kallmann syndrome: an investigation of the olfactory sulci mariza clement md mse 1, angela delaney...
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Kallmann Syndrome: An Investigation of the Olfactory Sulci
Mariza Clement MD MSE1, Angela Delaney MD2, and John Butman MD2
George Washington University Hospital1, Washington, DCNational Institute of Health2 , Washington, DC
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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RESULTS
Patient
Right Olfactory Bulb
Left Olfactory Bulb
Right Olfactory Sulcus
Left Olfactory Sulcus Age
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
MRI findings in patients with hypogonadism and hypo/anosmia
N= NormalA= AbsentH (SI)= Hypoplastic superior inferiorlyH (d-AP)= Hypoplastic, discontinuous Anterior posteriorly
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Normal
• 3.0 T STIR Coronal• 3.0mm slice thickness,
0.35mm resolution• Healthy volunteer
Olfactory bulbs
Olfactory sulci
Straight gyrus
Medial orbital gyrus
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Normal (Coronal STIR- Anterior to Posterior Imaging)
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RESULTSMorphologically 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.
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Normal Sulci, Absent BulbsDemonstrated in 35% of patients with Kallmann syndrome.
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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)
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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.
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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.
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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.
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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.
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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 2011:94:209-217.
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.