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

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

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

Normal

• 3.0 T STIR Coronal• 3.0mm slice thickness,

0.35mm resolution• Healthy volunteer

Olfactory bulbs

Olfactory sulci

Straight gyrus

Medial orbital gyrus

Normal (Coronal STIR- Anterior to Posterior Imaging)

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.

Normal Sulci, Absent BulbsDemonstrated 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 2011:94:209-217.

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.