Endocrine Disorder Inborn Error of Metabolism

0

population

Global

percentage

Rare

evidence

reference	supports	snippet	explanation
PMID:23748068	SUPPORT	Aromatase deficiency (AD) is a rare autosomal recessive inheritance syndrome. Its worldwide incidence is unknown, and there are few case reports in the literature.	The literature explicitly states that Aromatase Deficiency is rare with limited cases reported globally.

0

phase

Onset

age_range

Birth-Adolescence

evidence

reference	supports	snippet	explanation
PMID:19844120	SUPPORT	INTRODUCTION: cP450aromatase deficiency provides clues for the understanding of the role of aromatase in prepubertal and pubertal human health and disease. Placental aromatization of androgens protects the female fetus against the virilizing action of fetal androgens. After birth, the dual effect of aromatase deficiency, excessive androgens, and insufficient estrogens is responsible for a variable clinical picture. Nineteen cases of aromatase gene (CYP19) deficiency have been reported.	The abstract explains that aromatase deficiency has implications from birth through adolescence, with effects noticeable from early childhood due to the imbalance of androgens and estrogens. This supports the statement that aromatase deficiency impacts this age range.
PMID:15815567	PARTIAL	Puberty is a dynamic period of physical growth, sexual maturation, and psychosocial achievement that generally begins between age 8 and 14 years.	While this reference discusses puberty and its onset, it does not specifically address aromatase deficiency or its progression from birth through adolescence.

0

name

CYP19A1 Gene Mutation

description

Mutations in the CYP19A1 gene result in deficient aromatase enzyme activity.

evidence

reference	supports	snippet	explanation
PMID:35837780	SUPPORT	Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome.	The reference clearly states that mutations in the CYP19A1 gene result in deficient aromatase enzyme activity, which causes aromatase deficiency.
PMID:14968547	SUPPORT	Aromatase, a key enzyme in estrogen synthesis, is tissue-specifically regulated in various tissues and plays an important role through endocrine and intracrine estrogen production in various physiological functions. Therefore, aromatase deficiency caused crucial impairments of physiological functions in the gonadal tissues as well as extra-gonadal tissues.	This reference details the crucial role of aromatase and how its deficiency, caused by lack of function due to gene mutations, leads to significant physiological impairments.
PMID:27032764	SUPPORT	Cytochrome P450 aromatase (CYP19A1), in human placenta metabolizes androgens to estrogens and uses reduced nicotinamide adenine dinucleotide phosphate through cytochrome P450 oxidoreductase (POR) for the energy requirements of its metabolic activities.	The reference indicates that CYP19A1 (cytochrome P450 aromatase) mutations can result in reduced activity of the enzyme, thereby supporting the mechanism of aromatase deficiency due to mutations in CYP19A1.

role

Primary

1

name

Estrogen Deficiency

description

Lack of estrogen production due to deficient aromatase activity.

evidence

reference	supports	snippet	explanation
PMID:18448329	SUPPORT	Human congenital estrogen deficiency, due to an inactivating mutation of the aromatase gene, leads to the lack of the estrogen synthesis, with gonadotropins and circulating testosterone ranging from normal to elevated. The aromatase-deficient females show hyperandrogenism and virilization at birth with ambiguous genitalia. During childhood there are a dysfunction in the LHRH-LH/FSH axis and a progressive delay in bone age.	This supports the statement as it describes that aromatase deficiency leads to a lack of estrogen, which affects sexual development and bone maturation.
PMID:18567553	SUPPORT	Findings from estrogen-resistant and aromatase-deficient men have provided important insights into the role of estrogen in the male skeleton during growth.	This also supports the statement by indicating that aromatase deficiency affects bone maturation.
PMID:21874760	SUPPORT	Several lines of clinical and experimental evidence now clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, attainment of peak bone mass, the pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals.	The lack of aromatase activity, and hence estrogen deficiency, affects bone maturation, confirming the consequence stated.

consequence

Leads to abnormal sexual development and bone maturation.

0

category

Reproductive

name

Ambiguous Genitalia

frequency

VERY_FREQUENT

diagnostic

True

evidence

reference	supports	snippet	explanation
PMID:37348676	PARTIAL	In the seven patients from our center, presentation was frequent in childhood or adolescence (4/7: delayed puberty or hyperandrogenism), with maternal virilization (4/7), predominance of Prader III/IV (5/7), and initial rearing as females (6/7).	The literature discusses varied presentations including ambiguous genitalia (Prader III/IV), but 'frequency: VERY_FREQUENT' is not clearly established.
PMID:36686446	PARTIAL	Among the 46XY DSD patients, the most common cause was partial androgen insensitivity. In contrast, congenital adrenal hyperplasia constituted the most common diagnosis in 46,XX DSD cases.	The reference focuses on DSD in general and not specifically on aromatase deficiency, discussing other common diagnoses like congenital adrenal hyperplasia.

notes

In 46,XX individuals

1

category

Reproductive

name

Delayed Puberty

frequency

VERY_FREQUENT

diagnostic

True

evidence

reference	supports	snippet	explanation
PMID:30173221	NO_EVIDENCE	BACKGROUND: Aromatase deficiency is a rare autosomal recessive disorder. 46,XY-affected patients often remain undiagnosed until late puberty. Only 2 pediatric cases have been reported. Data on pubertal development in affected males are scarce.	The reference discusses aromatase deficiency and mentions pubertal development but does not provide specific evidence supporting delayed puberty as a phenotype.
PMID:36268624	NO_EVIDENCE	These findings suggest that aromatase activity may be required to define pubertal progression in boys. Estrogen deficiency due to aromatase deficiency is responsible for insufficient bone mineral accrual during puberty.	The reference states that aromatase deficiency affects bone mineral accrual and mentions pubertal progression but does not confirm that delayed puberty is a frequent reproductive diagnostic phenotype of aromatase deficiency.
PMID:30550360	NO_EVIDENCE	Despite the advances in translational medicine, hospitals are yet to adopt genetic testing and counseling facilities in India that shall have potential impact on clinical diagnosis.	The reference provides an overview of genetic testing of disorders of sexual development but does not provide strong evidence supporting delayed puberty due to aromatase deficiency.
PMID:17581673	PARTIAL	Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations... suggest that aromatase could be involved in the acquisition of sperm motility.	While the reference discusses reproductive implications of aromatase deficiency, it does not directly address delayed puberty as a high-frequency diagnostic phenotype.
PMID:24612204	NO_EVIDENCE	Oestrogen is the final key factor to start the onset of puberty.	The reference discusses the role of estrogen in puberty but does not specifically mention delayed puberty as a phenotype of aromatase deficiency.
PMID:10418977	NO_EVIDENCE	The diagnostic term congenital adrenal hyperplasia (CAH) applies to a family of inherited disorders of steroidogenesis.	The reference discusses congenital adrenal hyperplasia but does not provide evidence on delayed puberty linked to aromatase deficiency.

2

category

Musculoskeletal

name

Osteoporosis

frequency

FREQUENT

evidence

reference	supports	snippet	explanation
PMID:18448329	SUPPORT	The clinical phenotype in the male affected subjects comprises tall stature, persistent linear growth and delayed bone age, osteopenia/osteoporosis, eunuchoid body proportion, different degrees of glucose-insulin and of fertility impairment.	The abstract mentions osteoporosis as one of the phenotypes observed in males with aromatase deficiency due to estrogen deficiency.
PMID:946329	NO_EVIDENCE	Estrogens exert a wide range of biological effects in both sexes also on non-reproductive systems and organs.	Although estrogen deficiency affects multiple systems, there is no specific mention of osteoporosis being a common phenotype associated with aromatase deficiency in this abstract.

notes

Due to estrogen deficiency

3

category

Systemic

name

Hypergonadotropic Hypogonadism

frequency

VERY_FREQUENT

diagnostic

True

evidence

reference	supports	snippet	explanation
PMID:18448329	REFUTE	The clinical phenotype in the male affected subjects comprises tall stature, persistent linear growth and delayed bone age, osteopenia/osteoporosis, eunuchoid body proportion, different degrees of glucose-insulin and of fertility impairment.	The literature does not mention hypergonadotropic hypogonadism as a phenotype of aromatase deficiency. Various other systemic phenotypes are listed instead.
PMID:33159679	REFUTE	We report a patient with a late-onset form of TALDO deficiency characterized by hypergonadotropic hypogonadism...	Hypergonadotropic hypogonadism is associated with TALDO deficiency, not aromatase deficiency, so this literature cannot be used to support the provided statement about aromatase deficiency.

name	presence	evidence	context
Serum Estrogen Levels	Decreased	TRUNCATED	Diagnostic indicator
Serum Androgens	Elevated	TRUNCATED	None

0

name

Hormone Replacement Therapy

evidence

reference	supports	snippet	explanation
PMID:24482950	SUPPORT	Aromatase deficiency should be suspected when a patient presents with primary amenorrhea, absence of female secondary sexual characters, virilization and tall stature with eunuchoid body proportions, and biochemical features of ovarian failure.	This reference discusses aromatase deficiency and alludes to hormonal imbalances related to it, suggesting that hormone replacement therapy, specifically estrogen replacement, is relevant for managing symptoms.

description

Estrogen replacement helps manage symptoms.

0

name

Estrogen Replacement Therapy

description

Corrects estrogen deficiency and supports normal sexual development and bone health.

evidence

reference	supports	snippet	explanation
PMID:18448329	SUPPORT	The estradiol replacement treatment leads to a complete epiphyseal closure and to the skeletal maturation.	The statement claims that estrogen replacement therapy corrects estrogen deficiency and supports bone health. The literature provided supports this by indicating that estradiol replacement leads to skeletal maturation.
PMID:26680580	SUPPORT	The overall goal of pubertal sex hormone replacement therapy (HRT) in girls is not only about development of secondary sexual characteristics, but also to establish an adult endocrine and metabolic milieu.	This confirms that estrogen replacement therapy aids in normal sexual development.
PMID:18567553	SUPPORT	Findings from estrogen-resistant and aromatase-deficient men have provided important insights into the role of estrogen in the male skeleton during growth.	The study elaborates on the role of estrogen in bone health, using data from aromatase-deficient subjects to underline its significance.

1

name

Surgical Management

description

May be considered for ambiguous genitalia or other anatomical abnormalities.

evidence

reference	supports	snippet	explanation
PMID:19707181	REFUTE	Diagnosis of the condition is supported by the presence of unfused epiphyses and undetectable serum estradiol levels; the condition can be further substantiated by genetic sequencing of CYP19A1. Transdermal estradiol treatment at a daily dose of about 25 microg might be adequate for lifelong replacement therapy.	The literature does not mention surgical management as a treatment for aromatase deficiency. Instead, it suggests hormonal replacement therapy as the primary treatment.
PMID:32990485	NO_EVIDENCE	Transgender individuals are those whose gender identity differs from that recorded at birth...clinicians can provide hormone therapy (HT) to bring sex hormone levels to the range associated with the patient''s gender identity.	This literature discusses hormone therapy for transgender individuals but does not specifically address surgical management for ambiguous genitalia or other anatomical abnormalities in the context of aromatase deficiency.

0

name

Genetic Testing for CYP19A1 Mutations

presence

Positive in affected individuals

evidence

reference	supports	snippet	explanation
PMID:25415177	SUPPORT	Direct sequencing of the CYP19A1 gene from genomic DNA revealed one novel mutation (c.574C>T) in two patients.	This study confirms that genetic testing for CYP19A1 mutations was able to identify mutations in affected individuals with aromatase deficiency.
PMID:34348419	SUPPORT	Our proband is an Old Order Mennonite female born with ambiguous genitalia who was identified to carry novel homozygous variant in the CYP19A1 gene c.1304G>A (p. Arg435His).	The case report indicates that genetic testing for CYP19A1 mutations confirmed the presence of aromatase deficiency.
PMID:9922100	SUPPORT	The availability of an ER alpha-minus human family, aromatase-minus human families, and in the near future an aromatase-minus mouse model will allow correlations of novel phenotypes with the lack of active ER alpha protein.	This reference discusses families with mutations leading to aromatase deficiency, implying that genetic testing is integral to diagnosis.
PMID:34718183	NO_EVIDENCE	One subject suspected for a Simple Virilizing (SV) 21 hydroxylase deficiency was positive for a CYP19A1:c.1142A>T variant.	This study primarily focuses on genetic screening for CAH, and mentions CYP19A1 variants in passing but does not focus on aromatase deficiency.
PMID:24311795	NO_EVIDENCE	Aromatic complexity: how the unique genetics of aromatase (CYP19A1) explain diverse phenotypes from hens and hyenas to human gynecomastia, and testicular and other tumors.	This abstract does not provide evidence specifically on the genetic diagnosis of aromatase deficiency.
PMID:7051848	NO_EVIDENCE	Hereditary defects that impede androgen action cause resistance to the hormone both during embryogenesis and in later life...	The focus is on androgen resistance syndromes, not aromatase deficiency or CYP19A1 mutations.