Kallmann Syndromes MR Findings - Neuroradiology

l
Kallmann Syndromes MR Findings
John R. Knorr,r Ronald L. Ragland,t Rosalind S. Brown,2 and Nicholas Gelberl
PORPOSE: To evaluate patients with known hypogonadotropic hypogonadism, some with known
anosmia, for defective rhlnocephalon development that resulted in olfactory tract abnormalities,
an affliction known as Kallmann syndrome. METHODS: Six patients who clinically had hypogonadotropic
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.
RESOLTS: Olfactory tracts were not seen in three of the six cases; two of which had hypoplastic
olfactory sulci. CONCL0SIONS: Tl-weighted MR examination of the lnferior frontal region in the
coronal plane can help determine whether a patient with hypogonadotropic hypogonadism, with
or without clinically evident anosmia, is afflicted with Kallmann syndrome.
Index terms: Kallmann syndrome; Nervous system, disease; Olfactory lobe; Brain, magnetic
resonance; Brain, growth and development
AJNR 14:845-851, Jul/Aug 1993
Kallman syndrome is a form of congenital
hypogonadotropic hypogonadism with accompanying
hyposomia or anosmia (1). lts reported
incidence is on the order of 1 in 10,000 men and
1 in 50,000 women (2). This disease is believed
to be due to defective rhinocephalon development,
which results in hypoplasia or absence of
olfactory tract development (3). We used magnetic
resonance (MR) imaging to visualize the
olfactory tracts and to evaluate the olfactory sulci
in patients with this abnormality.
Materials and Methods
We examined six patients who appeared clinically to
have hypogonadotropic hypogonadism and anosmia, and
had a family history of Kallmann syndrome. The standard
examination included sagittal Tl-weighted and axial double-echo
T2-weighted images (for example, conventional
spin-echo ICSEI 400/11 (repetition time/echo time) and
2500/30 and 80, respectively). However, an additional
sequence was performed on each patient to evaluate the
Received Aug. 12, 1992; revision requested Sept. 17; final revision
received Jan. 19, 1993 and accepted Jan.26.
Departments of Radiologyt and Pediatric Endocrinology,2 (Jniversity
of /rlassachusetts lledical Center, Worcester, lvlA 01655.
Address reprint requests to: John R. Knorr, D.O., Department of
Radiology, University of Massachusetts Mdical Center, 55 Lake Avenue
North, Worcester, MA 01655
AJNR 1 4:845-85 l, July/Aus I 993 0 I 95-6 I 08 /93 / 1 404-0845
@ American Society of Neuroradiology
845
olfactory sulcus region further and to determine the presence
of the olfactory tract. Three-millimeter section thickness
with Tl-weighted technique (for example CSE 800/
12) images were obtained through the frontal lobe region
(see Fig. 1). Scans were performed on a 1.5-T system. The
images were evaluated by two neuropdiologists for the
appearance of the olfactory sulci as well as visualization of
the olfactory tracts (see Fig. 1). The coronal plane was
chosen for evaluation because the structures of interest are
well seen in this plane, and volume averaging, even with
3-mm section thickness, could not obscure them. As the
authors were unaware of a standard of depth for the
olfactory sulci, olfactory sqlcus depth was compared with
that of other sulci visualized in the same patient.
Results
The clinical and radiologic findings are displayed
in Table 1.
Case 1
The patient presented at age 16 years with
short stature and delayed puberty. He was the
product of a difficult delivery and clinically had
severe neonatal asphyxia. He also had severe
hydrops and hyperbilirubinemia, presumed to be
due to Rh incompatibility, requiring three exchange
transfusions. As a child, he had delayed
milestones, such as not walking or talking until 2
years of age, although it was not immediately
clear whether this was related to his neonatal
illnesses.

846
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AJNR: 14, JuIy/August 1993
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Fig. 1. A, Anatomic drawing of external view of the inferior frontal region.
8, Anatomic drawing of coronal section.
C, Normal coronal T1-weighted (SE 800/12) MR image.
The left olfactory bulb has been retracted in the drawing (A, small arrow). The
olfactory tract (large arrow) is seen on each image. The medial olfactory stria (curved
arrowl and lateral olfactory stria (/ong arrow\ are seen in A.
On presentation, his height was below the fifth
percentile, and weight was between the tenth and
twenty-fifth percentiles. His penis was small, and
his scrotum undervirilized. He remained cryptorchid,
although small testes (5 mm) were thought
palpable in the inguinal canals. He was unable to
perceive the odor of peppermint or lemon oil.
The patient was placed on monthly testosterone
and synthetic thyroid hormone therapy and
achieved full puberty after 4 years.
An MR examination of the brain was tailored
to the inferior frontal lobes (Fig. 2). Hypoplastic
and small olfactory sulci were noted. The olfactory
tracts and bulbs were not seen. The pituitary
gland was normal.
Case 2
The patient presented at 18 years of age with
short stature and delayed puberty. His family
history was notable for a maternal grandmother
who had anosmia, which she thought due to
chronic "sore throat." A maternal great uncle
never developed puberty and had no children.
A maternal aunt had a son with retardation, hypogonadism,
anosmia, and an undefined renal
affliction. Another maternal aunt bore a son
with cryptorchism, hypogonadism, and mental
retardation.
The patient's height and weight were below
the fifth percentile for his age. His penis was

AJNR: 14, July/August 1993
The olfactory sulcus lateral to the gyrus rectus
of the brain was absent unilaterally in one patient
(Fig. 2) with Kallmann syndrome and bilaterally
(Fig. 3) in the other patient. In the seven volunteers,
the gyrus rectus-olfactory sulcus regions
were readily identifiable and well formed.
Quantitative analysis of the temporal lobes of
the patients with Kallmann syndrome demonstrated
no significant difference in the temporal
lobe volume (228 + 5.6 cc) compared with that
in the healthy patients (233.47 + 36.5 cc). These
findings were duplicated in the hippocampal volumes
(27.0 + 0.9 cc vs 29.27 t 4.0 cc).
Intraobserver error for defining temporal lobe
volumes was 3Vo in one observer and 45% in
the second reviewer, For the olfactory bulbs and
tracts, the intraobserver variability was 10% and
KALLMANN SYNDROME 841
23% for the two reviewers. Interobserver variance
was3Vo for temporallobe volumes, butwas3}Vo
for olfactory bulbs and tracts. This is not unexpected
with such small volumed structures as the
bulbs and tracts.
No signal intensity abnormalities were visualized
in the temporal lobes or hippocampi in the
Kallmann syndrome patients.
Discussion
Kallmann described a familial occunence of
patients who failed to reach sexual maturity and
had a lack of the sense of smell (1). Testicular
biopsies have subsequently shown an arrest of
spermatogenesis with fibrotic infiltration (5). The
patients are completely anosmic by olfactory
Fig.2. A-D, Patient with Kallmann syndrome demonstrates absence of the olfactory bulbs and tracts with a flattened gyrus rectus
1Oy and no olfactory sulcus on the right side, but a normal-appearing gyrus rectus on the left side. (Figures proceed from anterior to
Posterior from A to 4 5OO/14.)

842 YOOSEM
14, July/August
Fig. 3. A-C, Second patient with Kallmann syndrome demonstrates
aplasia of the olfactory bulbs and tracts bilaterally on
these short repetition time images. The olfactory sulcus is not
well formed. Motion artifact limits image quality. (Figures proceed
from anterior to posterior from A to C;500/14.\
testing, but have normal intranasal examinations.
Short fourth metacarpal bones have also been
reported in Kallmann syndrome (5). Histopathologically,
the pituitary glands are reported to be
normal although the hypothalamus may be hypoplastic
(4).
The present study demonstrates the utility of
high-resolution surface-coil MR in evaluating patients
with congenital anosmia. MR showed aplasia
of the olfactory bulbs and tracts in both cases
of Kallmann syndrome and showed normal olfactory
structutes in control volunteers. The olfactory
nerve can be readily studied with MR and
can yield a complete analysis of the anatomy
governing olfaction.
Klingmuller et al evaluated the olfactory sulci
on axial MR images of the brain in four patients
with Kallmann syndrome (B). They found that
there was absence or hypoplasia of the olfactory
sulci of the frontal lobes, as seen on axial MR.
However, they did not evaluate the patients' olfactory
bulbs or tracts, possibly because of the
low spatial resolution of the MR scanner. A surface
coil was not employed to visualize the olfactory
bulbs and tracts.
Suzuki et al were the first to describe the
visualization of the olfactory bulbs and tracts on
MR scans (3). They found that with 256 x 256
matrix scanning, visualization of the olfactory
bulb was possible in 70 of 80 instances (87.5%).
However with 256 X 128 matrix scanning, only
34 of 50 (68%) olfactory bulbs were visualized.
The authors recommended coronalscanning with
large matrix size and decreased intersection gap
to visualize the olfactory bulbs optimally. The
authors suggested that this protocol could be
used to evaluate patients with Kallmann syndrome.
The olfactory system and the first cranialnerve
have received little attention in the radiologic
literature. Schellinger et al described their experience
with computed tomography in evaluating
patients with smell and taste disorders (9). They
found that encephalomalacic change in the low
frontal/gyrus rectus region and the temporal
lobes was the most common finding in patients
with olfactory deficits. These changes were most
common in patients with posttraumatic (53% of
patients) hyposmia. The yield by computed to-

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KALLMANN SYNDROME 843
mography in patients with congenital causes was
very low.
The olfactory nerve has been largely ignored
in imaging literature despite the association of
numerous neurologic diseases with smell dysfunction,
including Alzheimer disease, Parkinson
disease, schizophrenia, Huntington chorea, and
Korsakoff syndrome (10). Although there are a
number of causes of anosmia, including posttraumatic,
postinflammatory, degenerative disorders,
neoplasms (olfactory groove meningiomas, olfactory
neuroblastomas), and congenital etiologies
(11), total aplasia of the olfactory bulbs and tracts
is typically associated with Kallmann syndrome.
There are other congenital disorders associated
with decreased olfaction (12, 13), 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.
These lists of disease entities associated
with smell dysfunction are only partial; as smell
and taste testing has become more widespread,
the prevalence of lesions associated with hyposmia
has increased. Smell is one of the least
studied senses.
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
(4, 5). Since the olfactory system projects
fibers to the amygdala and hippocampus, we
analyzed the temporal lobe for volumetric
changes. Theoretically, without stimuli from the
olfactory apparatus peripherally, hypoplasia of
the hippocamPus or temporal lobes might be
expected. In fact, we found this not to be true,
although a larger sample size may be needed to
establish this point definitively. The hippocampi
and temporal lobe volumes were analogous to
those of control Patients.
With a surface coil placed over the bridge of
the nose and contiguous thin sections with large
matrix sizes, the olfactory bulbs and tracts should
always be seen in healthy patients. The absence
thereof in association with congenital anosmia
and hypothalamic hypogonadism supports the
diagnosis of Kallmann syndrome.
References
1. Kallmann FT, Schoenfeld WA, Barrera SE. The genetic asPects of
primary eunuchoidism. Am J Mental Deficits 1944;48:2O3-208
2. Meitinger T, Heye B, Petit C, et al. Definitive localization of X-linked
Kallmann syndrome to Xp22.3: close linkage to the hypervariable
repeat sequence CRI-S232. Am J Hum Genet 199O;47:664-669
3. Suzuki M, Takashima T, Kadoya lv\, Takahashi S, Miyayama S, Taira
S. MR imaging of olfactory bulbs and tracts. AJNR: Am J Neurorcdiol
1989;10:955-957
4. De Morsier Q, Gauthier C. Ln dysplasie olfacto-genitale. Bathol Biol
1963;11:7267-7272
5. Males JL, Townsend JL, Schneider RA' Hypogonadotrophic hypogonadism
with anosmia-Kallmann's syndrome. Arch Intern lvled
'1973:137:507-507
6. Doty RL, Shaman P, Dann M. Development of the University of
Pennsylvania Smell ldentification Test: a standardized microencapsulated
test of olfactory function (monogr). Physiol Behav
1984:32:489-5O2
7. Raya SP, Udupa JK, Warrett WA. A PC-based #D imaging system:
algorithms, software, and hardware considerations. Comp l4ed Imaging
Qrc Ph i c s 1990 ; 74 :353-37 O
8. Klingmuller D, Dewes W, Krahe T, Brecht C' Schweikert H0. Magnetic
resonance imaging of the brain in Patients with anosmia and hypothalamic
hypogonadism (Kallmann's syndrome). J Clin Endocrinol
hleta b 7987 i65 :587 -584
9. Schellinger D, Henkin RT, Smirniotopoulos JG. CT of the brain in
taste and smell dysfunction. AJNR: Am J Neurorcdiol 1983;4:752'
t)4
10. Doty RL. Olfactory dysfunction in neurodegenerative disorders' In:
Cetchell TV, Doty RL, Bartoshuk LM, Snow JB, eds. Smell and taste
in heatth and disease. New Yorkr Raven, 1991:35-751
11. Deems DA, Doty RL, Settle RG, et al. Smell and taste disorders; a
study of 750 patients from the University of Pennsylvania Smell and
Taste Center. Arch Otolaryngot Head Neck Surg 1991;717:5't9-528
12. Warner MD, Peabody CA, Berger PA. Olfactory deficits and Down's
syndrome. Biol Psychiatry 1988;23:833-836
13. Probst FP. The prosencephalies' Berlin: Springer-Verlag, 7979:46

AJNR: 14, July/August 1993
KALLMANN SYNDROME 851
in normal patients, visualization of the olfactory
tracts. Hypoplasia of the olfactory sulci or nonvisualization
of the olfactory tracts along with the
clinical findings of hypogonadotropic hypogonadism,
anosmia, or heredity (family history of Kallmann
syndrome) is consistent with the presence
of Kallmann syndrome.
Acknowledgments
Anatomic illustrations by Laura Perry, MD. Special
thanks for manuscript preparation to Kathy Delongchamp.
References
1. Kaltmann FJ, Schoenfeld WA, Barrera SE' The genetic asPects of
primary eunuchoidism. Am J l4ent Defic 7944;48:203-270
2. Jones JR, Kemmann E. Olfacto-genitaldysplasia in the female. Obstet
G yn ecol An n 797 6 ;5 :443-445
3. Maestre de San Juan A. Teratologia: falta total de los nervios
olfactorios con anosmian en un individuo en quien existia un atrofia
congentia de los testiculos y miembro v.ril. EI Siglo /4ed 1856;3:211-
zzl
4. lvloorman JR, Crain B, Osborne D. Kallmann's syndrome with associated
cardiovascular and intracranial abnormalities. Am J /vled
'1984:77:369-372
5. Kovacs K, Sheehan HL. Pituitary changes in Kallmann's syndrome: a
histologic immunocytologic, ultrastructural and immunoelectron microscopic
study. Fertil Steril 1982;37:83-89
6. Bardin CW, Ross GT, Rifkind AB, Cargille CM, LiPsette MB. Studies
of the pituitary-leydig cell assessing young men with hypogonadotropic
hypogonadism and hyposmia. Comparison wlth normal men,
prepuberal boys and hypopituitary parents. J Clin Invest
1969:48:2O46
7. Lieblich JM, Rogol AD, White BJ, Rosen SW. Syndrome of anosmia
with hypogonadotroPic hypogonadism in (Kallmanns syndrome).
Clinicaf and laboratory studies in 23 cases. Am J Med '1982;73:
506-519
8. Turner RC, Bobrow M, Bobrow LG, et al. Cryptorchidism in a family
member with Kallmann's syndrome. Proc R Soc Ned'1974;67:33-35
9. Rogol AD, et al. HLA compatible paternity in two "fertile eunuchs"
with congenital hypogonadotropic hypogonadism and anosmia (the
Kallmann's syndrome). J Clin Endocrinol Neab 1980;38:275
10. Klingsmuller D, Dewes W, Krahe Th, Brecht G, Shweikert H. Alagnetic
resonance imaging of the brain in Patient's with anosmia and hypothalamic
hypogonadism (Kallmann's syndrome). J Clin Endoctinol
fie tab 1987 :62:58.1 -584
11. lvlalat J, Virapongse C. Brain calcification in Kallmann's syndrome.
Computed tomograPhic appearance. Pediatr Neurosci'1985-
1986:72:257-259
12. Von Dewes W, Krahe Th, Klingmuller D, Harder Th. MR tomographie
beim Kallman syndrom. Fortschr Rontgenstr 7987 :147 :4OA-442
13. Williams PL, Warwick R (eds). Aray's anatomy.36th ed. Philadelphia:
WB Saunders, 1986:994-995