Rare causes of primary adrenal insufficiency: genetic and clinical characterization of a large nationwide cohort

May combine two claims.

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

“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).”

May combine two claims.

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

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

May combine two claims.

The most common presenting features in the cohort 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%).

“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%).”

Probably not a substantial claim: may not pass S3 (load-bearing).

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

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

May combine two claims.

Adrenal imaging was generally uninformative, showing normal sized or hypoplastic glands for most of these diagnoses, including many children with STAR mutations in which enlarged adrenals are reported.

“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).”

• cites [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. 8948562Not checked yet

  Not checked in the free run.

May combine two claims.

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%).

“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).”

May combine two claims.

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.

“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).”

May combine two claims.

Children with 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.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

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

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

May combine two claims.

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%).

“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%).”

May combine two claims.

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).

“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).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The remaining 21 mutations have been reported.

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

May combine two claims.

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.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

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

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

May combine two claims.

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

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

May combine two claims.

A molecular diagnosis was reached in all eight families with multiple affected siblings, including novel changes in five families.

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

May combine two claims.

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).

“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).”

May combine two claims.

Of the variations, 22 (51%) had not been reported previously but were considered causative because they segregated with the phenotype, were classed as damaging or probably damaging by bioinformatic predictions, and were not found in control samples or databases.

“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).”

May combine two claims.

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.

“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.”

May combine two claims.

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.

“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.”

May combine two claims.

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.

“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).”

May combine two claims.

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

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

May combine two claims.

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).

“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).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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.

“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.”

May combine two claims.

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

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

May combine two claims.

Nine of the children with STAR defects presented between 3 weeks and 3 months of age, whereas only two presented in the first week.

“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).”

May combine two claims.

Hemizygous mutations in NR0B1 were found in 12 boys, including in two families in which three sons were affected.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The one patient with hypospadias raised male is now showing evidence of hypergonadotropic hypogonadism in adolescence.

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

Probably not a substantial claim: may not pass S3 (load-bearing).

The novel p.L299 lies adjacent to the frequently mutated p.A300 residue.

“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).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Macrophallia in infancy was found in one boy in this cohort.

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

May combine two claims.

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).

“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).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

MCM4 and TXNRD2 mutations have to date been described only in Irish Traveler and Kashmiri families, respectively.

“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)”

• cites [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 PMC3287227Not checked yet

  Not checked in the free run.

• cites [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 PMC4207928Not checked yet

  Not checked in the free run.

• cites [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 PMC3287233Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Several genetic causes of adrenal hypoplasia, congenital lipoid adrenal hyperplasia, familial glucocorticoid deficiency and FGD-like conditions, and adrenal destruction are now well established.

“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).”

• cites [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 PMC5159745Not checked yet

  Not checked in the free run.

• cites [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 PMC1865080Not checked yet

  Not checked in the free run.

• cites [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 PMC3386373Not checked yet

  Not checked in the free run.

• cites [8] Meimaridou E Hughes CR Kowalczyk J Chan LF Clark AJ Metherell LA ACTH resistance: genes and mechanisms. Endocr Dev. 2013; 24: 57– 66. 23392095Not checked yet

  Not checked in the free run.

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

  Not checked in the free run.

• cites [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. 15654338Not checked yet

  Not checked in the free run.

• cites [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. 22538409Not checked yet

  Not checked in the free run.

• cites [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 PMC3287227Not checked yet

  Not checked in the free run.

• cites [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 PMC3386896Not checked yet

  Not checked in the free run.

• cites [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 PMC4207928Not checked yet

  Not checked in the free run.

May combine two claims.

Most causes of primary adrenal insufficiency in childhood have an inherited, monogenic origin, in contrast to the predominance of autoimmune etiologies in adults.

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

• cites [1] Hsieh S White PC Presentation of primary adrenal insufficiency in childhood. J Clin Endocrinol Metab. 2011; 96: E925– E928. 21470994Not checked yet

  Not checked in the free run.

• cites [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. 15811934Not checked yet

  Not checked in the free run.

• cites [3] Malikova J Flück CE Novel insight into etiology, diagnosis and management of primary adrenal insufficiency. Horm Res Paediatr. 2014; 82: 145– 157. 25096886Not checked yet

  Not checked in the free run.

May combine two claims.

There is considerable overlap in the clinical and biochemical presentation of these conditions; FGD/FGD-like conditions can present with salt loss suggestive of adrenal hypoplasia, and alterations in STAR and CYP11A1 may have a predominant FGD-like phenotype.

“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).”

• cites [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 PMC1859977Not checked yet

  Not checked in the free run.

• cites [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 PMC1865081Not checked yet

  Not checked in the free run.

• cites [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 PMC2860769Not checked yet

  Not checked in the free run.

• cites [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. 21880796Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

Variants in known disease genes were considered highly likely to be pathogenic if they segregated with the phenotype with an appropriate inheritance pattern, were determined damaging or likely damaging by several bioinformatic prediction models, and had been reported previously; novel missense changes were absent in at least 200 Turkish control samples and had a minor allele frequency less than 1:

“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”

Probably not a substantial claim: may not pass S3 (load-bearing).

The diverse geographical distribution of c.560delT in MC2R possibly reflects migration toward the west.

“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).”

May combine two claims.

Establishing a specific genetic diagnosis of primary adrenal insufficiency is valuable for identifying presymptomatic children, counseling family members, modifying treatments, and predicting comorbidities.

“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.”

• cites [1] Hsieh S White PC Presentation of primary adrenal insufficiency in childhood. J Clin Endocrinol Metab. 2011; 96: E925– E928. 21470994Not checked yet

  Not checked in the free run.

• cites [3] Malikova J Flück CE Novel insight into etiology, diagnosis and management of primary adrenal insufficiency. Horm Res Paediatr. 2014; 82: 145– 157. 25096886Not checked yet

  Not checked in the free run.

• cites [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. 21880796Not checked yet

  Not checked in the free run.

• cites [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. 11113848Not checked yet

  Not checked in the free run.

May combine two claims.

Congenital adrenal hyperplasia constitutes the largest subgroup of impaired steroidogenesis and is the most common cause of primary adrenal insufficiency in children.

“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).”

• cites [1] Hsieh S White PC Presentation of primary adrenal insufficiency in childhood. J Clin Endocrinol Metab. 2011; 96: E925– E928. 21470994Not checked yet

  Not checked in the free run.

• cites [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. 15811934Not checked yet

  Not checked in the free run.

• cites [4] Miller WL Auchus RJ The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011; 32: 81– 151. 21051590 PMC3365799Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Mutations in MC2R are well established as the cause of FGD1.

“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).”

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

  Not checked in the free run.

May combine two claims.

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

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The MC2R mutation c.560delT has been reported previously in the father of two siblings with FGD1 who originated from northern Iran, close to the Turkish border.

“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).”

• cites [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 PMC1859977Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Establishing the diagnosis of DAX-1 deficiency in childhood will help plan endocrine management of puberty, counseling, and potential assisted reproduction.

“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).”

• cites [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 PMC3037794Not checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [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 PMC1865081Not checked yet

  Not checked in the free run.

• cites [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 PMC2860769Not checked yet

  Not checked in the free run.

• cites [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. 21880796Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Approximately 40 different missense changes in MC2R have been reported.

“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).”

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

  Not checked in the free run.

Classified as probably not a substantial claim.

Obtaining a karyotype is important in phenotypic girls with salt-losing adrenal failure.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

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.

“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).”

• cites [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. 8948562Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Most NR0B1 mutations are frameshift or nonsense mutations that disrupt protein function, with clustering of missense changes in three regions of the ligand-like binding domain.

“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).”

• cites [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. 11443184Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Defects in STAR disrupt the transport of cholesterol into mitochondria and classically lead to congenital lipoid adrenal hyperplasia.

“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).”

• cites [4] Miller WL Auchus RJ The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011; 32: 81– 151. 21051590 PMC3365799Not checked yet

  Not checked in the free run.

• cites [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. 8948562Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

More than 100 different mutations in NR0B1 are reported.

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

• cites [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 PMC5159745Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Macrophallia in infancy is emerging as a rare feature of X-linked AHC.

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

• cites [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. 19508677Not checked yet

  Not checked in the free run.

May combine two claims.

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).

“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).”

• cites [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. 15507506Not checked yet

  Not checked in the free run.

• cites [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 PMC2266942Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Mutations in MRAP causing FGD2 were first described in 2005.

“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).”

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

  Not checked in the free run.

• cites [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. 15654338Not checked yet

  Not checked in the free run.

• cites [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 PMC2855830Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Complete loss of function mutations in MC2R are rare.

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

• cites [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 PMC1859977Not checked yet

  Not checked in the free run.

• cites [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 PMC2855830Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Codons p.V269 and p.W291 have been mutated previously in non-Turkish pedigree.

“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).”

• cites [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 PMC5159745Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Heterozygous mutations in NR5A1 usually cause 46,XY DSD or primary ovarian insufficiency.

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

• cites [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 PMC5159745Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

NNT mutations affect cellular oxidation.

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

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

  Not checked in the free run.

• cites [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 PMC3386896Not checked yet

  Not checked in the free run.

• cites [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 PMC4318891Not checked yet

  Not checked in the free run.

May combine two claims.

Adrenal insufficiency due to NR5A1 mutations is extremely rare and has been reported only once, in a 46,XX girl.

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

• cites [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 PMC1287931Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Approximately 20 children with NNT mutations have been reported to date.

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

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

  Not checked in the free run.

• cites [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 PMC3386896Not checked yet

  Not checked in the free run.

• cites [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 PMC4318891Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

NNT mutations were first described in 2012.

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

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

  Not checked in the free run.

• cites [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 PMC3386896Not checked yet

  Not checked in the free run.

• cites [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 PMC4318891Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

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.

“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.”