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Glucocorticoid deficiency 4(GCCD4)

MedGen UID:
766501
Concept ID:
C3553587
Disease or Syndrome
Synonym: Glucocorticoid deficiency 4 with or without mineralocorticoid deficiency
 
Gene (location): NNT (5p12)
 
Monarch Initiative: MONDO:0013874
OMIM®: 614736

Definition

Familial glucocorticoid deficiency is a rare autosomal recessive disorder characterized by an inability of the adrenal cortex to produce cortisol in response to stimulation by adrenocorticotropic hormone (ACTH). Affected individuals typically present within the first few months of life with symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, hypoglycemia, convulsions, and shock. The disease is life-threatening if untreated (summary by Meimaridou et al., 2012). For a discussion of genetic heterogeneity of familial glucocorticoid deficiency, see GCCD1 (202200). [from OMIM]

Additional description

From MedlinePlus Genetics
There are multiple types of familial glucocorticoid deficiency, which are distinguished by their genetic cause.

A shortage of adrenal hormones (adrenal insufficiency) causes the signs and symptoms of familial glucocorticoid deficiency. These signs and symptoms often begin in infancy or early childhood. Most affected children first develop low blood glucose (hypoglycemia). These hypoglycemic children can fail to grow and gain weight at the expected rate (failure to thrive). If left untreated, hypoglycemia can lead to seizures, learning difficulties, and other neurological problems. Hypoglycemia that is left untreated for prolonged periods can lead to neurological damage and death. Other features of familial glucocorticoid deficiency can include recurrent infections and skin coloring darker than that of other family members (hyperpigmentation).

Familial glucocorticoid deficiency is a condition that occurs when the adrenal glands, which are hormone-producing glands located on top of each kidney, do not produce certain hormones called glucocorticoids. These hormones, which include cortisol and corticosterone, aid in immune system function, play a role in maintaining normal blood sugar (glucose) levels, help trigger nerve cell signaling in the brain, and serve many other purposes in the body.  https://medlineplus.gov/genetics/condition/familial-glucocorticoid-deficiency

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Renal salt wasting
MedGen UID:
375868
Concept ID:
C1846347
Finding
A high concentration of one or more electrolytes in the urine in the presence of low serum concentrations of the electrolyte(s).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hypoglycemic coma
MedGen UID:
5710
Concept ID:
C0020617
Disease or Syndrome
Coma induced by low blood sugar.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hyperkalemia
MedGen UID:
5691
Concept ID:
C0020461
Finding
An abnormally increased potassium concentration in the blood.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Hyponatremia
MedGen UID:
6984
Concept ID:
C0020625
Finding
An abnormally decreased sodium concentration in the blood.
Congenital hypothyroidism
MedGen UID:
41344
Concept ID:
C0010308
Disease or Syndrome
Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.\n\nCongenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.\n\nSigns and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.\n\nCongenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.
Precocious puberty
MedGen UID:
18752
Concept ID:
C0034013
Disease or Syndrome
The onset of secondary sexual characteristics before a normal age. Although it is difficult to define normal age ranges because of the marked variation with which puberty begins in normal children, precocious puberty can be defined as the onset of puberty before the age of 8 years in girls or 9 years in boys.
Abnormal circulating aldosterone
MedGen UID:
808216
Concept ID:
C0857898
Finding
Decreased circulating cortisol level
MedGen UID:
322961
Concept ID:
C1836623
Finding
Abnormally reduced concentration of cortisol in the blood.
Abnormal circulating renin
MedGen UID:
866691
Concept ID:
C4021038
Finding
A deviation from the normal concentration of renin in the blood, a central hormone in the control of blood pressure and various other physiological functions.
Increased circulating ACTH level
MedGen UID:
867375
Concept ID:
C4021740
Finding
An abnormal increased in the concentration of corticotropin, also known as adrenocorticotropic hormone (ACTH), in the blood.

Professional guidelines

PubMed

Green PHR, Paski S, Ko CW, Rubio-Tapia A
Gastroenterology 2022 Nov;163(5):1461-1469. Epub 2022 Sep 19 doi: 10.1053/j.gastro.2022.07.086. PMID: 36137844
Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, Marinò M, Vaidya B, Wiersinga WM; EUGOGO †
Eur J Endocrinol 2021 Aug 27;185(4):G43-G67. doi: 10.1530/EJE-21-0479. PMID: 34297684
Vinit C, Dieme A, Courbage S, Dehaine C, Dufeu CM, Jacquemot S, Lajus M, Montigny L, Payen E, Yang DD, Dupont C
Arch Pediatr 2019 Apr;26(3):182-190. Epub 2019 Mar 1 doi: 10.1016/j.arcped.2019.02.005. PMID: 30827775

Recent clinical studies

Etiology

Stoopler ET, Villa A, Bindakhil M, Díaz DLO, Sollecito TP
JAMA 2024 Mar 26;331(12):1045-1054. doi: 10.1001/jama.2024.0953. PMID: 38530258
Franciosi AN, Ralph J, O'Farrell NJ, Buckley C, Gulmann C, O'Kane M, Carroll TP, McElvaney NG
J Am Acad Dermatol 2022 Oct;87(4):825-832. Epub 2021 Jan 29 doi: 10.1016/j.jaad.2021.01.074. PMID: 33516773
Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, Marinò M, Vaidya B, Wiersinga WM; EUGOGO †
Eur J Endocrinol 2021 Aug 27;185(4):G43-G67. doi: 10.1530/EJE-21-0479. PMID: 34297684
Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Lindén Hirschberg A, Juul A, Newell-Price J, Perry CG, Prete A, Rees DA, Reisch N, Stikkelbroeck N, Touraine P, Maltby K, Treasure FP, Porter J, Ross RJ
J Clin Endocrinol Metab 2021 Apr 23;106(5):e2063-e2077. doi: 10.1210/clinem/dgab051. PMID: 33527139Free PMC Article
Garrahy A, Thompson CJ
Ann Clin Biochem 2018 Jan;55(1):4-6. Epub 2017 Nov 27 doi: 10.1177/0004563217743776. PMID: 29096530

Diagnosis

Green PHR, Paski S, Ko CW, Rubio-Tapia A
Gastroenterology 2022 Nov;163(5):1461-1469. Epub 2022 Sep 19 doi: 10.1053/j.gastro.2022.07.086. PMID: 36137844
Zhu H, Galdos FX, Lee D, Waliany S, Huang YV, Ryan J, Dang K, Neal JW, Wakelee HA, Reddy SA, Srinivas S, Lin LL, Witteles RM, Maecker HT, Davis MM, Nguyen PK, Wu SM
Circulation 2022 Jul 26;146(4):316-335. Epub 2022 Jun 28 doi: 10.1161/CIRCULATIONAHA.121.056730. PMID: 35762356Free PMC Article
Auchus RJ, Sarafoglou K, Fechner PY, Vogiatzi MG, Imel EA, Davis SM, Giri N, Sturgeon J, Roberts E, Chan JL, Farber RH
J Clin Endocrinol Metab 2022 Feb 17;107(3):801-812. doi: 10.1210/clinem/dgab749. PMID: 34653252Free PMC Article
Athimulam S, Lazik N, Bancos I
Endocrinol Metab Clin North Am 2019 Dec;48(4):701-715. Epub 2019 Sep 25 doi: 10.1016/j.ecl.2019.08.003. PMID: 31655771
Nieman LK, Chanco Turner ML
Clin Dermatol 2006 Jul-Aug;24(4):276-80. doi: 10.1016/j.clindermatol.2006.04.006. PMID: 16828409

Therapy

Franciosi AN, Ralph J, O'Farrell NJ, Buckley C, Gulmann C, O'Kane M, Carroll TP, McElvaney NG
J Am Acad Dermatol 2022 Oct;87(4):825-832. Epub 2021 Jan 29 doi: 10.1016/j.jaad.2021.01.074. PMID: 33516773
Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Lindén Hirschberg A, Juul A, Newell-Price J, Perry CG, Prete A, Rees DA, Reisch N, Stikkelbroeck N, Touraine P, Maltby K, Treasure FP, Porter J, Ross RJ
J Clin Endocrinol Metab 2021 Apr 23;106(5):e2063-e2077. doi: 10.1210/clinem/dgab051. PMID: 33527139Free PMC Article
Schoini P, Karampitsakos T, Avdikou M, Athanasopoulou A, Tsoukalas G, Tzouvelekis A
Adv Respir Med 2019;87(1):63-67. Epub 2019 Mar 4 doi: 10.5603/ARM.a2019.0010. PMID: 30830960
Nieman LK, Chanco Turner ML
Clin Dermatol 2006 Jul-Aug;24(4):276-80. doi: 10.1016/j.clindermatol.2006.04.006. PMID: 16828409
Burke CW
Clin Endocrinol Metab 1985 Nov;14(4):947-76. doi: 10.1016/s0300-595x(85)80084-0. PMID: 3002680

Prognosis

Green PHR, Paski S, Ko CW, Rubio-Tapia A
Gastroenterology 2022 Nov;163(5):1461-1469. Epub 2022 Sep 19 doi: 10.1053/j.gastro.2022.07.086. PMID: 36137844
Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, Marinò M, Vaidya B, Wiersinga WM; EUGOGO †
Eur J Endocrinol 2021 Aug 27;185(4):G43-G67. doi: 10.1530/EJE-21-0479. PMID: 34297684
Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Lindén Hirschberg A, Juul A, Newell-Price J, Perry CG, Prete A, Rees DA, Reisch N, Stikkelbroeck N, Touraine P, Maltby K, Treasure FP, Porter J, Ross RJ
J Clin Endocrinol Metab 2021 Apr 23;106(5):e2063-e2077. doi: 10.1210/clinem/dgab051. PMID: 33527139Free PMC Article
Kamwa V, Welch C, Hassan-Smith ZK
Minerva Endocrinol (Torino) 2021 Dec;46(4):453-468. Epub 2020 Dec 17 doi: 10.23736/S2724-6507.20.03198-3. PMID: 33331737
Tudor RM, Thompson CJ
Pituitary 2019 Jun;22(3):296-304. doi: 10.1007/s11102-018-0917-z. PMID: 30334138

Clinical prediction guides

Stoopler ET, Villa A, Bindakhil M, Díaz DLO, Sollecito TP
JAMA 2024 Mar 26;331(12):1045-1054. doi: 10.1001/jama.2024.0953. PMID: 38530258
Tryfon S, Papadopoulou E, Psarros G, Agrafiotis M, Saroglou M
Postgrad Med 2022 Nov;134(8):732-742. Epub 2022 Aug 8 doi: 10.1080/00325481.2022.2109121. PMID: 35912848
Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Lindén Hirschberg A, Juul A, Newell-Price J, Perry CG, Prete A, Rees DA, Reisch N, Stikkelbroeck N, Touraine P, Maltby K, Treasure FP, Porter J, Ross RJ
J Clin Endocrinol Metab 2021 Apr 23;106(5):e2063-e2077. doi: 10.1210/clinem/dgab051. PMID: 33527139Free PMC Article
Tudor RM, Thompson CJ
Pituitary 2019 Jun;22(3):296-304. doi: 10.1007/s11102-018-0917-z. PMID: 30334138
O'Callaghan JP, Sriram K, Miller DB
Ann N Y Acad Sci 2008 Oct;1139:318-30. doi: 10.1196/annals.1432.032. PMID: 18991877

Recent systematic reviews

Guo X, Zhang Y, Yu Y, Zhang L, Ullah K, Ji M, Jin B, Shu J
Front Endocrinol (Lausanne) 2022;13:982953. Epub 2022 Aug 31 doi: 10.3389/fendo.2022.982953. PMID: 36120452Free PMC Article
Wall EC, Ajdukiewicz KM, Bergman H, Heyderman RS, Garner P
Cochrane Database Syst Rev 2018 Feb 6;2(2):CD008806. doi: 10.1002/14651858.CD008806.pub3. PMID: 29405037Free PMC Article
Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R
Hum Reprod Update 2017 Sep 1;23(5):580-599. doi: 10.1093/humupd/dmx014. PMID: 28582566
Mercè Fernández-Balsells M, Muthusamy K, Smushkin G, Lampropulos JF, Elamin MB, Abu Elnour NO, Elamin KB, Agrwal N, Gallegos-Orozco JF, Lane MA, Erwin PJ, Montori VM, Murad MH
Clin Endocrinol (Oxf) 2010 Oct;73(4):436-44. doi: 10.1111/j.1365-2265.2010.03826.x. PMID: 20550539
Tracz MJ, Sideras K, Boloña ER, Haddad RM, Kennedy CC, Uraga MV, Caples SM, Erwin PJ, Montori VM
J Clin Endocrinol Metab 2006 Jun;91(6):2011-6. Epub 2006 May 23 doi: 10.1210/jc.2006-0036. PMID: 16720668

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