Aromatase Deficiency

Overview

Epidemiology

• Prevalence unknown 
• Fewer than 20 cases worldwide have been reported to date.

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

• Karyotype: normal
• Etiology: mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the CYP19A1 gene, which plays a major role in aromatase enzyme synthesis
• Inheritance pattern: autosomal recessive

Pathophysiology

• The enzyme aromatase is needed to convert androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens (including testosterone) into estrogens.
  • Normally, aromatase is present in the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity, ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries, testes, adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, and brain.
  • Estrogen levels are maintained by aromatase activity in the ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries of women of childbearing age and in the adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue of men and postmenopausal women.
• Mutation causes ↓ aromatase enzyme production → impaired estrogen biosynthesis due to inability to convert androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens into estrogen → ↓ estrogen and ↑ testosterone
• The placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity of a developing fetus with aromatase deficiency also lacks aromatase.
• Placenta fails to convert precursor androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens to estrogens → dehydroepiandrosterone sulfate (DHEAS) from fetal adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands is converted to testosterone and androstenedione rather than estrogen.
• Uninhibited and excessive androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens cause virilization of the female fetus and of the mother.

Clinical Presentation

Clinical Phenotype

• Characteristics of the mother
  • Virilization begins during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care, between the 12th and 30th week of gestation:
    • Acne
    • Deepening of voice
    • Hirsutism (excessive hair growth in male-like pattern)
    • Clitoromegaly
  • Symptoms resolve spontaneously shortly after giving birth.
• Characteristics of females (46,XX):
  • Pseudohermaphroditism (external genitalia resembles that of opposite sex)
  • Ambiguous/masculinized genitalia noted at birth
    • Labioscrotal fusion
    • Greatly enlarged phallus with a single meatus at its base
    • Present by 12th week of gestation
  • Female reproductive organs present
  • Normal growth and development in infancy and childhood
  • Signs of lack of estrogen and excessive testosterone noticed at pubertal age
    • Absent growth spurt
    • Progressive virilization
    • Delayed or lack of onset of puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty
    • Absence of breast development
    • Primary amenorrhea
    • Hypergonadotropic hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism: ↑ follicle-stimulating hormone (FSH) and luteinizing hormone (LH) with ↓ estrogen levels
    • Clitoromegaly
    • Acne
    • Normal axillary and pubic hair development
• Characteristics of males (46,XY):
  • Tall stature with continued linear growth into adulthood
  • No pubertal growth spurt
  • Eunuchoid body habitus (disproportionately long limbs relative to trunk)
  • Delayed epiphyseal closures
  • Progressive genu valgum Genu valgum Genu valgum is a deformation of the knee joint(s) that creates angulation of the lower limb(s) toward the midline in the coronal plane. Children ages 1-5 years are commonly affected. Genu Valgum (“knock knees”)
  • Normal male external genitalia
  • Normal sexual development and maturation
  • May have low libido in adulthood
  • Possible cryptorchidism Cryptorchidism Cryptorchidism is one of the most common congenital anomalies in young boys. Typically, this asymptomatic condition presents during a routine well-child examination where 1 or both testicles are not palpable in the scrotum. Cryptorchidism (undescended testes)
  • Varying levels of spermatogenesis and fertility

Associated conditions

• Osteoporosis in men and women due to estrogen deficiency
• Glucose intolerance/diabetes
• Dyslipidemia
• Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
• Fatty liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
• Acanthosis nigricans (thickened, darkened skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin)

Diagnosis and Management

Diagnosis

• History and physical examination
• Labs:
  • Pregnant women
    • ↓↓ Estriol and estradiol levels
    • ↑↑ Testosterone concentration
  • Girls in infancy/early childhood
    • ↑ FSH
    • Undetectable estrogen levels
  • Girls of pubertal age
    • Undetectable estrogen levels 
    • ↑↑ FSH and LH
    • ↑ Testosterone and androstenedione
  • Boys
    • ↑ FSH and LH
    • ↑ Testosterone
    • Undetectable estrogen levels
    • ↑ Basal insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin
    • ↓ Low HDL/LDL cholesterol ratio with ↓↓ HDL
• Imaging:
  • Urogenitogram may show urogenital sinus (only 1 opening/exit for both tracts).
  • Ultrasound shows enlarged polycystic ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries. 
  • X-rays X-rays X-rays are high-energy particles of electromagnetic radiation used in the medical field for the generation of anatomical images. X-rays are projected through the body of a patient and onto a film, and this technique is called conventional or projectional radiography. X-rays of pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis and extremities show lack of epiphyseal fusion.
• Genetic testing

Management

• Females:
  • Surgical correction of ambiguous genitalia and urogenital sinus when present
  • Estrogen replacement starting as early as 2 years of age with close monitoring:
    • Maintains bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density
    • Decreases formation of ovarian cysts Ovarian cysts Ovarian cysts are defined as collections of fluid or semiliquid material, often walled off by a membrane, located in the ovary. These cysts are broadly categorized as either functional or neoplastic. Neoplastic ovarian cysts are subcategorized as either benign or malignant. Ovarian Cysts
    • In excess, can accelerate bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones age and induce premature breast development
  • Estrogen increased at pubertal age (10–12 years of age) to induce:
    • Breast development
    • Growth spurt (normal height may be reached with treatment)
    • Menstrual cycles 
    • Regression of ovarian cysts Ovarian cysts Ovarian cysts are defined as collections of fluid or semiliquid material, often walled off by a membrane, located in the ovary. These cysts are broadly categorized as either functional or neoplastic. Neoplastic ovarian cysts are subcategorized as either benign or malignant. Ovarian Cysts
    • Increased bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density
  • Progesterone replacement therapy added within 2 years of pubertal level estrogen replacement to prevent endometrial hyperplasia Endometrial Hyperplasia Endometrial hyperplasia (EH) is the abnormal growth of the uterine endometrium. This abnormal growth may be due to estrogen stimulation or genetic mutations leading to uncontrolled proliferation. Endometrial Hyperplasia and Endometrial Cancer
  • Combination oral contraceptives started at approximately 14 years of age for maintenance therapy
• Males:
  • Transdermal estradiol replacement beginning around age 14–16 years, or at time of diagnosis
  • Estrogen replacement necessary for:
    • Epiphyseal closure
    • Increasing and maintaining bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density
    • Improving sexual desire
    • Improving insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance
    • Improving lipid profile
    • Normalizing LH, FSH, and testosterone levels
  • Life-long estrogen replacement
  • Monitoring for development of gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia is necessary.
• All individuals:
  • Calcium and vitamin D supplementation
  • Genetic counseling

Differential Diagnosis

• True hermaphroditism True hermaphroditism True hermaphroditism, or ovotesticular disorder of sexual development (ODSD), is characterized by the presence of an ovotesticular gonad that contains both ovarian and testicular elements. Individuals are usually born with ambiguous genitalia, but the diagnosis is rarely confirmed before puberty. The most common karyotype is 46,XX, and less often, 46,XY can be identified. True Hermaphroditism: also known as ovotesticular disorder of sexual development (ODSD). The condition is characterized by the presence of an ovotesticular gonad that contains both ovarian and testicular elements. Patients have ambiguous genitalia at birth, with both male and female reproductive organs that can be seen on imaging. Karyotyping and gonadal biopsy help confirm the diagnosis. Treatment involves surgical reconstruction, removal of abnormal gonad, and hormone replacement therapy. 
• Congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia (CAH): consists of a group of autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorders that cause a deficiency of an enzyme used in cortisol and/or aldosterone synthesis. This deficiency results in an increased formation of androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens with virilization of the external female genitals and is the most common cause of ambiguous genitalia in 46,XX genotypic females. All forms of CAH are characterized by low levels of cortisol, high levels of adrenocorticotropic hormone (ACTH), and adrenal hyperplasia. Surgical correction of ambiguous genitalia and lifelong glucocorticoid replacement therapy are needed.