Aromatase Deficiency

Aromatase, also known as cytochrome P450, is an enzyme that converts androgens into oestrogens. A deficiency of this enzyme results in the absence or significant reduction of circulating oestrogens. During foetal development, this means that androgens do not convert into oestrogens, leading to virilisation of both the foetus with a 46,XX karyotype and the mother. In individuals with a 46,XX karyotype, the complete lack of oestrogens causes varying degrees of externally virilised genitalia at birth, such as clitoromegaly (enlarged clitoris). During puberty, individuals experience primary amenorrhoea (absence of the first menstrual cycle), lack of breast development, ovarian cyst formation, and increased virilisation. Additionally, bone development is delayed and there is no pubertal growth spurt, including no breast development in females and no testicular enlargement in males. Early identification of this Variation of Sex Characteristic (VSC)/Difference of Sex Development (DSD) through clinical assessment helps prevent severe complications related to oestrogen deficiency in adulthood.
In cases where the aromatase enzyme is partially active, the clinical presentation may be milder.
In individuals with a 46,XY karyotype, there are no clinical manifestations at birth, and the identification of the condition is typically delayed. Common findings in these cases include tall stature, eunuchoid skeletal proportions (narrow shoulders and broad hips), delayed bone development, osteoporosis, obesity, and type 2 diabetes.

Genetic traits
This Variation of Sex Characteristics (VSC)/Difference of Sex Development is an autosomal recessive condition caused by mutations in the CYP19A1 gene, located on chromosome 15q21.2. Transmission is autosomal recessive. This means that for the gene variation to occur, it must be inherited from both parents. Individuals who have inherited the gene variation from only one parent will not exhibit it in any way, but they may still pass it on to their offspring.

Identification
During the neonatal period, suspicion may arise from progressive maternal virilisation during the last trimester of pregnancy, regardless of foetus karyotype. The appearance of external genitalia at birth generally leads to an early diagnosis in individuals with a 46,XX karyotype, while it is often delayed in individuals with a 46,XY karyotype.
Laboratory tests show very low blood levels of oestrogens and high blood levels of gonadotropins (luteinizing hormone, LH, and follicle-stimulating hormone, FSH). However, the confirmatory diagnosis is based on genetic analysis through sequencing of the CYP19A1 gene.

Medical Options
Early “corrective” surgical interventions were carried out during the neonatal period on individuals with a 46,XX karyotype and ambiguous genitalia, especially in the past. However, current recommendations advocate for delaying partially reversible or irreversible interventions (including surgical procedures aimed at feminising the genitalia) until the individual can provide their informed consent. In cases where atypical genitalia cause distress to the individual or their family, professional multidisciplinary support and counselling should be offered.
In general, the therapy for aromatase deficiency involves administering oestrogens, preferably oestradiol. The dosage should be tailored to the individual's gender, age, and therapeutic goals.
During the prepubertal and pubertal stages, the main objective of treatment is to promote skeletal maturation and induce physiological changes that occur during puberty in a feminine direction.
In adulthood, oestradiol can be administered to individuals with a 46,XY karyotype, while individuals with a 46,XX karyotype may receive oestradiol combined with a progestin, following the same hormone replacement therapy used for cisgender individuals.
In addition, providing appropriate lifestyle counselling is essential to counteract the development of metabolic syndrome.

Bibliography
Belgorosky A et al. 2009 Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Hormone research. 2009;72(6):321-30
Rochira V, Carani C. Aromatase deficiency in men: a clinical perspective. [Abstract].  Nature reviews. Endocrinology. 2009 Oct;5(10):559-68

Further Links
Orphanet. Aromatase deficiency
MedLine Plus. Aromatase deficiency