rare causes of adrenal failure -...

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Rare causes of adrenal failure

Nils Krone MD FRCPCH [email protected]

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

mailto:[email protected]

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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)

http://www.biobase-international.com/product/hgmd

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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


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NNT MUTATIONS IN 15 KINDREDS WITH FGD

Sequencing of NNT in 100 patients with unknown cause of FGD


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)


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


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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


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PATIENT i3


IMAGe SYNDROME – FIRST PATIENTS


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

rare causes of adrenal failure -...

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