Transcript Kallmann Syndrome: An Investigation of the

Kallmann Syndrome: An
Investigation of the Olfactory Sulci
Mariza Clement MD MSE1, Angela Delaney MD2,
and John Butman MD2
George Washington University Hospital1, Washington, DC
National Institute of Health2 , Washington, DC
PURPOSE
• Kallmann syndrome is a rare genetic disorder characterized
by hypogonadotropic hypogonadism and hyposmia [1,2].
• Currently, the diagnosis of Kallmann syndrome is reliant on
MRI to establish the morphology of the olfactory bulbs
[1,3,4].
• When high resolution imaging of the skull base is
unavailable, the presence of the olfactory sulcus has been
used as an indirect marker of normal olfactory bulb
development.
• We examined whether the olfactory sulcus is indeed a
reliable marker for the development of the olfactory bulb.
BACKGROUND
• Kallman syndrome is a sporadic and inherited
chromosomal disorder, resulting in olfactogenital
dysplasia affecting 1:10,000 males and 1:50,000
females1,4.
• Failed neuronal migration from olfactory placode
to the hypothalamus1,4.
– Embryonic olfactory epithelium gives rise to cells that
differentiate into Gnrh secreting neurons.
– Abnormal migration of olfactory neurons and
gonadatropin-releasing hormone producing neurons.
– Failed migration causes rhinencephalon
hypoplasia/aplasia as well as GnRH deficiency.
Genetics
• Variable. Sporadic (majority) as well as X linked, autosomal
recessive and autosomal dominant3,5.
• Kal1 gene was the first mutated gene identified on the X
chromosome in many inherited forms.
• Kal1 gene encodes for anosmin-1, a protein with neuronal
cell adhesion properties, involved in neuronal migration,
and outgrowth of axons3.
• Speculated failure of anosmin-1 to direct olfactory nerves
and GnRH producing neurons during development.
• Mutations in other genes identified involved in neuronal
migration: fibroblast growth receptor 1 (FGFR1),
prokineticin-2 (PROK2) and prokineticin receptor-2
(PROK2R)3.
Olfaction
• Olfactory receptor neurons are
located in the nasal mucosa
epithelium. Axon bundles
travel through the cribiform
plate to the olfactory bulb.
• Olfactory bulb is the ganglion
of the olfactory nerve and
collects sensory afferents.
• Olfactory tract connects the
bulb with the perforate
substance and olfactory
cortex2,6.
Olfactory Sulci Development
• No studies to date exist on the embryologic
development of the human olfactory sulcus.
• Hypothesized that formation of the olfactory
sulcus depends on the presence of an
olfactory tract.
• Neuronal migration is thought to originate
from the olfactory placode which would in
turn affect the development of olfactory tracts
and olfactory sulci.
Hyposmia and Anosmia
Pennsylvania Smell Inventory
Test
• Quantifies ability to detect
odors by a threshold level
• Consists of four booklets
with a “scratch and sniff”
strip embedded with odor
on each page. The odor is
scratched with a pencil then
the patient selects the odor
from 4 multiple choices.
• Total 40 questions.
• Score is compared to
normative age and gender
matched base.
• Olfactory function is
graded- mild, moderate,
severe hyposomia or
anosmia.
• Self reported subjective
hyposmia/anosmia.
• Clinical evaluation.
Materials & Methods
• Seventeen males with Kallmann syndrome (15-67, mean
age=26) and nineteen healthy volunteers were enrolled and
consented under an IRB approved protocol including MRI at
3.0 T (Philips Achieva, SR 3.3.3).
• Coronal STIR images were oriented perpendicular to the
anterior skull base and extended from the sella through the
nasion (3.0mm slice thickness, 0.35mm resolution).
• The olfactory bulbs and sulci were characterized as either
normal, hypoplastic or absent. Hypoplastic sulci were
further classified by (1) superior-inferior and (2) anterior
posterior continuity.
RESULTS
MRI findings in patients
with hypogonadism and
hypo/anosmia
N= Normal
A= Absent
H (SI)= Hypoplastic
superior inferiorly
H (d-AP)= Hypoplastic,
discontinuous Anterior
posteriorly
Patient
Right
Olfactory
Bulb
Left
Olfactory
Bulb
Right
Olfactory
Sulcus
Left
Olfactory
Sulcus
1
H
A
N
N
18
2
A
A
A
H
17
3
A
A
N
N
21
4
A
A
H (SI)
H (d-AI)
39
5
A
A
H (d-AP)
H (d-AP)
19
6
A
A
H (d-AP)
H (d-AP)
24
7
A
A
N
N
30
8
H
A
H (SI)
H (d-AP)
15
9
A
A
N
H
31
10
A
A
N
N
16
11
H
H
N
N
17
12
A
A
N
H
52
13
A
A
N
H
67
14
A
A
H(SI)
H (SI)
15
15
A
A
N
N
20
16
A
A
H (d-AP)
H (SI)
36
17
N
A
N
H (d-AP)
18
Age
Normal
• 3.0 T STIR Coronal
• 3.0mm slice thickness,
0.35mm resolution
• Healthy volunteer
Normal (Coronal STIR- Anterior to
Posterior Imaging)
RESULTS
Morphologically normal olfactory sulci were present in 6 (35%)
patients with absent or hypoplastic olfactory bulbs.
Emissary veins are visualized in the expected location of the
olfactory bulbs within the olfactory grooves of the anterior
cranial fossa.
Normal Sulci, Absent Bulbs
Demonstrated in 35% of patients with Kallmann syndrome.
Hypoplastic Sulci, Absent Bulbs
•53% of patients with Kallmann
syndrome had absent bilateral bulbs and
hypoplastic sulci.
•In this example, the sulci are
discontinuous anterior to posterior
(rudimentary sulci present posteriorly)
RESULTS
The left olfactory bulb was absent in 16 patients and hypoplastic in 1 patient. The
left olfactory bulb was abnormal in all enrolled patients with Kallmann syndrome.
The right olfactory bulb was absent in 13 patients and hypoplastic in 3 patients.
RESULTS
The left olfactory sulcus was hypoplastic in 11 patients, but never entirely absent.
The right olfactory sulcus was hypoplastic in 7 patients and only absent in 1
patient.
Conclusion
• In our population, normal bulbs were nearly
always associated with a normal sulcus.
• However, the converse was not true. Normal
olfactory sulci were present in 35% of subjects
with absent or hypoplastic bulbs.
• Therefore, direct imaging of the bulbs is required
to exclude Kallmann syndrome. Reliance on the
olfactory sulci as an indirect marker of bulb
development is not adequate.
Conclusion
• Our findings also demonstrate that the left
olfactory bulb and the left olfactory sulcus
were more affected than the right in patients
with Kallmann syndrome.
• There is growing evidence that in humans
lateral differences exist in processing olfactory
information7, where the right hemisphere is
more involved in processing olfactory stimuli.
References
1.
Manara R, Savalaggio A, Favaro A, et al.Brain changes in Kallman’s syndrome.AJNR American Journal of
Neuroradiolol 2014: 1700-1706.
2.
Abolmaali N, Gudziol V, Hummel T. Pathology of the olfactory nerve. Neuroimag Clin N Am 2008:18:233-242.
3.
Koenigkam-Santos M, Santos A, Versiani B, et al. Quantitative magnetic resonance imaging evaluation of the
olfactory system in Kallman Syndrome: correlation with a clinical smell test. Neuroendocrinology 2011:94:209217.
4.
Zaghouani H, Slim I, Zina MB, et al. Kallman syndrome: MRI findings. Indian Journ of Endocrinology and
Metabolism 2013:17(7):142-145.
5.
Truwit C, Barkovich J, et al. MR Imaging of Kallmann Syndrome, a Genetic Disorder of Neuronal Migration
Affecting the Olfactory and Genital Systems. AJNR American Jounral of Neuroradiol 1993:14 827-838.
6.
Reeves A and Swenson R. Disorders of the Nervous System, A Primer. 2008. Retrieved from
http://www.dartmouth.edu/~dons/part_1/chapter_3.html.
7.
Abolmaali N, Hietchold V, et al. MR Evaluation in Patients with Isolated Anosmia Since Birth or Early Childhood.
syndrome.AJNR American Journal of Neuroradiolol 2002: 23: 157-163.