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	==Epidemiology==		==Epidemiology==
	Lipoid CAH is quite rare in European and North American populations. Most cases occur in Japan and Korea (where the incidence is 1 in 300,000 births) and Palestinian Arabs. Despite autosomal inheritance, there has been an unexplained preponderance of genetic females in reported cases.<ref>{{Cite journal \|~~last~~=Cantú-Reyna \|~~first~~=Consuelo \|last2=Zepeda \|first2=Luis Manuel \|last3=Montemayor \|first3=René \|last4=Benavides \|first4=Santiago \|last5=González \|first5=Héctor Javier \|last6=Vázquez-Cantú \|first6=Mercedes \|last7=Cruz-Camino \|first7=Héctor \|date=27 September 2016 \|title=Incidence of Inborn Errors of Metabolism by Expanded Newborn Screening in a Mexican Hospital \|journal=Journal of Inborn Errors of Metabolism and Screening \|volume=4 \|pages=232640981666902 \|doi=10.1177/2326409816669027 \|doi-access=free}}</ref>		Lipoid CAH is quite rare in European and North American populations. Most cases occur in Japan and Korea (where the incidence is 1 in 300,000 births) and Palestinian Arabs. Despite autosomal inheritance, there has been an unexplained preponderance of genetic females in reported cases.<ref>{{Cite journal \|last1=Cantú-Reyna \|first1=Consuelo \|last2=Zepeda \|first2=Luis Manuel \|last3=Montemayor \|first3=René \|last4=Benavides \|first4=Santiago \|last5=González \|first5=Héctor Javier \|last6=Vázquez-Cantú \|first6=Mercedes \|last7=Cruz-Camino \|first7=Héctor \|date=27 September 2016 \|title=Incidence of Inborn Errors of Metabolism by Expanded Newborn Screening in a Mexican Hospital \|journal=Journal of Inborn Errors of Metabolism and Screening \|volume=4 \|pages=232640981666902 \|doi=10.1177/2326409816669027 \|doi-access=free}}</ref>

	==See also==		==See also==

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{{Infobox medical condition (new)
| name = Lipoid congenital adrenal hyperplasia
| synonyms = Congenital lipoid adrenal hyperplasia due to StAR deficiency<ref>{{Cite web |title=Congenital lipoid adrenal hyperplasia {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |url=https://rarediseases.info.nih.gov/diseases/1465/index |url-status=dead |archive-url=https://web.archive.org/web/20190414150926/https://rarediseases.info.nih.gov/diseases/1465/index |archive-date=14 April 2019 |access-date=14 April 2019 |website=rarediseases.info.nih.gov}}</ref>
| image = Autosomal recessive - en.svg
| caption = Lipoid congenital adrenal hyperplasia is inherited in an autosomal recessive manner
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| onset =
| duration =
| types =
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'''Lipoid congenital adrenal hyperplasia''' is an [[endocrine disorder]] that is an uncommon and potentially lethal form of [[congenital adrenal hyperplasia]] (CAH). It arises from defects in the earliest stages of [[steroid hormone]] synthesis: the transport of [[cholesterol]] into the [[mitochondrion|mitochondria]] and the conversion of cholesterol to [[pregnenolone]]—the first step in the synthesis of all [[steroid hormone]]s. Lipoid CAH causes [[mineralocorticoid]] deficiency in affected infants and children. Male infants are severely [[virilization|undervirilized]] causing their external genitalia to look feminine. The adrenals are large and filled with [[lipid]] globules derived from cholesterol.{{cn|date=October 2021}}

==Presentation==
Problems that emerge in persons with lipoid CAH can be divided into:{{citation needed|date=August 2020}}
# mineralocorticoid deficiency,
# [[glucocorticoid deficiency]],
# sex steroid deficiency, and
# damage to gonads caused by lipid accumulation.

===Mineralocorticoid deficiency===
Most infants born with lipoid CAH have had genitalia female enough that no disease was suspected at birth. Because the adrenal [[zona glomerulosa]] is undifferentiated and inactive before delivery, it is undamaged at birth and can make [[aldosterone]] for a while, so the eventual salt-wasting crisis develops more gradually and variably than with severe [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase-deficient CAH]].{{citation needed|date=August 2020}}

Most come to medical attention between 2 weeks and 3 months of age, when after a period of poor weight gain and vomiting, they were found to be dehydrated, with severe [[hyponatremia]], [[hyperkalemia]], and [[metabolic acidosis]] ("Addisonian or [[adrenal crisis]]"). [[Renin]] but not [[aldosterone]] is elevated. Many infants born with this condition died before a method for diagnosis was recognized for proper treatment to begin. In some cases, the condition is more mild with signs and symptoms of mineralocorticoid and glucocorticoid deficiency appearing after months or even years ([[Late onset congenital adrenal hyperplasia|late onset]]).{{citation needed|date=August 2020}}

===Glucocorticoid deficiency===
Insufficiency of [[cortisol]] synthesis has several consequences. Elevated ACTH is accompanied by and contributes to marked [[hyperpigmentation]] even in the newborn period. An inadequate cortisol response to stress undoubtedly hastens the deterioration as dehydration develops, can cause [[hypoglycemia]], and contributes to the high mortality rate in infancy.{{citation needed|date=August 2020}}

===Sex steroid deficiency and gonadal damage===

====In development====
Prenatal production of [[dehydroepiandrosterone|DHEA]] by the fetal adrenal glands is impaired, resulting in abnormally low maternal [[estriol]] levels by the middle of pregnancy. The effects of impaired progesterone production from placental cells that originate from the affected baby ([[trophoblasts]]) in the case of lipoid CAH due to [[Cholesterol side-chain cleavage enzyme|P450scc]] deficiency are still unclear, but are thought to result in miscarriage when the deficit in the enzyme's activity are severe enough. {{citation needed|date=August 2020}}The results of reduced or absent testosterone output by fetal Leydig cells in the male is detailed below.

====Female patients====
Genetic XX females with lipoid CAH are born with normal external and internal pelvic anatomy. They come to medical attention when they develop a salt-wasting adrenal crisis or other signs of progressive [[adrenal insufficiency]].{{citation needed|date=August 2020}}

With glucocorticoid and mineralocorticoid replacement, these girls will reach the age of puberty. Because the ovaries are relatively inactive in fetal life and childhood, they sustain little damage from lipid accumulation during childhood. In the case of lipoid CAH due to StAR deficiency, when rising [[gonadotropin]] levels initiate [[puberty]], despite the inefficiency of [[sex steroid]] synthesis, the [[ovary|ovaries]] will usually make enough [[estradiol]] to produce breast development, and in some cases even [[menarche]], with menses continuing for some years. Ovarian and adrenal androgen production is minimal and produces little pubic or other body hair.{{citation needed|date=August 2020}}

However insufficient estradiol and [[progesterone]] are produced to induce maturation of an egg and [[ovulation]]. Although prepubertal ovaries are inactive enough that no lipid accumulates to cause damage, once they have begun to produce estrogen, lipid damage begins to accrue and the ability to produce estrogen, as well as ovulate, is slowly degraded. Cysts also form in the ovaries. Women with lipoid CAH have been infertile presumably due to [[anovulation]].{{citation needed|date=September 2020}}

====Male patients====
The genitalia of XY fetuses with lipoid CAH are severely undervirilized due to impairment of steroid hormone synthesis. The fetal testes make [[antimullerian hormone|AMH]], which prevents a uterus and inner vagina from forming, but since the Leydig cells fail to make testosterone during development even in response to [[human chorionic gonadotropin|hCG]], the testes are usually remain in the abdomen or lodge in the [[inguinal canal]]s (undescended testes) and are nonfunctional. Consequently, XY patients do not undergo puberty and remain infertile.{{citation needed|date=August 2020}}

In addition to the testes remaining inside, formation of the [[human penis|penis]], also dependent on testosterone, is compromised. Hence, the external genitalia in most of infants resemble that of normal females (though the vagina is a short, blind pouch), or is slightly ambiguous (more female than male). Nearly all reported XY cases have been assumed to be girls and raised as such.{{citation needed|date=August 2020}}

===Late onset forms of the disease===
Milder, [[Late onset congenital adrenal hyperplasia|late onset]] cases of lipoid CAH have been described that arise from less severe mutations that compromise but do not eliminate the ability of StAR to instigate steroid production.<ref name="pmid16968793">{{Cite journal |vauthors=Baker BY, Lin L, Kim CJ, Raza J, Smith CP, Miller WL, Achermann JC |date=December 2006 |title=Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=16968793 |journal=[[J. Clin. Endocrinol. Metab.]] |volume=91 |issue=12 |pages=4781–5 |doi=10.1210/jc.2006-1565 |pmc=1865081 |pmid=16968793}}</ref> In these cases, mineralocorticoid deficiency emerges up to several years after birth. Sex steroid production may be sufficient to allow for normal sexual development as well and even fertility.{{cn|date=October 2021}}

These nonclassic forms of the disorder are sometimes diagnosed as [[familial glucocorticoid deficiency]] type 3.<ref name="pmid19773404">{{Cite journal |vauthors=Metherell LA, Naville D, Halaby G, Begeot M, Huebner A, Nürnberg G, Nürnberg P, Green J, Tomlinson JW, Krone NP, Lin L, Racine M, Berney DM, Achermann JC, Arlt W, Clark AJ |date=October 2009 |title=Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=19773404 |journal=[[J. Clin. Endocrinol. Metab.]] |volume=94 |issue=10 |pages=3865–3871 |doi=10.1210/jc.2009-0467 |pmc=2860769 |pmid=19773404}}</ref>

==Genetics==
This inherited disease is [[autosomal recessive]]. Understanding of the molecular basis for it has been advanced in the last decade by better understanding of adrenal steroidogenesis as well as genetic studies of affected patients.<ref name="pmid16639391" /> It used to be assumed that lipoid CAH resulted from a defect of the enzyme that converted cholesterol to pregnenolone. The conversion reactions are mediated by a single enzyme, formerly referred to as 20,22-desmolase, but now identified as [[cytochrome]] [[P450scc]] (cholesterol [[side chain]] cleavage enzyme). However, few cases of lipoid CAH due to a mutation and defect of P450scc have been identified. Although the disorder is considered autosomal recessive, a single mutation in P450scc can be sufficient to cause the condition.<ref name="pmid11502818">{{Cite journal |vauthors=Tajima T, Fujieda K, Kouda N, Nakae J, Miller WL |date=August 2001 |title=Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency |journal=J Clin Endocrinol Metab |volume=86 |issue=8 |pages=3820–5 |doi=10.1210/jcem.86.8.7748 |pmid=11502818 |doi-access=free}}</ref> All other cases of lipoid adrenal hyperplasia that have been studied have been found to be due to mutations of the [[gene]] for the primary protein that transports cholesterol into the mitochondria, StAR, encoded by a gene on [[chromosome 8]]p11.2 in the human.{{cn|date=October 2021}}

[[Congenital adrenal hyperplasia]]s are a family of [[autosomal recessive]] diseases resulting from defects in steps of the [[Biosynthesis|synthesis]] of [[steroid hormones]] from [[cholesterol]]. All forms of CAH involve excessive or defective production of [[sex steroid]]s and can prevent or impair development of [[primary sex characteristic|primary]] or [[secondary sex characteristic]]s in affected infants, children, and adults. Many also involve excessive or defective production of [[mineralocorticoid]]s, which can cause [[hypertension]] or salt-wasting.{{citation needed|date=August 2020}}

Lipoid CAH is one of the rarer forms of CAH and results from defects in the steps from cholesterol to pregnenolone.<ref name="pmid16639391">{{Cite journal |vauthors=Bhangoo A, Anhalt H, Ten S, King SR |date=March 2006 |title=Phenotypic variations in lipoid congenital adrenal hyperplasia |journal=Pediatr Endocrinol Rev |volume=3 |issue=3 |pages=258–71 |pmid=16639391}}</ref> This results in the catastrophic loss of most or all steroid hormones in the body. It is caused by mutations in either of two [[protein]]s: [[cytochrome]] [[P450scc]] and [[steroidogenic acute regulatory protein]] (StAR).{{citation needed|date=August 2020}}

==Pathophysiology==
The deficiency results in impaired synthesis of all three categories of adrenal steroids (cortisol, mineralocorticoids, sex steroids) and high levels of [[adrenocorticotropic hormone]] (ACTH). A low level of steroid synthesis proceeds even without efficient transport, but is rarely enough to prevent the consequences of deficiency. While severe loss of steroid production results in manifestation of the disease within a few weeks of birth, milder forms ([[Late onset congenital adrenal hyperplasia|late onset]]) can present years after birth. Unlike in models of the disease in mice, patients with lipoid CAH do not always have enlarged adrenals due to lipid accumulation. This may in part be due to [[hormone therapy|hormone replacement]] used to keep them alive preventing hyperstimulation of the gland by the [[pituitary]].{{citation needed|date=August 2020}}

ACTH stimulates growth of the adrenal cells and increases [[Low density lipoprotein|LDL]] receptors to amplify transport of cholesterol into the cells of the adrenal cortex which make adrenal steroids, where it accumulates since little can enter the mitochondria for conversion to steroid. Normally, adrenal steroids then signal their presence to the brain to moderate ACTH levels ([[feedback]] inhibition). However, in the absence of this, ACTH levels are elevated and cholesterol uptake by the cortical cells continues unabated. The adrenals become markedly enlarged (hyperplastic) by the accumulated lipid. Lipid accumulation is thought to damage the cells further ("second hit hypothesis").{{citation needed|date=August 2020}}

Because P450scc and StAR are also essential for sex steroid synthesis in the [[testis]] and [[ovary]], the production of [[testosterone]] by [[Leydig cell]]s in the testis and [[androgen]]s (which leads to [[estrogen]] production by [[granulosa cells]]) and [[progesterone]] by ovarian [[theca cell]]s and [[luteal cells]], respectively, can also be impaired. Similar to the adrenal gland, cholesterol accumulation damages the [[Leydig cell]]s of the testes. In the ovary, the damage begins after [[puberty]], the time when the ovary starts making steroid with [[ovarian follicle|follicle]] development. The [[placenta]] also makes steroid to help maintain [[pregnancy]]. However, since StAR is not required for placental steroid production, pregnancy goes to term. When the mutation in P450scc that causes lipoid CAH is either [[heterozygous]] or its presence on both [[allele]]s does not completely destroy all function, affected babies can survive to birth as well. Also of note, enlargement of the adrenal gland is not always found in the patient, especially in cases where a mutation in the gene for P450scc is the cause.<ref name="pmid18182448">{{Cite journal |vauthors=Kim CJ, Lin L, Huang N, Quigley CA, AvRuskin TW, Achermann JC, Miller WL |date=March 2008 |title=Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=18182448 |url-status=dead |journal=[[J. Clin. Endocrinol. Metab.]] |volume=93 |issue=3 |pages=696–702 |doi=10.1210/jc.2007-2330 |pmc=2266942 |pmid=18182448 |archive-url=https://web.archive.org/web/20210406050443/http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=18182448 |archive-date=2021-04-06 |access-date=2010-02-24}}</ref>

The pathophysiology of lipoid CAH differs from other forms of CAH in certain aspects. First, the affected gene in most cases is that for a transport protein (StAR) rather than a steroidogenic enzyme. Second, because the defect compromises all steroid synthesis. Thus, there are no problems due to excessive mineralocorticoids or androgens. Third, lipid accumulation damages the testes and ovaries so that even with appropriate adrenal hormone replacement (and in the absence of other intervention), gonadal function and fertility cannot be preserved.{{citation needed|date=August 2020}}

==Diagnosis==
In terms of diagnosis of this condition, gene sequencing can be done.<ref>{{Cite journal |last=Kim |first=Chan Jong |date=December 2014 |title=Congenital lipoid adrenal hyperplasia |journal=Annals of Pediatric Endocrinology & Metabolism |volume=19 |issue=4 |pages=179–183 |doi=10.6065/apem.2014.19.4.179 |issn=2287-1012 |pmc=4316413 |pmid=25654062}}</ref>

==Management==
Management of salt-wasting crises and mineralocorticoid treatment are as for other forms of salt-wasting congenital adrenal hyperplasias: saline and [[fludrocortisone]]. Glucocorticoids can be provided at minimal replacement doses because there is no need for suppression of excessive adrenal androgens or mineralocorticoids. As with other forms of adrenal insufficiency, extra glucocorticoid is needed for stress coverage.{{citation needed|date=August 2020}}

===Female patients===
XX females with lipoid CAH may need estrogen replacement at or after puberty. Active intervention has been used to preserve the possibility of fertility and conception in lipoid CAH females.<ref name="pmid18084157">{{Cite journal |vauthors=Bhangoo A, Buyuk E, Oktay K, Ten S |date=December 2007 |title=Phenotypic features of 46, XX females with StAR protein mutations |journal=Pediatr Endocrinol Rev |volume=5 |issue=2 |pages=633–41 |pmid=18084157}}</ref> In a case report in 2009, a woman with late onset lipoid CAH due to StAR deficiency underwent [[hormone therapy|hormone replacement therapy]] in combination with an assisted fertility technique, [[intracytoplasmic sperm injection]].<ref name="pmid18829024">{{Cite journal |vauthors=Sertedaki A, Pantos K, Vrettou C, Kokkali G, Christofidou C, Kanavakis E, Dacou-Voutetakis C |date=March 2009 |title=Conception and pregnancy outcome in a patient with 11-bp deletion of the steroidogenic acute regulatory protein gene |journal=Fertil Steril |volume=91 |issue=3 |pages=934.e15–8 |doi=10.1016/j.fertnstert.2008.07.1770 |pmid=18829024 |doi-access=free}}</ref> This led to ovulation and with implantation of the [[in vitro]] fertilized egg, a successful birth.{{cn|date=October 2021}}

===Male patients===
Most XY children are so undervirilized that they are raised as girls. The testes are uniformly nonfunctional and undescended; they are removed when the diagnosis is made due to the risk of cancer development in these tissues.<ref name="pmid17666473">{{Cite journal |vauthors=Abdulhadi-Atwan M, Jean A, Chung WK, Meir K, Ben Neriah Z, Stratigopoulos G, Oberfield SE, Fennoy I, Hirsch HJ, Bhangoo A, Ten S, Lerer I, Zangen DH |date=October 2007 |title=Role of a founder c.201_202delCT mutation and new phenotypic features of congenital lipoid adrenal hyperplasia in Palestinians |journal=J Clin Endocrinol Metab |volume=92 |issue=10 |pages=4000–8 |doi=10.1210/jc.2007-1306 |pmid=17666473 |doi-access=free}}</ref>

==Epidemiology==
Lipoid CAH is quite rare in European and North American populations. Most cases occur in Japan and Korea (where the incidence is 1 in 300,000 births) and Palestinian Arabs. Despite autosomal inheritance, there has been an unexplained preponderance of genetic females in reported cases.<ref>{{Cite journal |last=Cantú-Reyna |first=Consuelo |last2=Zepeda |first2=Luis Manuel |last3=Montemayor |first3=René |last4=Benavides |first4=Santiago |last5=González |first5=Héctor Javier |last6=Vázquez-Cantú |first6=Mercedes |last7=Cruz-Camino |first7=Héctor |date=27 September 2016 |title=Incidence of Inborn Errors of Metabolism by Expanded Newborn Screening in a Mexican Hospital |journal=Journal of Inborn Errors of Metabolism and Screening |volume=4 |pages=232640981666902 |doi=10.1177/2326409816669027 |doi-access=free}}</ref>

==See also==
* [[Inborn errors of steroid metabolism]]
* [[Congenital adrenal hyperplasia]]
* [[Adrenal insufficiency]]
* [[Disorders of sexual development]]
* [[Intersex]]uality, [[pseudohermaphroditism]], and [[ambiguous genitalia]]
* [[Steroidogenic acute regulatory protein]]
* [[Cholesterol side-chain cleavage enzyme]]
* [[Cholesterol]], [[sex hormone]], and [[corticosteroid]]

==References==
{{Reflist}}

== External links ==
{{Medical resources
| DiseasesDB = 2565
| ICD10 = E25.0
| ICD9 =
| ICDO =
| OMIM = 201710
| MedlinePlus =
| eMedicineSubj =
| eMedicineTopic =
| MeshID =
| Orphanet = 90790
}}
{{Adrenal gland disorder}}
{{Defects of cholesterol and steroid metabolism}}

[[Category:Adrenal gland disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Cholesterol and steroid metabolism disorders]]
[[Category:Endocrine gonad disorders]]
[[Category:Estrogens]]
[[Category:Rare diseases]]
[[Category:Intersex variations]]
[[Category:Congenital disorders of endocrine system]]

Lipoid congenital adrenal hyperplasia - Revision history

imported>Fabvill: Add: authors 1-1. Removed parameters. Some additions/deletions were parameter name changes. | Use this tool. Report bugs. | #UCB_Gadget

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