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3 beta-Hydroxysteroid dehydrogenase deficiency(HSDB)

MedGen UID:
452446
Concept ID:
C0342471
Disease or Syndrome
Synonyms: 3-beta-HSD deficiency; 3-beta-Hydroxysteroid Dehydrogenase-Deficient Congenital Adrenal Hyperplasia; 3b-hydroxysteroid dehydrogenase deficiency; Adrenal hyperplasia 2; Adrenal hyperplasia II; ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 3-BETA-HYDROXYSTEROID DEHYDROGENASE 2 DEFICIENCY; Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency; HSD3B deficiency; Type II 3-beta-hydroxysteroid dehydrogenase deficiency
SNOMED CT: CAH - 3 beta-dehydrogenase deficiency (54470008); 3 beta-Hydroxysteroid dehydrogenase deficiency (54470008); 3 beta-HSD deficiency (54470008); Congenital adrenal hyperplasia, type 4 (54470008)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): HSD3B2 (1p12)
 
Monarch Initiative: MONDO:0008727
OMIM®: 201810
Orphanet: ORPHA90791

Definition

Classic 3-beta-hydroxysteroid dehydrogenase deficiency is an autosomal recessive form of CAH characterized by a severe impairment of steroid biosynthesis in both the adrenals and the gonads, resulting in decreased excretion of cortisol and aldosterone and of progesterone, androgens, and estrogens by these tissues. Affected newborns exhibit signs and symptoms of glucocorticoid and mineralocorticoid deficiencies, which may be fatal if not diagnosed and treated early, especially in the severe salt-wasting form. Moreover, male newborns exhibit pseudohermaphroditism with incomplete masculinization of the external genitalia due to an impairment of androgen biosynthesis in the testis. In contrast, affected females exhibit normal sexual differentiation or partial virilization (summary by Rheaume et al., 1992). [from OMIM]

Additional description

From MedlinePlus Genetics
3-beta (ß)-hydroxysteroid dehydrogenase (HSD) deficiency is an inherited disorder that affects hormone-producing glands including the gonads (ovaries in females and testes in males) and the adrenal glands. The gonads direct sexual development before birth and during puberty. The adrenal glands, which are located on top of the kidneys, regulate the production of certain hormones and control salt levels in the body. People with 3ß-HSD deficiency lack many of the hormones that are made in these glands. 3ß-HSD deficiency is one of a group of disorders known as congenital adrenal hyperplasias that impair hormone production and disrupt sexual development and maturation.

There are three types of 3ß-HSD deficiency: the salt-wasting, non-salt-wasting, and non-classic types. In the salt-wasting type, hormone production is extremely low. Individuals with this type lose large amounts of sodium in their urine, which can be life-threatening. Individuals affected with the salt-wasting type are usually diagnosed soon after birth due to complications related to a lack of salt reabsorption, including dehydration, poor feeding, and vomiting. People with the non-salt-wasting type of 3ß-HSD deficiency produce enough hormone to allow sodium reabsorption in the kidneys. Individuals with the non-classic type have the mildest symptoms and do not experience salt wasting.

In males with any type of 3ß-HSD deficiency, problems with male sex hormones lead to abnormalities of the external genitalia. These abnormalities range from having the opening of the urethra on the underside of the penis (hypospadias) to having external genitalia that do not look clearly male or female. The severity of the genital abnormality does not consistently depend on the type of the condition. Because of the hormone dysfunction in the testes, males with 3ß-HSD deficiency are frequently unable to have biological children (infertile).

Females with 3ß-HSD deficiency may have slight abnormalities of the external genitalia at birth. Females affected with the non-salt-wasting or non-classic types are typically not diagnosed until mid-childhood or puberty, when they may experience irregular menstruation, premature pubic hair growth, and excessive body hair growth (hirsutism). Females with 3ß-HSD deficiency have difficulty conceiving a child (impaired fertility).  https://medlineplus.gov/genetics/condition/3-beta-hydroxysteroid-dehydrogenase-deficiency

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Male pseudohermaphroditism
MedGen UID:
68666
Concept ID:
C0238395
Congenital Abnormality
Hermaphroditism refers to a discrepancy between the morphology of the gonads and that of the external genitalia. In male pseudohermaphroditism, the genotype is male (XY) and the external genitalia are imcompletely virilized, ambiguous, or complete female. If gonads are present, they are testes.
Microphallus
MedGen UID:
66816
Concept ID:
C0240701
Finding
Length of penis more than 2 SD below the mean for age accompanied by hypospadias.
Ambiguous genitalia
MedGen UID:
78596
Concept ID:
C0266362
Congenital Abnormality
A genital phenotype that is not clearly assignable to a single gender. Ambiguous genitalia can be evaluated using the Prader scale
Bifid scrotum
MedGen UID:
90968
Concept ID:
C0341787
Congenital Abnormality
Midline indentation or cleft of the scrotum.
Absent scrotum
MedGen UID:
488897
Concept ID:
C0426320
Finding
Congenital absence of the scrotum.
Penoscrotal hypospadias
MedGen UID:
105291
Concept ID:
C0452147
Congenital Abnormality
A severe form of hypospadias in which the urethral opening is located at the junction of the penis and scrotum.
Perineal hypospadias
MedGen UID:
105292
Concept ID:
C0452148
Congenital Abnormality
Hypospadias with location of the urethral meatus in the perineal region.
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Scrotal hypospadias
MedGen UID:
786371
Concept ID:
C2197691
Finding
Hypospadias with location of the urethral meatus in the scrotum.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Hyperkalemia
MedGen UID:
5691
Concept ID:
C0020461
Finding
An abnormally increased potassium concentration in the blood.
Hyponatremia
MedGen UID:
6984
Concept ID:
C0020625
Finding
An abnormally decreased sodium concentration in the blood.
Adrenal insufficiency
MedGen UID:
1351
Concept ID:
C0001623
Disease or Syndrome
Insufficient production of steroid hormones (primarily cortisol) by the adrenal glands.
Premature pubarche
MedGen UID:
575093
Concept ID:
C0342541
Disease or Syndrome
The onset of growth of pubic hair at an earlier age than normal.
Adrenal hyperplasia
MedGen UID:
301220
Concept ID:
C1621895
Disease or Syndrome
Enlargement of the adrenal gland.
Impaired cortisol response to corticotropin releasing hormone stimulation test
MedGen UID:
1378460
Concept ID:
C4476957
Finding
Failure of cortisol levels to respond adequately (by increasing) to the corticotropin releasing hormone stimulation test.
Elevated circulating 17-hydroxyprogesterone concentration
MedGen UID:
1613419
Concept ID:
C4531273
Finding
An increased level of 17-hydroxyprogesterone in the blood. 17-hydroxyprogesterone is an intermediate steroid in the adrenal biosynthetic pathway from cholesterol to cortisol and is the substrate for steroid 21-hydroxylase.
Increased circulating 17 hydroxypregnenolone concentration
MedGen UID:
1788603
Concept ID:
C5539825
Finding
Increased concentration of 17alpha-hydroxypregnenolone in the blood circulation. 17alpha-hydroxypregnenolone is a 21-carbon steroid that is converted from pregnenolone by steroid 17-alpha-hydroxylase, as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids.
Increased circulating dehydroepiandrosterone-sulfate concentration
MedGen UID:
1841988
Concept ID:
C5826501
Finding
Concentration of dehydroepiandrosterone-sulfate in the blood circulation above the upper limit of normal.

Professional guidelines

PubMed

Ladjouze A, Donaldson M, Plotton I, Djenane N, Mohammedi K, Tardy-Guidollet V, Mallet D, Boulesnane K, Bouzerar Z, Morel Y, Roucher-Boulez F
Front Endocrinol (Lausanne) 2022;13:867073. Epub 2022 Jun 10 doi: 10.3389/fendo.2022.867073. PMID: 35757411Free PMC Article
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Recent clinical studies

Etiology

Ladjouze A, Donaldson M, Plotton I, Djenane N, Mohammedi K, Tardy-Guidollet V, Mallet D, Boulesnane K, Bouzerar Z, Morel Y, Roucher-Boulez F
Front Endocrinol (Lausanne) 2022;13:867073. Epub 2022 Jun 10 doi: 10.3389/fendo.2022.867073. PMID: 35757411Free PMC Article
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Clin Endocrinol (Oxf) 1992 Apr;36(4):383-8. doi: 10.1111/j.1365-2265.1992.tb01464.x. PMID: 1330378

Diagnosis

Ladjouze A, Donaldson M, Plotton I, Djenane N, Mohammedi K, Tardy-Guidollet V, Mallet D, Boulesnane K, Bouzerar Z, Morel Y, Roucher-Boulez F
Front Endocrinol (Lausanne) 2022;13:867073. Epub 2022 Jun 10 doi: 10.3389/fendo.2022.867073. PMID: 35757411Free PMC Article
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Nishi Y, Tezuka T
Eur J Pediatr 1992 Jan;151(1):19-23. doi: 10.1007/BF02073883. PMID: 1309452

Therapy

Pang S
Endocrinol Metab Clin North Am 2001 Mar;30(1):81-99, vi-vii. doi: 10.1016/s0889-8529(08)70020-3. PMID: 11344940
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Prognosis

Walker BR, Skoog SJ, Winslow BH, Canning DA, Tank ES
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Mathieson J, Couzinet B, Wekstein-Noel S, Nahoul K, Turpin G, Schaison G
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Clinical prediction guides

Ladjouze A, Donaldson M, Plotton I, Djenane N, Mohammedi K, Tardy-Guidollet V, Mallet D, Boulesnane K, Bouzerar Z, Morel Y, Roucher-Boulez F
Front Endocrinol (Lausanne) 2022;13:867073. Epub 2022 Jun 10 doi: 10.3389/fendo.2022.867073. PMID: 35757411Free PMC Article
Simard J, Rheaume E, Mebarki F, Sanchez R, New MI, Morel Y, Labrie F
J Steroid Biochem Mol Biol 1995 Jun;53(1-6):127-38. doi: 10.1016/0960-0760(95)00043-y. PMID: 7626445
Whorwood CB, Montalto J, Sandars SR, Connelly JF
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Mendonca BB, Bloise W, Arnhold IJ, Batista MC, Toledo SP, Drummond MC, Nicolau W, Mattar E
J Steroid Biochem 1987 Dec;28(6):669-75. doi: 10.1016/0022-4731(87)90396-7. PMID: 2826919
Zachmann M, Forest MG, De Peretti E
Horm Res 1979;11(6):292-302. doi: 10.1159/000179067. PMID: 295036

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