Aromatase deficiency
Aromatase deficiency is a very rare condition characterised by the extremely low or absence of the enzyme aromatase activity in the body. It is an autosomal recessive disease resulted from various mutations of gene CPY19 which can lead to delayed puberty in females, osteoporosis in males and virilisation in pregnant mothers. As of 2016, only 35 cases have been described in medical literature.
Signs and symptoms
The deficiency causes the virilization of XX fetuses. The onset of the symptoms usually displayed during adolescent or early adulthood. The lack of estrogen results in the presentation of primary amenorrhea and tall stature. The taller than expected height occurs because estrogen normally causes fusion of the epiphyseal growth plates in the bones, and in its absence, the patient will keep growing longer. The gonadotropins LH and FSH will both be elevated and patients present with polycystic ovaries. Furthermore, the low oestrogen will predispose those with the condition to osteoporosis.Female
- After birth, female infant usually displays ambiguous genitalia including labioscrotal fusion, clitoromegaly, and phallic-structure genitalia. Hyperandrogenism is present at birth along with low level of estrogen in the blood. However, they have normal internal female genitalia. Other presented symptoms assist with the correct diagnostics.
- During pubertal age, progressive sign of virilisation such as growing of body hair can be observed along with puberty failure due to the lack of estradiol action. The disruption of the LHRH-LH/FSH axis causes bone age to delay with the absence of growth spurt.
- In adulthood, symptoms include virilisation, absent of breast development, primary amenorrhea and infertility, and multicystic ovaries.
- Other symptoms include hypergonadotropic hypogonadism, polycystic ovaries, hypoplastic ovaries and tall stature.
Male
- Tall stature, osteopenia, osteoporosis, Type II Diabetes, hyperinsulinemia, acanthusis nigricans, lipid metabolism disorders and liver function impairment.
During pregnancy
Comorbidity
Aromatase deficiency may be comorbid with Autism through their mutual relationship with RORA deficiency. This affects both males and females however the effect on males is more common due to the female protective effect. RORA is the gene for aromatase, an enzyme that converts male to female hormones. Thus, RORA deficiency is linked to aromatase deficiency, which in turn can lead to elevated testosterone levels, a proposed risk factor for autism.Complications
Pregnant mother
Aromatase is an estrogen synthase that synthesize estrone and estradiol from Androstenedione and Testosterone respectively. During pregnancy, the placenta, which is fetal tissue, synthesizes large amounts of the intermediates in the biosynthesis of the estrogens, androstenedione and testosterone, but cannot convert them to estrogens due to the absence of aromatase. The levels of accumulated androgens in the mother can elevate 100-fold higher than normal cycling levels which subsequently virilise both the mother and the fetus. The mother will experience cystic acne, deepening of the voice and hirsutism. However, these symptoms are normally resolved following parturition.If the fetus is a male, it will develop a normal male genitalia and will proceed to grow normally and exhibit secondary male sex characteristics. If the fetus is a female, it will be born with ambiguous genitalia including labioscrotal fusion and a greatly enlarged phallus.
Female
Aromatase deficient female cannot synthesize estrone or estradiol in the absence of aromatase. The amount of androgen will accumulate at a very high rate in the blood, disrupting the LHRH-LH/FSH axis that can potentially lead to polycystic ovaries in adulthood . In the absence of estrogen, high level of circulating LH and FSH can results in Hypergonadotropic hypogonadism.While females begin to virilise and grow hair in various places during adolescent, they are unable to menstruate without the presence of estradiol, subsequently causing primary amenorrhea, clitormegaly, and absence of breast development. As puberty fails, the growth spurt is absence and bone age is delayed. Without treatment, the collection of excessive androgen in the blood can lead to development of polycystic ovaries.
Male
Aromatase deficient males experience a normal growth into adulthood. With a very low level of circulating estrogen, resulting in a higher level of FSH and LH in the blood. Elevated level of androgens do not contribute to harmonic skeletal muscle growth like estrogen, thus, patients exhibits eunuchoid body habitus.Patients are generally tall in stature and have a pattern of persistent linear bone growth into adulthood. Without estrogen, the epiphyseal plates cannot fuse together properly, resulting in continuous height growth. As a necessary steroid to maintain bone homeostasis, low level of estrogen also result osteopenia and osteoporosis of the lumbar spine and cortical bone. Estrogen is also thought to be linked to the abnormal lipid profile and hyperinsulinemia in men, however, the detail mechanism is unknown. Similarly, men with aromatase deficiency are likely to present with different degrees of type II diabetes and acanthosis nigricans.
Cause
Gene Mutation
Aromatase deficiency is an autosomal recessive disease with most of the mutations occur along the highly conservative regions of the gene. Both homozygous and heterozygous mutations have been identified along various location of the exon on the P450 arom gene localized on chromosome15p21.1. In addition, mutations in cytochrome P450 oxidoreductase, which is required for enzymatic activity of aromatase, can also cause aromatase deficiency.| Gender | Mutation | Transcription Results | Aromatase Activity |
| Female | GT to GC at the 5’ Terminus of intron VI | An extra 87 bp insertion, between exon VI and intron VI | 0.3% |
| Female/Male | Single base change at bp 1123: C to T in exon X | Cysteine being transcribed instead of Arginine at position 375 | 0.2% |
| Female | Point mutation in exon X | No Transcription | - |
| Female | Mutation Valine 370 to Methionine in exon IX | - | - |
| Female | 1600 bp deletion in exon V | Aromatase lacking 59 Amino Acids | - |
| Female | Point mutation in exon X | Missense mutation that causes loss of function | - |
| Female | Deletion of a single Phenylalanine residue at codon 234 in exon VI | - | - |
| Female | 568C insertion in CYP19A1 | 190 Leucine was changed to Proline | - |
| Female | Single base change at bp 1094 in exon IX | Glutamine instead of Arginine being transcribed at position 365 | 0.4 |
| Male | C-base deletion in exon V | Resulting in a stop codon after 21 codons | 0.0 |
| Male | C to A substitution in intron V, at 3’ splicing acceptor site before exon VI | Premature stop codon | - |
| Male | Insertion of 21 bp at the codon 353 in exon IX | - | - |
| Male | Single base change at bp 628 in the last nucleotide of exon V | Glutamic acid instead of a Lysine being transcribed at position 210 | 1.0 |
| Gender | Mutation | Transcription Results | Aromatase Activity |
| Female | Single base changes in exon X at bp 1303: C to T | Cysteine was transcribed instead of Arginine at position 435 | 1.1 |
| Female | Single base changes in exon X at bp 1310: G to A | Tyrosine was transcribed instead of Cysteine at position 437 | 0.0 |
| Female | Point mutation at the splicing point between exon and intron III | No transcription | 0.0 |
| Female | Base pair deletion occurring at P408 in exon IX | Nonsense codon 111 bp were transcribed down in the CYP19 | 0.0 |
| Female | Point mutation at bp 628 in exon V | Glutamic acid transcribed instead of lysine at position 210 | 0.0 |
| Female | A Base pair deletion occurring at E412 in exon IX | Transcribed a stop codon 98 bp downstream | 0.0 |
| Male | Point mutation at bp 380 in exon IV | Methionine was transcribed instead of arginine at position 127 | - |
| Male | Point mutation at bp 1123 in exon IX | 2. Arginine was transcribed instead of histidine at position 375 | - |
| Male | 23 bp deletion in exon IV | Premature stop codon in exon IV | - |
| Male | Point mutation at first bp in intron IX | Alternative splicing? | - |
Diagnosis
A fetus can be predicted to be suffering from aromatase deficiency when its pregnant mother is displaying virilisation. A female infant can be physically diagnosed due to the abnormal genitalia along with hormonal blood test. Excessively low level of estrogen and elevated level of androgens are diagnostic markers for aromatase deficiency in both males and females. Testosterone level in the urine may be normal or elevated.Treatment
In males, transdermal estradiol replacement enable epiphyseal plates closure, increases bone density, promote skeletal maturation, lower FSH and LH level to normal and decrease insulin blood concentration. In a young man with high stature due to unfused epiphysis, estrogen patch treatment daily possibly for life resolved the issue with further growth and osteoporosis.In females, hormonal replacement therapy such as cyclic oral therapy of conjugated estrogen leads to breast development, menses, pubertal growth spurt, resolution of ovarian cysts, suppression of elevated FSH and LH levels in the blood, and proper bone growth. Ambiguous genitalia, clitoromegaly, and ovarian cysts can be remove in surgery.