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Published in final edited form as: Clin Perinatol. 2018 March ; 45(1): 103-118. doi:10.1016/j.clp.2017.10.002.

Neonatal Cushing Syndrome: A rare but potentially devastating disease

Christina Tatsi, MD, PhD1,2 and Constantine A. Stratakis, MD, DSc1,2

1Section on Endocrinology & Genetics, Developmental Endocrine Oncology and Genetics Group, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

2Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

Synopsis

Neonatal Cushing syndrome (CS) is most commonly caused by exogenous administration of glucocorticoids and rarely by endogenous hypercortisolemia. CS due to adrenal lesions is the most common cause of endogenous CS in neonates and infants, and adrenocortical tumors (ACTs) represent the majority of cases. Many of the ACTs develop in the context of a TP53 gene mutation, which causes Li-Fraumeni syndrome. More rarely neonatal CS presents as part of other syndromes such as McCune-Albright syndrome (MAS) or Beckwith-Wiedemann syndrome (BWS). The management of the patients usually includes resection of the primary tumor with or without additional medical treatment, but manifestations may persist after resolution of hypercortisolemia.

Keynote words

Cushing syndrome; hypercortisolemia; Adrenocortical tumors; adrenal hyperplasia; infant

Corresponding Author: Constantine A. Stratakis M.D., D(Med)Sc., SEGEN, PDEGEN, NICHD, NIH, 10 Center Drive, Building 10, NIH-Clinical Research Center, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA, tel 001-301-496-4686; 001-301-4020574; stratakc@mail.nih.gov.

Author Contact Information:

Christina Tatsi MD, PHD, 10 Center Drive, Building 10, NIH-Clinical Research Center, Room 1-3330, MSC1103, Bethesda, Maryland 20892, christina.tatsi3@nih.gov

Constantine A. Stratakis M.D., D(Med)Sc., SEGEN, PDEGEN, NICHD, NIH, 10 Center Drive, Building 10, NIH-Clinical Research Center, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA, tel 001-301-496-4686; 001-301-4020574; stratakc@mail.nih.gov

Disclosure statement: The authors of this article declare that they have nothing to disclose.

Supplemental content is included in the online version of this article.

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Introduction

Cushing syndrome (CS) is named after Dr Harvey Cushing, an American neurosurgeon who first described the condition in a patient with weight gain, round face, hypertrichosis, muscle weakness, and irregular menstruations in 1912.1 The term CS is currently used to describe the constellation of signs and symptoms that result from the chronic effects of hypercortisolemia.2

The etiology of CS is divided into exogenous (or iatrogenic) CS and endogenous [Adrenocorticotropin Hormone (ACTH)-dependent and ACTH-independent] CS. The widespread use of glucocorticoid (GC) treatment for various conditions (autoimmune, malignant, allergic) has rendered exogenous CS a common condition.34 The endogenous type is much more rare, with an estimated incidence of 2 to 5 new cases per million people diagnosed every year; of these only 10% refer to children. Endogenous neonatal CS remains extremely rare. Most of the cases present as part of an isolated adrenocortical tumor (ACT), commonly an adrenocortical carcinoma (ACC). Nearly 100 patients with neonatal and infantile CS not associated with isolated ACTs have been described until now (Supplemental Tables). 5

CS is associated with significant clinical findings, such as hypertension, hyperglycemia, hyperlipidemia, decreased bone mineral density and muscular atrophy. More characteristically in children CS also leads to growth arrest, despite continuous weight gain.5 Given the severity of the various comorbidities, which may result in long term and irreversible complications, it is essential to recognize and appropriately manage CS as soon as possible.

The fetal and neonatal Hypothamamic-Pituitary-Adrenal (HPA) axis

The adrenal glands derive from the urogenital ridge of the intermediate mesoderm, which also differentiates into the gonads and the mesonephros.67 The development of the steroid producing cells starts at 4 weeks of gestation, and at 5 weeks the adrenal cells are clearly separated from the gonads.8 Around the same period (7 weeks of gestation), sympathetic nerve cells from the neural crest, migrate to the center of the adrenals to form the adrenal medulla.6 At 8 weeks of gestation, adrenals are distinct organs and the adrenal cortex consists of two separate zones, the fetal and the definitive zone.910

The fetal zone comprises almost 80% of the adrenal gland volume at term and it is a hormonally active region. However, it has low levels of 3-beta hydroxysteroid dehydrogenase (HSD) and high levels of sulfotransferase enzyme concentrations, which renders dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) the main product of the fetal zone.11 Those are further used by the placenta to maintain the estriol levels.12

The fetal zone starts to involute after birth and disappears by the end of the first year of life. 10 The definitive zone, the outer zone that surrounds the fetal cortex, increases in size with age and it gives rise to the three known zones of the adult adrenal cortex (glomerulosa,

fasciculata, and reticularis) within the first 1-3 years of life, although its development is not completed until the puberty years.13

Cortisol has been detected as early as 8 weeks of gestation, and it has significant functions during the intrauterine life, including the lung, liver, thyroid and other organ maturation. 14 The human fetal adrenal gland starts also secreting aldosterone, desoxycorticosterone (DOC), and corticosterone between 10 and 20 weeks.10 As mentioned above, DHEAS levels are high at birth but decline rapidly afterwards as the fetal zone involutes.10

The adrenal production of cortisol is under the control of the HPA axis. Corticotropin- releasing hormone (CRH) production has been reported in primates by the third trimester.15 However sources of CRH production outside the hypothalamus, such as the placenta, have also been documented to contribute significantly in the cortisol production during embryogenesis.16 The anterior lobe of the pituitary, where ACTH hormone is produced, derives from the oral ectoderm and it is fully formed by 5 weeks of gestation. Although ACTH is detected in the fetal pituitary by the 7th week of gestational age, its trophic properties become important for the maintenance of the fetal zone of the adrenals only after the first 4-5 months of gestation. 96 After birth, ACTH is the sole significant trophic factor of the definitive zone; however the fetal zone gradually involutes.

CRH is synthesized in the hypothalamus and carried to the anterior pituitary in the portal system; this may first happen after the second trimester in fetal life. CRH stimulates ACTH release from the anterior pituitary, which in turn stimulates the adrenal cortex to secrete cortisol.1718 Cortisol further inhibits the synthesis and secretion of both CRH and ACTH in a negative feedback regulation system (Figure 1). In children and adults (not prior to age 6 months), the hormones of the HPA axis follow a circadian rhythm of secretion. ACTH reaches a peak level between 06:00-09:00h, and a nadir level at 23:00-02:00h.19 Similarly, cortisol levels peak some time between 07:30 and 08:30h and then decrease with a nadir value at midnight. 20

The understanding of the physiology of the HPA axis is very important for the diagnostic workup of patients with CS, where autonomous secretion of ACTH and/or cortisol does not comply with the above rules.

Causes of Cushing Syndrome

1. Exogenous Cushing syndrome

The most commonly encountered cause of neonatal CS is the exogenous administration of pharmacologic doses of GCs, which comprises more than 95% of all cases. Although the report of the long-term complications of neonatal exposure to GCs (mainly metabolic and CNS related) has placed their perinatal use under consideration, GCs remain part of various therapeutic approaches, such as the management of fetal lung maturation prenatally, as well as respiratory, neurologic and other conditions postnatally.21222324 The effects of GCs on the suppression of the HPA is seen not only in systemic administration of the medications, but also in topically applied GCs. 25

2. Endogenous Cushing syndrome

The causes of endogenous CS are divided into ACTH-dependent and ACTH-independent (Table 1). Adrenal disorders cause ACTH-independent CS and they are the commonest cause of endogenous CS in neonates and infants. This category is very diverse, involving various adrenal diseases.

ACTs represent 0.2% of all pediatric tumors and they constitute the commonest cause of adrenal dependent CS in the first years of life.526 Although not all ACTs are associated with CS, signs of hypercortisolemia, isolated or in combination with hyperandrogenemia, have been identified in up to 50% of ACT cases.2728 Adrenocortical tumors are commonly malignant ACCs with poor prognosis (70% of cases), but they may also represent benign unilateral adrenocortical adenomas (ACAs).27 ACTs present at a median age of 3-4 years old, but cases present even at birth have been previously described.2728

More rare benign bilateral adrenocorticortical hyperplasia may result in autonomous, ACTH-independent hypercortisolemia. This category is further divided according to the size of the nodules into macronodular (>1cm) and micronodular (<1cm) disease.2930 The micronodular adrenocortical nodular disease can be secondary to primary pigmented adrenocortical nodular disease (PPNAD) or non-pigmented isolated micronodular adrenocortical disease (iMAD). On the other hand, macronodular hyperplasia may present with multiple bilateral cortisol secreting nodules with internodular atrophy (bilateral macroadenomatous hyperplasia or BMAH) or without atrophy (massive macronodular adrenal hyperplasia or MMAD).2930

In older children and adults, ACTH-dependent CS results usually from pituitary corticotropin secreting adenomas (this is known as Cushing disease - CD).2 The pituitary adenomas are commonly microadenomas (size <1cm) and more rare macroadenomas (size > 1cm) that exhibit a semiautonomous secretion of ACTH, which further leads to bilateral adrenal stimulation and cortisol production. 3132 Although CD is the commonest cause of CS in older children, its prevalence is rare under the age of 7 years. 533 Recently many of the previously reported infantile ACTH-secreting pituitary adenomas have been reclassified as pituitary blastomas.34 These tumors are considered embryonal tumors, containing cells from all the stages of pituitary development as well as epithelial Rathke cells, which is a unique feature. In most of the reported cases, ACTH-dependent hypercortisolemia has been reported, but additional pituitary hormones might be oversecreted as well.35

In rare occasions, ACTH-dependent CS may result from ectopic ACTH and/or CRH production, where the source of the ectopic hormone production is located in the lungs, the liver, the thymus, the pancreas or other neuroendocrine tumors.36 In infancy specifically reports of ectopic ACTH production from neuroblastomas represent the majority of ectopic CS.37

Genetic causes of neonatal and infantile Cushing Syndrome

Various genetic causes have been associated with the pathogenesis of adrenal CS, both in the adult and the pediatric population. TP53 gene mutations are the most common cause of

adrenocortical tumors and are identified in almost 70% of ACTs.3839 This percentage is higher in pediatric patients with ACTs from Southern Brazil, where a point mutation of TP53 gene (Arg337His) has been reported in 78 - 97% of cases.4041 Germline TP53 gene mutations may cause Li-Fraumeni syndrome (LFS) which is an autosomal dominant inherited syndrome predisposing to various cancers.42 Patients with LFS present with early onset (childhood) ACTs and increased risk for other malignancies (osteosarcoma, soft tissue sarcoma, breast cancer, brain tumors, leukemia and others).43 The penetrance of the germline mutations is variable and it has been suggested that any child with ACT should be assessed for TP53 mutations, irrespective of the family history.39

Defects of various steps of the cyclic adenosine monophosphate - protein kinase A (cAMP/ PKA) pathway have been also implicated in the pathogenesis of adrenal causes of CS.3338 McCune-Albright syndrome (MAS) presents with the clinical triad of bone fibrous dysplasia, café au-lait macules and precocious puberty. MAS results from postzygotic somatic mutations of the GNAS gene, which codes for the Gsa subunit of the G-protein coupled receptors, causing their constitutive activation which leads to elevated levels of the intracellular cAMP, irrespective of the ligand concentration.44 Given the fact that many of the hormone receptors are G-coupled protein receptors, MAS may manifest as activating endocrinopathies of various types (hyperthyroidism, GH excess, precocious puberty and others).44 The presence of CS in MAS has been described as early as in the neonate period and it is uncommon after the first year of life.45 It presents as either unilateral adrenal nodules or bilateral adrenal hyperplasia.46 The course of the disease is usually severe, even leading to death, but contrary to other CS cases, the patients who survive the acute phase of the disease without requiring adrenalectomy might experience spontaneous resolution.45

Additional defects of the cAMP/PKA pathway include mutations in the PRKAR1A gene, which codes for the regulatory subunit R1a of the PKA, and are the leading cause of Carney Complex (CNC).47 CNC describes the association of myxomas, spotty skin pigmentation, endocrine overactivity, and psammomatous melanotic schwannomas. Up to 30% of CNC patients present with PPNAD some of them as children; however, no patient with PPNAD has ever been diagnosed with CS before the age of 1 year. 48 This may point to the different developmental origin of the adrenal lesions in PPNAD compared to other ACTs and MAS that present with CS in infancy.

Defects of the 11p15 locus involving IGF2, H9 and CDKI genes, either in the somatic state in the adrenal tumors or identified as germline defects, as in patients with Beckwith- Wiedemann syndrome (BWS), have also been associated with the presence of adrenal dependent CS in the neonatal period.49 BWS is a genetic overgrowth and cancer predisposition syndrome characterized by hemihypertrophy, macrosomia, macroglossia, organomegaly, hyperinsulinism, omphalocele/umbilical hernia, and distinct facial features.50 Patients with BWS have an increased risk of developing intrabdominal tumors including hepatoblastomas, Wilm’s tumors, rhabdomyosarcomas and ACTs, which are commonly identified early in life.51 Although most of the adrenocortical tumors are not resulting in CS, cases of hypercortisolemia have been reported in a few patients. CS in BWS may present as bilateral adrenal hyperplasia and it has been postulated to result from the delay of the maturation of the fetal adrenal gland.52 More recently an ACTH-secreting pituitary adenoma

has been reported in a 17yo patient with BWS and CD, however this is an infrequent presentation of the syndrome.53

Other genetic defects that cause ACTs and CS, include MEN1 gene mutations causing multiple endocrine neoplasia type 1 (MEN1), APC gene defects causing familial adenomatous polyposis (FAP), and others such as SF1, PRKACA, PDE11A, PDE8B, and ARMC5 genetic changes. However, none of these conditions are known to cause CS in infancy, and they are very rarely the cause of hypercortisolemia before the age of 10 years. 335455

The genetic background of CD in children has been largely unknown until recently. Some of the known genes implicated in pituitary tumors, such as MEN1, AIP, PRKAR1A, CDK1B, and CDKN2C, explained only a small percentage of the pediatric cases.56 Recently Reincke et al reported a high frequency of somatic mutations of the USP8 gene, which has also been confirmed in 31% of pediatric CD.5758 However CD secondary to pituitary adenomas is extremely rare in infants.

On the contrary, pituitary blastomas represent the majority of the ACTH-dependent CS in infancy and most of these patients present with a germiline or somatic DICER1 gene mutation.34 The DICER1 protein is a small RNA processing endoribonuclease that cleaves precursor microRNAs (miRNA) into mature miRNAs. Germline mutations of the DICER1 gene cause the pleuropulmonary blastoma familial tumor and dysplasia syndrome, which involves the presence of multiple benign and malignant tumors in addition to pituitary blastomas.59

Clinical manifestations of Cushing Syndrome

The clinical presentation of CS can be rather insidious and initially the signs may easily be confused with other more common entities, such as obesity or constitutional delay of growth.30 However as hypercortisolemia persists, the typical Cushinoid findings develop: central obesity, posterior neck fat deposition (buffalo hump), round facies, facial plethora, hirsutism, easy bruising, acne and decreased bone mineral density (Table 2, Figure 2).606162 Certain Cushing related manifestations, such as the violaceous striae, has been suggested to be less common in the infant population. 527

In the growing infant and child specifically, one of the most important and earlier signs of isolated CS is the height deceleration along with continuous weight gain, which can be easily identified with review of the patient’s growth chart.63 Given however the high incidence of ACTs that co-secrete cortisol and androgens, an accelerated growth velocity has also been reported in 15-29% of these patients, and subsequently the absence of height deceleration cannot rule out the presence of hypercortisolemia. Furthermore, signs of hyperandrogenemia, including the presence of pubic hair, hypertrophy of the clitoris or the penis, acne and hirsutism, may sometimes be the presenting finding.2728

Hypercortisolemia may also induce suppression of the immune system and increased risk for severe and/or opportunistic infections. This is usually depicted on the abnormal white blood cell counts (leukocytosis, neutrophila and lymphopenia), while clinical cases of severe

infections and even death secondary to cortisol induced immunosuppression have been reported.6465 Additional findings that result from the hypercortisolemia include hypokalemia, hypercalcemia and hyperglycemia, while hypernatremia is less common.6066 Hypertension is a finding of outmost significance in the pediatric CS population because it can be difficult to manage. 67 Patients with hypertensive complications such as seizures, intracerebral hemorrhage, and hypertensive crisis, leading even to death, have been previously described.276869

Diagnostic approach of Neonatal Cushing Syndrome

Although iatrogenic CS can easily be delineated by the review of the medical history of the patient and his previous and current medications, the diagnostic workup for endogenous CS involves various additional steps (Figure 3).

The establishment of the diagnosis of hypercortisolemia is usually based on three criteria: (1) the loss of the circadian rhythm of the cortisol secretion as documented with an elevated midnight serum or salivary cortisol level, (2) the elevation of the 24 h urine free cortisol (UFC) and (3) the lack of suppression of cortisol production after the administration of low dose overnight dexamethasone (1 mg or equivalent weight-based dose of 15mcg/kg in children). The presence of two abnormal test results strongly supports the diagnosis of CS.70 The completion of the above tests can be complicated by the fact that the circadian rhythm of the neonates and infants does not necessarily follow the regular day/night rhythm of older children and adults. Circadian rhythms are just being established between 6 and 12 months of age. Additionally the 24 hour urine collection can be uncomfortable to obtain, since the presence of an indwelling catheter is usually necessary. Thus the interpretation of the above tests should be done in conjunction with the clinical presentation of the patient.

The biochemical evaluation should also include the measurement of the adrenal androgens in order to identify the cases of glucocorticoid and androgen co-secretion by adrenal tumors. DHEAS is the most specific adrenal hormone since the enzyme sulfatase that converts DHEA to DHEAS is found almost exclusively in the adrenals and 95% of the circulating DHEAS is coming from the adrenals. Additional hormones to be measured include androstenedione, testosterone and estradiol. Other markers of accelerated cell turnover, such as LDH, as well as tumor markers, such as aFP, CEA, and Ca125, should also be sent as part of the evaluation before the surgery and they can be used postoperatively for monitoring of recurrence.

After the establishment of the diagnosis of endogenous CS, ACTH levels should be measured to differentiate between ACTH-dependent (usually ACTH > 30 pg/ml) or ACTH- independent causes (suppressed ACTH < 5 pg/mL). In ACTH-dependent CS, MRI of the pituitary along with high dose dexamethasone suppression test (8mg or equivalent weight- based dose of 120 mcg/kg in children) and the CRH test are used to define the source of hypercortisolemia as either in the pituitary or ectopic. If those results are inconclusive, the bilateral inferior petrosal sinus sampling (BIPSS) could assist in defining the source of hypercortisolemia.2

In cases of ACTH-independent CS, imaging of the adrenals is the next diagnostic step in order to assess the presence of a unilateral tumor or bilateral adrenal disease. Ultrasound of the adrenals has not been proven to be sensitive in identifying adrenal masses beyond large ACTs and sizable carcinomas; thus, CT primarily (sensitive for small lesions less that 1 cm) or MRI (not as good for lesions less than 1 cm due to motion artifacts) are the recommended techniques. In the presence of bilateral adrenal disease or in cases of intermediate levels of ACTH, the standard 6-day low- and high-dose dexamethasone suppression test (Liddle’s test) is used to differentiate between the various causes of CS. Calculation of the level of suppression of serum cortisol levels, and urinary free cortisol and 17-hydroxy steroids can lead towards a specific cause.271

In more complicated cases, additional imaging studies, such as 8F-fluorodeoxyglucose (FDG) PET scan, octreotide scan or imaging studies of additional parts of the body may be indicated.70

Management of Cushing Syndrome

The management of neonatal CS depends on the underlying cause of the disease. Although in the past the survival rate of neonates and infants diagnosed with CS was low (See Supplemental Tables), the advances of medicine have improved this over the last decades.

Adrenocortical carcinomas are managed with laparoscopic or open (depending on the size of the tumor and the suspicion of local invasion) complete en bloc resection of the primary tumor and the peritumoral/periadrenal retroperitoneal fat, and adjuvant chemotherapy with mitotane.727374 Benign adrenal tumors are usually managed with surgical resection with no need for additional treatment.

In cases of bilateral adrenal hyperplasia, patients are managed with bilateral adrenalectomy, which requires life-long glucocorticoid and mineralocorticoid replacement. Unilateral adrenalectomy or bilateral partial adrenalectomy has been also suggested as an alternative option, reserving the endogenous glucocorticoid production.75 However in these cases regular monitoring for recurrence of CS should be undertaken. In CS associated with MAS specifically, given the possibility of spontaneous resolution of the disease, initial medical management or subtotal adrenalectomy could be attempted to preserve the adrenal function later in life. 76

Pituitary corticotropinomas are generally managed with transsphenoidal resection (TSS) with a high rate of success in specialized centers.7778 TSS approach however is difficult in young infants, given the limited space in the nostrils and the lack of pneumatisation of the sphenoid sinus, which starts around the age of 2 years. Thus transcranial approach of the pituitary is usually required. Recently transsphenoidal approach has been successfully used even in young infants and provides an alternative less invasive technique. 79 Given the possibility of pituitary hormone deficiencies as a result of the manipulation of the pituitary gland and their long-term effects in the developing child, referral to a center with neurosurgeon specialized in pediatric tumors is highly recommended. In cases of persistent disease, repeat surgery may be considered, but the success rate is lower (60%) and the

possibility of persistent pituitary hormone deficiencies is higher.3880 If hypercortisolemia persists, then radiation or medical treatment (ketoconazole, metyrapone, mitotane, mifepristone) are additional options to control the hypercortisolemia.81

Postoperatively the patients require glucocorticoid replacement with hydrocortisone until the recovery of the HPA is documented, which usually requires 12-18 months.82

Documentation of recovery is based on a normal 8am serum cortisol level (> 6 mcg/dL) or a sufficient response of cortisol production (>18 mcg/dL) after administration of cosyntropin. 83

Despite the resolution of hypercortisolemia, patients with history of CS present with persistent features that need life long monitoring.77 Those include persistent elevation of BMI, several risk factors for metabolic syndrome (hypertension, hyperlipidemia and impaired glucose tolerance), bone manifestations, and cognitive and psychological problems.77

Summary

Neonatal CS is a rare condition in the neonate and infantile period. It is usually caused by an adrenal disease, most commonly adrenocortical tumor. Genetic causes explain a large portion of the patients, and the clinical presentation of the patient should guide appropriate genetic testing which is important for the prognosis and follow up evaluation. The diagnostic evaluation of CS should follow the recommended steps in order to distinguish ACTH- dependent from ACTH-independent etiologies and guide the appropriate management of the patient. Although surgical management of the source of hypercortisolemia may result in cure, long term manifestations of CS may persist and require regular monitoring.

Supplementary Material

Refer to Web version on PubMed Central for supplementary material.

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Key points

· Neonatal Cushing Syndrome (CS) is a rare disorder, but it can lead to significant complications and even death, if not diagnosed and treated promptly.

· Adrenocortical tumors (ACTs) are the most common cause of neonatal CS and they usually represent adrenocortical carcinomas (ACCs).

· Neonatal CS may present as part of a genetic syndrome, such as Li-Fraumeni syndrome (LFS), McCune-Albright syndrome (MAS), Beckwith-Wiedemann syndrome (BWS), and DICER1 mutations.

· The diagnosis of CS includes the documentation of loss of the circadian rhythm of cortisol production, elevation of urine free cortisol (UFC) and lack of suppression of cortisol production after dexamethasone administration.

· Surgical resection of the adrenal tumor is the current approach of treatment for ACTs. Adjuvant chemotherapy should be considered in cases of ACCs.

Best Practices Box

What is the current practice?

· Cushing syndrome is suspected on the basis of the patient’s clinical presentation (see Table 2).

· Confirmation of hypercortisolemia requires at least two abnormal results in the screening tests:

1. Abnormal circadian rhythm of cortisol secretion (may not be definitive at age < 1 year)

2. Elevated urine free cortisol levels and

3. Lack of suppression of cortisol production after dexamethasone administration.

· After confirmation of hypercortisolemia, further evaluation of the source is suggested according to the diagnostic algorithm in Figure 3.

Figure 1. Illustration of the HPA axis.

Hypothalamus

CRH

(-)

Anterior Pituitary Gland

ACTH

Cortisol

Adrenal Glands

Figure 2. Picture of patient with neonatal Cushing syndrome and MAS. Note the round cushinoid face, the body obesity, the hypertrichosis of the face (A) and the characteristic caf -au-lait macules on the abdomen (B).

Figure 3. Diagnostic approach of Cushing syndrome

Screening for CS

Serum cortisol > 1.8mcg/dl after administration of low dose dexamethasone (15 mcg x weight in kg, max 1mg))

. Elevated urine free cortisol level (corrected for body surface area)

Midnight serum cortisol level > 4.4 mcg/dL or salivary cortisol > 0.13 mcg/dL

Confirmation of CS

Measurement of ACTH level

High ACTH level

Intermediate ACTH level

Low ACTH level

MRI pituitary CRH test

· CRH test

· Measurement of serum cortisol after administration of high dose dexamethasone (120 mcg x weight in kg, max 8mg)

Adrenal CT

Measurement of serum cortisol after administration of high dose dexamethasone (120 mcg x weight in kg, max 8mg)

Normal or micronodules

Bilateral macronodules

Unilateral tumor

. Liddle’s test

CRH test:

. >35% increase of ACTH levels at time 15 and 30minutes

Results inconclusive

Paradoxical stimulation of cortisol or 17-hydroxy steroids during Liddle’s test

. >20% increase of the serum cortisol level at 30 and 45 minutes

MMAD or other bilateral hyperplasias

Adrenocortical adenoma (ACA)

Adrenocortical carcinoma (ACC)

. > 68% reduction of serum cortisol after the administration of high dose dexamethasone (120 mcg x weight in kg, max 8mg)

Bilateral Inferior Pertrosal sinus sampling (BIPSS)

PPNAD or iMAD

Central : Peripheral ACTH ratios without gradient

Baseline Central : Peripheral ACTH ratio > 2 and

Central : Peripheral ACTH ratio > 3 after CRH or DDAVP stimulation

Cushing Disease

Ectopic CS