J. Paediatr.

Child Health (2004) 40, 596–599

Primary adrenal insufficiency in childhood and adolescence:

Advances in diagnosis and management

PJ Simm, CM McDonnell and MR Zacharin

Department of Endocrinology and Diabetes, Royal Children’s Hospital, Melbourne, Victoria, Australia

Objectives: Primary adrenal insufficiency occurring in childhood and adolescence is due to abnormalities of gland
development, gland responsiveness, and steroid biosynthesis or target organ response. Causes include autoimmune
Addison’s disease, tuberculosis, HIV, adrenoleukodystrophy, adrenal hypoplasia congenita and syndromes including triple A
and IMAGe. We aimed to define the causes of adrenal insufficiency for a cohort of children in Melbourne.
Methods: We reviewed the frequency and variety of presentation of primary adrenal insufficiency to the Royal Children’s
Hospital over the past 10 years through an audit of patient records, collating demographic information, presentation and
investigations.
Results: Sixteen cases (13 male, 3 female) of primary adrenal insufficiency were diagnosed at this hospital between
January 1993 and July 2003. Median age at presentation was 7.7 years (range: birth to 14.8 years). Symptoms at presentation
included weakness, increased pigmentation, abdominal pain, nausea, developmental delay or a reduction in school
performance. Four patients presented with adrenal crisis. Median adrenocorticotrophic hormone (ACTH) at diagnosis was
246 pmol/L (range 30–969 pmol/L). Autoantibodies were positive in five patients. Five patients had elevation of very long
chain fatty acids. Five patients were diagnosed with autoimmune adrenal insufficiency, five with adrenal hypoplasia
congenita, five with adrenoleukodystrophy and one with IMAGe syndrome.
Conclusions: A high index of suspicion results in earlier detection and possible prevention of adrenal crisis with a
reduction in associated morbidities. Definitive diagnosis is now possible for almost all cases of primary adrenal insufficiency
using technologies for screening autoimmunity, adrenoleukodystrophy (ALD) and genetic screening.

Key words: Addison’s disease; adrenal hypoplasia congenita; adrenal insufficiency; adrenoleukodystrophy; IMAGe syndrome.

Primary adrenal insufficiency is a relatively rare disorder, with
an incidence of 120 per million population.1 Many causes have
been identified, from abnormalities in gland development and
gland responsiveness to steroid biosynthesis and target organ
response, which can have varied presentation, management and
outcomes.1 Tuberculosis and other granulomatous disorders are
the commonest causes worldwide but are seen less frequently
in first world countries. Other infectious agents that can cause
adrenal insufficiency are human immunodeficiency virus
(HIV) (chronic adrenal failure) and meningococcaemia (Water-
house Friedrichson syndrome or acute adrenal failure due to
haemorrhage). This review describes the frequency of presenta-
tion of primary adrenal insufficiency to the Royal Children’s
Hospital, Melbourne over the last 10 years including clinical
features, diagnosis and outcomes. The importance of early
recognition of this condition is underlined, as treatment is
relatively straightforward and missed diagnosis can lead to a
variety of problems, ranging from short stature to hypotensive
shock or death. This review does not include congenital adrenal
hyperplasia (CAH), which is a neonatal cause of adrenal
insufficiency. Late onset CAH in childhood and adolescence
usually presents with tall stature and virilization rather than
adrenal failure.
METHODS
An audit of all patients attending the Royal Children’s Hospital
from January 1993 until July 2003 with a diagnosis of primary
adrenal insufficiency (as listed in the ICD 10 database) was
compiled. A concordant search was made of the database
compiled by the Department of Endocrinology to ensure no
cases were missed.
Laboratory investigations used, included Cortisol (Immulite
assay – Biomediq DPC), Adrenocorticotrophic hormone
(Immulite assay), adrenal autoantibodies (Indirect immuno-
fluorescence assay – manual), and very long chain fatty acids
(VLCFA) analysed as methyl esters (gas liquid chromato-
graphy, Women and Children’s Hospital, Adelaide).
RESULTS
Sixteen cases (13 male, 3 female) of primary adrenal insuffi-
ciency were seen at the RCH in this 10-year period. One pair of
brothers is included in the analysis (patients 8 and 12). Median
age at presentation was 7.7 years (Range: Birth to 14.8 years).
Type of presentation is summarized in Table 1, with a review
of biochemical features shown in Table 2.
Delay in diagnosis was noted in five of 16 patients. In these
five patients, a median of 2 years existed between symptom
recognition and diagnosis of adrenal insufficiency (range
0.5–5.0 years). Four of the five patients eventually presented
with adrenal crisis. Of the remaining 11 patients, five presented
in the neonatal period while the remaining six patients pre-
sented with either pigmentation or neurological symptoms.
Median ACTH was 246 pmol/L (Range: 30–969 pmol/L),
with a median random cortisol of 110 nmol/L (Range:

Correspondence: Dr MR Zacharin, Department of Endocrinology and Diabetes, Royal Children’s Hospital, Parkville, Vic 3052, Australia.
Fax: + 61 3 9347 7763; email: margaret.zacharin@rch.org.au
Accepted for publication 16 April 2004.
Adrenal insufficiency in childhood 597

Table 1 Clinical features at presentation

No. Gender Age of Presenting complaint Pigmentation Lethargy Hypotension Other features Diagnosis
onset

1 f 12.5 Weakness‡ Present + + Vitiligo Autoimmune

2 f 12.8 Pigmentation Present – – Poor growth Autommune
3 m 14.8 Pigmentation Present + + Salt craving ALD
4 f 14 Nausea dizziness‡ Present + + Myalgia Autoimmune
5 m 8.1 Weakness/poor growth Present + + Anorexia Autoimmune
6 m 7.3 Poor school performance Present + + – ALD
7 m 10.8 Recurrent abdominal pain‡ Present + + Hypoglycaemia Autoimmune
8 m† 0.1 Family history Present – – – AHC
9 m 0.05 Hypoglycaemia Absent – – Low FSH/LH AHC
10 m 0.1 Lethargy/unwell Absent – – Hypoglycaemia Low FSH/LH AHC
11 m 0.05 Electrolyte abnormality Absent – – Dysmorphism AHC
12 m† Birth Family history Present – – – AHC
13 m 5.0 Pigmentation Present – – Poor growth IMAGe
14 m 3.9 Developmental delay Absent – – – ALD
15 m 8.3 Flu-like illness‡ Present + + – ALD
16 m 8.4 Decreased school performance Present + – Poor balance, thirst ALD
†
siblings; ‡ presented in adrenal crisis.

< 28–468 nmol/L). In the majority of cases, electrolytes were
suggestive of adrenal insufficiency with a median sodium of
130 mmol/L (Range: 108–141 mmol/L) and a median potas-
sium of 5.1 mmol/L (Range: 3.9–7.8 mmol/L). There were no
subjects where the diagnosis was ascertained by an incidental
finding of a raised ACTH.
Five of the 16 subjects underwent a short synacthen test with
minimal or no elevation in cortisol levels seen in all five cases.
The other 11 patients had clear deficiencies of adrenal function
and did not require dynamic testing.
Adrenal autoantibodies were checked in eight of the 16 cases
where family or clinical history was suggestive of autoimmun-
ity. The other eight cases had clear indication of a different
adrenal pathology so antibody testing was not performed.
Positive autoantibodies in five cases confirmed a diagnosis of
autoimmune Addison’s disease in these patients. Only two
patients (1, 4) had a clearly positive adrenal Ab titre (1 : 160),
and the remaining three patients (2, 5 and 7) had weakly
positive results (1 : 10).
The diagnosis of adrenoleukodystrophy (ALD) was con-
firmed in five of the 11 children tested. An abnormally high
ratio of C: 26 to C: 22 very long chain fatty acids (with normal
range < 0.035) or C: 24 to C: 22 (normal range 0.55–1.15)
confirmed the diagnosis. The other five patients did not have
testing, as a different clinical diagnosis was already evident.
Neurological symptoms were present in three of the five
patients with ALD at time of presentation with the remaining
two presenting with features of adrenal insufficiency.
Five patients had features of adrenal hypoplasia congenita,
with associated hypogonadotrophic hypogonadism and micro-
phallus in two (9, 10), a strong family history in two siblings
(8, 12) and dysmorphism in the other baby (11). Genetic
screening demonstrated absence of the DAX – 1 gene in one
patient. Three further patients had screening for mutations of
the DAX-1 and SF-1 genes, which were negative.
Patient 13 presented with intrauterine growth retardation,
gonadal anomalies and pigmentation, which led to the diagno-
sis of IMAGe syndrome. Metaphyseal dysplasia of bone was
demonstrated on X-ray.

Table 2 Biochemical features at presentation

No. ACTH Cortisol† Na+ K+ PRA‡ VLCFA§ Antibodies

(< 20) pmol/L (200–750) nmol/L (135–145) mmol/L (3.5–5.0) mmol/L (1–4)

1 250 23 136 5 – N 1 in 160

2 169 52 – – 22.9 N 1 in 10
3 341 111 141 3.9 – Nd
4 250 < 28 131 5.1 – nd 1 in 160
5 250 72 120 5 40 N 1 in 10
6 91 108 136 4.2 40 Negative
7 171 80 118 5.4 29 N 1 in 10
8 46 267 – – – nd Nd
9 969 < 28 – – 25.3 nd Nd
10 > 344 < 28 108 7.8 > 40 nd Nd
11 30 468 127 7.2 – nd Nd
12 290 67 127 6.9 – N Negative
13 130 263 135 5.2 9.7 N Negative
14 242 231 141 3.9 – Nd
15 > 800 < 10 129 4.1 – Negative
16 153 286 – – – Nd
†
Random cortisol levels; ‡ plasma renin activity; §very long chain fatty acids ratio; nd, not done; –, no result available at time of presentation for this
patient.
598
In summary, of the 16 subjects identified, five were diag-
nosed with autoimmune adrenal insufficiency, five with adrenal
hypoplasia congenita, five with adrenoleukodystrophy and one
with IMAGe syndrome. Three of the four children who pre-
sented in adrenal crisis were subsequently shown to have
autoimmune hypoadrenalism.
Acute management included normal saline rehydration and
intravenous corticosteroids followed by oral glucocorticoid
and mineralocorticoid treatment. Median dose at diagnosis in
this cohort was 17 mg hydrocortisone per metre squared body
surface area (range 10–25 mg/m2). Dosage was based on age at
commencement and not related to diagnosis. Fludrocortisone
replacement was 0.05–0.10 mg daily also based on age at
commencement.
Following diagnosis, bone marrow transplant (BMT) had
been undertaken in one of the five patients with ALD in an
attempt to further slow symptoms of neurological degeneration
and a second patient is currently being assessed for suitability
for BMT.
According to our records, five of 16 patients successfully
transitioned to adult services. Eight of 16 are followed up by a
specialist paediatric endocrinologist on a 3–6 month basis. One
patient moved interstate. There have been two deaths to date.
Patient 11 died following an episode of aspiration in the
neonatal period. Patient 14 died following complications
related to bone marrow transplantation. No deaths occurred as
a consequence of adrenal crisis, with only one patient known to
have a presentation of frank adrenal crisis after diagnosis.
DISCUSSION
Adrenal insufficiency has many varied presentations ranging
from asymptomatic patients screened due to a positive family
history and patients presenting with low grade, non-specific
symptoms of lethargy and weight loss to those presenting with
acute onset hypotensive collapse and shock. Missed diagnosis
can result in significant morbidity related to lethargy, weight
loss and electrolyte disturbance while mortality due to adrenal
failure and circulatory collapse in unrecognized adrenal insuffi-
ciency continues to be of significant concern, particularly in the
setting of an intercurrent illness or surgical procedure. The
interval from symptom onset to diagnosis in this review under-
lines this point. This was attributed to the wide range of
symptoms reported by families. These included increasing
pigmentation, lethargy and in one case recurrent abdominal
pain, where diagnostic laparotomy had been undertaken prior to
the diagnosis of adrenal insufficiency being made.
The treatment of adrenal insufficiency can be straight-
forward, with replacement of glucocorticoid and mineralocorti-
coid according to body surface area. In addition, monitoring of
auxological parameters to ensure normal growth velocity and
compliance to treatment is necessary in all patients with adrenal
insufficiency. Both ACTH and Plasma Renin Activity have
proved to be accurate markers of compliance amongst our
patient group.
The underlying cause of adrenal insufficiency may be asso-
ciated with other more substantive problems. Surveillance must
continue for other autoimmune disorders in those with positive
autoimmune profiles. Hormones to induce and maintain puber-
tal progress may be required in adrenal hypoplasia congenita if
the recognized association of hypogonadotrophic hypogonad-
ism is present.
With recent advances in antibody and genetic screening
providing more definitive diagnoses, there remain few
PJ Simm et al.
patients who can be labelled as idiopathic Addison’s
disease. Genetic screening brings the added implication of
diagnosing a degenerative disease, for example, ALD in a well
asymptomatic child and the effect this can have on a family. A
greater understanding of the underlying conditions may aid
both clinical assessment and further progress toward better
therapies.
Autoimmunity
The testing of adrenal autoantibodies was not as definitive in
our cohort as data reported in the literature.2 For the five
patients presumed to have autoimmune Addison’s disease, only
two had a clearly positive adrenal Ab titre (1 : 160). The three
inconclusive patients all had other risk factors for autoimmune
disease, with either a family history of autoimmunity or the
presence of other autoimmune phenomena. As adrenal auto-
antibodies are usually of low titre these children were therefore
presumed to have autoimmune disease. Autoimmune Addi-
son’s disease in childhood is almost invariably associated with
other autoimmune phenomena,3 with three recognized poly-
glandular syndromes. Autoimmune polyendocrinopathy I
presents in early childhood. Features include mucocutaneous
candidiasis, hypoparathyroidism and pernicious anaemia.
Autoimmune polyendocrinopathy II develops in adolescence or
adulthood and has other features including thyroiditis and
diabetes. Any patient with persistent mucocutaneous candi-
diasis, autoimmune thyroid disease or hypoparathyroidism,
should be strongly considered for adrenal autoantibody test-
ing.4,5 Clinically, the adrenal insufficiency often follows after
thyroid or candidal manifestations. One child of our cohort has
subsequently developed vitiligo. No therapy exists to modify
the course of autoimmunity to date. Lifelong surveillance is
therefore required, for other system involvement and replace-
ment therapy as appropriate.
Adrenal hypoplasia congenita (AHC)
Hypogonadotropic hypogonadism and adrenal hypoplasia
occur together due to mutations in the DAX-1 gene.6 DAX-1
(DSS–AHC critical region on the X chromosome, gene 1 with
DSS referring to dosage sensitive sex reversal) is a hormone
receptor gene, expressed in the urogenital ridge, ovary, testis,
adrenal cortex, hypothalamus and anterior pituitary gland. It
colocalizes with steroidogenic factor -1 (SF- 1), which has also
been implicated in the development of gonads, adrenals and
hypothalamus. Many mutations have been isolated in DAX-1,
mainly gene deletions or premature stop codons. The function
of the DAX-1 gene is to inhibit the transcription of genes
driven by SF- 1. Clinical correlation between the specific
mutation and phenotype is still unclear. Affected patients
typically present with early onset adrenal failure and hypo-
gonadotropic hypogonadism. Delayed puberty has been found
in female heterozygotes.6
Within our cohort, all five patients were male infants
(< 1 years) at presentation. Although only one of our patients
has been confirmed with AHC to date due to the presence of a
DAX-1 mutation, the remaining four all have clinical features
suggestive of this condition, including association of hypo-
gonadotrophic hypogonadism and microphallus in two and a
strong family history in two siblings, together with undetect-
able levels of plasma steroids. They await further mutational
analysis.
Adrenal insufficiency in childhood
Adrenoleukodystrophy
Adrenoleukodystrophy (ALD) is an X-linked condition with a
defect in beta – oxidation of very long chain fatty acids (greater
or equal to 24 carbons), which leads to progressive demyelina-
tion within the central nervous system as well as adrenal
insufficiency.7 Presentation is often in the first decade of life.
Neurological involvement or adrenal insufficiency can present
as the primary feature. Neurological features have a broad
spectrum of progression and the later the onset the better the
outcome for the affected male. Boys less than 7 years of age
usually progress to rapid onset quadriplegia and death, whereas
those who progress to adulthood before developing neuro-
logical symptoms may only display evidence of peripheral
neuropathy. In heterozygote females, objective neuropathic
changes can be occasionally seen. Adrenal insufficiency occurs
at any age or stage of the disease, however, can be well
managed with steroid replacement. Dietary management with
Lorenzo’s oil (a 4 : 1 mixture of glycerol trioleate and glycerol
trierucate) has been shown to reduce serum C: 26 levels but
appears to have little benefit on disease progression. Bone
marrow transplant has been shown to stabilize or slow the
course of the disease in some patients but due to the 10–20%
mortality associated with the procedure, application is
restricted to patients with significant but mild cerebral involve-
ment.7 The availability of treatment justifies screening of all
male children and adolescents for ALD with primary adrenal
insufficiency. Identification of an affected patient gives the
family the option of bone marrow transplantation before
progression of the neurological disorder. Also, through making
a specific diagnosis of the adrenal insufficiency, families with
X-linked disorders can receive appropriate genetic counselling
and support.
IMAGe
IMAGe is a rare syndrome (eight cases in the literature)
associating adrenal hypoplasia congenita with intrauterine
growth retardation, metaphyseal dysplasia and genital abnor-
malities. Seven males and one female have been described.8–11
Subject no. 13 in our study fulfills the criteria for this
syndrome. As yet, no candidate gene has been found. In the
literature four patients have undergone normal pubertal
development, however, all have short stature. Further research
needs to be undertaken to determine the true frequency of this
syndrome, and the underlying genetic basis.
599
CONCLUSION
Sixteen cases of primary adrenal insufficiency have been seen
at the Royal Children’s Hospital, Melbourne over a 10-year
period. While a rare disorder, a high index of suspicion can lead
to early detection and prevention of years of morbidity from
lethargy or poor weight gain. The features of increased pigmen-
tation, lethargy, hypotension or electrolyte abnormalities
should lead to a consideration of adrenal insufficiency. Most
patients will be given a definitive diagnosis with the advent of
improved techniques in testing for ALD, antibody testing and
genetic screening. This, in turn, provides more accurate prog-
nosis, and an ability to screen for other potential problems.
Genetic counselling can be offered for the X-linked conditions.
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