CYP21A2 Enzyme, Fertility, & Stress

Detection of mutations in the CYP21A2 gene: genotype-phenotype correlation in Slovenian couples with conceiving problems

CYP21A2 Enzyme, Fertility, & Stress

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026265/

The impact of CYP21A2 (P30L/I172N) genotype on female fertility in one family

CYP21A2 Enzyme, Fertility, & Stress

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Source: https://eurjmedres.biomedcentral.com/articles/10.1186/s40001-019-0379-4

A unique case of female pseudohermaphroditism with 21-hydroxylase deficiency and small supernumerary marker chromosome 7

CYP21A2 Enzyme, Fertility, & Stress

Small supernumerary marker chromosomes (sSMCs) havebeen defined as structurally abnormal chromosomes that cannot beidentified or characterized unambiguously by conventional bandingcytogenetics alone, and are (in general) equal in size or smallerthan chromosome 20 of the same metaphase spread.

As they are toosmall for their chromosomal origin to be considered by traditionalbanding techniques, molecular cytogenetic techniques (includingarray-based comparative genomic hybridization) are required fortheir characterization (1). sSMCsare found in approximately 4.

4/100,000 newborns (2) and they are found in three differentshapes: ring, inverted duplicated and centric minute (3). Partial trisomy 7 or partial monosomy7 share some common clinical features, such as mental retardation,growth deficiency and finger abnormalities as well as eye and earanomalies.

In addition, certain patients present variable features,such as triangular face, high frontal hairline, high arched palate,clinodactyly and asymmetry of limbs (4).

Uniparental disomy (UPD), the abnormal inheritanceof both chromosomes from only one parent, has been described fordifferent human chromosomes. UPD can be associated with an sSMC asa result of an original trisomy with consecutive trisomic rescue(5).

Congenital adrenal hyperplasia (CAH) is one of themost common autosomal recessive disorders, with an estimatedcarrier frequency of 1 in 50 (6),and is due to 21-hydroxylase deficiency (21-OHD), one of theenzymes required for the synthesis of cortisol in the adrenalcortex.

Impaired 21-hydroxylase activity causes accumulation ofsteroid precursors, which then flow into biosynthetic pathwaysunaffected by the enzymatic block, resulting in the production ofexcess androgens. When androgens are over-secreted from the adrenalglands, the female fetus is virilized (7).

Complete enzyme inactivation or lowbut measurable enzyme activity leads to the salt wasting (SW) form,3–7% residual enzyme activity leads to the simple virilizing typeand more than 30% residual enzyme activity leads to the non-classictype (7).

Approximately 75% ofpatients with classic 21-OHD have the SW form, which is associatedwith severe impairment of 21-hydroxylation of progesterone and17-hydroxyprogesterone (17-OHP) (7).

The 21-hydroxylase gene, CYP21 (CYP21A2, OMIM No.201910), is located on chromosome 6p21.3 within the HLAhistocompatibility complex in close proximity to the highlyhomologous inactive pseudogene, CYP21P (CYP21A1P) (8,9).

Recombinations and conversions between CYP21A1P and CYP21A2 resultin the generation of dysfunctional CYP21A2 alleles (7,10).Approximately 90% of CYP21A2 mutations are a result ofCYP21A1P-derived conversions and recombinations (7,11).

CYP21A2 genotyping can be useful in the diagnosis of CAH and canalso predict the phenotype in 80–90% of cases (12,13).

In this study, we present a femalepseudohermaphroditism/adrenogenital syndrome (AGS) case with a 45%mosaicism for a small supernumerary ring chromosome 7 associatedwith a homozygous mutation in the CYP21A2 gene.

Case report

The patient is the sixth child of non-relatedparents. Her mother was 35 and her father 49 years of age when shewas born. She is now 10 years old, 135 cm in height, and wasreferred to a cytogenetic analysis due to a gender determinationproblem in July 2009.

She was born in the 37th week of gestationwith a birth weight of 3,250 g. She has a facial dysmorphism(triangular face, high frontal hairline, asymmetry of limbs(Fig. 1) and long fingers(Fig. 2).

Her speech was delayed;her first words were not until 2 years of age, and her languageskills were poor until 8 years, especially concerning herperformances on the expressive side.

She has a uterus withoutovaries, dense hair distribution on her body (especially in thepubic area), a large genital vagina; the clitoris is verypronounced (5 cm in length) and lift cornet. However, she does nothave testes.

A CT scan showed enlargement of the adrenal glands:left, 32×7 mm; right, 38×8 mm (normal adrenal gland size is 14×2mm) (Fig. 3). The bone massdensitometry (BMD) using the lunar prodigy advance system(manufactured by GE Healthcare; analysis version 13.20), measuredat AP spin L1–L4 was 0.964 g/cm2 with a Z-score of 2.1,which is significantly higher than normal limits for her age andgender. The bone age was 18 years. The ACTH level was 228 pg/ml(normal value

Source: http://www.spandidos-publications.com/mmr/7/5/1545

Recommendations for Treatment of Nonclassic Congenital Adrenal Hyperplasia (NCCAH): an Update

CYP21A2 Enzyme, Fertility, & Stress

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Congenital adrenal hyperplasia

CYP21A2 Enzyme, Fertility, & Stress

Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive defects in the enzymes that are responsible for cortisol, aldosterone, and, in very rare cases, androgen synthesis. All forms of CAH are characterized by low levels of cortisol, high levels of ACTH, and adrenal hyperplasia.

The exact clinical manifestations depend on the enzyme defect. The most common form of CAH is caused by a deficiency of 21β-hydroxylase and manifests with hypotension, ambiguous genitalia, virilization (in the female genotype), and/or precocious puberty (in both males and females).

All newborn infants in the US are screened for 21β-hydroxylase deficiency by measuring 17-hydroxyprogesterone in a blood sample obtained from a heel prick. CAH treatment involves lifelong glucocorticoid and fludrocortisone replacement therapy. Certain rare forms of CAH (e.g.

, 11β-hydroxylase and 17α-hydroxylase deficiencies) manifest with symptoms of mineralocorticoid excess (e.g., hypertension) and therefore require spironolactone (aldosterone receptor inhibitor) in addition to glucocorticoid replacement. Individuals with a virilizing form of CAH have an increased lihood of experiencing gender dysphoria.

Intersex medical interventions may be considered in cases of ambiguous genitalia. Complications of CAH include severe hypoglycemia, adrenal insufficiency, and failure to thrive.

A deficiency in both 17α-hydroxylase and 11β-hydroxylase tends to result in overproduction of mineralocorticoids DOC and underproduction of aldosterone.“1 DOC:” If the deficient enzyme starts with 1 (11β-, 17‑), there is increased DOC.
“AND 1:” If the deficient enzyme ends with 1 (21-, 11β‑), androgens are increased.

Infants with 21β-hydroxylase deficiency can present with shock within the first few weeks of life because of severe dehydration due to an adrenal crisis and salt-wasting due to hypoaldosteronism.

Classic CAH Nonclassic CAH21β-hydroxylase deficiencyDetection by neonatal screeningPrevalenceOnset of symptomsClinical manifestationsEthnic predisposition
  • Early onset (during the neonatal period or early infancy)
  • Late onset (manifests during late childhood, adolescence, or adulthood)
  • Salt-wasting type
  • Non-salt-wasting type (simple virilizing)
    • ∼ 33% of all classic forms
    • No signs of shock
    • Males present with precocious puberty at age 2–4.
    • Females present with ambiguous genitalia.
  • Inuit and Alaska native populations
  • Ashkenazi and white populations

Individuals with a virilizing form of CAH have an increased lihood of experiencing gender dysphoria.

The differential diagnoses listed here are not exhaustive.

All newborns in the US are screened for CAH by measuring changes in 17-hydroxyprogesterone levels from a heel prick blood sample.

The dose of glucocorticoids must be increased during severe infection, critical illness, and perioperatively to meet increased demands to prevent adrenal crisis.

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