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==Overview==
==Overview==
3β-Hydroxysteroid dehydrogenase II-deficient congenital adrenal hyperplasia (3βHSD CAH) is an uncommon form of [[congenital adrenal hyperplasia|CAH]] 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.
3 beta-hydroxysteroid dehydrogenase deficiency is a rare disease due to [[congenital adrenal hyperplasia]]. It is characterized by impaired biosynthesis pathway of [[progestins]], [[mineralocorticoids]], [[glucocorticoids]], and [[androgens]]. As a result of [[cortisol]] absence, [[corticotropin]] ([[ACTH]]) secretion increases and leads to produce 3-hydroxy-delta-5-steroids pregnenolone, [[17-hydroxypregnenolone]], and [[dehydroepiandrosterone]] ([[DHEA]]), also their sulfates. In peripheral tissues the conversion of [[DHEA sulfate]] ([[DHEAS]]) to [[testosterone]], is responsible for [[virilization]] in females. 3 beta-hydroxysteroid dehydrogenase deficiency is caused by a [[mutation]] in the HSD3B2 [[gene]]. Symptoms of 3 beta-hydroxysteroid dehydrogenase deficiency may include symptoms of both [[cortisol]] and [[aldosterone]] deficiency such as [[feeding difficulties]], [[vomiting]], [[volume depletion]], [[undervirilization]] in [[newborn]] [[males]], and mild [[virilization]] and [[clitoromegaly]] in [[newborn]] [[female]]. Diagnosis for 3 beta-hydroxysteroid dehydrogenase deficiency is based on [[17-hydroxypregnenolone|delta-5-17-hydroxypregnenolone]] high levels in serum laboratory tests. The mainstay of therapy for this disease is [[hydrocortisone]] and [[fludrocortisone acetate]]. The reconstruction surgery for [[ambiguous genitalia]] in genetically male patients may be applied.  
==Historical Perspective==
Severe 3β-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.  
3 beta-hydroxysteroid dehydrogenase deficiency was first time described in 1962, in 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 two types of 3 beta-hydroxysteroid dehydrogenase deficiency:
* [[Salt]]-wasting
* Non-salt-wasting


==Congenital Adrenal Hyperplasia==
==Pathophysiology==
[[Image:DHEA1.svg|thumb|center|300px|Production of DHEA from Cholesterol. ([[Cortisol]] is a [[glucocorticoid]].)]]
The pathogenesis of 3 beta-hydroxysteroid dehydrogenase deficiency is characterized by impaired pathway of biosynthesis of [[progestins]], [[mineralocorticoids]], [[glucocorticoids]], and [[androgens]]. As a result of [[cortisol]] absence, [[corticotropin]] ([[ACTH]]) secretion increases the production of 3-hydroxy-delta-5-steroids [[pregnenolone]], [[17-hydroxypregnenolone]], and [[dehydroepiandrosterone]] ([[DHEA]]). [[Adrenocorticotropic hormone|ACTH]] secretion also increases the production of their [[sulfates]]. In peripheral [[tissues]] the conversion of [[DHEA sulfate]] ([[DHEAS]]) to [[testosterone]] is responsible for [[virilization]] in [[females]].<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>
* ''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.  
==Causes==
* 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 CAH due to deficiencies of other proteins and enzymes involved in cortisol synthesis.  
3 beta-hydroxysteroid dehydrogenase deficiency is caused by a [[mutation]] in the HSD3B2 [[gene]].
== Pathophysiology ==
==Differentiating 3 Beta-hydroxysteroid Dehydrogenase Deficiency From Other Diseases==
* 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.
 
* 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 CAH. 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 CAH. 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.
=== Differentials of ambiguous genitalia ===
== Mineralocorticoid aspects of 3&beta;-HSD CAH ==
3 beta-hydroxysteroid dehydrogenase deficiency must be differentiated from diseases that cause [[ambiguous genitalia]]:<ref name="pmid17875484">{{cite journal |vauthors=Hughes IA, Nihoul-Fékété C, Thomas B, Cohen-Kettenis PT |title=Consequences of the ESPE/LWPES guidelines for diagnosis and treatment of disorders of sex development |journal=Best Pract. Res. Clin. Endocrinol. Metab. |volume=21 |issue=3 |pages=351–65 |year=2007 |pmid=17875484 |doi=10.1016/j.beem.2007.06.003 |url=}}</ref><ref name="pmid10857554">{{cite journal |vauthors=White PC, Speiser PW |title=Congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=Endocr. Rev. |volume=21 |issue=3 |pages=245–91 |year=2000 |pmid=10857554 |doi=10.1210/edrv.21.3.0398 |url=}}</ref>
* The [[mineralocorticoid]] aspect of severe 3&beta; -HSD CAH 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 CAH ==
{| class="wikitable"
* The [[sex steroid]] consequences of severe 3&beta; -HSD CAH is unique among the congenital adrenal hyperplasias: it is the only form of CAH that can produce ambiguity in both sexes. As with 21-hydroxylase deficient CAH, the degree of severity can determine the magnitude of over- or undervirilization.
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Disease name
* In an XX (genetically female) fetus, elevated amounts of DHEA 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.
! colspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Steroid status
* The extent to which mild 3&beta; -HSD CAH 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 CAH 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 CAH.
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Important clinical findings
* Undervirilization of genetic males with 3&beta; -HSD CAH occurs because synthesis of testosterone is impaired in both adrenals and testes. Although DHEA 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.
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Increased
* 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}}
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Decreased
|-
|3 beta-hydroxysteroid dehydrogenase deficiency
|
* [[Dehydroepiandrosterone]]
* [[17-hydroxypregnenolone]]
* [[Pregnenolone]]
|
* [[Cortisol]]
* [[Aldosterone]]
|
* [[Vomiting]], [[volume depletion]], [[hyponatremia]], and [[hyperkalemia]]
* 46-XY infants often show [[undervirilization]], due to a block in [[testosterone]] synthesis
|-
|[[21-hydroxylase deficiency|Classic type of 21-hydroxylase deficiency]]
|
* [[17-Hydroxyprogesterone|17-hydroxyprogesterone]]
* [[Progesterone]]
* [[Androstenedione]]
* [[DHEA]]
|
* [[Aldosterone]]
* [[Corticosterone]] (salt-wasting)
* [[Cortisol]] ([[virilization]])
|
* [[Ambiguous genitalia]] in female
* [[Virilization]] in female
* Salt-wasting
* [[Hypotension]] and [[hyperkalemia]]
|-
|[[11β-hydroxylase deficiency|11-β hydroxylase deficiency]]
|
* [[Deoxycorticosterone]]
* 11-Deoxy-[[cortisol]]
* [[17-Hydroxyprogesterone|17-hydroxyprogesterone]] (mild elevation)
|
* [[Cortisol]]
* [[Corticosterone]]
* [[Aldosterone]]
|
* [[Ambiguous genitalia]] in female
* [[Hypertension]] and [[hypokalemia]]
* [[Virilization]]
|-
|[[17 alpha-hydroxylase deficiency|17-α hydroxylase deficiency]]
|
* [[Deoxycorticosterone]]
* [[Corticosterone]]
* [[Progesterone]]
|
* [[Cortisol]]
* [[Aldosterone]]
|
* [[Ambiguous genitalia]] in male
* [[Hypertension]]
 
* [[Primary amenorrhea]]
 
* Absence of [[secondary sexual characteristics]]
 
* Minimal [[body hair]]
|-
| Gestational [[hyperandrogenism]]
| colspan="2" |
* Maternal serum [[androgen]] concentrations (usually [[testosterone]] and [[androstenedione]]) are high
* If [[virilization]] is caused by exogenous hormone administration, the values may be low because the offending hormone is usually a synthetic [[steroid]] not measured in assays for [[testosterone]] or other [[androgens]]
|
* [[Androgen]] excess in mother
* History of [[androgen]] containing [[medication]]  consumption during [[pregnancy]] in mother
* [[Virilization]] in a 46,XX individual with normal female internal anatomy
* Causes include maternal [[luteoma]] or theca-[[lutein]] [[cysts]], and [[placental]] [[aromatase]] enzyme deficiency
|}
 
=== Differentials based on virilization and hirsutism ===
3 beta-hydroxysteroid dehydrogenase deficiency must be differentiated from diseases that cause [[virilization]] and [[hirsutism]] in female:<ref name="pmid24830586">{{cite journal |vauthors=Hohl A, Ronsoni MF, Oliveira Md |title=Hirsutism: diagnosis and treatment |journal=Arq Bras Endocrinol Metabol |volume=58 |issue=2 |pages=97–107 |year=2014 |pmid=24830586 |doi= |url=}}</ref><ref name="pmid10857554">{{cite journal |vauthors=White PC, Speiser PW |title=Congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=Endocr. Rev. |volume=21 |issue=3 |pages=245–91 |year=2000 |pmid=10857554 |doi=10.1210/edrv.21.3.0398 |url=}}</ref><ref name="ISBN:978-0323297387">{{cite book | last = Melmed | first = Shlomo | title = Williams textbook of endocrinology | publisher = Elsevier | location = Philadelphia, PA | year = 2016 | isbn = 978-0323297387 }}=</ref>
 
{| class="wikitable"
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Disease name
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Steroid status
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Other laboratory
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Important clinical findings
|-
|3 beta-hydroxysteroid dehydrogenase deficiency
|Increased:
* [[DHEA]]
* [[17-hydroxypregnenolone]]
* [[Pregnenolone]]
Decreased:
* [[Cortisol]]
* [[Aldosterone]]
|
* Low [[testosterone]] levels
|
* Salt-wasting [[adrenal crisis]] in infancy
 
* Mild [[virilization]] of genetically female infants
* [[Undervirilization]] of genetically male infants, making it the only form of [[CAH]] which can cause [[ambiguous genitalia]] in both genetic sexes.  
|-
|Non-classic type of [[21-hydroxylase deficiency]]
|Increased:
* [[17-Hydroxyprogesterone|17-hydroxyprogesterone]]
* Exaggerated [[Androstenedione]], [[DHEA]], and [[17-Hydroxyprogesterone|17-hydroxyprogesterone]] in response to [[ACTH]]
|
* Low [[testosterone]] levels
|
* No symptoms in infancy and male
 
* [[Virilization]] in females
|-
|[[11β-hydroxylase deficiency|11-β hydroxylase deficiency]]
|Increased:
* DOC
* 11-Deoxy-[[Cortisol]]
Decreased:
* [[Cortisol]]
* [[Corticosterone]]
* [[Aldosterone]]
|
* Low [[testosterone]] levels
|
* [[Hypertension]] and [[hypokalemia]]
* [[Virilization]]
|-
|[[Polycystic ovary syndrome ]]
|
* High [[DHEAS]] and [[androstenedione]] levels
|
* Low [[testosterone]] levels
|
* [[Polycystic ovaries]] in sonography
* [[Obesity]]
* [[PCOS]] is the most common cause of [[hirsutism]] in women
* No evidence another diagnosis
|-
|[[Adrenal tumor|Adrenal tumors]]
|
* Variable levels depends on [[tumor]] type
|
* Low [[testosterone]] level
|
* Older age
* Rapidly progressive symptoms
|-
|[[Ovarian]] [[virilizing]] [[tumor]]
|
* Variable levels depends on [[tumor]] type
|
* [[Testosterone]] is high
|
* Older age
* Rapidly progressive symptoms
|-
|[[Cushing's syndrome]]
|
* Increase [[cortisol]] & [[metabolites]]
* Variable other [[steroids]]
|
* Variable [[mineralocorticoid]] excess
|
* [[Cushingoid appearance]]
|-
|[[Hyperprolactinemia]]
|
* Normal levels of most of [[steroids]]
|
* Increased [[prolactin]]
|
* [[Infertility]], [[galactorrhea]]
|}
 
==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 ==
== Diagnosis ==
* Like the other forms of CAH, suspicion of severe 3&beta;  -HSD CAH 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, DHEA, and renin. In clinical circumstances, this form of CAH has sometimes been difficult to distinguish from the more common 21-hydroxylase deficient CAH because of the 17OHP elevation, or from simple premature adrenarche because of the DHEA elevation.
=== Symptoms ===
== Management of 3&beta;-HSD II-deficient CAH after infancy ==  
Symptoms of 3 beta-hydroxysteroid dehydrogenase deficiency may include symptoms of both [[cortisol]] and [[aldosterone]] deficiency such as [[feeding difficulties]], [[vomiting]], [[volume depletion]], [[muscle weakness]], [[undervirilization]] in male newborns, and mild [[virilization]] and [[clitoromegaly]] in newborn female. <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>
* Some of the childhood management issues are similar those of 21-hydroxylase deficiency:
=== Physical Examination ===
:* Replacing mineralocorticoid with fludrocortisone;
Physical examination may be remarkable for:
:* Suppressing DHEA and replacing cortisol with glucocorticoid;
* [[Undervirilization]] in [[newborn]] [[males]]
:* Providing extra glucocorticoid for stress;
* Mild [[virilization]] and [[clitoromegaly]] in [[newborn]] [[female]].
:* Close monitoring and perhaps other adjunctive measures to optimize growth.
 
:* Deciding whether surgical repair of virilized female genitalia is warranted
=== Laboratory Findings ===
* However, unlike 21-hydroxylase CAH, children with 3&beta;- HSD CAH 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.
Diagnosis for 3 beta-hydroxysteroid dehydrogenase deficiency is based on high levels of delta-5-17-hydroxypregnenolone. <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> Other laboratory findings incliude, [[hyponatremia]] and [[hyperkalemia]].
== See also ==
 
*[[Lipoid congenital adrenal hyperplasia]]
== Treatment ==
*[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency|Congenital adrenal hyperplasia due to 17&#945; -hydroxylase deficiency]]  
=== Medical Therapy ===
*[[Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency|Congenital adrenal hyperplasia due to 11&#946; -hydroxylase deficiency]]
The mainstay of therapy for 3 beta-hydroxysteroid dehydrogenase deficiency is [[hydrocortisone]] and [[fludrocortisone acetate]] adiminstration. Gender-appropriate replacement of [[androgens]] or [[estrogens]] with [[progestins]] is necessary at the [[puberty]] time.
*[[Adrenal insufficiency]]
The goal of therapy includes the following: <ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume= |issue= |pages= |year=2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref><ref name="pmid24622419">{{cite journal |vauthors=Merke DP, Poppas DP |title=Management of adolescents with congenital adrenal hyperplasia |journal=Lancet Diabetes Endocrinol |volume=1 |issue=4 |pages=341–52 |year=2013 |pmid=24622419 |pmc=4163910 |doi=10.1016/S2213-8587(13)70138-4 |url=}}</ref><ref name="pmid3060026">{{cite journal| author=Hughes IA| title=Management of congenital adrenal hyperplasia. | journal=Arch Dis Child | year= 1988 | volume= 63 | issue= 11 | pages= 1399-404 | pmid=3060026 | doi= | pmc=1779155 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3060026  }}</ref>
 
* Correct the effects of [[mineralocorticoid excess]]
* Prevent [[glucocorticoid]] deficiency
* Restore desired secondary [[sexual characteristics]]
 
*Treatment for 3 beta-hydroxysteroid dehydrogenase deficiency is by the use of [[glucocorticoids]] such as:
** Preferred regimen (1): [[Hydrocortisone]] 10 to 25 mg/m2 body surface area/day PO.
** Preferred regimen (2): [[Prednisolone]] 0.1 mg/kg/day PO.
** Preferred regimen (3): [[Dexamethasone]] up to 0.5 mg/day PO.
 
=== Surgery ===
The reconstruction surgery for [[ambiguous genitalia]] in genetically male patients may be applied.<ref name="pmid11344932">{{cite journal |vauthors=Schnitzer JJ, Donahoe PK |title=Surgical treatment of congenital adrenal hyperplasia |journal=Endocrinol. Metab. Clin. North Am. |volume=30 |issue=1 |pages=137–54 |year=2001 |pmid=11344932 |doi= |url=}}</ref>


[[Category:Pediatrics]]
==References==
[[Category:Endocrinology]]
{{Reflist|2}}
[[Category:Genetic disorders]]
[[Category:Intersexuality]]
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Latest revision as of 15:32, 6 November 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

3 beta-hydroxysteroid dehydrogenase deficiency is a rare disease due to congenital adrenal hyperplasia. It is characterized by impaired biosynthesis pathway of progestins, mineralocorticoids, glucocorticoids, and androgens. As a result of cortisol absence, corticotropin (ACTH) secretion increases and leads to produce 3-hydroxy-delta-5-steroids pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA), also their sulfates. In peripheral tissues the conversion of DHEA sulfate (DHEAS) to testosterone, is responsible for virilization in females. 3 beta-hydroxysteroid dehydrogenase deficiency is caused by a mutation in the HSD3B2 gene. Symptoms of 3 beta-hydroxysteroid dehydrogenase deficiency may include symptoms of both cortisol and aldosterone deficiency such as feeding difficulties, vomiting, volume depletion, undervirilization in newborn males, and mild virilization and clitoromegaly in newborn female. Diagnosis for 3 beta-hydroxysteroid dehydrogenase deficiency is based on delta-5-17-hydroxypregnenolone high levels in serum laboratory tests. The mainstay of therapy for this disease is hydrocortisone and fludrocortisone acetate. The reconstruction surgery for ambiguous genitalia in genetically male patients may be applied.

Historical Perspective

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

Classification

There are two types of 3 beta-hydroxysteroid dehydrogenase deficiency:

  • Salt-wasting
  • Non-salt-wasting

Pathophysiology

The pathogenesis of 3 beta-hydroxysteroid dehydrogenase deficiency is characterized by impaired pathway of biosynthesis of progestins, mineralocorticoids, glucocorticoids, and androgens. As a result of cortisol absence, corticotropin (ACTH) secretion increases the production of 3-hydroxy-delta-5-steroids pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA). ACTH secretion also increases the production of their sulfates. In peripheral tissues the conversion of DHEA sulfate (DHEAS) to testosterone is responsible for virilization in females.[1]

Causes

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

Differentiating 3 Beta-hydroxysteroid Dehydrogenase Deficiency From Other Diseases

Differentials of ambiguous genitalia

3 beta-hydroxysteroid dehydrogenase deficiency must be differentiated from diseases that cause ambiguous genitalia:[2][3]

Disease name Steroid status Important clinical findings
Increased Decreased
3 beta-hydroxysteroid dehydrogenase deficiency
Classic type of 21-hydroxylase deficiency
11-β hydroxylase deficiency
17-α hydroxylase deficiency
Gestational hyperandrogenism

Differentials based on virilization and hirsutism

3 beta-hydroxysteroid dehydrogenase deficiency must be differentiated from diseases that cause virilization and hirsutism in female:[4][3][5]

Disease name Steroid status Other laboratory Important clinical findings
3 beta-hydroxysteroid dehydrogenase deficiency Increased:

Decreased:

Non-classic type of 21-hydroxylase deficiency Increased:
  • No symptoms in infancy and male
11-β hydroxylase deficiency Increased:

Decreased:

Polycystic ovary syndrome
Adrenal tumors
  • Variable levels depends on tumor type
  • Older age
  • Rapidly progressive symptoms
Ovarian virilizing tumor
  • Variable levels depends on tumor type
  • Older age
  • Rapidly progressive symptoms
Cushing's syndrome
Hyperprolactinemia

Epidemiology and Demographics

The prevalence of 3 beta-hydroxysteroid dehydrogenase deficiency is unknown. At least 60 affected individuals have been reported.[6]

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 symptoms of both cortisol and aldosterone deficiency such as feeding difficulties, vomiting, volume depletion, muscle weakness, undervirilization in male newborns, and mild virilization and clitoromegaly in newborn female. [7]

Physical Examination

Physical examination may be remarkable for:

Laboratory Findings

Diagnosis for 3 beta-hydroxysteroid dehydrogenase deficiency is based on high levels of delta-5-17-hydroxypregnenolone. [8] Other laboratory findings incliude, hyponatremia and hyperkalemia.

Treatment

Medical Therapy

The mainstay of therapy for 3 beta-hydroxysteroid dehydrogenase deficiency is hydrocortisone and fludrocortisone acetate adiminstration. Gender-appropriate replacement of androgens or estrogens with progestins is necessary at the puberty time. The goal of therapy includes the following: [9][10][11]

  • Treatment for 3 beta-hydroxysteroid dehydrogenase deficiency is by the use of glucocorticoids such as:

Surgery

The reconstruction surgery for ambiguous genitalia in genetically male patients may be applied.[12]

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. ↑ Hughes IA, Nihoul-Fékété C, Thomas B, Cohen-Kettenis PT (2007). "Consequences of the ESPE/LWPES guidelines for diagnosis and treatment of disorders of sex development". Best Pract. Res. Clin. Endocrinol. Metab. 21 (3): 351–65. doi:10.1016/j.beem.2007.06.003. PMID 17875484.
  3. ↑ 3.0 3.1 White PC, Speiser PW (2000). "Congenital adrenal hyperplasia due to 21-hydroxylase deficiency". Endocr. Rev. 21 (3): 245–91. doi:10.1210/edrv.21.3.0398. PMID 10857554.
  4. ↑ Hohl A, Ronsoni MF, Oliveira M (2014). "Hirsutism: diagnosis and treatment". Arq Bras Endocrinol Metabol. 58 (2): 97–107. PMID 24830586. Vancouver style error: initials (help)
  5. ↑ Melmed, Shlomo (2016). Williams textbook of endocrinology. Philadelphia, PA: Elsevier. ISBN 978-0323297387.=
  6. ↑ "3-beta-hydroxysteroid dehydrogenase deficiency - Genetics Home Reference".
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ El-Maouche D, Arlt W, Merke DP (2017). "Congenital adrenal hyperplasia". Lancet. doi:10.1016/S0140-6736(17)31431-9. PMID 28576284.
  10. ↑ Merke DP, Poppas DP (2013). "Management of adolescents with congenital adrenal hyperplasia". Lancet Diabetes Endocrinol. 1 (4): 341–52. doi:10.1016/S2213-8587(13)70138-4. PMC 4163910. PMID 24622419.
  11. ↑ Hughes IA (1988). "Management of congenital adrenal hyperplasia". Arch Dis Child. 63 (11): 1399–404. PMC 1779155. PMID 3060026.
  12. ↑ Schnitzer JJ, Donahoe PK (2001). "Surgical treatment of congenital adrenal hyperplasia". Endocrinol. Metab. Clin. North Am. 30 (1): 137–54. PMID 11344932.

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