Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

CASE REPORT

Neurofibromatosis 1-associated panhypopituitarism
presenting as hypoglycaemic seizures and stroke-like
symptoms
Waqar Waheed,1 Muriel H Nathan,2 Gilman B Allen,3 Neil M Borden,4 M Ali Babi,1
Rup Tandan1
1

Department of Neurological
sciences, University of
Vermont, Burlington, Vermont,
USA
2
Division of Endocrinology,
Department of Medicine,
University of Vermont College
of Medicine, South Burlington,
Vermont, USA
3
Division of Pulmonary &
Critical Care, Department of
Medicine, University of
Vermont College of Medicine,
Burlington, Vermont, USA
4
Department of Radiology,
University of Vermont College
of Medicine, Burlington,
Vermont, USA
Correspondence to
Dr Waqar Waheed,
waqar.waheed@uvmhealth.org
Accepted 15 October 2015

SUMMARY
A 37-year-old man with a known history of
neurofibromatosis 1 (NF1) presented within 2 days of
diarrhoeal illness followed by encephalopathy, facial
twitching, hypoglycaemia, hypotension, tachycardia and
low-grade fever. Examination showed multiple café-aulait spots and neurofibromas over the trunk, arms and
legs and receptive aphasia with right homonymous
hemianopia, which resolved. Workup for cardiac,
inflammatory and infectious aetiologies was unrevealing.
A brain MRI showed gyral swelling with increased T2
fluid-attenuated inversion recovery signal and diffusion
restriction in the left cerebral cortex. Neuroendocrine
findings suggested panhypopituitarism with centrally
derived adrenal insufficiency. Supportive treatment,
hormone supplementation, antibiotics, antivirals and
levetiracetam yielded clinical improvement. A follow-up
brain MRI showed focal left parieto-occipital atrophy
with findings of cortical laminar necrosis. In conclusion,
we describe a case of NF1-associated panhypopituitarism
presenting as hypoglycaemic seizures and stroke-like
findings, hitherto unreported manifestations of NF1.
Prompt recognition and treatment of these associated
conditions can prevent devastating complications.

BACKGROUND

To cite: Waheed W,
Nathan MH, Allen GB, et al.
BMJ Case Rep Published
online: [ please include Day
Month Year] doi:10.1136/
bcr-2015-210816

Neurofibromatosis 1 (NF1) is one of the most
common inherited autosomal dominant neurological disorders, affecting about 1 in every 3000
individuals, with established diagnostic criteria.1
NF1 is a multisystem disorder with several neurological and non-neurological manifestations;2
however, involvement of the pituitary—hypothalamic axis is rarely reported.3–5 While some reports
identified structural causes, such as pituitary
adenoma and hydrocephalus,3 4 others describing
short stature related to growth hormone (GH) deficiency noted the absence of sellar or suprasellar
pathology on neuroimaging.5 There is limited published literature on hypoglycaemic seizures and
stroke-like symptoms related to NF1-associated
panhypopituitarism. We describe a case of
NF1-associated panhypopituitarism presenting as
hypoglycaemic seizures and stroke-like symptoms
and features indicating an adrenal crisis-like presentation; further, our case manifested several other
rare systemic complications of NF1.

CASE PRESENTATION
A 35-year-old man with known NF1, learning disability and a history of NF1 in his father presented
to an outside hospital with diarrhoea and dehydration, which improved with intravenous fluids. Two
days later, his roommate found him confused and
minimally responsive with facial twitching. Initial
evaluation showed sinus tachycardia, systolic blood
pressure ranging from 70 to 100 mm Hg, temperature 99.5°F and a Glasgow Coma Scale score of 8
(withdrawal to pain, non-verbal, opening eyes to
commands). Rapid intravenous administration of
25 g dextrose, to correct a blood glucose level of
32 mg/dL, produced no change in mental status
and prompted emergent intubation for airway protection. There had been no prior reported episodes
of hypotension, hypoglycaemia or altered
responsiveness.

INVESTIGATIONS
Initial testing
Laboratory studies revealed polymorphonuclear
leucocytosis, mild normocytic normochromic
anaemia (haemoglobin 11.2 g/dL and haematocrit
33.1%), metabolic acidosis with an anion gap of
25, acute kidney injury with a newly elevated creatinine of 1.5 mg/dL and a mild troponin elevation
(1.42 ng/mL; normal <0.05), but no ischaemic ST
or T-wave ECG changes. Urine toxicology screen,
liver function tests, electrolytes, lactic acid level and
erythrocyte sedimentation rate (ESR) were normal.
Chest X-ray showed left lower lobe opacity suggestive of an infiltrate or effusion; serial follow-up
studies suggested basilar atelectasis.
The initial clinical impression was of a patient
with encephalopathy with possible seizures, in the
setting of low-grade fever, hypotension, hypoglycaemia and mild metabolic derangements.
Diagnostic testing was undertaken to address the
following identified pathologic disorders.

Seizures and obtunded mental status
Lumbar puncture performed after a normal CT of
the brain yielded traumatic cerebrospinal fluid
(CSF) with an opening pressure of 32 cm H2O,
>10 000 red blood cell/mm3 in tubes 1 and 3, 346
white cell count/mm3 in tube 3 (91% polymorphs),
glucose 43 mg/dL (serum glucose 74 mg/dL
obtained after 25 g intravenous dextrose) and total
protein 370 mg/dL (normal 15–60). Gram’s stain,
bacterial culture, Lyme antibody titre, herpes

Waheed W, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2015-210816

1

Findings that shed new light on the possible pathogenesis of a disease or an adverse effect
simplex virus PCR, venereal disease research laboratory, cryptococcal antigen and cytology were normal or negative.
The MRI of the brain showed gyral swelling, increased T2
fluid-attenuated inversion recovery signal and diffusion restriction in the left frontal, parietal and occipital cortices (figure 1).
The CT angiogram, as well as subsequent conventional angiography, of the head and neck was normal. Electroencephalogram
showed delta activity over the left parieto-occipital and temporal
regions without interictal epileptiform discharges.
Vasculitis related and cardioembolic causes were excluded by
autoimmune panel testing (ESR, antinuclear antibodies, antineutrophil cytoplasmic antibody and rheumatoid factor) and
echocardiography.

Hypotension and suspected sepsis
Search for a source of sepsis with cultures of blood, urine, CSF
and stools, and serum viral antibody panels was negative. CT of
the abdomen and pelvis, done for evaluation of diarrhoea,
anaemia and hypotension, showed no fluid collection or free
air, but revealed enhancement of a large portion of the small
bowel and most of the colon suggestive of hypoperfusion
complex (shock bowel), which improved with appropriate fluid
management. Additionally, the CT of the pelvis showed a
moderate-sized left hip effusion; arthrocentesis yielded normal
joint fluid.

Hypoglycaemia
A CORTROSYNTM (cosyntropin) stimulation test with 250 μg
of synthetic adrenocorticotropic hormone (ACTH), performed
to investigate hypoglycaemia and shock on the day of hospitalisation, demonstrated baseline, 30 and 60 min post-stimulation
cortisol levels of <1.0 mg/dL. A full thyroid profile performed

on the day of presentation, and subsequent pituitary-related
testing obtained approximately 2 weeks after the presentation,
confirmed findings of panhypopituitarism (table 1). The normal
prolactin level was probably related to seizures prior to testing;
the follicle-stimulating hormone level was not obtained. On the
basis of the results of the static neuroendocrine test battery, a
subsequent MRI of the brain obtained with dedicated pituitary
views showed no abnormality (figure 2).

TREATMENT
The patient was treated with intravenous fluids, broad-spectrum
antibiotics and antiviral drugs for possible sepsis and/or meningoencephalitis (ceftriaxone 2 g q12 h for 2 days, vancomycin
1 g q12 h for 6 days, ampicillin 2 g q4 h for 1 day, ciprofloxacin
400 mg intravenous q12 h for 5 days and acyclovir 5 mg/kg
q8 h for 1 day), and levetiracetam for facial twitching concerning seizures. Hormone replacement therapy was provided with
hydrocortisone, followed later by thyroid hormone and testosterone therapy.

OUTCOME AND FOLLOW-UP
The patient improved quickly, with resolution of cardiac, renal
and metabolic abnormalities. After extubation, over the next
week, antibiotic and antiviral drugs were discontinued. Since
the possible seizures were deemed to be provoked by hypoglycaemia and metabolic abnormalities, levetiracetam was discontinued approximately 1 month later.
Post-extubation, a focused skin examination showed multiple
café-au-lait spots and neurofibromas on the trunk, arms and
legs. Neurological examination revealed a mild receptive aphasia
and partial right homonymous hemianopia, both of which
improved during rehabilitation over the ensuing few months.
Further evaluation of left hip pain with an MRI showed
several intra-articular and extra-articular plexiform neurofibromas (figure 3) and a meningocele in the sacral spinal canal
(figures 4).
A follow-up MRI of the brain obtained 6 months following
discharge (figure 5A, B) showed abnormalities in the left
parieto-occipital region compatible with the sequelae of cortical
laminar necrosis, with injury/atrophy of the underlying white
matter, and post-injury atrophy and signal abnormality in the
splenium of the corpus callosum.
An additional review of the patient’s previous medical
records, which were subsequently made available, revealed two
separate remote episodes of spontaneous pneumothorax (figures
6 and 7), believed to be related to extensive blebs and bullae
seen in both lungs on CT imaging, most notably in the upper

Table 1

Figure 1 MRI of the brain—axial T2 fluid-attenuated inversion
recovery sequence just above the lateral ventricles showing areas of
gyral swelling and increased signal intensity (white arrows) limited to
the cortex in the left middle cerebral, posterior cerebral and distal
anterior ( precuneus) cerebral artery territories. These areas were
matched for abnormalities in diffusion-weighted images and the
apparent diffusion coefficient map (not shown).
2

Endocrine testing

Test

Patient result

Normal range

Adrenocorticotropic hormone levels
Insulin-like growth factor
TSH
T3
Free T4
Testosterone
Free testosterone
Luteinising hormone
Prolactin

<10 pg/mL
77 ng/mL
7.02 μU/mL
58 ng/dL
0.7 ng/dL
192 ng/dL
2.6 ng/dL
2.8 mIU/mL
11.2 ng/mL

10–60
113–297
0.35–5.00
60–181
0.8–1.8
241–827
5.0–24.0
2–9
2.1–17.1

TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine.

Waheed W, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2015-210816

Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

Figure 2 MRI of the brain—sagittal T1-weighted image through the
mid-sagittal plane showing a normal pituitary gland (white arrow).
lobes. These pulmonary findings were felt to be in keeping with
the diagnosis of NF1-related lung disease.

Figure 4 MRI of the lumbosacral spine—sagittal T2-weighted MRI
demonstrating dural ectasia (black asterisk) of the sacral thecal sac
remodelling and expanding the surrounding bone of the spinal canal
(white arrows). The black arrows indicating the nerve roots normally
dispersed within the sacral thecal sac.

DISCUSSION
The diagnosis of NF1 in our case was primarily based on the
presence of multiple café-au-lait spots, neurofibromas (including
1 plexiform neurofibroma) and a first-degree relative with NF1.

Additional features that supported the diagnosis included: (1)
central nervous system (CNS) manifestations of panhypopituitarism, seizures and learning disability; (2) peripheral nervous
system manifestations of plexiform neurofibromas in the hip
and sacral spinal canal meningocele and (3) systemic manifestations of recurrent spontaneous pneumothorax.
NF-1 is an autosomal dominant disorder caused by a mutation in the gene encoding neurofibromin, located on chromosome 17q11.2. Neurofibromin is a multifunctional tumour
suppressor protein involved in the regulation of many cellular
pathways related to cell growth and proliferation.6
Neurofibromin acts by negatively modulating the activity of Ras,
an important intracellular signalling protein critical for regulation of cell growth and survival (figure 8). In addition, neurofibromin is a positive regulator of adenylyl cyclase,7 the enzyme
responsible for the generation of intracellular cyclic AMP
(cAMP). Thus, neurofibromin regulates nervous system development along both Ras-dependent and cAMP-dependent
pathways.
The salient features of our case pertain to endocrine, neurological, radiological and systemic manifestations.

Endocrine manifestations

Figure 3 MRI of the left hip—coronal post-contrast fat-suppressed
T1-weighted image showing the plexiform neurofibroma with both
intracapsular (black asterisk) and extracapsular components (double
white arrows) (biopsy proven). The single white arrow indicating an
extracapsular component eroding the bone in the lateral
supra-acetabular region.
Waheed W, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2015-210816

The case we describe presented with confusion and hypoglycaemia in the absence of exogenous insulin use or insulin secretagogues. Testing during hospitalisation showed undetectably
low ACTH and cortisol levels, suggesting a central cause for the
adrenal insufficiency. In primary adrenal insufficiency caused by
lack of adrenal secretion, the ACTH level is elevated and not
<10, as in our case.8 While the ACTH level was not measured
at the time of the CORTROSYN™ stimulation test, it is unlikely
that it would be totally suppressed by exogenous steroids given
3

Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

Figure 5 (A) MRI of the brain—axial T2 fluid-attenuated inversion recovery images at and above the level of the splenium of the corpus callosum
demonstrating the sequela of hypoglycaemic injury to the brain. Black arrows indicating focal areas of accentuated abnormal increased signal within
the cortex compatible with cortical laminar necrosis. Double black asterisks demonstrating injury to the white matter underlying the cortical injury.
The single black asterisk showing the late effects of injury to the left parieto-occipital region with atrophy along the left side of the splenium of the
corpus callosum and abnormal increased signal. The single white asterisk indicating mild ex vacuo enlargement of the atrium of the left lateral
ventricle due to adjacent parenchymal volume loss. (B) MRI of the brain—axial T2-weighted image at location as in (A) demonstrating cortical
volume loss (white arrows), injury to the underlying white matter (double white asterisk), atrophy and abnormal increased signal in the splenium of
the corpus callosum (single white asterisk) and ex vacuo enlargement of the atrium of the left lateral ventricle (single black asterisk).
for <3 weeks. There are several other lines of evidence that
support a central cause of the adrenal crisis-like presentation in
our case: (1) although primary adrenal insufficiency can cause
confusion, hypoglycaemia is more pronounced in hypopituitarism than in hypoadrenalism, due to loss of both cortisol and
growth hormone; (2) our case also revealed low levels of
insulin-like growth factor-I (IGF-I), a surrogate for growth
hormone, which regulates hepatic production of IGF-I; (3) in
pituitary-based (central) adrenal insufficiency, hyponatraemia
and hypoglycaemia are seen due to loss of ACTH and cortisol,
while in primary adrenal insufficiency hyponatraemia and

Figure 6 Chest X-ray—frontal projection demonstrating the
right-sided pneumothorax (white arrows).
4

hyperkalaemia (due to mineralocorticoid loss), and hyperpigmentation (due to high-ACTH levels), are more characteristic;
our case demonstrated neither hyperkalaemia nor hyperpigmentation and (4) thyroid testing also supported a diagnosis of
pituitary-derived adrenal insufficiency. In sick euthyroidism, the,
thyroid-stimulating hormone (TSH) level is usually normal or
low at presentation with low triiodothyronine and low or
normal free thyroxine (FT4) levels.9 In our case, the free
hormone levels were lower than normal, but the TSH level was
mildly elevated. If this were due to primary hypothyroidism,
with a FT4 level of 0.7, the TSH level would be expected to be
>15. Furthermore, the undetectable level of thyroperoxidase
antibody would argue against a diagnosis of chronic thyroiditis,
the most common cause of primary hypothyroidism. However,
in panhypopituitarism, the diagnosis is made with low levels of
free hormones and low or inappropriately normal TSH due to

Figure 7 Chest CT scan—axial lung window showing extensive
emphysematous changes with peripheral blebs and bullae anteriorly on
the right, indicating by white asterisks.
Waheed W, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2015-210816

Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

Figure 8 Neurofibromin pathways (modified from Diggs-Andrews and Gutmann24). Neurofibromin inhibits RasGTPase, which converts inactive Ras
(bound to GDP) to active Ras (Ras-GTP); loss of neurofibromin thus results in excessive Ras and downstream pathway components, thus promoting
upregulated cell growth and tumourigenesis seen as multiple systemic manifestations in neurofibromatosis 1 (NF1). Neurofibromin positively
regulates adenylyl cyclase, which is responsible for generation of cAMP; decreased cAMP and components of downstream pathways through
impaired cytoskeletal dynamics cause smaller growth cones and attenuated axons. Hypothalamic-pituitary axis involvement in NF1 is explained on
the basis of reduced cAMP levels and decreased activation of the cAMP responsive transcription factor (cAMP-response element binding protein,
CREB). Cognitive deficits are explained on the basis of: (1) increased GABA release from inhibitory neurons mediated through hyperactivation of
Ras-dependent MAPK-mediated synapsin 1 phosphorylation, which shifts the balance between excitatory versus inhibitory networks leading to
impaired synaptic plasticity required for learning and memory and (2) impaired cAMP-dependent cytoskeletal dynamics and synaptic efficacy.
Therapeutic interventions for cognitive and attention deficits might include blocking of Ras by lovastatin or release of dopamine by methylphenidate
(MAKP, mitogen-activated protein kinases; GABA, γ-aminobutyric acid; mTOR, mammalian target of rapamycin; PKA, protein kinase A).
abnormal glycosylation (although in some cases the TSH level
can be elevated, but usually not to >10).10 Once the adrenal
deficiency was addressed in our case, replacement with levothyroxine was started to treat fluid retention and bradycardia, and
to improve alertness.
Two critical regulators in the development of the
hypothalamic-pituitary axis are cAMP and the transcription
factor, cAMP-response element binding protein (CREB).11 A
number of key transcription factors and hormones expressed in
the pituitary gland have CREB-binding sites in their promoter
regions. Utilising an NF1 mouse model, Hegedus et al12 demonstrated that loss of neurofibromin expression in the hypothalamus decreased cAMP level and CREB activation, resulting in
reduced body weight and smaller anterior pituitary glands.
These rodents also exhibited reduced GH-releasing hormone,
pituitary GH and liver IGF-I production. These data suggest
that neurofibromin regulates somatic growth through the
hypothalamic-pituitary axis via modulation of cAMP, and this
helps explain the panhypopituitarism exhibited in our case.

Neurological manifestations
Our patient had evidence of left hemispheric stroke-like symptoms and possible seizures. Cerebrovascular and cardiovascular
complications of NF1 may manifest at all ages, with reports of
stroke as early as 7 weeks of life.13 Postulated mechanisms
include: (1) vasculopathy from loss of neurofibromin expression
in endothelial and smooth muscle cells of both intracranial and
extracranial vessels, resulting in increased intimal and medial
proliferation of vascular smooth muscle cells with malformation
or steno-occlusive disease;14 15 (2) dysregulation of vascular
homeostasis, manifesting as hypertension, via loss of neurofibromin expression in circulating, marrow-derived monocytes,
Waheed W, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2015-210816

which are critical to the regulation of vascular homeostasis16
and (3) congenital heart disease, through loss of neurofibromin
expression in cardiac myocytes.17 This improved scientific
understanding of the pathogenesis of disease has recently led to
the successful use of Ras inhibitors, and the kinase inhibitor,
imatinib, in mitigation of the neointimal vasculopathy in animal
models of NF1 disease.18 Seizures are also more common in
individuals with NF1 than in the general population. They can
occur at any age, are typically focal and may be associated with
brain tumour or infarction.19
An extensive workup in our case failed to identify any specific
cause for the left hemispheric stroke-like symptoms and seizures,
particularly any unequivocal CNS, cardiac, autoimmune or
vasculitis-related aetiology. The abnormal CSF findings, including elevated white cell count and protein, were probably on the
basis of a traumatic tap, as calculated using published correction
formulas.20 We ultimately attributed the seizures to severe hypoglycaemia resulting from panhypopituitarism-associated adrenal
insufficiency. Once treated for the underlying endocrine abnormalities, our patient remained seizure-free off antiepileptic
medications.

Radiological manifestations
The MRI findings were probably related to hypoglycaemia,
aggravated by a prolonged postictal state. While the typical MRI
finding in hypoglycaemic encephalopathy is bilateral symmetrical grey and white matter involvement, also reported is
restricted diffusion in a focal or unilateral cortical and adjacent
subcortical distribution, as seen in our patient.21 22 The likelihood that the cortical injury in our case was secondary to hypoglycaemia was further supported by the fact that the
neuroimaging abnormalities did not conform to a specific
5

Findings that shed new light on the possible pathogenesis of a disease or an adverse effect
vascular distribution, as would be expected with vascular compromise, but rather occurred in overlapping and multiple vascular territories.

Systemic manifestations
Other findings in our case included the discovery of plexiform
neurofibromas, a sacral spinal canal meningocele and prior episodes of pneumothorax. Plexiform neurofibromas develop in
30–50% of individuals with NF1; they arise from multiple
nerve fascicles and can extend into surrounding structures,
often causing local bone destruction. This was the likely explanation for the left hip pain and effusion in our case.23 Sacral
spinal canal meningocele, a rare association in NF1, was also
discovered in our case but was asymptomatic.
Our detailed case report underscores the need for a careful
laboratory assessment to screen for subclinical hypothalamicpituitary axis involvement in NF1, as well as in symptomatic
patients presenting with short stature, hypoglycaemia or signs of
adrenal insufficiency. To the best of our knowledge, this is the
first report of NF1-associated panhypopituitarism with central
adrenal insufficiency presenting as hypoglycaemic seizures and
stroke-like symptoms, which are hitherto unreported clinical
manifestations of NF1 disease. In such cases, prompt recognition and treatment with hormone supplementation and steroids
can prevent devastating complications.
In conclusion, our patient with NF1 displayed many rare and
uncommon characteristics of the disease, confirming multisystem involvement. In addition, he also exhibited some novel features of the disease, which could confound the diagnosis of
NF1 when determining the aetiology of certain atypical clinical
presentations. The combination of these rare systemic features
makes this a unique case of NF1, with many important lessons
for future diagnosis and even treatment of atypical cases.

Contributors WW, MHN, GBA, NB, M. Ali Babi* and Rup Tandan* all made
substantive contributions to the following: (1) conception and design, acquisition of
data, and/or analysis and interpretation of data; (2) Drafting and/or revising the case
report for important intellectual content; and (3) Final approval of the manuscript.
We have attached the BMJ authorship form including the names and signatures of
all five authors (*Institution/Department and contact information for Drs Babi and
Tandan is included with the cover letter that accompanies this submission).
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.

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6

Learning points

14

▸ Hypothalamic-pituitary axis involvement in neurofibromatosis
1 (NF1) can occur in the absence of sellar or suprasellar
pathology on brain neuroimaging. Screening for assessment
of hypothalamic-pituitary axis involvement in NF1 is
recommended in the absence of symptoms of
hypopituitarism, as well as in symptomatic patients
presenting with short stature, hypoglycaemia or signs of
adrenal insufficiency.
▸ Genetically engineered NF1 mouse models, together with an
understanding of neurofibromin pathways, provide critical
insights into the pathogenesis of NF1-associated central and
peripheral neurological and systemic manifestations, with
many therapeutic implications.
▸ Hypoglycaemic encephalopathy can present with stroke-like
symptoms. While the typical brain MRI finding in
hypoglycaemic encephalopathy is bilateral symmetrical grey
and white matter involvement, restricted diffusion in a focal
or unilateral cortical and adjacent subcortical distribution is
also seen.

15

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Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

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