3 beta-hydroxysteroid dehydrogenase deficiency: Difference between revisions

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==Overview==
==Overview==
3β-Hydroxysteroid dehydrogenase II-deficient congenital adrenal hyperplasia (3βHSD CAH) is an uncommon form of [[congenital adrenal hyperplasia]] resulting from a defective [[gene]] for one of the key [[enzyme]]s in [[cortisol]] synthesis by the [[adrenal gland]]s. 3βHSD Congenital adrenal hyperplasia can cause salt-wasting adrenal crises in infancy. It can also cause mild [[virilization]] of genetically female infants and undervirilization of genetically male infants, making it the only form of CAH which can cause [[ambiguous genitalia]] in both genetic sexes.
 
==Historical Perspective==
3 beta-hydroxysteroid dehydrogenase deficiency first time described in 1962, a patient with ambiguous genitalia and salt wasting.<ref name="pmid13968789">{{cite journal |vauthors=BONGIOVANNI AM |title=The adrenogenital syndrome with deficiency of 3 beta-hydroxysteroid dehydrogenase |journal=J. Clin. Invest. |volume=41 |issue= |pages=2086–92 |year=1962 |pmid=13968789 |pmc=291138 |doi=10.1172/JCI104666 |url=}}</ref>
 
==Classification==
There are three types of 3 beta-hydroxysteroid dehydrogenase deficiency: the salt-wasting, non-salt-wasting, and non-classic types.
==Pathophysiology==
*The pathogenesis of 3 beta-hydroxysteroid dehydrogenase deficiency is characterized by impaired pathway biosynthesis of progestins, mineralocorticoids, glucocorticoids, and androgens (therefore estrogen. As a result of [[cortisol]] absence, [[corticotropin]] ([[ACTH]]) secretion increases leads to produce 3-hydroxy-delta-5-steroids pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA), also their sulfates.<ref name="pmid13968789">{{cite journal |vauthors=BONGIOVANNI AM |title=The adrenogenital syndrome with deficiency of 3 beta-hydroxysteroid dehydrogenase |journal=J. Clin. Invest. |volume=41 |issue= |pages=2086–92 |year=1962 |pmid=13968789 |pmc=291138 |doi=10.1172/JCI104666 |url=}}</ref>
==Causes==
* 3 beta-hydroxysteroid dehydrogenase deficiency is caused by a mutation in the HSD3B2 gene.
==Differentiating [disease name] from other Diseases==
* 3 beta-hydroxysteroid dehydrogenase deficiency must be differentiated from other diseases that cause ambiguous genitalia such as:
* [[21-hydroxylase deficiency]]
* [[11-β hydroxylase deficiency]]
* [[17-α hydroxylase deficiency]]
* Gestational [[hyperandrogenism]]
* [[P450-oxidoreductase deficiency]]
   
   
Severe 3&beta;-HSD II-deficient congenital adrenal hyperplasia is uncommon, and can cause salt-wasting due to mineralocorticoid deficiency. The most distinctive aspect of sex hormone metabolism in severe deficiency is that the newborn genitalia of both sexes can be affected.
==Epidemiology and Demographics==
* The prevalence of 3 beta-hydroxysteroid dehydrogenase deficiency is unknown. At least 60 affected individuals have been reported.<ref name="url3-beta-hydroxysteroid dehydrogenase deficiency - Genetics Home Reference">{{cite web |url=https://ghr.nlm.nih.gov/condition/3-beta-hydroxysteroid-dehydrogenase-deficiency#statistics |title=3-beta-hydroxysteroid dehydrogenase deficiency - Genetics Home Reference |format= |work= |accessdate=}}</ref>
==Risk Factors==
*Common risk factors in the development of 3 beta-hydroxysteroid dehydrogenase deficiency is family history of this disease.
 
== Diagnosis ==
=== Symptoms ===
* Symptoms of 3 beta-hydroxysteroid dehydrogenase deficiency may include the following:<ref name="pmid7626445">{{cite journal |vauthors=Simard J, Rheaume E, Mebarki F, Sanchez R, New MI, Morel Y, Labrie F |title=Molecular basis of human 3 beta-hydroxysteroid dehydrogenase deficiency |journal=J. Steroid Biochem. Mol. Biol. |volume=53 |issue=1-6 |pages=127–38 |year=1995 |pmid=7626445 |doi= |url=}}</ref>
Symptoms of both cortisol and aldosterone deficiency:
:* Feeding difficulties
:* [[Vomiting]]
:* [[Volume depletion]]
:* [[Muscle weakness]]


==Congenital Adrenal Hyperplasia==
* Undervirilization in newborn males.
[[Image:DHEA1.svg|thumb|center|300px|Production of DHEA from Cholesterol. ([[Cortisol]] is a [[glucocorticoid]].)]]
* Mild virilization and clitoromegaly in newborn female because of peripheral conversion of DHEA sulfate (DHEAS) to testosterone.
* ''Congenital adrenal hyperplasia'' refers to any of several [[autosomal]] [[recessive]] diseases resulting from defects in steps of the [[synthesis]] of [[cortisol]] from [[cholesterol]] by the [[adrenal gland]]s. All of the forms of congenital adrenal hyperplasia involve the excessive or defective production of [[sex steroid]]s and can pervert or impair the development of [[primary sex characteristic|primary]] or [[secondary sex characteristic]]s in affected infants, children, and adults. Many also involve the excessive or defective production of [[mineralocorticoid]]s, which can cause [[hypertension]] or salt wasting.  
* The most common type of congenital adrenal hyperplasia is due to deficiency of 21-hydroxylase and is covered in detail in the main article on [[congenital adrenal hyperplasia]]. 3&beta; HSD CAH is one of the less common types of [[congenital adrenal hyperplasia]] due to deficiencies of other proteins and enzymes involved in cortisol synthesis.
=== Physical Examination ===
== Pathophysiology ==
*Physical examination may be remarkable for:
* 3&beta;-HSD II mediates three parallel dehydrogenase/isomerase reactions in the adrenals that convert &Delta;4 to &Delta;5 steroids: [[17-Hydroxypregnenolone]] to [[17-Hydroxyprogesterone]], [[dehydroepiandrosterone|DHEA]] to [[androstenedione]], and [[pregnenolone]] to [[progesterone]]. 3&beta; -HSD II also mediates an alternate route of [[testosterone]] synthesis from androstenediol in the testes. 3β-HSD deficiency results in large elevations of pregnenolone, 17-hydroxypregnenolone, and DHEA.
Undervirilization in newborn males and mild virilization and clitoromegaly in newborn female.  
* However, complexity arises from the presence of a second [[3β-HSD]] (3β-HSD I) coded by a different gene, expressed in the liver and placenta, and unaffected in 3β-HSD deficient [[congenital adrenal hyperplasia]]. The presence of this second enzyme has two clinical consequences. First, 3β-HSD II can convert enough of the excess 17-hydroxypregnenolone to 17OHP to produce 17OHP levels suggestive of common 21-hydroxylase deficient [[congenital adrenal hyperplasia]]. Measurement of the other affected steroids distinguishes the two. Second, 3β-HSD II can convert enough DHEA to testosterone to moderately virilize a genetically female fetus.
== Mineralocorticoid aspects of 3&beta;-HSD Cogenital Adrenal Hyperplasia==
* The [[mineralocorticoid]] aspect of severe 3&beta; -HSD congenital adrenal hyperplasia is similar to those of 21-hydroxylase deficiency. Like other enzymes involved in early stages of both aldosterone and cortisol synthesis, the severe form of 3&beta; -HSD deficiency can result in life-threatening salt-wasting in early infancy. Salt-wasting is managed acutely with saline and high-dose hydrocortisone, and long-term [[fludrocortisone]].
== Sex steroid aspects of 3&beta;-HSD Cogenital Adrenal Hyperplasia ==
* The [[sex steroid]] consequences of severe 3&beta; -HSD congenital adrenal hyperplasia is unique among the congenital adrenal hyperplasias: it is the only form of congenital adrenal hyperplasia that can produce ambiguity in both sexes. As with 21-hydroxylase deficient congenital adrenal hyperplasia, the degree of severity can determine the magnitude of over- or undervirilization.
* In an XX (genetically female) fetus, elevated amounts of dehydroepiandrosterone can produce moderate [[virilization]] by conversion in the liver to testosterone. Virilization of genetic females is partial, often mild, and rarely raises assignment questions. The issues surrounding corrective surgery of the virilized female genitalia are the same as for moderate 21-hydroxylase deficiency but surgery is rarely considered desirable.
* The extent to which mild 3&beta; -HSD congenital adrenal hyperplasia can cause the early appearance of pubic hair and other aspects of hyperandrogenism in later childhood or adolescence is unsettled. Early reports about 20 years ago suggesting that mild forms of 3&beta; -HSD congenital adrenal hyperplasia comprised significant proportions of girls with premature pubic hair or older women with hirsutism have not been confirmed and it now appears that premature pubarche in childhood and [[hirsutism]] after adolescence are not common manifestations of 3&beta; -HSD congenital adrenal hyperplasia.
* Undervirilization of genetic males with 3&beta; -HSD congenital adrenal hyperplasia occurs because synthesis of testosterone is impaired in both adrenals and testes. Although dehydroepiandrosterone is elevated, it is a weak androgen and too little testosterone is produced in the liver to offset the deficiency of testicular testosterone. The degree of undervirilization is more variable, from mild to severe. Management issues are those of an underutilized male with normal sensitivity to testosterone.
* If the infant boy is only mildly underutilized, the hypospadias can be surgically repaired, testes brought into the scrotum, and testosterone supplied at puberty.
* Management decisions are more difficult for a moderately or severely underutilized genetic male whose testes are in the abdomen and whose genitalia look at least as much female as male. Male sex can assign and major reconstructive surgery was done to close the midline of the perineum and move the testes into a constructed scrotum. Female sex can be assigned and the testes removed and vagina enlarged surgically. A recently advocated third choice would be to assign either sex and defer surgery to adolescence. Each approach carries its own disadvantages and risks. Children and their families are different enough that none of the courses is appropriate for all.  {{see|Intersex}}


== Diagnosis ==
=== Laboratory Findings ===
* Like the other forms of congenital adrenal hyperplasia, suspicion of severe 3&beta;  -HSD congenital adrenal hyperplasia is usually raised by the appearance of the genitalia at birth or b the development of a salt-wasting crisis in the first month of life. The diagnosis is usually confirmed by the distinctive pattern of adrenal steroids: elevated pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, and renin. In clinical circumstances, this form of congenital adrenal hyperplasia has sometimes been difficult to distinguish from the more common 21-hydroxylase deficient congenital adrenal hyperplasia because of the 17OHP elevation, or from simple premature adrenarche because of the dehydroepiandrosterone elevation.
Hormonal criteria described for 3 beta-hydroxysteroid dehydrogenase deficiency based on delta-5-17-hydroxypregnenolone levels as following:<ref name="pmid12050224">{{cite journal |vauthors=Lutfallah C, Wang W, Mason JI, Chang YT, Haider A, Rich B, Castro-Magana M, Copeland KC, David R, Pang S |title=Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=6 |pages=2611–22 |year=2002 |pmid=12050224 |doi=10.1210/jcem.87.6.8615 |url=}}</ref>
* Neonates ≥12,600 ng/dL
* Tanner stage I children ≥5490 ng/dL
* Children with premature pubarche ≥9790 ng/dL
* Adults ≥9620 ng/dL


== Management of 3&beta;-HSD II-deficient Congenital Adrenal Hyperplasia after Infancy ==
Other laboratory findings include:
* Some of the childhood management issues are similar those of 21-hydroxylase deficiency:
* [Hyponatremia]
:* Replacing mineralocorticoid with fludrocortisone;
* [Hyperkalemia]
:* Suppressing dehydroepiandrosterone and replacing cortisol with glucocorticoid;
:* Providing extra glucocorticoid for stress;
:* Close monitoring and perhaps other adjunctive measures to optimize growth.
:* Deciding whether surgical repair of virilized female genitalia is warranted
* However, unlike 21-hydroxylase congenital adrenal hyperplasia, children with 3&beta;- HSD congenital adrenal hyperplasia may be unable to produce adequate amounts of testosterone (boys) or estradiol (girls) to effect normal [[puberty|pubertal]] changes. Replacement testosterone or [[estrogen]] and [[progesterone]] can be initiated at adolescence and continued throughout adult life. [[Fertility]] may be impaired by the difficulty of providing appropriate sex hormone levels in the gonads even though the basic anatomy is present.


== See also ==
== Treatment ==
*[[Lipoid congenital adrenal hyperplasia]]
=== Medical Therapy ===
*[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency|Congenital adrenal hyperplasia due to 17&#945; -hydroxylase deficiency]]  
*The mainstay of therapy for 3 beta-hydroxysteroid dehydrogenase deficiency is [[hydrocortisone]] and [[fludrocortisone acetate]].
*[[Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency|Congenital adrenal hyperplasia due to 11&#946; -hydroxylase deficiency]]
* Gender-appropriate replacement of androgens or estrogens with progestins is necessary at the puberty time.
*[[Adrenal insufficiency]]
=== Surgery ===
The reconstruction surgery for ambiguous genitalia in genetically male patients may be applied.
==References==
{{Reflist|2}}


[[Category:Pediatrics]]
[[Category:Endocrinology]]
[[Category:Genetic disorders]]
[[Category:Intersexuality]]
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Revision as of 19:08, 8 August 2017


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

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Overview

Historical Perspective

3 beta-hydroxysteroid dehydrogenase deficiency first time described in 1962, a patient with ambiguous genitalia and salt wasting.[1]

Classification

There are three types of 3 beta-hydroxysteroid dehydrogenase deficiency: the salt-wasting, non-salt-wasting, and non-classic types.

Pathophysiology

  • The pathogenesis of 3 beta-hydroxysteroid dehydrogenase deficiency is characterized by impaired pathway biosynthesis of progestins, mineralocorticoids, glucocorticoids, and androgens (therefore estrogen. As a result of cortisol absence, corticotropin (ACTH) secretion increases leads to produce 3-hydroxy-delta-5-steroids pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA), also their sulfates.[1]

Causes

  • 3 beta-hydroxysteroid dehydrogenase deficiency is caused by a mutation in the HSD3B2 gene.

Differentiating [disease name] from other Diseases

Epidemiology and Demographics

  • The prevalence of 3 beta-hydroxysteroid dehydrogenase deficiency is unknown. At least 60 affected individuals have been reported.[2]

Risk Factors

  • Common risk factors in the development of 3 beta-hydroxysteroid dehydrogenase deficiency is family history of this disease.

Diagnosis

Symptoms

  • Symptoms of 3 beta-hydroxysteroid dehydrogenase deficiency may include the following:[3]

Symptoms of both cortisol and aldosterone deficiency:

  • Undervirilization in newborn males.
  • Mild virilization and clitoromegaly in newborn female because of peripheral conversion of DHEA sulfate (DHEAS) to testosterone.

Physical Examination

  • Physical examination may be remarkable for:

Undervirilization in newborn males and mild virilization and clitoromegaly in newborn female.

Laboratory Findings

Hormonal criteria described for 3 beta-hydroxysteroid dehydrogenase deficiency based on delta-5-17-hydroxypregnenolone levels as following:[4]

  • Neonates ≥12,600 ng/dL
  • Tanner stage I children ≥5490 ng/dL
  • Children with premature pubarche ≥9790 ng/dL
  • Adults ≥9620 ng/dL

Other laboratory findings include:

  • [Hyponatremia]
  • [Hyperkalemia]

Treatment

Medical Therapy

  • The mainstay of therapy for 3 beta-hydroxysteroid dehydrogenase deficiency is hydrocortisone and fludrocortisone acetate.
  • Gender-appropriate replacement of androgens or estrogens with progestins is necessary at the puberty time.

Surgery

The reconstruction surgery for ambiguous genitalia in genetically male patients may be applied.

References

  1. ↑ 1.0 1.1 BONGIOVANNI AM (1962). "The adrenogenital syndrome with deficiency of 3 beta-hydroxysteroid dehydrogenase". J. Clin. Invest. 41: 2086–92. doi:10.1172/JCI104666. PMC 291138. PMID 13968789.
  2. ↑ "3-beta-hydroxysteroid dehydrogenase deficiency - Genetics Home Reference".
  3. ↑ Simard J, Rheaume E, Mebarki F, Sanchez R, New MI, Morel Y, Labrie F (1995). "Molecular basis of human 3 beta-hydroxysteroid dehydrogenase deficiency". J. Steroid Biochem. Mol. Biol. 53 (1–6): 127–38. PMID 7626445.
  4. ↑ Lutfallah C, Wang W, Mason JI, Chang YT, Haider A, Rich B, Castro-Magana M, Copeland KC, David R, Pang S (2002). "Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency". J. Clin. Endocrinol. Metab. 87 (6): 2611–22. doi:10.1210/jcem.87.6.8615. PMID 12050224.


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