Wit JM, Ranke MB, Kelnar CJH (eds): ESPE classification of paediatric endocrine diagnosis. 8. Adrenal disorders. Horm Res 2007;68(suppl 2):55 57

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1 Wit JM, Ranke MB, Kelnar CJH (eds): ESPE classification of paediatric endocrine diagnosis. 8. Adrenal disorders. Horm Res 2007;68(suppl 2):55 57 ESPE Code Diagnosis OMIM ICD10 8 ADRENAL DISORDERS 8A PRIMARY ADRENAL INSUFFICIENCY # A.1 Congenital adrenal hyperplasia (CAH) E25 8A.1a Cholesterol side-chain cleavage deficiency (lipoid CAH) E25.0 (P450scc) 1 8A.1b 3beta-Hydroxysteroid dehydrogenase deficiency * A.1c 21-Hydroxylase deficiency (P450c21) E25.0 8A.1c.1 Salt-wasting 21-OHD 4 8A.1c.2 Simple virlising 21-OHD 5 8A.1c.3 Non-classical 21-OHD 6 8A.1d 11beta-Hydroxylase deficiency 7 # E25.0 8A.1e P450c11AS deficiency * E25.0 8A.1e.1 Corticosterone methyl oxidase deficiency type I 8 E25.0 8A.1e.2 Corticosterone methyl oxidase deficiency type II 9 E25.0 8A.1e.3 Glucocorticoid suppressible hypertension 10 # E25.0 8A.1f 17alpha-Hydroxylase/17/20 lyase deficiency 11 # E25.0 8A.1g P450 oxidoreductase deficiency (may be part of Antley Bixler congenital malformation syndrome) 12 # E25.0 8A.1h Glucocorticoid receptor defect E25.0 8A.1z Other disorders, unspecified E25.9 8A.2 Other causes of adrenal insufficiency 8A.2a Congenital adrenal hypoplasia # Q89.1 8A.2a.1 DAX-1 (NROB1) mutation 14 (also classified as 6A.3a.2 if combined with hypogonadotrophic hypogonadism) 8A.2a.2 Idiopathic 8A.2b Adrenoleukodystrophy (Schilder s disease) and # E71.3 adrenomyeloneuropathy 15 8A.2c Primary xanthomatosis (Wolman s disease) Q89.1 8A.2d Familial glucocorticoid deficiency (ACTH insensitivity, hereditary # Q89.1 unresponsiveness to ACTH) 17 8A.2e Triple A (Allgrove) syndrome 18 # Q89.1 8A.2f Pseudohypoaldosteronism, type 1 19 # Q89.1 8A.2z Other syndromes, unspecified Q89.1 E25.0 8A.3 Autoimmune adrenalitis (Addison s disease) 20 E27.1 Adrenal Disorders 55

2 ESPE Code Diagnosis OMIM ICD10 8A.3a 8A.3b Disorders classified elsewhere: Part of autoimmune polyglandular syndromes: Type 1 classified as 14C.4a Type 2 classified as 14C.4b Other types (see 14C.4c, d and e) Part of Steinert syndrome (14B.35) Isolated 8A.4 Infections E27.8 8A.4a Tuberculosis 21 A18.7, E35.1 8A.4b Fungal infections 22 E27.4 8A.4c Bacterial sepsis 23 E27.4 8A.4d AIDS 24 E27.4 8A.4y Other specified infections 8A.5 Haemorrhage 8A.5a Associated with meningococcal infection (Waterhouse-Friedrichsen syndrome) 25 A39.1, E35.1 8A.5y Other specified causes 26 E27.4 8A.5z Idiopathic E27.4 8A.9 Idiopathic E27.4 8B SECONDARY ADRENAL INSUFFICIENCY Classified elsewhere: 6A.1 8C ADRENAL EXCESS 8C.1 Glucocorticoid excess (Cushing syndrome) 27 [primary] E24 [secondary 14C.1] 8C.1a Caused by ACTH excess E24.0 8C.1a.1 Cushing s disease (ACTH-producing pituitary adenoma) E24.0 8C.1a.2 CRF excess 29 E24.3 8C.1a.3 Ectopic ACTH syndrome 30 E24.3 8C.1b Increased peripheral glucocorticoid production E24.8 8C.1b.1 ACTH-independent macronodular adrenal hyperplasia # E24.8 8C.1b.2 Multinodular adrenal hyperplasia, isolated or as part of the # E24.8 Carney complex 31 8C.1b.3 Adrenal adenoma 32 E24.8 ESPE Classification of Paediatric Endocrine Diagnoses 56

3 ESPE Code Diagnosis OMIM ICD10 8C.1b.4 Adrenal carcinoma 33 E24.8 8C.1c Glucocorticoids from other sources E24.8 8C.1c.1 Iatrogenic Cushing syndrome 34 E24.2 8C.1c.z Other E24.2 8C.2 Virilising and feminising adrenal tumours 35 8C.3 Mineralocorticoid excess E26.0 8C.3a Conn syndrome 36 E26.0 8C.3b Substances with mineralocorticoid action (liquorice) 37 E26.0 8D DISORDERS OF THE ADRENAL MEDULLA 8D.1 Adrenal medulla defect 8D.1a Haemorrhage A39.1, E35.1 8D.1b Infection E35.1 8D.1c Tumour E35.1 8D.1z Idiopathic E35.1 8D.2 Primary tumour in adrenal medulla 8D.2a Phaeochromocytoma 38 M8700/0 8D.2b Neuroblastoma 39 M9500/3 1 Cholesterol side-chain cleavage deficiency (congenital lipoid adrenal hyperplasia; P450scc) Phenotype: Deficiency of all gonadal and adrenal steroid hormones including progesterone, which is required to maintain normal pregnancy. Rare cases survive untreated for several years. Life-threatening adrenal insufficiency and sex reversal in 46,XY individuals. Comments: Disruption of the P450 side-chain cleavage enzyme. Autosomal-recessive mutations of the CYP11A1 gene. Heterozygous carriers are healthy and fertile. 2 3beta-Hydroxysteroid dehydrogenase deficiency Phenotype: Various degrees of salt wasting, premature pubarche and hirsutism in girls and incomplete masculinisation in boys, growth acceleration, advanced bone age. Heterogenous clinical presentation. 17alpha-OHP ( ), DHEAS (+), 17alpha-hydroxypregnenolone (+). Comments: Mutations in the type II 3beta-HSD gene. Wide spectrum of mutations associated with different phenotypic manifestations Hydroxylase deficiency (P450c21) (21-OHD) Comment: Most common cause of congenital adrenal hyperplasia. Adrenal Disorders 57

4 4 Salt-wasting 21-OHD Phenotype: Most severe form of CAH with total deficiency of enzymes of cortisol and aldosterone biosynthesis. In female newborns masculinised external genitalia (ambiguous genitalia with clitoral enlargement and urogenital sinus). Life-threatening salt wasting crises, Na ( ), K (+), cortisol ( ), ACTH (+), 17OHP (+), androstenedione (+). Accelerated growth and advanced bone age, peripheral precocious puberty, early epiphyseal closure and reduced final height. Comments: CYP21 gene deletion/conversion that totally ablates enzyme activity. Approximately 30% of CAH cases. Autosomal-recessive inheritance. 5 Simple virilising 21-OHD Phenotype: Milder form of CAH without salt wasting crisis, adequate aldosterone synthesis. Comment: Mutations in the CYP21 gene with 1 2% of normal enzyme activity, mainly I172N mutations. 6 Non-classical 21-OHD (late onset CAH) Phenotype: Symptoms of hirsutism and early pubertal onset, advanced bone age. Comment: Mildest form of CAH with 20 to 60% of enzyme activity, e.g. V281L and P30L mutations. In compound heterozygous forms of CAH the milder defect predicts the phenotype. 7 11beta-Hydroxylase deficiency (P450c11) Phenotype: Androgen excess and hypertension. In females ambiguous genitalia, virilisation, clitoromegaly. Accelerated growth, advanced bone age. Mineralocorticoid excess, sodium retention, volume expansion. Cortisol ( ), ACTH (+), deoxycortisol (+), deoxycorticosterone (+), PRA ( ), aldosterone ( ), androgens (+). Comments: Second most common form of CAH. Mutations in CYP11B1 gene. Autosomal recessive. 8 Corticosterone methyl oxidase deficiency type I Phenotype: Caused by disorders of P450c11AS, the isoenzyme of P450c11, that is exclusively expressed in the zona glomerulosa. Aldosterone ( ), 18-OH corticosterone ( ), corticosterone (+), ACTH (+), cortisol (N). Comment: Autosomal-recessive inheritance. 9 Corticosterone methyl oxidase deficiency type II (aldosterone synthase deficiency) Phenotype: Congenital hypoaldosteronism, life-threatening salt loss, failure to thrive. Na ( ), K (+), aldosterone ( ), renin (+), cortisol (N). Comment: Mutations in the CYP11B2 gene encoding aldosterone synthase (P450c11Aldo), under control of the renin-angiotensin system. Autosomal-recessive inheritance. 10 Glucocorticoid suppressible hypertension (glucocorticoid remediable aldosteronism, GRA) Phenotype: Hypertension of variable degree, familial hyperaldosteronism type I. Aldosterone (+), ACTH (+). Only partial suppression of ACTH by glucocorticoids required for correction of hypertension. Comment: ACTH-regulated hybrid CYP11B1/CYP11B2 gene. ESPE Classification of Paediatric Endocrine Diagnoses 58

5 11 17alpha-Hydroxylase/17/20 lyase deficiency (P450c17) Phenotype: Hypertension, undervirilised genitalia in males, lack of pubertal development, salt retention. Cortisol ( ), ACTH (+), deoxycorticosterone (+), T ( ), estrogens ( ), renin ( ), K ( ), alkalosis. Comment: Mutations in CYP17 gene, autosomal recessive. 12 P450 oxidoreductase deficiency (may be part of Antley Bixler syndrome) Phenotype: Skeletal defects like craniosynostosis and radiohumeral synostosis, ambiguous genitalia. In addition, cytochrome P450 enzymes affected and abnormalities in steroidogenesis (17alphahydroxylase, 17,20-lyase, 21-hydroxylase). Cortisol ( ), 17OHP (+), adrenal androgens ( ). Comments: Mutations of POR gene encoding NADPH: cytochrome P450 oxidoreductase (CYPOR) in patients with Antley Bixler syndrome. Mutations in FGFR2 gene in some patients described. 13 Glucocorticoid receptor defect Phenotype: Hirsutism, fatigue, menstrual disorders, obesity, hypokalaemic hypertension. Cortisol (+), adrenal androgens (+), ACTH (+). Comments: Mutations in the glucocorticoid receptor gene. 14 DAX-1 mutation (familial hypogonadotrophic hypogonadism and adrenal hypoplasia congenita) Phenotype: X-linked congenital adrenal hypoplasia and lack of pubertal development, abnormalities in spermatogenesis. Variable clinical presentation; in female carriers delayed puberty. LH ( ), FSH ( ), T ( ), glucocorticoid and mineralocorticoid deficiency. Comments: Deletion or mutation of the NROB1 (DAX1) gene, encoding DAX1, an orphan nuclear receptor. DAX1 expression has been shown in regions of the hypothalamo/pituitary/adrenal/gonadal axis. 15 Adrenoleukodystrophy and adrenomyeloneuropathy (X-ALD) Phenotype: Inherited neurometabolic disease associated with demyelination of the central nervous system, adrenal insufficiency, and accumulation of very long chain fatty acids in plasma and tissues. Clinically heterogeneous disorder ranging from severe childhood cerebral form to asymptomatic persons. Adrenomyeloneuropathy and adrenoleukodystrophy are different presentations of the same single gene disorder. Frequently associated with adrenal insufficiency (Addison s disease) which may remain the only clinical expression of ALD. Comment: Mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein. 16 Primary xanthomatosis (Wolman s disease) Phenotype: Rapidly fatal lysosomal storage disease caused by complete absence of lysosomal acid lipase activity. Failure to thrive, anaemia, hepatomegaly, enlarged and calcified adrenal glands and decreased cortisol secretion develop during the first months of life. Successful cure by umbilical cord stem cell transplantation has been reported. Comments: Autosomal-recessive inheritance. Gene encoding lysosomal acid lipase deficiency mapped to chromosome 10q23.2-q23.3. Adrenal Disorders 59

6 17 Familial glucocorticoid resistance Phenotype: Partial end-organ resistance to glucocorticoids; variable phenotype from asymptomatic to severe hyperandrogenism (sex reversal in females), fatigue and/or mineralocorticoid excess, hypertension. Cortisol (+), ACTH (+), mineralocorticoids (+), androgens (+). Comment: Mutations in the glucocorticoid receptor-alpha (hgralpha) which impair normal glucocorticoid signal transduction, familial and sporadic cases. 18 Triple A (Allgrove) syndrome Phenotype: Rare autosomal-recessive disorder characterised by ACTH-resistant adrenal failure, achalasia, alacrimia and a progressive neurological syndrome. Genotype/phenotype analysis shows high variability in occurrence, age of onset and severity of clinical symptoms even in patients with the same mutations. Comment: Mutations in the AAA gene which encodes the ALADIN protein. 19 Pseudohypoaldosteronism type 1 Phenotype: Severe salt loss by a defect in one of the subunits of the epithelial sodium channel (autosomal recessive). An autosomal-dominant form is caused by a defect in the mineralocorticoid receptor gene NR3C2. 20 Autoimmune adrenalitis (Addison s disease) Phenotype: Weakness, fatigue, weight loss, hyperpigmentation of the skin and/or mucosae, anorexia, vomiting, hypotension, hypoglycaemia. Glucocorticoid and mineralocorticoid deficiency. ACTH (+), PRA (+). May be associated with other autoimmune diseases (Hashimoto s thyroiditis, coeliac disease, etc., autoimmune polyglandular diesease, Schmidt syndrome). Comment: Adrenal autoantibodies may be transferred transplacentally from an affected mother to the baby. 21 Tuberculosis Phenotype: Impairment of adrenal function may occur in active tuberculosis. Also primary adrenal tuberculosis. Comment: Rifampicin treatment has an effect on adrenal steroid metabolism. 22 Fungal infections Phenotype: Histoplasmosis or coccidiomycosis may cause Addison s disease. 23 Bacterial sepsis Phenotype: Adrenal crisis may occur during an acute meningococcal, pneumococcal, streptococcal or Haemophilus infection. Waterhouse-Friderichsen syndrome in meningococcal sepsis with meningitis: massive adrenal haemorrhage with very poor prognosis. 24 AIDS Phenotype: High incidence of adrenal insufficiency in critically ill HIV patients. ESPE Classification of Paediatric Endocrine Diagnoses 60

7 25 Associated with meningococcal infection (Waterhouse- Friderichsen syndrome) Phenotype: Acute adrenal insufficiency occurring with meningococcaemia. High fever, circulatory collapse, skin haemorrhage, subcapsular adrenal haemorrage. Very high mortality. 26 Haemorrhage other specified causes Phenotype: Adrenal haemorrhage of the newborn may occur after prolonged labour and traumatic delivery. Acute shock, hypoglycaemia, hyponatraemia, hyperkalaemia, acidosis. 27 Glucocorticoid excess (Cushing syndrome) Phenotype: Truncal obesity and moon facies, acne, hypertension, striae, loss of muscle mass, decreased growth velocity, emotional instability. Cortisol (+), androgens (+), estrogens (N/+), aldosterone (+), ACTH (+/N/ ). Elevated blood glucose, hyperlipidaemia, insulin-resistant diabetes. Comment: Symptoms of hypercortisolism are similar whatever its cause. 28 Cushing s disease (ACTH-producing pituitary adenoma) Phenotype: See 8C.1. ACTH (+), cortisol (+), adrenal androgens (+), urinary 17-hydroxycorticosteroid (+), urinary free cortisol (+). ACTH and cortisol response to CRH stimulation and suppression to dexamethasone indicates pituitary-dependent disease. MRI of the brain, eventually with sinus petrosus sampling for exact localisation of the tumour. May occur as a rare manifestation of MEN1. 29 CRF excess Phenotype: See 8C.1. ACTH (+), cortisol (+). Ectopic tumors secreting CRH (e.g. phaeochromocytoma, ganglioneuroblastoma). Most CRH-producing tumours also secrete ACTH. 30 Ectopic ACTH syndrome (EAS) Phenotype: See 8C.1. Ectopic, nonpituitary ACTH secretion. ACTH (+), cortisol (+). Dynamic tests not very reliable. Bilateral inferior sinus petrosus sampling shows absent central gradient. Imaging discovers 2/3 of cases. Bronchial carcinoid, neuroendocrine tumors, gastrinomas, etc. In 20% no source of EAS detectable. 31 Multinodular adrenal hyperplasia, isolated or as part of the Carney complex. Phenotype: Primary adrenocortical hyperplasias leading to Cushing syndrome include primary pigmented nodular adrenocortical disease and ACTH-independent macronodular adrenal hyperplasia. Carney complex is a familial multiple endocrine neoplasia syndrome characterised by spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas. Cortisol (+), ACTH ( ), impaired response to CRH stimulation and dexamethasone suppression. Comments: Carney complex inherits autosomal dominant. Mutations in the PRKAR1A gene coding for protein kinase A. Somatic mutations in adrenal neoplasms. 32 Adrenal adenoma Phenotype: See 8C.1. Autonomous production of cortisol by an adrenal adenoma. Cortisol (+), adrenal androgens (+), ACTH ( ). No response of ACTH and cortisol to CRH stimulation and dexamethasone suppression. Comment: Adrenal masses may be detected incidentally by imaging procedures (incidentaloma), approximately 10% produce glucocorticoids. Adrenal Disorders 61

8 33 Adrenal carcinoma Phenotype: See 8C.1. Hormonally active tumours. Cortisol (+), ACTH ( ). 34 Iatrogenic Cushing syndrome Phenotype: See 8C.1. Oral, parenteral, inhaled, topical or intra-articular administration of glucocorticoids causes Cushing syndrome in a dose-dependent manner. Adrenal suppression, osteoporosis, growth retardation. Cortisol (+ or ), ACTH ( ). 35 Virilising and feminising adrenal tumours Phenotype: Virilising tumours: peripheral precocious puberty, virilisation, accelerated growth. T (+), cortisol (N/+). LH, FSH (N), but no response to LHRH stimulation. Diagnostic imaging. Adenoma or carcinoma. Feminising tumours: peripheral precocious puberty, gynaecomastia in boys. E2 (+), unresponsiveness of LH and FSH to GnRH stimulation. 36 Conn syndrome (primary hyperaldosteronism) Phenotype: Hypertension, pollakisuria, muscular weakness, tetany. Na (+), K (N/ ), metabolic alkalosis. Aldosterone (+), renin ( ). Primary aldosteronism is caused by bilateral hyperplasia in 2/3 cases and by aldosterone-producing adenoma in 1/3. Imaging and adrenal vein sampling to distinguish unilateral and bilateral adrenal aldosterone production. Comment: Subtype of glucocorticoid-suppressible aldosteronism. Elevated aldosterone synthase which increases 18-hydroxycortisol in plasma. See 8A.1e Substances with mineralocorticoid action (liquorice) Phenotype: Hypertension, hypokalaemia, aldosterone ( ), renin ( ). Liquorice contains glycyrrhizic acid, which inhibits 11 -hydroxysteroid dehydrogenase activity. 38 Phaeochromocytoma Phenotype: Hypertension, sweating, headache, palpitations, weight loss, polyuria, pallor/flushing. Epinephrine (+), norepinephrine (+) in plasma and urine. Imaging procedures for exact localisation, 90% from adrenomedullary tissue, <10% malignant. Frequently familial. 39 Neuroblastoma Phenotype: Hypertension and flushing are found rarely. Symptoms and signs depend largely on size and localisation of the tumour and whether it has metastasised (lymph nodes, liver, skin, bone, bone marrow). Excretion of catecholamines (+), dopamine (+), vanillylmandelic acid (+). Localisation by imaging procedures. High rate of spontaneous regression. Mainly in children <5 years. Comments: Several chromosomal loci show loss of heterozygosity, indicative of a tumour suppressor gene. Gain of the long arm of chromosome 17q is the most frequent chromosomal abnor mality. ESPE Classification of Paediatric Endocrine Diagnoses 62