Isolated 17,20-lyase deficiency (ILD), also called isolated 17,20-desmolase deficiency, is a rare

endocrine The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the ...

and

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorde ...

which is characterized by a complete or partial loss of

17,20-lyase Cytochrome P450 17A1 (steroid 17α-monooxygenase, 17α-hydroxylase, 17-alpha-hydroxylase, 17,20-lyase, 17,20-desmolase) is an enzyme of the hydroxylase type that in humans is encoded by the ''CYP17A1'' gene on chromosome 10. It is ubiquitously exp ...

activity and, in turn, impaired production of the

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...

and

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal a ...

sex steroid Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects ar ...

s. The condition manifests itself as pseudohermaphroditism (partially or fully underdeveloped

genitalia A sex organ (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, ...

) in males, in whom it is considered to be a form of

intersex Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical b ...

, and, in both sexes, as a reduced or absent

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a b ...

/lack of development of secondary sexual characteristics, resulting in a somewhat childlike appearance in adulthood (if left untreated). Unlike the case of combined 17α-hydroxylase/17,20-lyase deficiency, isolated 17,20-lyase deficiency does not affect

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every verte ...

production (or

mineralocorticoid Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances ( electrolyte balance and fluid balance). The primary ...

levels), and for that reason, does not result in adrenal hyperplasia or hypertension.

Symptoms and signs

The

symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...

s of isolated 17,20-lyase deficiency, in males, include pseudohermaphroditism (i.e., feminized,

ambiguous Ambiguity is the type of meaning in which a phrase, statement or resolution is not explicitly defined, making several interpretations plausible. A common aspect of ambiguity is uncertainty. It is thus an attribute of any idea or statement ...

, or mildly underdeveloped (e.g., micropenis, perineal hypospadias, and/or

cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...

(undescended testes))

external genitalia A sex organ (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, ...

), female

gender identity Gender identity is the personal sense of one's own gender. Gender identity can correlate with a person's assigned sex or can differ from it. In most individuals, the various biological determinants of sex are congruent, and consistent with the ...

, and, in non-complete cases of deficiency where partial

virilization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...

occurs,

gynecomastia Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ...

up to Tanner stage V (due to low androgen levels, which results in a lack of suppression of estrogen); in females,

amenorrhoea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...

or, in cases of only partial deficiency, merely

irregular menses Irregular menstruation is a menstrual disorder whose manifestations include irregular cycle lengths as well as metrorrhagia (vaginal bleeding between expected periods). The possible causes of irregular menstruation may vary. The common factors of ...

, and enlarged cystic ovaries (due to excessive stimulation by high levels of gonadotropins); and in both sexes, hypergonadotropic hypogonadism (

hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low est ...

despite high levels of gonadotropins), delayed, impaired, or fully absent adrenarche and

with an associated reduction in or complete lack of development of secondary sexual characteristics ( sexual infantilism), impaired

fertility Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Ferti ...

or complete sterility, tall stature (due to delayed epiphyseal closure),

eunuch A eunuch ( ) is a male who has been castration, castrated. Throughout history, castration often served a specific social function. The earliest records for intentional castration to produce eunuchs are from the Sumerian city of Lagash in the 2n ...

oid

skeletal A skeleton is the structural frame that supports the body of an animal. There are several types of skeletons, including the exoskeleton, which is the stable outer shell of an organism, the endoskeleton, which forms the support structure inside ...

proportions, delayed or absent bone maturation, and osteoporosis.

Cause

Isolated 17,20-lyase deficiency is a rare disorder caused by

genetic mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...

s in the

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

CYP17A1 Cytochrome P450 17A1 (steroid 17α-monooxygenase, 17α-hydroxylase, 17-alpha-hydroxylase, 17,20-lyase, 17,20-desmolase) is an enzyme of the hydroxylase type that in humans is encoded by the ''CYP17A1'' gene on chromosome 10. It is ubiquitously ex ...

'', while not affecting

17α-hydroxylase Cytochrome P450 17A1 (steroid 17α-monooxygenase, 17α-hydroxylase, 17-alpha-hydroxylase, 17,20-lyase, 17,20-desmolase) is an enzyme of the hydroxylase type that in humans is encoded by the ''CYP17A1'' gene on chromosome 10. It is ubiquitously ex ...

. Isolated 17,20 lyase deficiency is a rare disease with only a small number of confirmed reports due to mutations in the

gene. Observed

physiological Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemica ...

abnormalities of the condition include markedly elevated

serum Serum may refer to: *Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity * Serous fluid, any clear bodily fluid * Truth serum, a drug that is likely to mak ...

levels of

progestogen Progestogens, also sometimes written progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen in the bod ...

s such as

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

and 17α-hydroxyprogesterone (due to

upregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...

of precursor availability for androgen and estrogen synthesis), very low or fully absent peripheral concentrations of

s such as dehydroepiandrosterone (DHEA),

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehy ...

, and

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...

and

s such as

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...

(due to the lack of 17,20-lyase activity, which is essential for their production), and high serum concentrations of the

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chori ...

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...

(FSH) and

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (Gn ...

(LH) (due to a lack of

negative feedback Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...

on account of the lack of sex hormones).

Diagnosis

Treatment

Males and females may be treated with

hormone replacement therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...

(i.e., with androgens and estrogens, respectively), which will result in normal sexual development and resolve most symptoms. In the case of 46,XY (genetically male) individuals who are phenotypically female and/or identify as the female gender, they should be treated with estrogens instead. Removal of the undescended testes should be performed in 46,XY females to prevent their malignant degeneration, whereas in 46,XY males surgical correction of the genitals is generally required, and, if necessary, an

orchidopexy Orchiopexy (or orchidopexy) is a surgery to move and/or permanently fix a testicle into the scrotum. While orchiopexy typically describes the operation to surgically correct an undescended testicle, it is also used to resolve testicular torsion. ...

(relocation of the undescended testes to the scrotum) may be performed as well. Namely in genetic females presenting with ovarian cysts, GnRH analogues may be used to control high FSH and LH levels if they are unresponsive to estrogens.

References

External links