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Aromatase deficiency is a rare condition resulting from insufficient production of the enzyme aromatase, which participates in the synthesis of estrogen. Lack of Estrogen can influence especially females because it is responsible for development of female characteristics. Its absence can lead to inappropriate virilization in females such as born with an ambiguous genitalia, have neither breast growth nor menstrual periods. Males in this condition present normal virilization. However, both gender can mainly develop osteopenia, osteoporosis, disproportional and overgrowth of the long bones.

The first described case was a placental aromatase deficiency, in which it was observed pseudohermaphrodism of the fetus and maternal virilization during pregnancy. Later on it was found aromatase deficiency is caused for an autossomal recessive genetic mutation. The incidence of this disease is unknown, and it can also be called disorder of sex development (DSD), estrogen synthetase deficiency or oestrogen synthetase deficiency.

Mechanism
Aromatase deficiency is an autosomal recessive disease, which means that it develops when the individual inherit both copies of the gene with a mutation. Genes are fragments of DNA that provide information used to produce proteins and enzymes according to the body necessity. In this case the gene that contains information for making the enzyme aromatase, CYP19A1 gene on chromosome 15q21.1, presents mutations that can cause total disfunction or decrease the activity of this enzyme.

The enzyme aromatase is responsible for catalyze androgens hormones: androstenedione, testosterone and 16α-hydroxydehydroepiandrosterone sulfate (responsible for male characteristics development), into estrogen: estrone, estradiol and estriol (responsible for female characteristics development). A malfunction of this enzyme cause non conversion of androgen in estrogen resulting in high levels of androgen and low levels of estrogen, what disturbs the hormonal equilibrium. In female fetus, estrogen deficiency causes disorder of sex development such as ambiguous genitalia; later on, during adolescence they do not develop secondary characteristics such as breast growth and menstrual periods. Also, due to excess androgen levels in the placenta that goes to her bloodstream, women who is pregnant can develop temporary hirsutism, acne, clitoromegaly, and a deep voice. In males with this condition there is no sexual development problems, but they may present reduced fertility.

Estrogen is also related to bones healthy and grown because is responsible for bone maturation and maintenance mass. Its absence can cause osteopenia, osteoporosis, disproportional and overgrowth of the long bones in males and females.

Symptoms
The main symptoms of aromatase deficiency are: female pseudohermaphrodism, late puberty, underdeveloped breasts, primary amenorrhea, multicystic ovaries, males with small testes, eunucoid males, sterility, reduced fertility, obesity, hypogonadism,metabolism anomalies, osteoporosis, osteopenia, tall stature. Pregnant woman can present temporary hirsutism, acne, clitoromegaly, virilization, and a deep voice.

The deficiency causes the virilization of XX fetuses. Although they will have normal female internal genitalia, clitoromegaly often results from the high androgen levels in utero, along with ambiguous external genitalia upon birth.

Testosterone may be normal or elevated.

Later, 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 girl will keep growing longer. The gonadotropins LH and FSH will both be elevated and patients present with polycystic ovaries. Furthermore, the low estrogen will predispose those with the condition to osteoporosis.

In pregnancy

Aromatase deficiency in the baby can also affect the mother during gestation, with increased facial hair growth and deepening of the mother's voice. Increased circulating testosterone levels are the primary cause. The mother's symptoms resolve after she gives birth.

Diagnosis
Females are usually diagnosed at birth by observing an ambiguous genitalia. Male are usually diagnosed when adults due to continuing linear growth in height or unfused epiphyses that are revealed by hand radiography.

During the third trimester of gestation, mothers exhibit severe acne, deep voice and in some cases clitoral enlargement and hirsutism, and in this case genetic testing is recommended.

Cause and prevention
Due to be an autosomal recessive disease, which develops when the individual inherit both copies of the gene with a mutation, the cause of aromatase deficiency is hereditary. In this case the gene presents mutations that can cause total disfunction or decrease the activity of this enzyme.

There is no prevention for this condition, but it can be done genetic testing if a pregnant women present any symptom such as severe acne, deep voice and in some cases clitoral enlargement and hirsutism. If detected it can be treated before it causes any damage in the fetus.

Treatment and Prognosis
The main treatment is the estrogen replacement therapy that should start as early as possible.

For women it is recommended observing for ovarian cysts.

In pregnancy, the symptoms go away after women give birth.

Recent Research
Genetic and Clinical Spectrum of Aromatase Deficiency in Infancy, Childhood and Adolescence

Belgorosky A. · Guercio G. · Pepe C. · Saraco N. · Rivarola M.A. Endocrine Service, Hospital de Pediatria Garrahan, Buenos Aires, Argentina

Aromatase Deficiency, a Rare Syndrome: Case Report

Emine Kartal Baykan,1,* Mehmet Erdoğan,1 Samim Özen,2 Şükran Darcan,2 and L. Füsun Saygılı1