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Rare causes of adrenal failure
Nils Krone MD FRCPCH n.p.krone@bham.ac.uk
Centre for Endocrinology, Diabetes and Metabolism School for Clinical and Experimental Medicine
University of Birmingham &
Diana Princess of Wales Children’s Hospital Birmingham Children’s Hospital
NHS Foundation Trust
Patient with AI
Parameter Concentrations
Na 125 mmol/L
K 6.8 mmol/L
Cortisol 120 nmol/L
17OHP 1.9 nmol/L
ACTH > 600 pmol/ L
PRA >50 ng/ml per h (NR 2.0–35.0)
CAUSES OF ADRENAL FAILURE
• Primary or secondary?
• Isolated or combined hormonal deficiency?
Infective Tuberculosis, sepsis, AIDS, fungal infections
Infarction and haemorrhage Adrenal infarction, Waterhouse–Friderichsen syndrome
Infiltrative Metastatic tumour, amyloid, lymphoma, haemochromatosis
Autoimmune Addison disease, autoimmune polyglandular syndromes
Iatrogenic Drugs, bilateral adrenalectomy
Metabolic Adrenoleukodystrophy, mitochondrial diseases, primary xanthomatosis
Inherited syndromes Congenital adrenal hyperplasia, adrenal hypoplasia congenita, triple A syndrome, familial glucocorticoid deficiency
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ADRENAL INSUFFICIENCY SYNDROMES
X-chromosomal Adrenal Hypoplasia – DAX1 (NR0B1)
Autosomal Adrenal Hypoplasia – Steroidogenic factor-1 (SF1;
NR5A1)
– Pena-Shokeir syndrome I
– Pseudotrisomy 13
– Meckel syndrome
– Phalister Hall (GLI3)
– IMAGE
ACTH resistance – FGD1, MC2R
– FGD2, MRAP
– Triple A (Algrove)
Metabolic Disorders – X-ALD
– Peroxisome Biogenesis Disorders
– Wolman Syndrome
– Smith-Lemli-Opitz
– Mitochondrial disorders
Autoimmune Disorders – Autoimmune Addisons
– APS1
– APS2
Secondary adrenal insufficiency – TPITX
– MPHD
ORGANOGENESIS OF ADRENAL AND GONADS
Fujieda K & Tajima T , 2005 Pediatr Res 57:62R-69R
DAX1 PROTEIN INTERACTIONS
Jadhav U et al., Mol Cell Endocrinol 2011 22;346:65-73
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DAX1 GENE LOCALISATION
Gene Disease
STS steroid sulfatase deficiency
HH hypogonadotropic hypogonadism
GKD glycerol kinase deficiency
DMD Duchenne muscular dystrophy
CGD chronic granulomatous disease
RP retinitis pigmentosa
OTC ornithine transcarbamylase deficiency
AR androgen receptor
ALD adrenoleucodystrophy
AHC adrenal hypoplasia congenita
DAX1 GENE AND DAX1 PROTEIN
- Coding sequence 1410 bp
- 2 exons, 1 intron (ca. 3 kb)
- Expression in hypothalamus, pituitary, gonads, adrenal, ES cells
- Nuclear hormone receptor
- N-terminal DNA bindung domain
- C-terminal ligand bindung domaine
- > 200 inactivating mutations
C
470
1 2
DAX1 gene
N E1
1 67 133 200 253 265 288
DAX1 protein
83
DBD LBD
DAX1 (NR0B1) MUTATIONS
Mutation type Number of mutations
Missense/nonsense 71
Splicing 1
Regulatory 0
Small deletions 48
Small insertions 24
Small indels 4
Gross deletions 8
Gross insertions/duplications 2
Complex rearrangements 3
Repeat variations 0
Get all mutations by type
Public total (HGMD Professional 2012.4 total)
161 (202)
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DAX1 – DIFFERENT ROLES
Nuclear receptor
• function as a transcriptional repressor
• particularly of pathways by other nuclear receptors, like SF1
Developmental factor
• Adrenal abnormality in transition of fetal to adult zone
• Precise role in adrenal morphogenesis is not fully understood
• ? important role in fetal adrenal regression rather directing zonation of adult adrenal gland
• ?related to its role in maintaining pluripotency (Niakan et al., 2006)
• DAX1 and SF1 expressed in subcapsular cortex
• Mature steroidogenic layers of the cortex express only SF1
• ? DAX1 maintains a progenitor pool whereas SF1 directs various stages of cell differentiation (Kim et al., 2009)
DAX1 – DIFFERENT ROLES
Developmental factor
• DAX1 is expressed in the VMH, Rathke’s pouch, and in the pituitary (Ikeda et al., 2001)
• ?Role in development of the pituitary and hypothalamus.
• HHG a combined/ variable deficiency of hypothalamic GnRH secretion and/or pituitary response
• Primary testicular failure and Sertoli cell failure
• First signs and symptoms: mineralocorticoid deficiency Salt loss
• Cortisol initially often normal in infants
• Diagnosis might be challenging Misdiagnosis: CAH (21OHD), CYP11B2 deficiency
• Variability of:
– Age of manifestation
– Degree of adrenocortical insuffiency
– Degree of hypogonadism
AHC – CLINICAL PRESENTATION
Family history of adrenal failure, unexplained deaths “sepsis”, pubertal abnormalities in male
relatives of a boy with adrenal failure suggests AHC
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AHC: GONADAL FUNCTION AND PUBERTY (1)
• Often cryptorchidism
• Often disordered puberty
• Normal function of HPG axis in first months with mini-puberty reported in few cases
• LH deficiency first described by Prader Prader et al., J Pediatr 1975, 86:421-422
• Hypogonadotrophic hypogonadism of hypothalamic and pituitary origin
• Primary hypogonadism due to impact on testicular developement
AHC: GONADAL FUNCTION AND PUBERTY(1)
• Induction of puberty by androgens, hCG, pulsatile GnRH therapy
• Progressive loss of testicular function indicated by decreases in testosterone and inhibin B levels Galeotti C et al., PLos One 2012;7(6):e39828
• Severe hypospermatogenesis
• First case of a child born after TESE–ICSI, with the sperm induced by gonadotrophin treatment, in a man with classic X-linked AHC due to a nonsense mutation in NR0B1/DAX1 Hum Reprod 2011 26: 724–728
Differential diagnosis – AH, Addisons
Infancy-Childhood Onset (n=88) Adult Onset (n=29)
46,XY male
46,XY underandrogenised
46,XX female
46,XY male
46,XX female
Patients 64 13 4 7 14 15
Median age (range)
10d (birth-13y)
7d (birth-2.5y)
10d (birth-3w)
2y (6d-6y)
29y (15-67y)
38y (28-70y)
Mutations
DAX1 37 0 0 0 0 0
SF1 0 0 2 0 0 0
Lin L. et al., JCEM 2006; 91: 3048–3054
Total of 117 individuals with primary adrenal failure
No Müllerian structures
Müllerian structures
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Boys (46,XY) with and without DAX1 mutations/deletions
Total cohort (46,XY boys)
DAX1 mutation detected
No mutation detected
Total number 64 37 (58%) 27 (42%)
Age at presentation
- early infancy 51 30 (59%) 21 (41%)
- childhood 13 7 (54%) 6 (46%)
Puberty/family history
- Prepubertal/No FH 44 20 (45%) 24 (55%)
- Prepubertal/FH 9 6 (67%) 3 (33%)
- HH/No FH 3 3 (100%) 0 (0%)
- HH/FH 8 8 (100%) 0 (0%)
Additional features 12 1 (8%) 11 (92%)
Transient/mild adrenal dysfunction
5 0 (0%) 5 (100%)
Hypogonadotropic hypogonadism (HH) Family history (FH) of adrenal failure or unexplained death Presence of additional clinical features (e.g. skeletal abnormalities, intrauterine growth retardation); and severity of adrenal dysfunction.
Lin L. et al., JCEM 2006; 91: 3048–3054
SF1 (NR5A2)
• Master regulator of reproduction
• Targets: – genes at every level of the HPG axis – most genes in gonadal and adrenal steroidogenesis
• Orphan nuclear receptor – No known ligand regulating SF-1-mediated transcription
(?sphingolipids)
• In most cases, functions cooperatively with other transcription factors to modulate the timing and level of gene expression
=> Regulation of many target genes differing widely in their expression patterns and regulation
SF1 (NR5A1) AND HUMAN DISEASE
Ferraz-de-Souza B et al., Mol Cell Endocrinol 2011 ;336:198-205
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SF1 (NR5A1) AND HUMAN DISEASE
• SF-1 mutations not commonly found in patients with adrenal failure
• Variations in SF-1 found in association with range of human reproductive phenotypes – 46,XY DSD
– Hypospadias, anorchia, male factor infertility,
– Primary ovarian insufficiency in women
• Overexpression/ overactivity of SF-1 reported in some adrenal tumours or endometriosis
PATIENT
• Male born at term, birth weight 2.8 kg • At birth intense generalised hyperpigmentation • Non-consanguineous Indian parents • Normal male genitalia • At 36 h of life, high fever, lethargy, poor feeding • Hypoglycaemic with blood glucose of 20 mg/dl • 4 further episodes of hypoglycaemia, 2x seizures
Investigations • U&E’s normal • Cortisol 0.22 μg/dl (NR 1.7–14) – flat SST • PRA 5.72 ng/ml per h (NR 2.0–35.0) • Aldo 97.9 ng/l (NR supine 10–160) • 17OHP 2 ng/ml; no rise after SST • ACTH 170 pg/ml (NR 10–50); 3 days on HC
• Adrenal glands MRI reported as bilaterally small Jain V et al., EJE 2011
Familial glucocorticoid deficiency type ?
FAMILIAL GLUCORTICOID DEFICIENCY - FGD
Biochemical • Very high plasma ACTH levels (difficult to suppress) • Low or undetectable cortisol • Normal RAAS (mild derangements at the time of diagnosis)
Clinical • Highly pigmented (early onset) • Some FGD type 1 may have tall stature • Absent adrenarche or delayed puberty
History • Consanguinity (not always observed) • Previous neonatal deaths or deaths in childhood due to infection • Onset of pigmentation is often very early • Jaundice and hypoglycaemic episodes in newborn period or childhood • Frequent infections, fits, seizures • Late presentation, can present with learning difficulties/ neurological symptoms
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PATIENT
Jain V et al., EJE 2011
Familial glucocorticoid deficiency type 2
Homozygous mutation c.106+2_3dupTA
in MRAP gene
FGD GENES AND PROTEINS MC2R
Mutations in about 25% of FGD
MRAP
Mutations in about 20% of FDG
FGD1 FGD2
• ACTH receptor • 297 aa G protein-coupled receptor • 7 transmembrane-spanning domains forming the ligand binding site
• Melanocortin-2 receptor accessory protein • 2 transcripts MRAPα (exons1–5)
MRAPβ (exons 1–4 and 6) • Differ only in the C-terminus • In humans 19 kDa and 11.5 kDa
MC2R AND MRAP
cAMP response
Nucleus ER
Mito
Zona fasciculata
• Protein folding & translocation across ER • Escorting MC2R to cell surface • Stabilising of MC2R at cell surface • Ligand specificity
MC2R MRAP
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FGD1 vs FGD2
• 40 patient with FGD1, 22 patients with FGD2 • FGD type 2 appears to present earlier • Tall stature associated with mutations in MC2R but not in MRAP • No other significant clinical distinctions between FGD1 and FGD2
Chung TTLL et al., Clin Endocrinol (2010) 72, 589–594
DISCOVERY OF NOVEL CAUSES
• SNP array genotyping using the GeneChip Human Mapping 10K Array Xba142 (Affymetrix) in nine probands from consanguineous families with FGD of unknown aetiology
• Targeted exome sequencing of the proband from one kindred with chromosome 5 linkage
Meimaridou E et al., Nat Genet. 2012 44:740-2.
NNT MUTATIONS IN 15 KINDREDS WITH FGD
Sequencing of NNT in 100 patients with unknown cause of FGD
Meimaridou E et al., Nat Genet. 2012 44:740-2.
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NNT MUTATIONS IN 15 KINDREDS WITH FGD
Sequencing of NNT in 100 patients with unknown cause of FGD
Meimaridou E et al., Nat Genet. 2012 44:740-2.
NNT FUNCTION
• Integral protein of the inner mitochondrial membrane
• NNT pumps protons across mitochondrial IMM
• Detoxification in mitochondria of ROS by glutathione peroxidases depends on NADPH for regeneration of reduced glutathione (GSH) from oxidized glutathione (GSSG) to maintain a high GSH/GSSG ratio
NNT - NICOTINAMIDE NUCLEOTIODE TRANSAMINASE
• Antioxidant defence protein
• Widely expressed in humans, most readily detectable in adrenal, heart, kidney, thyroid, adipose tissue
• Mice with nnt loss – Higher levels of adrenocortical cell apoptosis
– Impaired glucocorticoid production
• NNT knockdown in human H295R cells – Impaired redox potential
– Increased reactive oxygen species (ROS) levels
• Affected individuals may develop other organ pathologies related to impaired antioxidant defence
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MCM4 – CLINICAL PRESENTATION
Hughes CR at al., J Clin Invest 2012 122:814-20
• Genetically isolated Irish population, 3 families • Hypocortisolaemia, milder than in other FGD forms • Growth failure • Increased chromosome breakage • NK cell deficiency, only 1 patient increased infections
MCM4 FAMILIES
• Targeted exome sequencing in 8 patients from 3 families
• c.71-1insG in minichromosome maintenance–deficient 4 (MCM4)
• Predicted severely truncated protein (p.Pro24ArgfsX4)
Hughes CR at al., J Clin Invest 2012 122:814-20
Mcm4-DEPLETED MICE
• Histologically abnormal adrenal morphology
• Non-steroidogenic GATA4- and Gli1-positive cells within steroidogenic cortex
• Reduced number of steroidogenic cells in zona fasciculata of adrenal cortex
Hughes CR at al., J Clin Invest 2012 122:814-20
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MCM4
• Component of the MCM2-7 complex
• Part of pre-replication complex
• Licenses origins for DNA synthesis in the S phase
• New DNA replication disorder
• Patients might have an increased risk of neoplasia
PATIENT i1
Vilain et al., 1999 J Clin Endocrinol Metab
PATIENT i2
Vilain et al., 1999 J Clin Endocrinol Metab
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PATIENT i3
Vilain et al., 1999 J Clin Endocrinol Metab
IMAGe SYNDROME – FIRST PATIENTS
Vilain et al., 1999 J Clin Endocrinol Metab
Intrauterine growth retardation Metaphyseal dysplasia Adrenal hypoplasia congenita
Genital anomalies
INDEX FAMILY
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IMAGe SYNDROME – THE GENETIC CAUSE
Arboleda VA, et al., Nat Genet. 2012 44:788-92
• Targeted exon array capture of the disease locus • High-throughput genomic sequencing • Validation by dideoxy sequencing (Sanger) • Missense mutations in imprinted gene CDKN1C (P57KIP2) • In two familial and four unrelated patients • Familial analysis an imprinted mode of inheritance, maternal transmission
CDKN1C GENE MUTATATIONS CAUSE IMAGe SYNDROME
Arboleda VA, et al., Nat Genet. 2012 44:788-92
• Five heterozygous missense mutations in CDKN1C • Cluster within six amino acids of PCNA-binding domain • All variants localized to a highly conserved region
CDKN1C FUNCTION
• Inhibits cell-cycle progression
• Located in imprinted cluster of genes regulating prenatal and postnatal growth and development
• Paternal allele repressed by distant imprinting control regions
• Expression primarily from maternal allele
• Inheritance of IMAGe syndrome in family A only through maternal transmission of CDKN1C mutation
• In vitro and in vivo BWS mutants different effects relative to IMAGe mutants
• Domain-specific mutations differential effects on cell-cycle progression and developmental processes
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SUMMARY
• DAX1 mutations not commonly associated with DSD
• SF1 mutation not common cause for PAI
• Recent definition of novel syndromes associated with adrenal insufficiency
• Important due to high risk of potential comorbidities
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