Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort

In the paper

“Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP.”

• Also stated in: § Results · plain

  “Recurrent mutations were detected in several genes, such as c.560delT in MC2R (10 patients from nine unrelated families), p.R451W in CYP11A1 (nine patients from eight unrelated families), c.IVS3ds+1delG in MRAP (five patients from five unrelated families), and p.S13P in STAR (three patients from two unrelated families).”

In the paper

“One boy with a NR0B1 mutation and X-linked adrenal hypoplasia congenita (AHC) had macrophallia and another one had cryptorchidism.”

In the paper

“The most common presenting features were hyperpigmentation (94%), salt-wasting crisis/electrolyte imbalance (51%), hypoglycemia with/without convulsions (47%), vomiting/abdominal pain (26%), prolonged jaundice (24%), fatigue (18%), neonatal respiratory distress (17%), frequent infections (11%), and failure to thrive or weight loss (7%).”

In the paper

“Eight families had multiple affected siblings (six pairs, two trios, n = 18).”

In the paper

“Adrenal imaging was generally uninformative, showing normal sized or hypoplastic glands for most of these diagnoses, including many children with STAR mutations (congenital lipoid adrenal hyperplasia) in which enlarged adrenals are reported (22).”

What the sources say

• Not checked yetcites [22] Bose HS Sugawara T Strauss JF 3rd Miller WL International Congenital Lipoid Adrenal Hyperplasia Consortium. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med. 1996; 335: 1870– 1878. 8948562

In the paper

“Salt-wasting states requiring mineralocorticoid replacement occurred in all children with NR0B1 (DAX-1) and STAR mutations and in most children with the CYP11A1 p.R451W change (six of nine, 66%) (Table 1).”

In the paper

“Geographical hot spots were found for the p.R451W CYP11A1 mutation in eastern Turkey and for the c.IVS3ds+1delG MRAP mutation in the west (Figure 3, A and B).”

In the paper

“Children with nicotinamide nucleotide transhydrogenase (NNT) changes presented at different ages in the first 2 years, whereas boys with NR0B1 (DAX-1) mutations had a bimodal pattern, presenting either in the first month of life or else after 18 months.”

In the paper

“Coincidental hypospadias and unilateral cryptorchidism was found in one boy with disruption of MC2R.”

In the paper

“Most patients were homozygous for recessive changes (62 of 77, 80%), one patient carried compound heterozygous changes (1 of 77, 1.3%), and 14 patients had hemizygous mutations in X-linked genes (NR0B1, ABCD1) (14 of 77, 18%).”

In the paper

“There was no history of preterm birth associated with CYP11A1 mutations, but there were reports of multiple stillbirths in three families in which a child had severe disruption of MC2R (deletion or c.560delT frameshift).”

In the paper

“The remaining 21 mutations have been reported (Supplemental Table 1).”

In the paper

“Stature was variable in the 25 children with MC2R mutations with seven children (28%) having tall stature (>2 SD score or two percentile lines above parental target height), four having short stature (<−2 SD score) and the rest being within the normal range.”

In the paper

“Seven patients had 46,XY disorders of sex development (DSD).”

In the paper

“The one boy with severe hypospadias due to STAR deficiency developed hypergonadotropic hypogonadism in puberty and needed T replacement.”

In the paper

“A molecular diagnosis was reached in all eight families with multiple affected siblings, including novel changes in five families (Table 1).”

In the paper

“These changes were all confirmed by Sanger sequencing and included missense mutations (n = 24), nonsense mutations (n = 7), frameshift mutations (n = 5), in-frame single codon deletions (n = 3), splice site disruptions (n = 2), and whole gene/exon deletions (n = 2).”

In the paper

“Of these variations, 22 (51%) had not been reported previously but were considered to be causative because they segregated with the phenotype in the family, they were classed as damaging or probably damaging by several bioinformatic predictions, and they were not found in the control samples or databases (Supplemental Table 2).”

In the paper

“Five of these children were phenotypic females who presented with a salt-losing crisis, and in two cases a karyotype was not available prior to this genetic analysis.”

In the paper

“Abnormalities in thyroid function such as subclinical hypothyroidism were common (n = 20, 26%), whereas thyroglossal cysts (n = 2), primary hypothyroidism (n = 2), and transient hypothyroidism (n = 1) were also found.”

In the paper

“Fewer children with NNT (two of seven, 28%), MRAP (two of nine, 22%), and MC2R (2 of 25, 8%) mutations required mineralocorticoid replacement, although four additional children with MC2R defects had transient hyponatremia (sodium 117–133 mmol/L) that resolved without fludrocortisone treatment (Supplemental Table 1).”

In the paper

“Most children had extremely high ACTH levels at diagnosis and almost all children, even babies, were clinically hyperpigmented.”

In the paper

“For example, most patients with MC2R, MRAP, and STAR mutations presented in the first weeks or months of life, whereas children with the p.R451W mutation in CYP11A1 presented in early childhood (1–6 y) (Figure 4).”

In the paper

“A total of 51 patients were on hydrocortisone treatment alone, whereas 44 were also commenced on mineralocorticoid replacement due to salt wasting, high plasma renin activity, or low aldosterone.”

In the paper

“Parents of patients were consanguineous in 63 (74%) families, whereas 22 families did not report consanguinity.”

In the paper

“Interestingly, nine of the children presented between 3 weeks and 3 months of age, consistent with the two-hit hypothesis, whereas only two presented in the first week (22).”

In the paper

“Hemizygous mutations in NR0B1 (encoding the nuclear receptor DAX-1) were found in 12 boys, including in two families in which three sons were affected.”

In the paper

“Indeed, the one patient with hypospadias raised male is now showing evidence of hypergonadotropic hypogonadism in adolescence.”

In the paper

“The novel p.L299 lies adjacent to the frequently mutated p.A300 residue, whereas codons p.V269 and p.W291 have been mutated previously in non-Turkish pedigree (5).”

In the paper

“Macrophallia in infancy, found in one boy, is emerging as a rare feature of X-linked AHC (31).”

In the paper

“The six novel changes found here include familial homozygous deletions of exons 2–3 and homozygous missense mutations in the mitochondrial matrix region (p.D178G, p.H370R).”

In the paper

“Of note, no mutations were found in MCM4 orTXNRD2, which to date have been described only in Irish Traveler and Kashmiri families, respectively (12, 14, 23)”

What the sources say

• Not checked yetcites [12] Hughes CR Guasti L Meimaridou E MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012; 122: 814– 820. 22354170 PMC3287227
• Not checked yetcites [14] Prasad R Chan LF Hughes CR Thioredoxin reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. 2014; 99: E1556– E1563. 24601690 PMC4207928
• Not checked yetcites [23] Gineau L Cognet C Kara N Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest. 2012; 122: 821– 832. 22354167 PMC3287233

In the paper

“Several genetic causes of adrenal hypoplasia (NR0B1/dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region, on the X chromosome, gene 1 [DAX-1], NR5A1/SF-1, CDKN1C gene defects), congenital lipoid adrenal hyperplasia (CYP11A1, STAR gene defects), familial glucocorticoid deficiency (FGD) and FGD-like conditions (MC2R [FGD1], MRAP [FGD2], STAR, MCM4, NNT, TXNRD2 gene defects)”

• Also stated in: § Conclusion: · boosted

  “and adrenal destruction (AIRE, ABCD1, PEX1, LIPA gene defects) are now well established (5–16).”

What the sources say

• Not checked yetcites [5] Suntharalingham JP Buonocore F Duncan AJ Achermann JC DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015; 29: 607– 619. 26303087 PMC5159745
• Not checked yetcites [6] Lin L Gu WX Ozisik G Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years' experience. J Clin Endocrinol Metab. 2006; 91: 3048– 3054. 16684822 PMC1865080
• Not checked yetcites [7] Arboleda VA Lee H Parnaik R Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet. 2012; 44: 788– 792. 22634751 PMC3386373
• Not checked yetcites [8] Meimaridou E Hughes CR Kowalczyk J Chan LF Clark AJ Metherell LA ACTH resistance: genes and mechanisms. Endocr Dev. 2013; 24: 57– 66. 23392095
• Not checked yetcites [9] Meimaridou E Hughes CR Kowalczyk J Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013; 371: 195– 200. 23279877
• Not checked yetcites [10] Metherell LA Chapple JP Cooray S Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet. 2005; 37: 166– 170. 15654338
• Not checked yetcites [11] Dumic M Barišic N Kusec V Long-term clinical follow-up and molecular genetic findings in eight patients with triple A syndrome. Eur J Pediatr. 2012; 171: 1453– 1459. 22538409
• Not checked yetcites [12] Hughes CR Guasti L Meimaridou E MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012; 122: 814– 820. 22354170 PMC3287227
• Not checked yetcites [13] Meimaridou E Kowalczyk J Guasti L Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet. 2012; 44: 740– 742. 22634753 PMC3386896
• Not checked yetcites [14] Prasad R Chan LF Hughes CR Thioredoxin reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. 2014; 99: E1556– E1563. 24601690 PMC4207928

In the paper

“In contrast to the predominance in autoimmune etiologies in adults, most causes of PAI in childhood have an inherited, monogenic origin (1–3).”

What the sources say

• Not checked yetcites [1] Hsieh S White PC Presentation of primary adrenal insufficiency in childhood. J Clin Endocrinol Metab. 2011; 96: E925– E928. 21470994
• Not checked yetcites [2] Perry R Kecha O Paquette J Huot C Van Vliet G Deal C Primary adrenal insufficiency in children: twenty years‘ experience at the Sainte-Justine Hospital, Montreal. J Clin Endocrinol Metab. 2005; 90: 3243– 3250. 15811934
• Not checked yetcites [3] Malikova J Flück CE Novel insight into etiology, diagnosis and management of primary adrenal insufficiency. Horm Res Paediatr. 2014; 82: 145– 157. 25096886

In the paper

“However, it is also emerging that there is considerable overlap in the clinical and biochemical presentation of these conditions. For example, FGD/FGD-like conditions (MC2R, MRAP, NNT gene defects) can present with salt loss suggestive of adrenal hypoplasia, and alterations in STAR and CYP11A1 resulting in partial loss of protein function may have a predominant FGD-like phenotype (17–20).”

What the sources say

• Not checked yetcites [17] Lin L Hindmarsh PC Metherell LA Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia. Clin Endocrinol (Oxf). 2007; 66: 205– 210. 17223989 PMC1859977
• Not checked yetcites [18] Baker BY Lin L Kim CJ Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab. 2006; 91: 4781– 4785. 16968793 PMC1865081
• Not checked yetcites [19] Metherell LA Naville D Halaby G Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2009; 94: 3865– 3871. 19773404 PMC2860769
• Not checked yetcites [20] Parajes S Kamrath C Rose IT A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1). J Clin Endocrinol Metab. 2011; 96: E1798– 1806. 21880796

In the paper

“Variants in known disease genes were considered highly likely to be pathogenic if they segregated with the phenotype with an appropriate inheritance pattern within families, were determined damaging or likely damaging by several bioinformatic prediction models (Ensembl Variant Effector Predictor; SIFT; PolyPhen2; and Mutation Taster) and if they had been reported previously.”

• Also stated in: § Variant analysis · plain

  “In addition, novel missense changes were absent in at least 200 Turkish control samples and had a minor allele frequency less than 1:100 000 in the Exome Aggregation Consortium (ExAC) browser”

In the paper

“Other recurrent changes, such as the c.560delT in MC2R showed more diverse geographical distribution across the country, possibly reflecting migration toward the west (Figure 3B).”

In the paper

“Establishing a specific genetic diagnosis of PAI is extremely valuable for identifying presymptomatic children who could benefit from treatment before the onset of potentially life-threatening symptoms and for counseling family members appropriately about the risk of passing the condition on to their children (1, 3, 20, 21).”

• Also stated in: § Conclusion: · plain

  “Knowing the genetic etiology can also help to modify treatments, such as the need for long-term mineralocorticoid replacement, and can predict potential comorbidities, such as impaired puberty or fertility and neurological dysfunction.”

What the sources say

• Not checked yetcites [1] Hsieh S White PC Presentation of primary adrenal insufficiency in childhood. J Clin Endocrinol Metab. 2011; 96: E925– E928. 21470994
• Not checked yetcites [3] Malikova J Flück CE Novel insight into etiology, diagnosis and management of primary adrenal insufficiency. Horm Res Paediatr. 2014; 82: 145– 157. 25096886
• Not checked yetcites [20] Parajes S Kamrath C Rose IT A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1). J Clin Endocrinol Metab. 2011; 96: E1798– 1806. 21880796
• Not checked yetcites [21] Achermann JC Silverman BL Habiby RL Jameson JL Presymptomatic diagnosis of X-linked adrenal hypoplasia congenita by analysis of DAX1. J Pediatr. 2000; 137: 878– 881. 11113848

In the paper

“Congenital adrenal hyperplasia (CYP21A2, CYP11B1, HSD3B2, CYP17A1, POR deficiencies) constitutes the largest subgroup of impaired steroidogenesis and is the most common cause of PAI in children (1, 2, 4).”

What the sources say

• Not checked yetcites [1] Hsieh S White PC Presentation of primary adrenal insufficiency in childhood. J Clin Endocrinol Metab. 2011; 96: E925– E928. 21470994
• Not checked yetcites [2] Perry R Kecha O Paquette J Huot C Van Vliet G Deal C Primary adrenal insufficiency in children: twenty years‘ experience at the Sainte-Justine Hospital, Montreal. J Clin Endocrinol Metab. 2005; 90: 3243– 3250. 15811934
• Not checked yetcites [4] Miller WL Auchus RJ The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011; 32: 81– 151. 21051590 PMC3365799

In the paper

“Mutations in MC2R (encoding the ACTH receptor) are well established as the cause of FGD1, and approximately 40 different missense changes have been reported (9).”

What the sources say

• Not checked yetcites [9] Meimaridou E Hughes CR Kowalczyk J Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013; 371: 195– 200. 23279877

In the paper

“Because children could die from convulsions, respiratory distress, or salt-losing crises before reaching the hospital or get misdiagnosed with sepsis, the condition may be underdiagnosed.”

In the paper

“Indeed, this MC2R mutation has been reported previously in the father of two siblings with FGD1 who originated from northern Iran, close to the Turkish border (17).”

What the sources say

• Not checked yetcites [17] Lin L Hindmarsh PC Metherell LA Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia. Clin Endocrinol (Oxf). 2007; 66: 205– 210. 17223989 PMC1859977

In the paper

“Although currently preadolescent, they are likely to develop hypogonadotropic hypogonadism and infertility as part of their condition, so establishing the diagnosis in childhood will help plan endocrine management of puberty, counseling, and potential assisted reproduction (30).”

What the sources say

• Not checked yetcites [30] Frapsauce C Ravel C Legendre M Birth after TESE-ICSI in a man with hypogonadotropic hypogonadism and congenital adrenal hypoplasia linked to a DAX-1 (NR0B1) mutation. Hum Reprod. 2011; 26: 724– 728. 21227944 PMC3037794

In the paper

“These findings confirm that mild loss of CYP11A1/P450scc function can present with isolated adrenal insufficiency and normal male genitalia, similar to mild loss of function of STAR (18–20).”

What the sources say

• Not checked yetcites [18] Baker BY Lin L Kim CJ Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab. 2006; 91: 4781– 4785. 16968793 PMC1865081
• Not checked yetcites [19] Metherell LA Naville D Halaby G Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2009; 94: 3865– 3871. 19773404 PMC2860769
• Not checked yetcites [20] Parajes S Kamrath C Rose IT A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1). J Clin Endocrinol Metab. 2011; 96: E1798– 1806. 21880796

In the paper

“Mutations in MC2R (encoding the ACTH receptor) are well established as the cause of FGD1, and approximately 40 different missense changes have been reported (9).”

What the sources say

• Not checked yetcites [9] Meimaridou E Hughes CR Kowalczyk J Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013; 371: 195– 200. 23279877

In the paper

“Two girls were found to have 46,XY DSD only after genetic analysis revealed STAR deficiency, highlighting the importance of obtaining a karyotype in phenotypic girls with salt-losing adrenal failure.”

In the paper

“The two-hit hypothesis suggests that after an initial reduction in steroid production and increased ACTH drive, accumulation of intracellular lipid has a secondary toxic effect on cells (22).”

What the sources say

• Not checked yetcites [22] Bose HS Sugawara T Strauss JF 3rd Miller WL International Congenital Lipoid Adrenal Hyperplasia Consortium. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med. 1996; 335: 1870– 1878. 8948562

In the paper

“Most are frameshift or nonsense mutations that disrupt protein function, with a clustering of missense changes in three regions of the ligand-like binding domain (27).”

What the sources say

• Not checked yetcites [27] Achermann JC Ito M Silverman BL Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression. J Clin Endocrinol Metab. 2001; 86: 3171– 3175. 11443184

In the paper

“Defects in STAR (encoding steroidogenic acute regulatory protein) disrupt the transport of cholesterol into mitochondria and classically lead to congenital lipoid adrenal hyperplasia (4, 22).”

What the sources say

• Not checked yetcites [4] Miller WL Auchus RJ The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011; 32: 81– 151. 21051590 PMC3365799
• Not checked yetcites [22] Bose HS Sugawara T Strauss JF 3rd Miller WL International Congenital Lipoid Adrenal Hyperplasia Consortium. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med. 1996; 335: 1870– 1878. 8948562

In the paper

“Mutations in NR0B1 cause X-linked AHC and more than 100 different mutations are reported (5).”

What the sources say

• Not checked yetcites [5] Suntharalingham JP Buonocore F Duncan AJ Achermann JC DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015; 29: 607– 619. 26303087 PMC5159745

In the paper

“Macrophallia in infancy, found in one boy, is emerging as a rare feature of X-linked AHC (31).”

What the sources say

• Not checked yetcites [31] Landau Z Hanukoglu A Sack J Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations. Clin Endocrinol (Oxf). 2010; 72: 448– 454. 19508677

In the paper

“Severe loss of CYP11A1/P450scc function is usually associated with severe salt-losing adrenal failure in the neonatal period and a female phenotype in 46,XY children (46,XY DSD).”

What the sources say

• Not checked yetcites [32] Hiort O Holterhus PM Werner R Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure. J Clin Endocrinol Metab. 2005; 90: 538– 541. 15507506
• Not checked yetcites [33] Kim CJ Lin L Huang N Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. J Clin Endocrinol Metab. 2008; 93: 696– 702. 18182448 PMC2266942

In the paper

“MRAP is essential for trafficking the ACTH receptor (melanocortin 2 receptor) to the cell membrane, and mutations causing FGD2 were first described in 2005 (9, 10, 24).”

What the sources say

• Not checked yetcites [9] Meimaridou E Hughes CR Kowalczyk J Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013; 371: 195– 200. 23279877
• Not checked yetcites [10] Metherell LA Chapple JP Cooray S Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet. 2005; 37: 166– 170. 15654338
• Not checked yetcites [24] Chung TT Chan LF Metherell LA Clark AJ Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2. Clin Endocrinol (Oxf). 2010; 72: 589– 594. 19558534 PMC2855830

In the paper

“Children typically present with hypoglycemia or hyperpigmentation in early infancy or in childhood, but complete loss of function mutations are rare (17, 24).”

What the sources say

• Not checked yetcites [17] Lin L Hindmarsh PC Metherell LA Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia. Clin Endocrinol (Oxf). 2007; 66: 205– 210. 17223989 PMC1859977
• Not checked yetcites [24] Chung TT Chan LF Metherell LA Clark AJ Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2. Clin Endocrinol (Oxf). 2010; 72: 589– 594. 19558534 PMC2855830

In the paper

“The novel p.L299 lies adjacent to the frequently mutated p.A300 residue, whereas codons p.V269 and p.W291 have been mutated previously in non-Turkish pedigree (5).”

What the sources say

• Not checked yetcites [5] Suntharalingham JP Buonocore F Duncan AJ Achermann JC DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015; 29: 607– 619. 26303087 PMC5159745

In the paper

“Heterozygous mutations in NR5A1 (encoding the nuclear receptor steroidogenic factor-1) usually cause 46,XY DSD or primary ovarian insufficiency (5).”

What the sources say

• Not checked yetcites [5] Suntharalingham JP Buonocore F Duncan AJ Achermann JC DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015; 29: 607– 619. 26303087 PMC5159745

In the paper

“NNT mutations affect cellular oxidation and were first decribed in 2012; approximately 20 children have been reported to date (9, 13, 38).”

What the sources say

• Not checked yetcites [9] Meimaridou E Hughes CR Kowalczyk J Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013; 371: 195– 200. 23279877
• Not checked yetcites [13] Meimaridou E Kowalczyk J Guasti L Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet. 2012; 44: 740– 742. 22634753 PMC3386896
• Not checked yetcites [38] Novoselova TV Rath SR Carpenter K NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2015; 100: E350– E354. 25459914 PMC4318891

In the paper

“Adrenal insufficiency is extremely rare and has been reported only once, in a 46,XX girl (39).”

What the sources say

• Not checked yetcites [39] Biason-Lauber A Schoenle EJ Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency. Am J Hum Genet. 2000; 67: 1563– 1568. 11038323 PMC1287931

In the paper

“NNT mutations affect cellular oxidation and were first decribed in 2012; approximately 20 children have been reported to date (9, 13, 38).”

What the sources say

• Not checked yetcites [9] Meimaridou E Hughes CR Kowalczyk J Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013; 371: 195– 200. 23279877
• Not checked yetcites [13] Meimaridou E Kowalczyk J Guasti L Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet. 2012; 44: 740– 742. 22634753 PMC3386896
• Not checked yetcites [38] Novoselova TV Rath SR Carpenter K NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2015; 100: E350– E354. 25459914 PMC4318891

In the paper

“NNT mutations affect cellular oxidation and were first decribed in 2012; approximately 20 children have been reported to date (9, 13, 38).”

What the sources say

• Not checked yetcites [9] Meimaridou E Hughes CR Kowalczyk J Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013; 371: 195– 200. 23279877
• Not checked yetcites [13] Meimaridou E Kowalczyk J Guasti L Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet. 2012; 44: 740– 742. 22634753 PMC3386896
• Not checked yetcites [38] Novoselova TV Rath SR Carpenter K NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2015; 100: E350– E354. 25459914 PMC4318891

In the paper

“New genetic technologies are a powerful tool in defining population genetics of rare conditions and will allow more focused clinical genetic screening programs to be established.”