congenital adrenal hyperplasia

PO

Digital case

 HPC:400 : para-ovarian Leydig cell tumor in 11beta-hydroxylase deficiency

Definition: Congenital adrenal hyperplasia (CAH) represents a group of autosomal-recessive, inherited metabolic errors, each characterized by a deficiency or total lack of a particular enzyme involved in the biosynthesis of cortical steroids, particularly cortisol.

Synopsis

 marked adrenal enlargement (15g each gland) with cerebriform appearance, tan-brown
 diffuse cortical hyperplasia, particularly of zona reticularis-like compact cells

Differential diagnosis

 Bilateral hyperplasia due to ectopic ACTH

• not grossly cerebriform
• may have metastatic carcinoma and differentiate clinically

Congenital adrenal hyperplasia, unlike all other conditions responsible for the appearance of ambiguous genitalia in the newborn, may be life threatening because of a lack of synthesis of specific adrenal steroids.

Prompt diagnosis and appropriate therapy are essential. With early treatment, normal external genitalia and fertility can be achieved. The manifestations of the adrenogenital syndrome in the XX individual are most easily understood by examining the simplifi ed biosynthetic pathways of mineralocorticoid, glucocorticoid, and sex steroids.

Two enzymes, 21-hydroxylase and 11β-hydroxylase, participate in the formation of the glucocorticoids, desoxycorticosterone and cortisol, and the mineralocorticoid, aldosterone, but neither in testosterone nor the estrogens, estrone or estradiol.

Deficiency of either enzyme in the 46,XX female leads to elevated adrenocorticotropic hormone (ACTH) products and hence elevated levels of testosterone and other strongly androgenic intermediates, which may result in sexual ambiguity or marked virilization of the newborn’s external genitalia.

Steroidogenesis is then channeled into other pathways, leading to increased production of androgens, which accounts for virilization. Simultaneously, the deficiency of cortisol results in increased secretion of ACTH, resulting in adrenal hyperplasia. Certain enzyme defects may also impair aldosterone secretion, adding salt wasting to the virilizing syndrome.

Other enzyme deficiencies may be incompatible with life or, in rare instances, may involve only the aldosterone pathway without involving cortisol synthesis.

No gender preference, usually presents in children, rarely in adults

Symptoms depend on specific defect; include salt wasting, virilization, adrenogenital syndrome, hypertension.

Ambiguous genitalia

The congenital adrenal hyperplasia (CAH) is the most common cause of ambiguous genitalia. It manifests as various degrees of virilization in girls and as precocious puberty in boys. Most cases are secondary to 21-hydroxylase deficiency. An elevated 17-hydroxy-progesterone level indicates the diagnosis of CAH.

Adrenal glands with a limb over 20 mm long and 4 mm wide and with normal corticomedullary differentiation are suggestive of CAH.

Some authors believe that it is not just the size of the gland but a combination of its size, echogenicity, and surface contour that helps make the diagnosis of CAH.

Al-Alwan et al found that a combination of a limb width greater than 4 mm, a lobulated surface, and stippled echogenicity had a sensitivity of 92% and a specificity of 100% in making the diagnosis.

The presence of normal-sized adrenal glands does not exclude the diagnosis of CAH, and a cerebriform appearance of the adrenal glands is reportedly specific for CAH.

A normal uterus and ovaries are seen at US in female pseudohermaphroditism. Some boys with CAH may present with intratesticular nodularity (hyperplasia of Leydig cells).

Physiopathology

Congenital adrenal hyperplasia (CAH) results from a deficiency in one or another of the enzymes of cortisol biosynthesis.

In about 95% of cases, 21-hydroxylation is impaired in the zona fasciculata of the adrenal cortex so that 17-hydroxyprogesterone (17-OHP) is not converted to 11-deoxycortisol.

Because of defective cortisol synthesis, ACTH levels increase, resulting in overproduction and accumulation of cortisol precursors, particularly 17-OHP, proximal to the block. This causes excessive production of androgens, resulting in virilization.

Types

 21-hydroxylase deficiency (MIM.201910)
 17-hydroxylase deficiency (MIM.202110)
 11-hydroxylase deficiency (MIM.202010)
 3-hydroxysteroid dehydrogenase deficiency (MIM.201810)

Syndromes

Various autosomal recessive syndromes due to enzyme deficiencies in biosynthesis of adrenal steroids, diverting production to other pathways and causing elevated ACTH levels and adrenocortical hyperplasia

There is a spectrum of these syndromes, and with each one, there may be a total lack of a particular enzyme or a mutation that only mildly impairs the effectiveness of the enzyme.

 salt wasting syndrome
 simple virilizing syndrome
 nonclassic virilizing syndrome
 adrenogenital syndrome
 congenital adrenal hyperplasia tumors

Tumor predisposition

Congenital adrenal hyperplasia is associated with testicular tumors that arise from ectopic adrenal cortical rests (10782175), and rarely with similar ovarian tumors (11684964).

 ovarian tumor of the adrenogenital syndrome (11684964)

• 21-hydroxylase deficiency
• ovarian or paraovarian soft brown masses
• identical to the testicular tumor of the adrenogenital syndrome

 Leydig cell tumor

• testicular Leydig cell tumor
• ovarian Leydig cell tumor
  • bilateral ovarian Leydig cell tumors

 testicular adrenal rest tumor (18620332)

Macroscopy

 marked adrenal enlargement (15g each gland) with cerebriform appearance, - tan-brown
 secondary to elevated ACTH (due to reduced cortisol secretion)

Microscopy

 diffuse cortical hyperplasia, particularly of zona reticularis-like compact cells

Differential diagnosis

 bilateral adrenal hyperplasia due to ectopic ACTH

• not grossly cerebriform
• may have metastatic carcinoma
• differentiate clinically

Treatment

 exogenous glucocorticoids and mineralocorticoids to provide cortisol and suppress ACTH levels
 surgical correction of external genitalia

References

 Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003 Aug 21;349(8):776-88. PMID: 12930931