MCID: FML063
MIFTS: 35

Familial Glucocorticoid Deficiency

Categories: Rare diseases, Genetic diseases, Endocrine diseases

Aliases & Classifications for Familial Glucocorticoid Deficiency

MalaCards integrated aliases for Familial Glucocorticoid Deficiency:

Name: Familial Glucocorticoid Deficiency 49 24 55 36
Glucocorticoid Deficiency 24 69
Acth Resistance 49 24
Hereditary Unresponsiveness to Adrenocorticotropic Hormone 24
Isolated Glucocorticoid Deficiency 24
Adrenal Unresponsiveness to Acth 24
Glucocorticoid Deficiency 1 69

Characteristics:

Orphanet epidemiological data:

55
familial glucocorticoid deficiency
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Childhood;

Classifications:

Orphanet: 55  
Rare endocrine diseases


External Ids:

Orphanet 55 ORPHA361
ICD10 via Orphanet 33 E27.1
KEGG 36 H00256

Summaries for Familial Glucocorticoid Deficiency

NIH Rare Diseases : 49 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 361Disease definitionFamilial glucocorticoid deficiency (FGD) is a group of primary adrenal insufficiencies characterized clinically by neonatal hyperpigmentation, hypoglycemia, failure to thrive, and recurrent infections, and biochemically by glucocorticoid deficiency without mineralocorticoid deficiency.EpidemiologyThe prevalence is unknown. In Ireland there is a prevalence of around 1/200,000, but this is likely to be skewed by a high prevalence in the Irish Traveler sub-population.Clinical descriptionFGD usually presents in infancy or early childhood with hyperpigmentation of the skin and gums (present at birth or that develops over time), hypoglycemic seizures and failure to thrive. Recurrent infections are also a common finding (and may be the presenting sign in older children). Weakness, fatigue, weight loss, anorexia, vomiting, flank or abdominal pain, constipation and diarrhea are additional symptoms seen in some patients due to hypocortisolemia. Hypoglycemic crises resulting in convulsions can lead to coma or death if untreated and recurrent hypolglycemia may lead to neurological sequelae (i.e. learning disabilities, intellectual deficit, and sometimes severe, neuronal damage leading to major sensory and motor defects such as quadriplegia). Tall stature has been reported in some patients with FGD, typically those with MC2R gene defects. MRAP defects have been associated with a more severe disease and an earlier age of onset while a milder phenotype is seen in those with defects in the MCM4 gene (Irish Traveler FGD).EtiologyFGD is due, in most cases, to defects in the adrenocorticotropin (ACTH) receptor, or its signaling pathway, resulting in a failure of the cells of zona fasciculata in the adrenal cortex to respond appropriately to adrenocorticotrophic hormone (ACTH), leading to a glucocorticoid deficiency. These defects are most commonly caused by mutations in MC2R (18p11.2), accounting for 25% of cases, and MRAP (21q22.1), accounting for 20% of cases. Other mutations reported in patients with FGD include MCM4 (8q12-q13), probably uniquely in the Irish Traveler population; NNT (5p12), accounting for around 15% of cases; and TXNRD2 (22q11.21). Certain partially inactivating mutations of STAR (8p11.2) or CYP11A1 (15q23-q24) can cause a phenotype that masquerades as FGD.Diagnostic methodsDiagnosis is based on clinical and laboratory findings. Patients have high plasma ACTH and low serum morning cortisol levels that do not respond to exogenous ACTH stimulation. Mineralocorticoid function is normal. Molecular genetic testing revealing a mutation in one of the disease causing genes confirms diagnosis of FGD.Differential diagnosisThe main differential diagnosis of FGD is Addison's disease (usually of autoimmune origin), in which case a mineralocorticoid deficiency is present. Other differential diagnoses include triple A syndrome, congenital adrenal hyperplasia and other acquired causes of primary adrenal insufficiency (see these terms).Antenatal diagnosisPrenatal diagnosis is possible in families with a known disease causing mutation but is rarely performed.Genetic counselingFDG is inherited in an autosomal recessive manner. Genetic counseling is possible.Management and treatmentTreatment consists of a replacement therapy with oral hydrocortisone. A dosage of 10-12 mg/m2/day (usually divided into three doses) normalizes cortisol and reduces, but rarely normalizes, ACTH. Dose modification is necessary during stresses such as surgery or intercurrent illness, and patients should have injectable hydrocortisone available for emergencies and carry a medical alert type bracelet or card. Prompt and adequate treatment of a hypoglycemic crisis is essential. Treatment is life-long.PrognosisThe prognosis is good for patients who are diagnosed and treated early. Only when left untreated is FGD a disease with high morbidity (neurological sequelae) and mortality.Visit the Orphanet disease page for more resources. Last updated: 4/28/2015

MalaCards based summary : Familial Glucocorticoid Deficiency, also known as glucocorticoid deficiency, is related to glucocorticoid deficiency 2 and glucocorticoid deficiency 1. An important gene associated with Familial Glucocorticoid Deficiency is MC2R (Melanocortin 2 Receptor), and among its related pathways/superpathways is Aldosterone synthesis and secretion. Affiliated tissues include testes, adrenal cortex and skin.

Genetics Home Reference : 24 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 levels, help trigger nerve cell signaling in the brain, and serve many other purposes in the body.

Related Diseases for Familial Glucocorticoid Deficiency

Diseases related to Familial Glucocorticoid Deficiency via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 54)
# Related Disease Score Top Affiliating Genes
1 glucocorticoid deficiency 2 33.3 GCCD2 MRAP
2 glucocorticoid deficiency 1 33.2 MC2R MRAP POMC
3 lipoid congenital adrenal hyperplasia 29.2 MC2R POMC REN STAR
4 glucocorticoid deficiency 3 11.7
5 glucocorticoid deficiency 4 with or without mineralocorticoid deficiency 11.7
6 adrenocortical unresponsiveness to acth with postreceptor defect 11.0
7 glucocorticoid deficiency 5 11.0
8 sella turcica neoplasm 10.4 MRAP POMC
9 tuberculum sellae meningioma 10.4 MRAP POMC
10 adrenal cortical adenoma 10.3 MC2R POMC
11 acute adrenal insufficiency 10.3 POMC REN
12 hypoaldosteronism 10.3 POMC REN
13 testicular leydig cell tumor 10.3 POMC STAR
14 suprasellar meningioma 10.3 POMC REN
15 inappropriate adh syndrome 10.3 POMC REN
16 renal tuberculosis 10.3 MRAP REN
17 hyperaldosteronism, familial, type i 10.3 POMC REN
18 pituitary-dependent cushing's disease 10.3 NNT POMC
19 apparent mineralocorticoid excess 10.3 POMC REN
20 premenstrual tension 10.2 POMC REN
21 endocrine organ benign neoplasm 10.2 POMC REN
22 mineral metabolism disease 10.2 POMC REN
23 achalasia-addisonianism-alacrima syndrome 10.2 MC2R NNT POMC
24 adrenal rest tumor 10.2 MC2R NNT POMC
25 organ system benign neoplasm 10.2 POMC REN
26 thyroid gland disease 10.1 POMC TXNRD2
27 adrenal adenoma 10.1 MC2R POMC REN
28 adrenal insufficiency, congenital, with 46,xy sex reversal, partial or complete 10.1 NNT POMC STAR
29 aortic valve disease 1 10.1 MRAP POMC REN
30 conn's syndrome 10.1 MC2R POMC REN
31 steroid inherited metabolic disorder 10.1 POMC REN STAR
32 hypokalemia 10.0 POMC REN
33 cell type benign neoplasm 10.0 POMC REN
34 dowling-degos disease 1 9.9
35 adrenal hypoplasia, congenital 9.9 NR0B1 STAR
36 diabetes insipidus 9.8 POMC REN
37 gonadal disease 9.8 NR0B1 POMC
38 46 xy gonadal dysgenesis 9.8 NR0B1 STAR
39 achalasia 9.8
40 adrenocortical carcinoma, hereditary 9.8 MC2R NR0B1 STAR
41 adrenal cortical hypofunction 9.7 NR0B1 POMC REN
42 adrenal cortex disease 9.7 NR0B1 POMC REN
43 adrenal gland disease 9.7 NR0B1 POMC REN
44 hypophosphatemic rickets, x-linked recessive 9.6
45 focal segmental glomerulosclerosis 1 9.6
46 focal segmental glomerulosclerosis 9.6
47 rickets 9.6
48 dementia 9.6
49 pituitary adenoma 9.6
50 adenoma 9.6

Graphical network of the top 20 diseases related to Familial Glucocorticoid Deficiency:



Diseases related to Familial Glucocorticoid Deficiency

Symptoms & Phenotypes for Familial Glucocorticoid Deficiency

Drugs & Therapeutics for Familial Glucocorticoid Deficiency

Search Clinical Trials , NIH Clinical Center for Familial Glucocorticoid Deficiency

Genetic Tests for Familial Glucocorticoid Deficiency

Anatomical Context for Familial Glucocorticoid Deficiency

MalaCards organs/tissues related to Familial Glucocorticoid Deficiency:

38
Testes, Adrenal Cortex, Skin, Adrenal Gland, Cortex, Kidney, Brain

Publications for Familial Glucocorticoid Deficiency

Articles related to Familial Glucocorticoid Deficiency:

(show top 50) (show all 64)
# Title Authors Year
1
Early diagnosis in familial glucocorticoid deficiency. ( 28458768 )
2017
2
A Pilot Study Evaluating Therapeutic Response of Different Dosage of Oral Glucocorticoid in Two Children with Familial Glucocorticoid Deficiency Presenting with Diffuse Mucocutaneous Hyperpigmentation. ( 28400640 )
2017
3
Neonatal presentation of familial glucocorticoid deficiency with a MRAP mutation: A case report. ( 27660747 )
2016
4
Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency. ( 26309815 )
2015
5
A novel homozygous insertion and review of published mutations in the NNT gene causing familial glucocorticoid deficiency (FGD). ( 26548497 )
2015
6
NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency. ( 25459914 )
2015
7
Neonatal hyperpigmentation: diagnosis of familial glucocorticoid deficiency with a novel mutation in the melanocortin-2 receptor gene. ( 24224542 )
2014
8
Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). ( 24601690 )
2014
9
Familial glucocorticoid deficiency: New genes and mechanisms. ( 23279877 )
2013
10
A novel homozygous mutation of the nicotinamide nucleotide transhydrogenase gene in a Japanese patient with familial glucocorticoid deficiency. ( 23474776 )
2013
11
Familial glucocorticoid deficiency: a diagnostic challenge during acute illness. ( 23708259 )
2013
12
A case report: Familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis. ( 23232022 )
2012
13
An atypical case of familial glucocorticoid deficiency without pigmentation caused by coexistent homozygous mutations in MC2R (T152K) and MC1R (R160W). ( 22337906 )
2012
14
Familial glucocorticoid deficiency presenting with generalized hyperpigmentation in adolescence. Report of three siblings. ( 23565437 )
2012
15
Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. ( 22634753 )
2012
16
Familial glucocorticoid deficiency presenting with generalized hyperpigmentation in an Egyptian child: a case report. ( 22507176 )
2012
17
A novel mutation in the MC2R gene causing familial glucocorticoid deficiency type 1. ( 21701219 )
2011
18
Short stature in a patient with familial glucocorticoid deficiency. ( 21932602 )
2011
19
Neonatal presentation of familial glucocorticoid deficiency resulting from a novel splice mutation in the melanocortin 2 receptor accessory protein. ( 21951701 )
2011
20
Familial glucocorticoid deficiency in five Arab kindreds with homozygous point mutations of the ACTH receptor (MC2R): genotype and phenotype correlations. ( 21778684 )
2011
21
Familial glucocorticoid deficiency due to compound heterozygosity of two novel MC2R mutations. ( 21823545 )
2011
22
Isolated Addison's disease is unlikely to be caused by mutations in MC2R, MRAP or STAR, three genes responsible for familial glucocorticoid deficiency. ( 19903795 )
2010
23
Familial glucocorticoid deficiency type 2: a case report. ( 21274326 )
2010
24
Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2. ( 19558534 )
2010
25
Missense mutations in the melanocortin 2 receptor accessory protein that lead to late onset familial glucocorticoid deficiency type 2. ( 20427498 )
2010
26
A corticotroph pituitary adenoma as the initial presentation of familial glucocorticoid deficiency. ( 19423561 )
2009
27
Familial glucocorticoid deficiency with a point mutation in the ACTH receptor: a case report. ( 19795005 )
2009
28
Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency. ( 19170705 )
2009
29
Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. ( 19773404 )
2009
30
The genetics of familial glucocorticoid deficiency. ( 19500760 )
2009
31
A novel variant of familial glucocorticoid deficiency prevalent among the Irish Traveler population. ( 18430777 )
2008
32
The majority of adrenocorticotropin receptor (melanocortin 2 receptor) mutations found in familial glucocorticoid deficiency type 1 lead to defective trafficking of the receptor to the cell surface. ( 18840636 )
2008
33
A novel adrenocorticotropin receptor mutation alters its structure and function, causing familial glucocorticoid deficiency. ( 18492762 )
2008
34
Familial glucocorticoid deficiency type 1 due to a novel compound heterozygous MC2R mutation. ( 18504396 )
2008
35
Familial glucocorticoid deficiency: advances in the molecular understanding of ACTH action. ( 18059087 )
2008
36
Clinical and biological phenotype of a patient with familial glucocorticoid deficiency type 2 caused by a mutation of melanocortin 2 receptor accessory protein. ( 17893271 )
2007
37
Novel compound heterozygous mutation of the MC2R gene in a patient with familial glucocorticoid deficiency. ( 17128565 )
2006
38
Unusual presentation of familial glucocorticoid deficiency with a novel MRAP mutation. ( 16868047 )
2006
39
Possible relationship between elevated plasma ACTH and tall stature in familial glucocorticoid deficiency. ( 15673970 )
2005
40
Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. ( 15654338 )
2005
41
A novel presentation of familial glucocorticoid deficiency (FGD) and current literature review. ( 14960026 )
2004
42
Mutations in a novel gene, encoding a single transmembrane domain protein are associated with familial glucocorticoid deficiency type 2. ( 15666841 )
2004
43
Familial glucocorticoid deficiency type 2 in two neonates. ( 12556930 )
2003
44
Linkage of one gene for familial glucocorticoid deficiency type 2 (FGD2) to chromosome 8q and further evidence of heterogeneity. ( 12384787 )
2002
45
Functional relationships between three novel homozygous mutations in the ACTH receptor gene and familial glucocorticoid deficiency. ( 12110946 )
2002
46
Familial glucocorticoid deficiency syndromes. ( 12212552 )
2002
47
Tall stature in familial glucocorticoid deficiency. ( 11012566 )
2000
48
[ACTH receptor, ACTH receptor anomaly, and familial glucocorticoid deficiency]. ( 9702062 )
1998
49
ACTH receptor mutation in a girl with familial glucocorticoid deficiency. ( 9550364 )
1998
50
Exclusion of the adrenocorticotropin (ACTH) receptor (MC2R) locus in some families with ACTH resistance but no mutations of the MC2R coding sequence (familial glucocorticoid deficiency type 2). ( 9768670 )
1998

Variations for Familial Glucocorticoid Deficiency

ClinVar genetic disease variations for Familial Glucocorticoid Deficiency:

6 (show all 17)
# Gene Variation Type Significance SNP ID Assembly Location
1 MC2R NM_000529.2(MC2R): c.376G> T (p.Ala126Ser) single nucleotide variant Pathogenic rs267607231 GRCh37 Chromosome 18, 13885142: 13885142
2 MRAP NM_206898.1(MRAP): c.3G> A (p.Met1Ile) single nucleotide variant Pathogenic rs80358231 GRCh37 Chromosome 21, 33671285: 33671285
3 MC2R NM_000529.2(MC2R): c.752G> T (p.Cys251Phe) single nucleotide variant Pathogenic rs104894662 GRCh38 Chromosome 18, 13884767: 13884767
4 MC2R NM_000529.2(MC2R): c.409C> T (p.Arg137Trp) single nucleotide variant Pathogenic rs104894660 GRCh37 Chromosome 18, 13885109: 13885109
5 MC2R NM_000529.2(MC2R): c.761A> G (p.Tyr254Cys) single nucleotide variant Pathogenic rs28940892 GRCh37 Chromosome 18, 13884757: 13884757
6 MC2R MC2R, 1-BP INS, 1347A insertion Pathogenic
7 MC2R NM_000529.2(MC2R): c.221G> T (p.Ser74Ile) single nucleotide variant Pathogenic rs104894658 GRCh37 Chromosome 18, 13885297: 13885297
8 MC2R NM_000529.2(MC2R): c.601C> T (p.Arg201Ter) single nucleotide variant Pathogenic rs104894659 GRCh37 Chromosome 18, 13884917: 13884917
9 MC2R NM_000529.2(MC2R): c.360C> G (p.Ser120Arg) single nucleotide variant Pathogenic rs104894656 GRCh37 Chromosome 18, 13885158: 13885158
10 MC2R NM_000529.2(MC2R): c.382C> T (p.Arg128Cys) single nucleotide variant Pathogenic rs104894657 GRCh37 Chromosome 18, 13885136: 13885136
11 MC2R NM_000529.2(MC2R): c.319G> A (p.Asp107Asn) single nucleotide variant Pathogenic rs104894661 GRCh37 Chromosome 18, 13885199: 13885199
12 MC2R NM_000529.2(MC2R): c.674T> G (p.Leu225Arg) single nucleotide variant Pathogenic GRCh37 Chromosome 18, 13884844: 13884844
13 MC2R NM_000529.2(MC2R): c.459dup (p.Ile154Hisfs) duplication Pathogenic GRCh37 Chromosome 18, 13885059: 13885059
14 MC2R NM_000529.2(MC2R): c.424G> T (p.Val142Leu) single nucleotide variant Pathogenic rs199950178 GRCh37 Chromosome 18, 13885094: 13885094
15 MRAP NM_206898.1(MRAP): c.1A> G (p.Met1Val) single nucleotide variant Pathogenic GRCh37 Chromosome 21, 33671283: 33671283
16 MRAP NM_206898.1(MRAP): c.106+1delG deletion Pathogenic GRCh38 Chromosome 21, 32299078: 32299078
17 MC2R NM_000529.2(MC2R): c.702delC (p.Phe235Leufs) deletion Pathogenic GRCh38 Chromosome 18, 13884817: 13884817

Expression for Familial Glucocorticoid Deficiency

Search GEO for disease gene expression data for Familial Glucocorticoid Deficiency.

Pathways for Familial Glucocorticoid Deficiency

Pathways related to Familial Glucocorticoid Deficiency according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Show member pathways
11.6 MC2R MRAP POMC STAR

GO Terms for Familial Glucocorticoid Deficiency

Biological processes related to Familial Glucocorticoid Deficiency according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 steroid biosynthetic process GO:0006694 9.43 NR0B1 STAR
2 male gonad development GO:0008584 9.43 NR0B1 REN STAR
3 response to immobilization stress GO:0035902 9.4 NR0B1 REN
4 protein localization to cell surface GO:0034394 9.37 MRAP MRAP2
5 negative regulation of protein localization to plasma membrane GO:1903077 9.32 MRAP MRAP2
6 positive regulation of adenylate cyclase-activating G-protein coupled receptor signaling pathway GO:0106071 9.16 MRAP MRAP2
7 positive regulation of cAMP biosynthetic process GO:0030819 9.13 MC2R MRAP MRAP2
8 negative regulation of adenylate cyclase-activating G-protein coupled receptor signaling pathway GO:0106072 8.62 MRAP MRAP2

Molecular functions related to Familial Glucocorticoid Deficiency according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 type 3 melanocortin receptor binding GO:0031781 9.33 MRAP MRAP2 POMC
2 type 5 melanocortin receptor binding GO:0031783 9.32 MRAP MRAP2
3 corticotropin hormone receptor binding GO:0031780 9.26 MRAP MRAP2
4 type 4 melanocortin receptor binding GO:0031782 9.13 MRAP MRAP2 POMC
5 type 1 melanocortin receptor binding GO:0070996 8.8 MRAP MRAP2 POMC

Sources for Familial Glucocorticoid Deficiency

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
27 GO
28 GTR
29 HGMD
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 MedGen
41 MeSH
42 MESH via Orphanet
43 MGI
45 NCI
46 NCIt
47 NDF-RT
50 NINDS
51 Novoseek
53 OMIM
54 OMIM via Orphanet
58 PubMed
60 QIAGEN
65 SNOMED-CT via HPO
66 SNOMED-CT via Orphanet
67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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