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Descent at 6 to 9 months of age is rare (1).

ETIOLOGYAND PATHOPHYSIOLOGY

Not fully known

May involve alterations in

–Mechanical factors (gubernaculum, length of vas deferens and testicular vessels, groin anatomy, epididymis, cremasteric muscles, and abdominal pressure), hormonal factors (gonadotropin, testosterone, dihydrotestosterone, and müllerian-inhibiting substance [MIS]), and neural factors (ilioinguinal nerve and genitofemoral nerve)

–Major regulators of testicular descent from intra-abdominal location into the bottom of the scrotum are the Leydig cell–derived hormones, testosterone, and insulin-like growth factor 3 (IGF-3).

–Mutations in the gene for IGF-3 and in the androgen receptor gene have been evaluated as possible causes of cryptorchidism as well as chromosomal alterations (1).

–Environmental factors acting as endocrine disruptors of testicular descent also may contribute to the etiology of cryptorchidism.

Risk of ascent may be as high as 32% in retractile testis.

Genetics

Occurrence of UDT in siblings as well as fathers suggests a genetic etiology.

RISK FACTORS

Family history of cryptorchidism: highest risk if brother had UDT, followed by uncle and then father

Low birth weight, prematurity, and small for gestational age are associated with a substantial increase in incidence of cryptorchidism (1). Retractile testes are at increased risk for ascent.

COMMONLYASSOCIATED CONDITIONS

Inguinal hernia/hydrocele

Abnormalities of vas deferens and epididymis

Intersex abnormalities

Hypogonadotropic hypogonadism

Germinal cell aplasia

Prune-belly syndrome Meningomyelocele

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Hypospadias

Wilms tumor

Prader-Willi syndrome

Kallmann syndrome

Cystic fibrosis

DIAGNOSIS

HISTORY

≥1 testicles in a site other than the scrotum

May be an isolated defect or associated with other congenital anomalies

PHYSICALEXAM

Performed with warm hands, with child in sitting, standing, and squatting position

AValsalva maneuver and applied pressure to lower abdomen may help to identify the testes, especially a gliding testis.

Failure to palpate a testis after repeated exams suggests an intra-abdominal or atrophic testis.

An enlarged contralateral testis in the presence of a nonpalpable testis suggests testicular atrophy/absence.

Testes should be palpated for quality and position at each recommended wellchild visit (1)[B].

DIFFERENTIALDIAGNOSIS

Retractile testis (hypermobile testis), a normally descended testis that ascends into the inguinal canal because of an active cremasteric reflex (more common in males 4 to 6 years of age)

Atrophic testis: may occur as a result of neonatal torsion

Vanished testis may be the result of a lack of development or in utero torsion.

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

In phenotypic male newborn with bilateral, nonpalpable UDTs, hormone levels are helpful to determine whether the testes are present and should be evaluated for possible disorder of sexual development (1)[A].

– Luteinizing hormone (LH)

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–Follicle-stimulating hormone (FSH)

–MIS

–Testosterone

–Serum electrolytes

–Karyotype

If bilateral nonpalpable testes and presenting >3 months of age, a human chorionic gonadotropin (hCG) stimulation test to determine presence or absence of testicular tissue (hCG 2,000 IU/day for 3 days, and check testosterone before and after stimulation) as well as gonadotropins—to say testes are absent—needs negative stimulation test and elevated gonadotropins (3).

Ultrasound or other imaging modalities should not be performed in the evaluation of boys with cryptorchidism prior to referral to a specialist, as they are rarely needed in decision making (1)[B].

Follow-Up Tests & Special Considerations

In newborns and children <6 months of age, periodic examination to determine if testis is palpable and descended prior to considering further intervention (1)

Pediatric Considerations

In the absence of spontaneous testicular descent by 6 months of age (gestational age adjusted), infant should be referred to appropriate specialist, and surgery should be performed within 1 year (1)[B].

In children with retractile testes, examination should be performed at least yearly to rule out subsequent ascent (1)[B].

In boys 11 to 30 months of age with unilateral nonpalpable UDT, if the contralateral descended testis is 19 to 20 mm or greater in length measured by caliper, there is a greater likelihood of a vanished/atrophic testis (4)[B].

Diagnostic Procedures/Other

Laparoscopy is useful in a child with nonpalpable cryptorchidism to confirm testicular absence or presence accurately and to determine the feasibility of performing a standard orchidopexy.

Test Interpretation

Higher incidence of carcinoma in UDT and alterations in spermatogenesis. Histologic changes occur by 1.5 years of age and include smaller seminiferous tubules, fewer spermatogonia, and more peritubular tissue (5).

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TREATMENT

GENERALMEASURES

Rule out retractile testis.

Appropriate health care: outpatient until surgery is performed

Administration of chorionic gonadotropin may cause testicular descent in some boys. Reports of efficacy are inconsistent. American Urological Association (AUA) guidelines on cryptorchidism do not recommend use of hormonal therapy to induce testicular descent due to low response rate and lack of evidence for long-term efficacy (1).

MEDICATION

Medical therapy is not indicated in the United States per the AUAguidelines on cryptorchidism 2014 (1).

ISSUES FOR REFERRAL

≥1 testes not descended by 6 months age (1)[B]

Bilateral nonpalpable UDTs (1)

Newly diagnosed cryptorchidism after 6 months of age (1)[B]

SURGERY/OTHER PROCEDURES

Reasons to consider: avoids torsion, averts trauma, decreases but does not eliminate risk of malignancy, and prevents further alterations in spermatogenesis

In the absence of spontaneous testicular descent by 6 months of age (gestational age–adjusted), surgery should be performed within 1 year (1)[B].

Prepubertal orchidopexy decreases risk of testicular cancer and results in 2- to 6-fold reduction in relative risk compared to postpubertal orchidopexy (1).

Laparoscopy/abdominal exploration is performed first if testis is nonpalpable. If palpable, an inguinal approach is usually performed. If low-lying, a single incision scrotal approach can also be considered but may increase the risk of hernia.

ONGOING CARE

FOLLOW-UPRECOMMENDATIONS

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Initial follow-up within 1 month of surgery and periodically thereafter to assess testicular size/growth

Patients with retractile testes should be examined at least annually to monitor for secondary ascent until testis is no longer retractile (1)[B].

Patient Monitoring

Patients should be followed after surgery to evaluate testicular growth.

Testicular tumors occur mainly during or after puberty; thus, these children should be taught self-examination when they are older.

DIET

No restrictions

PATIENT EDUCATION

Discuss with parents about causes, available treatments, and possible effects on patient’s reproductive potential and also increased risk for testicular cancer and need for regular self-examination.

PROGNOSIS

Disorder is usually corrected with medical or surgical therapy; however, there are possible lifelong consequences.

If testicle is absent or orchiectomy is required, may consider placement of testicular prosthesis.

Early orchidopexy may decrease risk of testicular damage and risk of malignancy.

COMPLICATIONS

Paternity rates are similar to the general population for men with a unilateral UDT; however, are lower (33–65%) for men with bilateral UDT

Abnormalities also have been identified in the contralateral descended testis, although less severe.

REFERENCES

1.Kolon TF, Herndon CDA, Baker LA, et al. Evaluation and treatment of cryptorchidism. https://www.auanet.org/education/guidelines/cryptorchidism.cfm. Accessed October 3, 2017.

2.Sijstermans K, Hack WW, Meijer RW, et al. The frequency of undescended

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testis from birth to adulthood: a review. Int J Androl. 2008;31(1):1–11.

3.Docimo SG, Silver RI, Cromie W. The undescended testicle: diagnosis and management. Am Fam Physician. 2000;62(9):2037–2044, 2047–2048.

4.Braga LH, Kim S, Farrokhyar F, et al. Is there an optimal contralateral testicular cut-off size that predicts monorchism in boys with nonpalpable testicles? J Pediatr Urol. 2014;10(4):693–698.

5.Park KH, Lee JH, Han JJ, et al. Histological evidences suggest recommending orchiopexy within the first year of life for children with unilateral inguinal cryptorchid testis. Int J Urol. 2007;14(7):616–621.

ADDITIONALREADING

Agarwal PK, Diaz M, Elder JS. Retractile testis—is it really a normal variant? J Urol. 2006;175(4):1496–1499.

Al-Mandil M, Khoury AE, El-Hout Y, et al. Potential complications with the prescrotal approach for the palpable undescended testis? Acomparison of single prescrotal incision to the traditional inguinal approach. J Urol. 2008;180(2):686–689.

Braga LH, Lorenzo AJ. Cryptorchidism: a practical review for all community healthcare providers. Can Urol Assoc J. 2017;11(1–2 Suppl 1):S26–S32.

Cortes D, Thorup JM, Visfeldt J. Cryptorchidism: aspects of fertility and neoplasms. Astudy including data of 1,335 consecutive boys who underwent testicular biopsy simultaneously with surgery for cryptorchidism. Horm Res. 2001;55(1):21–27.

Fantasia J, Aidlen J, Lathrop W, et al. Undescended testes: a clinical and surgical review. Urol Nurs. 2015;35(3):117–126.

Foresta C, Zuccarello D, Garolla A, et al. Role of hormones, genes, and environment in human cryptorchidism. Endocr Rev. 2008;29(5):560–580.

Hutson JM, Balic A, Nation T, et al. Cryptorchidism. Semin Pediatr Surg. 2010;19(3):215–224.

Kollin C, Hesser U, Ritźen EM, et al. Testicular growth from birth to two years of age, and the effect of orchidopexy at age nine months: a randomized, controlled study. Acta Paediatr. 2006;95(3):318–324.

Lee PA. Fertility after cryptorchidism: epidemiology and other outcome studies. Urology. 2005;66(2):427–431.

Na SW, Kim SO, Hwang EC, et al. Single scrotal incision orchiopexy for children with palpable low-lying undescended testis: early outcome of a prospective randomized controlled study. Korean J Urol. 2011;52(9):637–641.

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Pettersson A, Richiardi L, Nordenskjold A, et al. Age at surgery for undescended testis and risk of testicular cancer. N Engl J Med. 2007;356(18):1835–1841.

Walsh TJ, Dall’Era MA, Croughan MS, et al. Prepubertal orchiopexy for cryptorchidism may be associated with lower risk of testicular cancer. J Urol. 2007;178(4 Pt 1):1440–1446.

Wilkerson ML, Bartone FF, Fox L, et al. Fertility potential: a comparison of intra-abdominal and intracanalicular testes by age groups in children. Horm Res. 2001;55(1):18–20.

Wood HM, Elder JS. Cryptorchidism and testicular cancer: separating fact from fiction. J Urol. 2009;181(2):452–461.

CODES

ICD10

Q53.9 Undescended testicle, unspecified

Q53.10 Unspecified undescended testicle, unilateral

Q53.20 Undescended testicle, unspecified, bilateral

CLINICALPEARLS

If testicular descent does not occur by 6 months of age, it is unlikely to occur. Therefore, refer patients to a specialist if a testis has not descended by 6 months of age.

Children with bilateral, nonpalpable UDTs require laboratory evaluation to determine if viable testicular tissue is present and to rule out disorder of sexual differentiation.

Radiologic imaging has no role in the initial evaluation of cryptorchidism. The risk of infertility is increased with bilateral UDTs.

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CUSHING DISEASE AND CUSHING SYNDROME

Linda Paniagua, MD

BASICS

DESCRIPTION

Clinical abnormalities associated with chronic exposure to excessive amounts of cortisol (the major adrenocorticoid)

Cushing syndrome is defined as excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc.) or tumor. Exogenous intake of steroids is the primary cause of Cushing syndrome.

Cushing disease is defined as glucocorticoid excess due to excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary tumor, the most common cause of primary Cushing syndrome.

System(s) affected: endocrine/metabolic, musculoskeletal, skin/exocrine, cardiovascular; neuropsychiatric

Pediatric Considerations

Rare in infancy and childhood

Cushing disease accounts for approximately 75% of all cases of Cushing syndrome in children >7 years.

In children <7 years, adrenal causes of Cushing syndrome (adenoma, carcinoma, or bilateral hyperplasia) are more common.

Most common presenting symptom is lack of growth consistent with the weight gain.

Pregnancy Considerations

Pregnancy may exacerbate disease.

Cortisol levels increase in normal pregnancy states.

EPIDEMIOLOGY

Incidence

Uncommon: 0.7 to 2.4/1 million per year

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Prevalence

2–5% prevalence reported in difficult-to-control diabetics with obesity and hypertension (HTN)

ETIOLOGYAND PATHOPHYSIOLOGY

Syndrome: excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc.) or tumor

Disease: pituitary tumor causing excess ACTH (corticotropin) General population

–Exogenous glucocorticoids

–Endogenous ACTH–dependent hypercortisolism: 80–85% ACTH-secreting pituitary tumor: 75%

Ectopic ACTH production (e.g., small cell carcinoma of lung, bronchial carcinoid): 20%

–Endogenous ACTH–independent hypercortisolism: 15–20% Adrenal adenoma

Adrenal carcinoma

Macronodular or micronodular hyperplasia

Pediatric/adolescent

–Adrenal hyperplasia secondary to McCune-Albright syndrome: mean age 1.2 years

–Adrenocortical tumors: mean age 4.5 years

–Ectopic ACTH syndrome: mean age 10.1 years

–Primary pigmented nodular adrenocortical disease: mean age 13.0 years

–Cushing disease: mean age 14.1 years

Pregnancy

–Pituitary-dependent Cushing syndrome: 33%

–Adrenal causes: 40–50%

–ACTH-independent adrenal hyperplasia: 3%

Genetics

Multiple endocrine neoplasia

Carney complex (an inherited multiple neoplasia syndrome)

McCune-Albright syndrome (mutation of GNAS1 gene)

Familial isolated pituitary adenomas (mutations in the aryl hydrocarbon receptor–interacting protein gene)

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RISK FACTORS

Prevalent sex: female > male (3:1)

Most often occurs between the ages of 25 and 40 years

Prolonged use of corticosteroids

GENERALPREVENTION

Avoid corticosteroid exposure, when possible.

DIAGNOSIS

HISTORY

Weight gain: 95%

Decreased libido: 90%

Menstrual irregularity: 80%

Depression/emotional lability: 50–80%

Easy bruising: 95%

Diabetes or glucose intolerance: 90%

PHYSICALEXAM

Obesity (usually central): 95%

Facial plethora: 90%

Moon face (facial adiposity): 90%

Thin skin: 85%

HTN: 75%

Skeletal growth retardation in children (epiphyseal plates remain open): 70– 80%

Hirsutism: 75%

Proximal muscle weakness: 90%

Purple striae on the skin

Increased adipose tissue in neck and trunk

Acne

DIFFERENTIALDIAGNOSIS

Obesity

Diabetes mellitus

HTN

Metabolic syndrome X

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