Kallmann syndrome: MRI findings.

Kallmann syndrome (KS) is a disease clinically characterized by the association of hypogonadotrophic hypogonadism and anosmia or hyposmia. It is a neuronal migration disorder. Magnetic resonance (MR) imaging is used to visualize the olfactory tracts and to evaluate the olfactory sulci. Five patients who clinically had hypogonadotrophic hypogonadism were examined by MR. Thin coronal images of the interior frontal region were used to determine presence or absence of olfactory tract and to evaluate the olfactory sulci.

INTRODUCTION

Kallmann syndrome (KS) is an inherited disorder characterized by hypogonadotrophic hypogonadism and anosmia or hyposmia. It was described by Maestre de San Juan in 1856 and characterized as a hereditary condition by Franz Josef Kallmann in 1944.[1] Actually, it is designated as olfactogenital dysplasia to emphasize the association between agenesis of the olfactory bulbs and hypogonadism. Associated with hormonal assays, magnetic resonance imaging (MRI) occupies a place of choice in the hierarchy of tests. In fact, the MRI findings in KS are characteristic, and MRI is a useful adjunct to the diagnosis. We report the MR findings in 5 patients with clinical and laboratory evidence of KS.

MATERIALS AND METHODS

We examined 5 patients (Age range 19-35 years) who appeared clinically to have hypogonadotrophic hypogonadism (Serum LH < 1.5 IU/L, Serum FSH <1.5 IU/L, Testosterone <20 ng/dl) and complete anosmia, and had a family history of Kallmann syndrome. They were evaluated with MR imaging. The standard examination included coronal T1-(TR/TE 600/15) and T2-(TR/TE 4500/90) weighted images from the anterior margin of the frontal sinus to the hypothalamus. Images were obtained at 3 mm thickness with 0.3 mm interslice gap. In addition, axial T1- and T2-weighted and sagittal T1-weighted images were obtained. Scans were performed on a 1.5-T GE system.

RESULTS

The olfactory sulci and bulbs were assessed as normal, hypoplastic, or absent. (Sulci were assessed as hypoplastic in comparison to rest of cerebral sulci). Pituitary gland was also evaluated, and anterior pituitary was assessed as normal or hypoplastic (Height < 4 mm). Abnormalities of olfactory sulci and bulbs were noted in all patients. All patients had absent olfactory bulbs [Figures 1 and 2]. Olfactory sulci were absent in 3 patients and hypoplastic in 2 patients [Figure 1]. Anterior and posterior pituitary appeared normal in all patients. There was a correlation between the imaging findings, particularly the absence of olfactory bulbs, and the degree of anosmia. In fact, the olfactory bulbs aplasia was found in the 5 patients presenting complete anosmia. There weren’t any other associated anomalies, either cerebral or extra-cerebral.

Figure 1

Coronal T2-weighted MR image through the anterior fossa. Olfactory bulbs are absent, and the left olfactory sulcus is hypoplastic

Figure 2

Coronal T2 images through the frontal lobes demonstrate abnormal anatomy with absence of the olfactory bulbs. Olfactory sulcus, the gyrus rectus, and medial orbital gyrus are normal

DISCUSSION

The Kallmann syndrome typically combines severe hypogonadotrophic hypogonadism with a complete absence of the sense of smell (anosmia).[2] When anosmia is absent, it is simply referred to as idiopathic hypogonadotrophic hypogonadism (IHH).

KS is an uncommon disorder due to abnormal migration of olfactory axons and gonadotropin-releasing hormone-producing neurons.[1] Cells that differentiate into Gonadotrophin-releasing hormone (GnRH) secreting neurons originate from within embryonic olfactory epithelium and migrate along fascicles of vomeronasal and terminalis nerves into forebrain. This migration of GnRH neurons does not occur in KS, resulting in GnRH deficiency with different degrees of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiencies.[3]

In addition, failed neuronal migration from the lateral olfactory placode along the olfactory fila to the forebrain results in aplasia or hypoplasia of the olfactory bulbs and tracts.[4]

KS is a rare genetic disorder with an estimated prevalence of one in 10,000 males and one in 50,000 females.[56] Both clinically and genetically, Kallmann is heterogeneous; and although most cases are sporadic, all modes of inheritance have been described.[56] Most cases have been recorded among men as it is an inherited disorder with a specific gene location on the X chromosome.

Clinical diagnosis of KS in adults is depending on the co-existence of anosmia with signs of hypogonadotrophic hypogonadism. However, the diagnosis may be difficult to establish in patients of pre-pubertal age and may require genetic testing and MRI. Moreover, even though anosmia is present from birth, it is not apparent to either the parents or the child. The diagnosis is only made when puberty does not occur. Occasionally, the diagnosis is made earlier due to investigation of other associated anomalies, including: cardiovascular abnormalities, renal agenesis, cryptorchidism, midline defects, sensorineural deafness, small anterior lobe of the pituitary gland, short fourth metacarpal and facial anomalies (cleft lip and palate, enlarged paranasal sinuses, septo-optic dysplasia).[78] The biological investigations show a low level of the gonadotrophin (FSH, LH, testosterone, and estradiol (in females)), whereas other pituitary hormones are normal.

MRI is the modality of choice in assessing the absence of olfactory bulbs. In fact, the introduction of MRI into clinical practice in the early 80s has greatly improved the value of radiological approach to olfactory disorders by allowing precise depiction of the olfactory bulb and olfactory tract, and very sensitive detection of even very little damage to the central projection areas of the sense of smell. In the mid-90s, the pioneering works by Yousem et al.[9] demonstrated the ability of MRI to yield accurate volumetric measurements of the olfactory bulb in various pathological conditions. This had major clinical relevance because the olfactory bulb is a unique central nervous organ, in which size and function closely correlate.[10]

A coronal scanning with large matrix size and decreased intersection gap is recommended to visualize the olfactory bulbs optimally. It is the best suited plane for anatomical olfactory tract overview, detection of parenchymal lesions and olfactory bulb volumetry.[710] Axial MR images allow the visualization of the olfactory sulci of the frontal lobes; however, they did not evaluate the patients’ olfactory bulbs or tracts, which are optimally visualized in coronal planes.[11] The paramedian sagittal sequences in thin slices objectify the tract within the olfactory sulcus, but their lower sensitivity make them more useful to the study of the pituitary gland, the corpus callosum or the posterior fossa. Gadolinium injection is not usually necessary. In some cases, it helps differentiate the bulbs of the nasal mucosa, which is enhanced.

High resolution coronal fast spin echo T2- and T1-weighted images are the preferred sequences for a morphologic evaluation of the olfactory system.[121314] Olfactory bulbs are normally seen as well-defined structures along cribriform plate. Olfactory sulci are seen between gyrus rectus and medial orbital gyrus.[15]

Held et al.[16] studied olfactory fibers, bulb, tract, and sulcus by MRI in 30 healthy volunteers, using 2D turbo spin echo sequences, 3D MP-RAGE (Magnetization Prepared Rapid Gradient Echo), and 3D CISS (Constructive Interference Steady State). They found that both 3D sequences were superior to 2D turbo spin echo and that MP-RAGE was better than CISS, since it enables also the detection of olfactory fibers. Therefore, they recommend including the MP-RAGE sequence in an MR imaging protocol of the olfactory nerve.

MRI findings in KS include absent or hypoplastic olfactory sulci and olfactory bulbs. A hypoplastic anterior pituitary may also be seen. Koenigkam-Santos et al.[17] found that olfactory bulb and sulcus aplasia were the most common findings in KS patients, and demonstrated agreement between MRI findings, especially the presence of bulb aplasia and anosmia. This was consistent with our findings.

Vogl et al.[5] documented the ability of MR imaging to demonstrate abnormalities of the olfactory pathway in patients with congenital anosmia. Eighteen patients diagnosed with KS and 10 patients diagnosed with IHH were included in that study. In 17 of the 18 patients with KS, the olfactory bulbs and tracts were absent; 8 of these 18 individuals had normal olfactory sulci. However, olfactory bulbs and tracts were present in the 10 patients with IHH. In other studies of patients with KS,[9] complete absence or hypoplasia of the olfactory bulbs and tracts was the predominant finding. The olfactory sulci were variably aplastic, hypoplastic, on normal.

There are other congenital disorders associated with decreased olfaction,[18] including holoprosencephaly, Down syndrome, Turner syndrome, and Riley-Day syndrome. However, complete absence of the olfactory bulbs and tracts has been well-documented only in Kallmann syndrome.

Pathologically, absence of the olfactory bulbs and tracts has been described with Kallmann Syndrome. However, there may be a variable degree of rudimentary olfactory apparatus present.[18]

Treatment is primarily aimed at restoring normal pubertal development and in some case normal fertility. The former can be achieved by administration of exogenous sex steroids, appropriate to the gender of the patient. If fertility is desired, pulsed gonadotrophin-releasing hormone can be administered with variable success.[18]

Our patient did not present with cryptorchidism. In KS with cryptorchidism (present in 73% of cases), chorionic gonadotropin therapy improved the cryptorchid state without the need of surgery. In such cases, medical therapy may benefit and surgery may not always be the first treatment to offer.[1]

Concerning olfactory disorders, usually there is no cure available. MR imaging can definitively answer questions regarding possible restoration of the sense of smell by revealing a complete absence of the means to regain olfaction, but even in individuals who have hypoplastic olfactory bulbs and tracts, the likelihood of restoration of function is slight.[19]

CONCLUSION

MRI is a useful tool to demonstrate abnormalities of the olfactory system, which are always present among patients suffering from Kallmann syndrome. MRI can also show, at the same time, a possible associated brain abnormality.