal virilizing tumors (e.g., luteomas)

Androgenic drugs

Other

Syndromic associations (e.g., cloacal anomalies)

Müllerian agenesis/hypoplasia (e.g., MRKH)

Uterine abnormalities (e.g., MODY5)

Vaginal atresia (e.g., McKusick-Kaufman)

Labial adhesions

a

Some experts and patient advocacy groups prefer to define DSD as differences of sex development rather than disorders of sex development.

Abbreviations: LH, luteinizing hormone; MODY, maturity-onset diabetes of the young; MRKH, Mayer-Rokitansky-Küster-Hauser syndrome.

Source: Reproduced with permission from IA Hughes et al: Consensus statement on management of intersex disorders. J Pediatr Urol 2:148, 2006.

TABLE 390-2 Presentation of Disorders of Sex Development (DSD) at Different Stages of Life

PRESENTATION FEATURES PROFESSIONAL EXAMPLES

Prenatal Karyotype-phenotype discordance Obstetrician; fetal medicine Many

Neonatal Atypical genitalia Obstetrician; neonatal medicine Many

Salt-losing crisis Pediatrician CAH (CYP21)

Childhood Hernia Surgeon CAIS

Androgenization Endocrinologist CAH (CYP21, CYP11B1)

Poor growth Pediatrician Turner, 45,X/46,XY

Associated features Oncologist/nephrologist Wilms’ tumor

Puberty Androgenization

Estrogenization

Endocrinologist

Endocrinologist

17β-HSD, 5α-reductase, SF1

Ovotestis

Absent puberty Endocrinologist Gonadal dysgenesis, CAH (CYP17A1), Turner

Post-puberty Amenorrhea Gynecologist CAIS

Adult Infertility Andrologist Klinefelter, 45,X/46,XY, SF1

Abbreviations: CAH, congenital adrenal hyperplasia; CAIS, complete androgen insensitivity syndrome; 17β-HSD, 17β-hydroxysteroid dehydrogenase deficiency; SF1,

steroidogenic factor 1 (NR5A1).

that testis development will occur even in the presence of multiple X

chromosomes (e.g., 47,XXY). Loss of an X chromosome impairs gonad

development (45,X or 45,X/46,XY mosaicism). Fetuses with no X chromosome (45,Y) are not viable.

Gonadal sex refers to the histologic and functional characteristics

of gonadal tissue as testis or ovary. The embryonic gonad is initially

“bipotential” and can develop (from ~42 days after conception) into

2999 Sex Development CHAPTER 390

Urogenital ridge

Granulosa cells Sertoli cells Leydig cells

WT1

SF1

SRY

SOX9

Other

genes

WNT4

RSPO1

FOXL2

46,XX

AMH Testosterone

DHT

46,XY

Bipotential gonad

Ovary Testis

Müllerian

regression

Follicle

development

Male sexual

differentiation

FIGURE 390-2 The genetic regulation of gonadal development. See text for

additional genes involved. AMH, anti-müllerian hormone (müllerian-inhibiting

substance); DHT, dihydrotestosterone; FOXL2, forkhead transcription factor L2;

RSPO1, R-spondin 1; SF1, steroidogenic factor 1 (also known as NR5A1); SOX9, SRYrelated HMG-box gene 9; SRY, sex-determining region on the Y chromosome; WNT4,

wingless-type MMTV integration site 4; WT1, Wilms’ tumor–related gene 1.

either a testis or an ovary (Fig. 390-2). Testis development is initiated

by expression of the gene SRY (sex-determining region on the Y chromosome). Disruption of SRY prevents testis development in 46,XY

individuals, whereas translocation of SRY in 46,XX individuals induces

testis development and a male phenotype. The main target of SRY

is SOX9 (SRY-related HMG-box gene 9). SOX9 is upregulated in the

developing testis but is suppressed in the ovary. Many other genes are

involved in testis development, including in Sertoli cell maturation and

Leydig cell differentiation/steroidogenesis. In addition to transcription

factors, these genes encode an array of signaling molecules and paracrine growth factors, some of which influence other organ systems. For

example, WT1 (Wilms’ tumor–related gene 1) acts early in the genetic

pathway and also regulates kidney development, whereas steroidogenic

factor 1 (SF1, NR5A1) influences both gonad and adrenal development.

Pathogenic variants causing loss of function of SF1 are found in ~10%

of XY patients with gonadal dysgenesis and impaired androgenization.

Of note, duplication of a related gene DAX1/NR0B1 impairs testis

development, revealing the exquisite sensitivity of the testis-determining

pathway to gene dosage effects.

Although ovarian development once was considered a “default”

genetic pathway, it is now clear that specific genes are expressed during

the earliest stages of ovary development. Some of these factors may

repress testis development (e.g., WNT4, R-spondin-1) (Fig. 390-2).

Once the ovary has formed, additional factors are required for normal

follicular development (e.g., follicle-stimulating hormone [FSH] receptor). Steroidogenesis in the ovary requires the development of follicles

that contain granulosa cells and theca cells surrounding the oocytes

(Chap. 392). Thus, there is relatively limited ovarian steroidogenesis

until puberty.

Germ cells also develop in a sex dimorphic manner. In the developing ovary, primordial germ cells (PGCs) proliferate and enter meiosis,

whereas they proliferate and then undergo mitotic arrest in the developing testis. PGC entry into meiosis is potentially initiated by retinoic

acid. The developing testis produces high levels of CYP26B1, an

enzyme that degrades retinoic acid, preventing PGC entry into meiosis.

Approximately 7 million germ cells are present in the fetal ovary in the

second trimester, and 1 million remain at birth. Only 400 are ovulated

during a woman’s reproductive life span (Chap. 392).

Phenotypic sex refers to the structures of the external and internal

genitalia and secondary sex characteristics. In addition to bipotential

gonads in the fetuses, they also initially possess internal and external

genitalia, which can develop along a male- or female-typical pathway,

with sex-specific development occurring as a result of hormone action

(Fig. 390-3). The developing testis releases anti-müllerian hormone

(AMH; also known as müllerian-inhibiting substance [MIS]) from

Sertoli cells and testosterone from Leydig cells. AMH acts through

specific receptors to cause regression of the müllerian structures from

60–80 days after conception. At ~60–140 days after conception, testosterone supports the maintenance of wolffian structures, including

the epididymides, vasa deferentia, and seminal vesicles. Testosterone is

the precursor for dihydrotestosterone (DHT), a potent androgen that

promotes development of the external genitalia, including the penis

and scrotum (60–100 days, and thereafter) (Fig. 390-3). The urogenital

sinus develops into the prostate and prostatic urethra in the male and

into the urethra and lower portion of the vagina in the female. The

genital tubercle becomes the glans penis in the male and the clitoris

in the female. The urogenital swellings form the scrotum or the labia

majora, and the urethral folds fuse to form the shaft of the penis and

the male urethra or the labia minora. In the female, wolffian ducts

regress and the müllerian ducts form the fallopian tubes, uterus, and

upper segment of the vagina. A female phenotype will develop in the

absence of the gonad, but estrogen is needed for maturation of the

uterus and breast at puberty.

The prenatal hormone environment is likely one of many factors

influencing aspects of gender identity and behavior. This is an area of

ongoing research and is beyond the scope of this chapter.

DISORDERS OF CHROMOSOMAL SEX

Variations in sex chromosome number and structure can present as

DSDs (e.g., 45,X/46,XY). KS (47,XXY) and TS (45,X) do not usually

present with genital ambiguity but are associated with gonadal dysfunction (Table 390-3).

■ KLINEFELTER SYNDROME (47,XXY)

Pathophysiology The classic form of KS (47,XXY) occurs after

meiotic nondisjunction of the sex chromosomes during gametogenesis

(40% during spermatogenesis, 60% during oogenesis). Other forms

of KS (including mosaic 46,XY/47,XXY [10–20%], 48,XXYY, and

48,XXXY) are less common. KS has an incidence of at least 1 in 1000

men, but ~75% of cases are not diagnosed. Of those diagnosed, historically only 10% were identified prepubertally. However, the advent

of noninvasive prenatal testing is leading to increased detection at an

earlier age.

Clinical Features KS is most commonly characterized by small

testes, infertility, gynecomastia, tall stature/increased leg length, and

hypogonadism in phenotypic males. At birth, most infants with KS

do not have clinical features, although there are higher rates of cryptorchidism and hypospadias. Most patients present in puberty with

arrested pubertal development caused by testicular insufficiency.

Others are diagnosed after puberty, based on low androgens, gynecomastia, or infertility. Testes are small and firm (median length 2.5 cm

[4 mL volume]; almost always <3.5 cm [12 mL]) and typically seem

inappropriately small for the degree of androgenization. Biopsies are

not usually necessary but typically reveal seminiferous tubule hyalinization and azoospermia. Other clinical features of KS are listed in

Table 390-3. Plasma concentrations of FSH and luteinizing hormone

(LH) are increased in most adults with 47,XXY, and plasma testosterone is decreased (50–75%), reflecting primary gonadal insufficiency.

Estradiol is often increased, resulting in gynecomastia (Chap. 391).

Patients with mosaic forms of KS have less severe clinical features, have

larger testes, and sometimes achieve spontaneous fertility.

TREATMENT

Klinefelter Syndrome

Growth, endocrine function, and bone mineralization should

be monitored, especially from adolescence. Educational and

psychological support is important for many individuals with

3000 PART 12 Endocrinology and Metabolism

Genital tubercle

Genital swelling

Urethral fold and groove

Clitoris

Labia minora

Labia majora

Vagina

B

Ovary

Fallopian

tube

Uterus

Vagina

Female Male

Female Male

Gonad

Mesonephros

Mullerian duct ..

Glans penis

Shaft of

penis

Scrotum

Penoscrotal

raphe

Wolffian duct

Urogenital

sinus

Epididymis

Testis

Vas

deferens

Seminal

vesicle

Prostate

A

FIGURE 390-3 Sex development. A. Internal urogenital tract. B. External genitalia.

KS. Androgen supplementation improves virilization, libido,

energy, hypofibrinolysis, and bone mineralization in men with

low testosterone levels but may occasionally worsen gynecomastia (Chap. 391). Gynecomastia can be treated by surgical reduction if it causes concern (Chap. 391). Fertility has been achieved by

using in vitro fertilization in men with oligospermia or with intracytoplasmic sperm injection (ICSI) after retrieval of spermatozoa

by testicular sperm extraction techniques. In specialized centers,

successful spermatozoa retrieval using this technique is possible in

>50% of men with nonmosaic KS. Results may be better in younger

men. After ICSI and embryo transfer, successful pregnancies can be

achieved in ~50% of these cases. The risk of transmitting chromosomal anomalies needs to be considered and counseling provided,

although this outcome is much less common than originally predicted. Long-term monitoring of men with KS is important given

the increased risk of breast cancer, cardiovascular disease, metabolic syndrome, osteoporosis, and autoimmune disorders. Because

most men with KS are never diagnosed, it is important that all

internists consider this diagnosis in men with these features who

might be seeking medical advice for other conditions.

■ TURNER SYNDROME

(GONADAL DYSGENESIS; 45,X)

Pathophysiology TS is caused by complete or partial loss of one

X chromosome and affects ~1 in 2500 women. Approximately onehalf of women with TS have a 45,X karyotype, ~20% have 45,X/46,XX

mosaicism, and the remainder have structural abnormalities of the X

chromosome such as X fragments, isochromosomes, rings, or Y chromosome material. The clinical features of TS result from haploinsufficiency of multiple X chromosomal genes (e.g., short stature homeobox,

SHOX), either directly or through effects on autosomal gene expression. However, imprinted genes are also proposed to be affected when

the inherited X has different parental origins.

Clinical Features TS is characterized by female external genitalia, short stature, hypergonadotropic hypogonadism, infertility, and

other phenotypic features (Table 390-3). Infants may present with

lymphedema, nuchal folds, low hairline, or left-sided cardiac defects or

later in childhood with unexplained growth failure or delayed puberty.

Although limited spontaneous pubertal development occurs in up to

30% of girls with TS (10%, 45,X; 60%, 45,X/46,XX) and up to 20%

have menarche, the vast majority of women with TS develop complete

ovarian insufficiency. Therefore, this diagnosis should be considered

in all women who present with primary or secondary amenorrhea and

elevated gonadotropin levels.

TREATMENT

Turner Syndrome

The management of girls and women with TS requires a multidisciplinary approach to address many potentially affected organ

systems according to TS practice guidelines. Individuals require

long-term monitoring by an experienced cardiologist to follow

3001 Sex Development CHAPTER 390

congenital heart defects (CHDs) (30%) (bicuspid aortic valve,

30–50%; coarctation of the aorta, 30%; aortic root dilation, 5%),

antibiotic prophylaxis for dental or surgical procedures, and serial

magnetic resonance imaging (MRI) of aortic root dimensions, as

progressive aortic root dilation is associated with increased risk

of aortic dissection. Individuals found to have congenital renal

and urinary tract malformations (30%) are at risk for urinary

tract infections, hypertension, and nephrocalcinosis. Hypertension

can occur independently of cardiac and renal malformations and

should be monitored and treated as in other patients with essential hypertension. Regular assessment of thyroid function, weight,

dentition, hearing, speech, vision, and educational issues should be

performed during childhood. Counseling about long-term growth

and fertility issues should be provided. Patient support groups are

active throughout the world and can play an invaluable role.

Short stature is common, and untreated final height rarely

exceeds 150 cm in nonmosaic 45,X TS. Recombinant growth hormone has been used in an attempt to increase growth, sometimes

with oxandrolone in older children. Girls with evidence of ovarian

insufficiency require estrogen replacement to induce breast and

uterine development, support growth, and maintain bone mineralization. Most physicians now initiate low-dose estrogen therapy

to induce puberty at an age-appropriate time (~11 years). Doses of

estrogen are increased gradually to allow development over a 2- to

4-year period. Progestins are added later to regulate withdrawal

bleeds. A very small percentage of women with TS have had spontaneous pregnancy, whereas others have achieved successful pregnancy after ovum donation and in vitro fertilization, but the risks of

cardiac complications are high, and expert counseling and management are needed. Long-term follow-up of women with TS includes

careful surveillance of sex hormone replacement and reproductive

function, bone mineralization, cardiac function and aortic root

dimensions, blood pressure, weight and glucose tolerance, hepatic

and lipid profiles, thyroid function, skin examination, and hearing.

This service is provided by a dedicated TS clinic in some centers.

■ 45,X/46,XY MOSAICISM

The phenotype of individuals with 45,X/46,XY mosaicism (sometimes

called mixed gonadal dysgenesis) can vary considerably. Some have a

predominantly female phenotype (see TS above). Most 45,X/46,XY

individuals have a male phenotype and testes, and the diagnosis is

made incidentally after amniocentesis or during investigation of

infertility. In practice, most newborns referred for assessment have

atypical genitalia and variable somatic features. There is often marked

asymmetry, with a streak gonad and hemiuterus on one side and a

partially descended dysgenetic testis and hemiscrotum on the other

side. Many children are raised as boys, but in some children, sex designation (whether to raise the baby as male or female) must be decided

by parents and the multidisciplinary team. In these children, gender

identity may be harder to predict. There is an increased risk of germ

cell cancer (GCC), up to 35% in intraabdominal gonads, so prophylactic removal of intraabdominal gonads is usually considered. Individuals raised as males often have reconstructive surgery for hypospadias

and removal of dysgenetic or streak gonads if the gonads cannot be

brought down into the scrotum. Scrotal testes can be preserved but

require regular examination for tumor development and sonography

at the time of puberty. Biopsy for carcinoma in situ is recommended

in adolescence, and testosterone supplementation may be required to

support androgenization in puberty or if low testosterone is detected

in adulthood. As 45,X/46,XY mosaicism can be associated with other

features (e.g., cardiac, renal), individuals should be monitored according to TS guidelines. Infertility is typical, but non-azoospermia or focal

spermatogenesis has been reported, highlighting the importance of

individualized approaches to management.

■ OVOTESTICULAR DSD

Ovotesticular DSD (OTDSD) is a condition in which an individual has

both ovarian and testicular tissue, either by having both an ovary and

a testis or by having an ovotestis. Most individuals with this diagnosis

have a 46,XX karyotype (especially in individuals of African ancestry),

although 46,XX/46,XY chimerism and rarely a 46,XY karyotype is

also possible. OTDSD usually presents with atypical genitalia at birth

TABLE 390-3 Possible Associated Clinical Features of Chromosomal Disorders of Sex Development (DSDs)

GENITALIA

DISORDER COMMON CHROMOSOMAL COMPLEMENT GONAD EXTERNAL INTERNAL BREAST DEVELOPMENT

Klinefelter

syndrome

47,XXY or 46,XY/47,XXY Hyalinized testes Male Male Gynecomastia

Clinical Features

Small testes, azoospermia, decreased facial and axillary hair, decreased libido, tall stature and increased leg length, decreased penile length,

increased risk of breast tumors, thromboembolic disease, learning difficulties, anxiety, speech delay and decreased verbal IQ, obesity, diabetes

mellitus, metabolic syndrome, varicose veins, hypothyroidism, systemic lupus erythematosus, epilepsy

Turner syndrome 45,X or 45,X/46,XX Streak gonad or immature

ovary

Female Hypoplastic female Immature female

Clinical Features

Infancy: lymphedema, web neck, shield chest, low-set hairline, cardiac defects and coarctation of the aorta, urinary tract malformations, and

horseshoe kidney

Childhood: short stature, cubitus valgus, short neck, short fourth metacarpals, hypoplastic nails, micrognathia, scoliosis, otitis media and

sensorineural hearing loss, ptosis and amblyopia, multiple nevi and keloid formation, autoimmune thyroid disease, visuospatial learning

difficulties

Adulthood: absent puberty and primary amenorrhea, hypertension, obesity, dyslipidemia, impaired glucose tolerance and insulin resistance,

autoimmune thyroid disease, cardiovascular disease, aortic root dilation, osteoporosis, inflammatory bowel disease, chronic hepatic dysfunction,

increased risk of colon cancer, hearing loss

45,X/46,XY

mosaicism

45,X/46,XY Testis or streak gonad Variable Variable Usually male

Clinical Features

Short stature, increased risk of gonadal tumors, some Turner syndrome features

Ovotesticular DSD 46,XX/46,XY Testis and ovary or ovotestis Variable Variable Gynecomastia

Clinical Features

Possible increased risk of gonadal tumors