Reminder of important clinical lesson

Adrenoleukodystrophy: a forgotten diagnosis in children with

primary Addison’s disease
Marta Nascimento, Nádia Rodrigues, Filipa Espada, Marcelo Fonseca

Department of Pediatrics, Hospital Pedro Hispano, Matosinhos, Portugal

Correspondence to Dr Marta Nascimento, marta.r.n.nascimento@gmail.com

Summary
The X linked adrenoleukodystrophy (X-ALD) is a peroxisomal disease caused by defects of the ABCD1 gene on chromosome Xq28 leading
to accumulation of very long chain fatty acids (VLCFA), progressive demyelination and adrenal insufficiency. An 8-year-old boy was referred
to our paediatric endocrinology clinic due to fatigue and hyperpigmentation with onset at 2-years old. Blood tests revealed
mineralocorticoid insufficiency. Serum adrenocorticotropic hormone and cortisol concentrations were compatible with adrenal insufficiency.
Adrenal antibodies were negative. The elevated plasmatic concentration of VLCFA and the genotype analysis with sequencing of ABCD1
gene established the diagnosis of X-ALD. Brain MRI showed demyelination of white matter in the peritrigonal regions. Steroid replacement
was started with good response. He initiated restriction of VLCFA by reducing the intake of fatty foods. The authors highlight the
importance of suspecting of X-ALD in the aetiology of primary adrenal insufficiency as the first sign of the disease.

BACKGROUND adrenocorticotropic hormone (ACTH) on the adrenocorti-

X linked adrenoleukodystrophy (X-ALD, OMIM number cal cells, or indirectly by initiating an autoimmune
300100) is a genetic disease characterised by progressive response. Usually, adrenocortical failure occurs along with
demyelination within the central and peripheral nervous irreversible degenerative neurological defects. Adrenal
system, adrenal insufficiency (Addison’s disease) and accu- failure may predate, occur simultaneously with, or follow
mulation of very-long-chain fatty acids (VLCFA) in the onset of the neurological deterioration.4
plasma, fibroblasts and tissues.1 X-ALD is caused by muta- The incidence of X-ALD has been estimated to be
tions in the ABCD1 gene, located at Xq28, which encodes approximately 1:17 000 if one takes into account the
the ALD protein which belongs to the subfamily D of ABC homozygotes and symptomatic forms in heterozygotes
transporters (ATP-binding cassette). The ABC transporter females.1 The clinical spectrum is very broad but three
helps form the channel through which VLCFAs move into main phenotypes can be distinguished including the child-
the peroxisome, probably as Co-A esters. Therefore, any hood cerebral form, adrenomyeloneuropathy (AMN) and
ABCD1 gene mutation causes a loss of function of ALD ‘Addison disease only’. According to Moser,5 childhood
protein that is localised in the membrane of peroxisomes.2 cerebral X-ALD occurs most frequently (37% of cases), fol-
The phenotype does not correlate with the genotype lowed by AMN (32%) and ‘Addison disease-only type’
which suggests that of modifier genes or environmental/ (13%). The childhood cerebral form normally presents
epigenetic/stochastic factors modulate the clinical between 4 and 8 years of age. Initially resembles attention
outcome of the disease. Recent studies suggest for a ‘three- deficit hyperactivity disorder and may respond to stimu-
hit hypothesis’ for ALD. The first hit in the physiopatho- lant medication. Progressive central demyelination occurs
genesis of axonal damage in X-ALD is proposed to be an with neurological deterioration that includes impairment
oxidative burden as a direct consequence of peroxisomal of cognition, behaviour, vision, hearing and motor func-
metabolic impairment. The increased oxidative stress/ tion and often leading to total disability within 2 years
damage and reduction in plasmalogens participate in the and death within 5–10 years of diagnosis.6 AMN usually
transition of VLCFA-mediated metabolic disease into neu- affects adults (second to fourth decade) and is charac-
roinflammatory disease. This transition is driven by the terised by a pure mylopathy and peripheral neuropathy.
‘second hit’. Studies also indicate that derangements in The neuropathological hallmark of AMN is an axonopa-
VLCFA and plasmalogens induce oxidative damage leading thy, resembling spastic paraparesis or spastic paraplegia,
to expression of lipolytic enzymes and their products fol- without significant myelin degeneration or neuroinflam-
lowed by enhanced expression of proinflammatory media- mation. However, about 35% of AMN patients subse-
tors. Finally, observations indicate a generalised loss of quently develop cerebral demyelination. These patients
peroxisomes and thereby their functions in the inflamma- share the same poor prognosis as children with cerebral
tory regions of central nervous system suggesting that a ALD. They manifest progressive paraparesis, sphincter
generalised loss of peroxisomal function participates in disturbances, sexual dysfunction, and not infrequently,
X-ALD neuropathology (third hit).3 impaired adrenocortical function. All symptoms are pro-
In the adrenal gland, abnormal VLCFA may directly gressive over decades.7 The third phenotype, ‘Addison
alter cellular function by inhibiting the effects of disease only’, presents in males between age 2 years and

BMJ Case Reports 2012; doi:10.1136/bcr-2012-006308 1 of 5

adulthood, but usually before 7.5 years, without evidence the diagnosis of adrenal insufficiency. Antiadrenal anti-
of neurological abnormality. Signs include unexplained body levels were negative excluding autoimmune adrenal
vomiting, weakness, coma or hyperpigmentation due to insufficiency. Testosterone concentrations (552 ng/dl,
increased ACTH secretion. Biochemical evidence of normal range 166–811 ng/dl), dehydroepiandrosterone sul-
adrenal insufficiency can be present for up to 2 years phate (61.4 μg/dl, normal range 70.2–492.0 μg/dl), serum
before the development of clinical signs. Some men with follicle-stimulating hormone and luteinising hormone
ABCD gene mutations are reported to have biochemical (3.16 mUI/ml and 2.58 mUI/ml, respectively) were within
evidence but no clinical features of adrenal insufficiency.8 normal limits. Given the laboratory findings concentra-
Most individuals who present with isolated adrenal insuf- tions of VLCFA in the plasma were determined and
ficiency develop AMN by middle age. Female carriers may proved to be increased (C26:0, 0.8 μg/ml (normal
be symptomatic depending upon the pattern of 0.16–0.57 μg/ml), C24:0/C22:0 ratio 1.48 (normal ratio
X-chromosome inactivation. Approximately 50% develop 0.63–1.10), C26:0/C22:0, 0.047 (normal ratio 0.004–
neurological manifestations similar to AMN but have a 0.022)) establishing the diagnosis of X-ALD. Abdominal
later onset (age ≥35 years), a milder disease, cerebral dis- MRI showed no structural abnormalities. Brain MRI
turbance is uncommon and adrenal insufficiency is rare.9 revealed symmetrical T2-weighted signal intensities of the
The diagnosis of X-ALD may be raised by the above posterior peritrigonal regions bilaterally, and involvement
clinical signs or symptoms, including isolated adrenal of the splenium of the corpus callosum (Loes pattern 1),
insufficiency and is commonly achieved by laboratory without calcification areas (figure 1). Spinal cord and cer-
evaluation of increased concentrations of VLCFA in vical MRI was normal. The diagnosis was confirmed by
plasma. Testing typically includes three VLCFA para- molecular genetic testing of the ABCD1 gene locus which
meters: the level of hexacosanoic acid (C26:0), and the detected the presence, in hemozygosity, the c.1534G>A
ratio of hexacosanoic acid to tetracosanoic acid (C26:0/ ( p.G512S) mutation, described as causal for X-ALD. The
C24:0), and to docosanoic acid (C26:0/C22:0).7 family tree was provided for genetic assessment in order
We report a case of a patient with X-ALD presenting to allow the family genetic counselling.
with adrenal insufficiency and highlight the importance
of testing for ALD in males with idiopathic Addison’s DIFFERENTIAL DIAGNOSIS
disease. Even though X-ALD is an important cause of primary
adrenocortical insufficiency in males with Addison
CASE PRESENTATION disease, if primary adrenal insufficiency is diagnosed,
An 8-year-old boy was referred to our paediatric endocrin- further testing should be performed to exclude other
ology clinic due to progressive fatigue and generalised conditions. These may include autoimmune polyglandular
hyperpigmentation beginning at 2-years old. He had no syndromes, congenital adrenal hypoplasia, tuberculosis
episodes of loss of consciousness, salt-craving or gastro- and, less commonly, Allgrove syndrome (achalasia, ala-
intestinal complaints of nausea and vomiting. The patient crima and adrenal hypoplasia). The differential diagnosis
attended the third grade and had been retained because of for individuals presenting with learning disabilities, behav-
learning disabilities. There were no other relevant facts of iour problems and other signs of neurological deterioration
his medical history. He was the third child of unrelated with cerebral involvement includes other leukodystrophies
healthy parents with uneventful family history, namely such as metachromatic leukodystrophy and Krabbe
no relatives with identified psychiatric, neurological or disease. Multiple sclerosis and other dementing disorders
endocrine disorders. On clinical examination, he presented such as juvenile neuronal ceroid-lipofuscinosis (Batten
with prominent adynamia and muscle weakness. He had disease) may also be discarded.7 Nevertheless, these late
generalised skin hyperpigmentation, especially of palmar conditions are less common and primarily thought
creases and of the buccal mucosa. Pubic hair growth was usually when childhood cerebral form is the main
absent and testicular volume was estimated inferior to phenotype.
4 ml bilaterally (Tanner stage I). There was no hypoten-
sion and growth parameters (weight on 10th–25th per- TREATMENT
centile, stature on 10th percentile) were normal for sex Glucocorticoid replacement therapy was started with
and age. His mental status and neurological evaluation clinical improvement. The patient became more active
were normal. There were no other significant findings in and cheerful, with increased appetite and decreased hyper-
the remaining clinical examination. pigmentation and improved academic performance.
Restriction of dietary VLCFA was accomplished by redu-
INVESTIGATIONS cing the intake of fatty foods although it is of our knowl-
Laboratory results showed hyponatraemia (124 mmol/l, edge that this approach does not decrease the VLCFA
normal range 135–145 mmol/l) and hyperkalaemia concentration because endogenous synthesis continues.
(6.5 mmol/l, normal range 3.5–4.6 mmol/l). Serum con- ‘Lorenzo’s oil’, a 4:1 mixture of glyceryl trioleate and gly-
centrations for creatinine, blood urea nitrogen, calcium ceryl trierucate, combined with moderate reduction of fat
and complete blood count were within normal limits. in the diet, normalises or significantly lowers the levels of
Plasma renin activity (46.5 ng/ml/h, normal range VLCFA in plasma within 4 weeks, but its clinical efficacy
0.9–1.9 ng/ml/h) and aldosterone (15 pg/ml, normal range and clinical indications for its use have been controversial
40–760 pg/ml) serum concentrations confirmed mineralo- for more than 15 years.10 The limited evidence suggests
corticoid deficiency. The measurement of morning cortisol that ‘Lorenzo’s oil’ may delay the progression of disease in
(2.9 μg/dl, normal range 5.0–11.0 μg/dl) and ACTH levels individuals with early or mild ALD and perhaps also for
(9279.0 pg/ml, normal range 0.0–46.0 pg/ml) established AMN.11 Therefore, it should be offered to individuals

2 of 5 BMJ Case Reports 2012; doi:10.1136/bcr-2012-006308

Figure 1 T2 weighted images of the brain showing hyperintensities (and corresponding hypointense signal on T1) in the peritrigonal
regions, bilaterally and symmetrical, involving the splenium of the corpus callosum (Loes pattern 1), without recoverable expansion or
mass effect (a, b - axial T2 FSE; c, d - axial FLAIR; e,f - axial T1 FSE).

with presymptomatic ALD, this is, those with laboratory (30 mg/m2). Presently, at 17-years old, there is no evi-
studies diagnostic of ALD, but without abnormal neuro- dence of neurological deficits and no new demyelinating
logical or MRI findings, and those with ‘Addison disease lesions in other areas of the brain at follow-up MRI
only’ and normal MRI, as many of the patients with this imaging.
phenotype will become symptomatic. Even though our
patient has no evidence of neurological deficits to date,
DISCUSSION
taking into account his brain MRI abnormalities, we
Primary adrenal insufficiency, also known as Addison’s
decided not to start dietary therapy with ‘Lorenzo’s oil’.
disease, results from disease intrinsic to the adrenal
Another suggested therapeutic agent for X-ALD is lovasta-
cortex and is caused by either genetic defects or
tin given its ability to reduce VLCFA concentration in
acquired disease that affect the adrenal function. Its
ALD fibroblasts. However, it was concluded that lovasta-
incidence is unknown but a retrospective review of 103
tin should not be prescribed as a therapy to lower levels
children with primary adrenal insufficiency identified
of VLCFA in patients with X-ALD and has no clinical
congenital adrenal hyperplasia (73%) as the most preva-
benefit for the neurological symptoms.12 This therapeutic
lent cause followed by autoimmune adrenal failure
agent was not considered for our patient. At present,
(13%) and peroxisomal disorders (5%), including
haematopoietic cell transplantation (HCT) is emerging as
adrenoleukoystrophy.13
the treatment of choice for patients with early stages of
While in the 1940s tuberculosis was responsible for
cerebral involvement in X-ALD. There are a variety of
most cases, ALD is currently considered as an aetiological
haematological sources from which stem cells can be har-
factor of primary adrenocortical insufficiency for up to
vested, including peripheral blood, bone marrow and
20% of boys with idiopathic Addison’s disease.14
umbilical cord blood. The ideal candidates for HCT are
However, adrenocortical insufficiency is present in at least
males with neurological deficits and abnormalities on
50% of patients with cerebral-ALD/AMN, but may be the
brain MRI presenting early in their disease course. For
only clinical manifestation of X-ALD in up to 10% of
those without MRI evidence of cerebral involvement or
cases.15 This case report highlights the challenges of diag-
advanced neurological disease, HCT is not recommended
nosing this rare peroxisomal disorder especially in patients
because almost half of the first group will remain free of
presenting with ‘Addison disease-only’ type. It also
neurological disease and there is scarce evidence that HCT
emphasises that confirmation or exclusion of X-ALD in
provides clinical improvement for patients included in this
males presenting with primary adrenal insufficiency is
second group.10 Based on the neurological examination
mandatory since the late diagnosis compromises the man-
and neuroimaging assessment, we concluded that our
agement of both patients and their extended families.
patient is an appropriate candidate for HCT. Thus, the
Assay of plasma VLCFA is the most frequently used
patient was referred for psychology evaluation to define
test for diagnosis of X-ALD and is accurate in almost all
the follow-up strategy.
cases. For patients with high index suspicion but normal
or borderline plasma VLCFA, concentrations should also
OUTCOME AND FOLLOW-UP be measured in the cultured skin fibroblasts before exclud-
On follow-up visits there was complete improvement of ing the diagnosis of X-ALD.7 In our patient the plasma
adrenal insufficiency symptoms. The patient maintains VLCFA levels established the diagnosis and molecular ana-
glucocorticoid replacement therapy with hydrocortisone lysis of ABCD1 gene confirmed the presence of a causal

BMJ Case Reports 2012; doi:10.1136/bcr-2012-006308 3 of 5

mutation of X-ALD. The definitive test for suspected
female carriers and asymptomatic individuals is a muta- Learning points
tion analysis.16
All individuals with confirmed ALD/AMN complex, ▸ X linked adrenoleukodystrophy (X-ALD) should always
including symptomatic female heterozygotes, should be suspected in males with primary adrenal
undergo neuroimaging to determine if cerebral involve- insufficiency.
ment is present and testing of adrenal function.16 Our ▸ Prompt diagnosis of X-ALD is essential because
patient’s brain MRI showed Loes pattern 1 imaging find- haematopoietic stem cells transplantation is the
ings consisting of bilateral symmetric involvement of the standard option treatment for those with early
parieto-occipital white matter (66% of cases, mainly in neuropsychological deterioration.
children) and follow-up MRI imaging revealed stabilisa- ▸ The clinical course of X-ALD is highly variable and its
tion of lesions. Eleven years after disease onset and phenotypes not definitive requiring close endocrine,
although the patient presents with identified brain lesions neurological and neuroimaging follow-up.
in neuroimaging, he maintains no deficit neurological ▸ Early diagnosis brings the possibility of genetic
symptoms. It is important to refer that symptoms and counselling, carrier detection and antenatal diagnosis.
MRI imaging findings do not always match since some
patients with demyelinating lesions at MRI imaging may
be asymptomatic.16 It also must be remembered that the
delay from onset of adrenal insufficiency to the develop- Competing interests None.
ment of neurological disability is highly variable and may Patient consent Obtained.
be as long as 32 years.17 There is still no clear explanation
for the highly variable course of this disease, but it is REFERENCES
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Nascimento M, Rodrigues N, Espada F, Fonseca M. Adrenoleukodystrophy: a forgotten diagnosis in children with primary Addison’s disease.
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