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The importance of testing for adrenoleucodystrophy inmales with idiopathic Addison’s disease M D Ronghe, J Barton, P E Jardine, E C Crowne, M H Webster, M Armitage, J T Allen,C G Steward. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
X linked adrenoleucodystrophy (X-ALD) is considered to be a rare cause of Addison’s disease, although several small series suggest a high incidence in young Addisonian males. A survey in the south west of . . . . . . . . . . . . . . . . . . . . . . .
England identified 12 male patients diagnosed with Addison’s disease in the period 1987–99. In 10 of these (83%) X-ALD was the underlying cause; the other two were of autoimmune aetiology. Five boys had developed Addison’s disease subsequent to the diagnosis of X-ALD. Of the remaining five, in three boys the diagnosis of X-ALD was considerably delayed (by six months to two years from that of Addi- Children, Upper MaudlinStreet, Bristol BS2 8BJ, UK; son’s disease) and in two it was only made as a result of this survey. We also identified a patient who presented with Addison’s disease at the age of 5 years but was only diagnosed as having X-ALD at theage of 34 years; in the interim his diagnosis of adrenomyeloneuropathy had been missed. Our experi- ence highlights the absolute necessity of measuring very long chain fatty acids in all males with idio- . . . . . . . . . . . . . . . . . . . . . . .
ThetermXlinkedadrenoleucodystrophy(X-ALD)denotes whenhedevelopedbehaviouralproblemsandschoolfailure a group of diseases caused by defects in the ALD gene at (patient A in table 2). We subsequently performed a search of Xq28, which encodes a peroxisomal ATP binding cassette the diagnostic index at the Royal Hospital for Sick Children, transporter protein.1 Gene defects result in an extremely vari- Bristol and sent a questionnaire to paediatricians and able phenotype (see table 1), including a presymptomatic endocrinologists throughout the south west of England form, isolated adrenal insufficiency, devastating childhood asking for notification of previous cases of Addison’s disease in cerebral ALD (C-ALD), adult C-ALD, and adrenomyeloneu- boys aged less than 16 years. Children with established ropathy (AMN)—a disease causing spastic paraparesis and aetiology (such as multiple endocrine deficiencies caused by peripheral neuropathy in the second decade or beyond and autoimmune disease or autoimmune polyendocrinopathy leading to progressive impairment and early death. Despite candidiasis ectodermal dystrophy) were excluded.
this array of subtypes and identification of at least 200 differ- The diagnosis of primary adrenal failure was made on the ent mutations, there appears to be no phenotype/genotype basis of raised basal adrenocorticotrophic hormone (ACTH) concentrations, together with a subnormal cortisol response The tissues and body fluids of patients with X-ALD contain to a standard Synacthen test. A standard dose of 250 µg of abnormally high concentrations of unbranched saturated very synthetic ACTH was administered and a peak cortisol value of long chain fatty acids (VLCFA), particularly hexacosanoic acid less than 500 nmol/l indicated adrenal insufficiency.
(C26:0) and tetracosanoic acid (C24:0). This excess is moststriking in the cholesterol ester and ganglioside fractions of affected brain white matter and adrenal cortex, but is present Serum cortisol concentrations were estimated using quantita- to varying degrees in virtually all tissues and body fluids.1 tive sequential immunometric assay on the Immulite 2000 Diagnosis is made on the basis of raised concentrations of analyser. Serum ACTH concentrations were measured on the VLCFA in plasma and/or cultured skin fibroblasts.1–3 Nichols Advantage by a two site chemiluminescence immu- Adrenocortical insufficiency is present in at least 50% of noassay, utilising one mouse monoclonal antibody and a goat patients with C-ALD/AMN, but may be the only clinical mani- polyclonal antibody. Plasma renin activity was measured festation of X-ALD in up to 10% of cases. As a consequence of using radioimmunoassay following generation of angiotensin the rarity of X-ALD (minimum incidence of approximately 1 I formed after incubation of plasma at 37°C for three hours in in 20 000 white males1), this disease only accounts for a small the presence of angiotensin converting enzyme inhibitor.
proportion of all cases of adrenal insufficiency. However, it has Plasma concentrations of VLCFA were measured by recently been recognised in high frequency in young males capillary gas chromatography–mass spectrometry in the with idiopathic Addison’s disease; representative series report regional laboratory. The reference range for C26 was 0.33–1.39 5/8 boys,4 and 2/2,5 4/12,6 5/14,7 and 5/248 adolescent or adult µmol/l; ranges for coefficients C26/C22 and C24/C22 were 0–0.03 and 0.32–0.90 respectively.
In order to both emphasise and extend these observations we report our findings in the only 12 boys in whom Addison’s disease has been diagnosed in the south west of England since In addition to the index patient, our enquiry revealed 11 other 1987. Ten of these boys were affected by X-ALD.
boys with Addison’s disease and a 34 year old man who had . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
This study was prompted by a child who had presented with Abbreviations: ACTH, adrenocorticotrophic hormone; ALD, Addisonian crisis in response to pneumonia but whose under- adrenoleucodystrophy; AMN, adrenomyeloneuropathy; C-ALD, cerebral lying diagnosis of cerebral ALD was only made two years later ALD; VLCFA, very long chain fatty acid; X-ALD, X linked ALD Diminishes with ageCommon <4 yearsVery rare >40 years presented to paediatric care with Addison’s disease at the age disease to that of X-ALD ranged from 6 months to 29 years in of 5 years. Of these 12 patients, none had idiopathic disease; two had autoimmune disease proven by positive adrenal Assay of VLCFA in plasma is the most frequently used test autoantibodies, and the remaining 10 all had elevation of for diagnosis of X-ALD and is accurate in almost all cases. No VLCFA, diagnostic of underlying X-ALD.
false negative results were documented in the largest series Table 2 gives clinical and biochemical data on the six which included samples from more than 30 000 individuals patients with X-ALD (including the index case) presenting analysed at the Kennedy Krieger Institute.1 However, two false with Addison’s disease; table 3 presents the remaining five negative plasma VLCFA assays have been reported.2 3 In both patients with X-ALD who went on to develop Addison’s these cases the diagnosis of X-ALD was subsequently disease later in their disease course.
confirmed by assays of VLCFA concentrations in cultured skin In addition to a subnormal response to a standard fibroblasts. Hence in patients with a high index of suspicion Synacthen test, ACTH concentrations were raised in each boy but normal or borderline plasma VLCFA, concentrations studied (see tables 2 and 3), indicating primary adrenocortical should also be measured in the cultured skin fibroblasts before insufficiency. The reference range of ACTH used was 5–36 ng/l.
excluding the diagnosis of X-ALD, and a close interaction In addition, renin activity was measured; the reference range between clinicians and the laboratory is of utmost import- Of the 10 patients identified by the survey, five had The current study does not purport to be free of ascertain- Addison’s disease as their initial presentation, but in only one ment bias, perhaps the best example being inclusion of an case was a prompt diagnosis of biochemical ALD made adult patient originally diagnosed with Addison’s disease in because of physician awareness (patient B). Of the remaining 1968. However, as a result of the comprehensive tertiary refer- four boys, two were diagnosed only as a consequence of this ral service maintained in South West England it is most study, another because his mother requested a test on the unlikely that any boys presenting with Addison’s disease in basis of a previous family history (when her son became Add- the past decade would have been missed. The finding that 11 isonian at 9 years of age), and the fourth 29 years after his ini- of 13 paediatric presentations of Addison’s disease were tial presentation with Addison’s disease. This last patient had caused by underlying X-ALD is also consistent with the only undergone bladder neck excision for presumed outflow tract previous paediatric series, where 5/8 boys with Addison’s dis- obstruction, but his underlying diagnosis of AMN was only appreciated when he developed paresthesiae and gait prob- Although accurate diagnosis of X-ALD does not affect the lems during convalescence from surgery.
management of endocrine problems in the index case, it opens The remaining five had developed Addison’s disease after a the possibility of therapy before the onset of overt neurologi- primary diagnosis of X-ALD. Two of these five developed cal disease. Neurological manifestations of X-ALD range from Addison’s disease subsequent to an initial diagnosis of severe devastating leucoencephalopathy (fig 1 shows a magnetic C-ALD (one had a previous family history of C-ALD in a cousin resonance imaging (MRI) scan in the index case) within the and could have been screened three years previously, although first decade to spastic paraparesis or psychiatric presentations this had not been offered). The remaining three had a diagno- in later adult life; all may occur within the same family. It is sis of biochemical ALD (raised VLCFA but no other indicator of thought that neurological disease will develop in up to 90% of disease); these patients had all been diagnosed because of a patients with the biochemical defect of X-ALD. In the current preceding family history of ALD/AMN. In these five patients, series, although the median follow up is only 5 years, only four the interval between the diagnosis of biochemical ALD or of the 11 males remain completely free of radiological or clini- C-ALD and the onset of adrenocortical insufficiency ranged cal signs of this disease. It must be remembered that the delay from six months to five years (see table 3).
from onset of adrenal insufficiency to the development ofneurological disability is highly variable and may be as long as32 years.12 This is exemplified by patient F in whom Addison’s disease was diagnosed almost 30 years before developing X-ALD is described as a “rare” cause of Addison’s disease in the current editions of the Oxford textbook of medicine and Harri- Current therapeutic choices lie between dietary therapy son’s principles of internal medicine, and an “uncommon (including Lorenzo’s Oil) for those with presymptomatic association” in Forfar and Arneil’s textbook of paediatrics.9–11 This is disease and bone marrow transplantation for those with early largely a consequence of the majority of cases being females with autoimmune disease or patients with tuberculosis. How- C-ALD.12–15 Benefit from the latter appears to rely on slow ever, in the small subset of patients who are young and male, replacement of CNS microglial cells with cells of donor origin, we believe these statements to be dangerously misleading and since these arise from the bone marrow. As the childhood cer- likely to result in recurrent late diagnosis of X-ALD. This com- ebral form of this disease usually progresses rapidly over 6–18 promises the management of both patients and their extended months, it is imperative to identify patients at a presympto- families. In this series, delay from the diagnosis of Addison’s matic stage. Careful monitoring can then be conducted, Summary of clinical and laboratory data in patients with X-ALD presenting with Addison’s disease uncle who developedAddison’s disease at11 y, AMN at 39 y,died at 42 y) obstruction,parasthaesia and gaitproblems *Age at diagnosis of Addison’s disease.
FTT, failure to thrive.
Reference ranges: ACTH, 5–36 ng/l; renin, 0.5–3.1 pmol/ml/h; C26, 0.33–1.39 µmol/l.
MRI scan of brain, showing diffuse high signal abnormalities in the periventricular white matter of both parietal and occipital lobes (marked by arrows) in an advanced case of allowing patients who are developing cerebral ALD to be referred for bone marrow transplantation before overt neuro- logical involvement. More recently lovastatin and sodiumphenylacetate have been shown to lower VLCFA in cultured skin fibroblasts, although their therapeutic potential remainsunclear.16 Of equal importance to these therapeutic considerations are the implications for the patient’s extended family. The identi- fication of X-ALD in a family allows screening of other malerelatives who may be at risk for developing Addison’s disease or neurological complications. In addition to providing the option of early treatment, this may avoid deaths in affected males—at least 10 patients are known to have died of Addiso- nian crisis secondary to X-ALD, some of whom were free of neurological disease.1 Similarly, carrier females may develop milder neurological problems such as spastic paraparesis (although curiously Addison’s disease is extremely rare in Most importantly, early diagnosis brings the possibility of genetic counselling, carrier detection, and antenatal diagno- sis, and so the potential for radically reducing the incidence of this devastating disease. For this reason above all, assessment of plasma VLCFA concentrations should be regarded as man- datory in the investigation of males with unexplained We gratefully acknowledge the support of the COGENT Trust; Drs Julian Pleydell-Pearce and Sunil Pullaperuma, who kindly provided patient details; and Drs Charles Pennock and Janet Stone for manyhelpful biochemical discussions.
Adrenoleucodystrophy in Addison’s disease . . . . . . . . . . . . . . . . . . . . .
6 Schafer JR, Ehlenz K, Steinmetz A, et al. Adrenomyeloneuropathy. A frequent cause of Addison’s disease. Dtsch Med Wochenschr M D Ronghe, C G Steward, Department of Haematology/Oncology, 7 Laureti S, Casucci G, Santeusanio F, et al. X-linked Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ, UK adrenoleukodystrophy is a frequent cause of idiopathic Addison’s P E Jardine, Department of Neurology, Royal Hospital for Children disease in young adult male patients. J Clin Endocrinol Metab E C Crowne, Department of Endocrinology, Royal Hospital for Children J Barton, Department of Paediatrics, Royal Gwent Hospital, Cardiff 8 Jorge P, Quelhas D, Oliveira P, et al. X-linked adrenoleukodystrophy in patients with idiopathic Addison’s disease. Eur J Pediatr M H Webster, Department of Paediatrics, Taunton and Somerset Hospital, Musgrove Park, Taunton TA1 5DA, UK 9 Edwards RW. Adrenocortical diseases. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford textbook of medicine. Oxford: Oxford M Armitage, Department of Endocrinology, The Royal Bournemouth Medical Publications, 1996:1652–3.
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Obesity and asthma are linked . . . really Toavoiddevelopingasthmafatchildrenshouldloseweight.Alargecrosssectionalstudyofchildren in the United States confirms that obesity increases the likelihood of asthma, but not atopy, as anindependent risk factor.
Previous studies linking body mass index (BMI) and respiratory symptoms including asthma have been called into question by the recent finding that breastfeeding, which protects against asthma andatopy, is strongly inversely related to BMI in children starting school and is therefore a potential Von Mutius et al sought to determine whether the apparent association between BMI and asthma is a true one by analysing data on more than 7000 children from the National Health and Nutrition Exam- ination Study (NHANES) III and data collected for a comprehensive range of variables. Among these were prevalence of asthma and atopy and a whole array of known or potential confounders including birth weight (children aged <12 years) and breastfeeding (children aged <6 years).
Prevalence of asthma and atopy increased significantly across the quartiles of BMI. The relation held true for asthma after adjustment for potential confounders—age, sex, ethnicity, household size, and pas-sive exposure to smoke—and after further controlling for breastfeeding and birth weight. No independ-ent relation was seen between BMI and atopy. As cause and effect cannot be determined by a cross sec-tional study, the authors point to evidence from studies over time in nurses and children in support oftheir conclusion—that obesity predisposes to asthma.
m Thorax 2001;56:835–838.

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