Sensory cranial nerves
Before we continue our discussion of the cranial nerves, perhaps we should address the elephant in the room. It’s quite large and loud, and awfully difficult to miss… Can’t you see it? Smell it? How about hear it? How are you able to do this?
Actually, forget the elephant; the best way to answer these questions may be just to continue our exploration of the cranial nerves. Sight, smell and sound signals, as well as vestibular signals informing our sense of balance, are all carried by sensory cranial nerves. Although exceptionally complex, the following article attempts to delve a little deeper into the sensory cranial nerves responsible for transmitting signals to our brain for interpretation, informing us of the world that surrounds us (including, of course, the elephant).
- Cranial nerves
- Olfactory nerve
- Optic nerve
- Vestibulocochlear nerve
- Terminal nerve
- Clinical notes
- Related diagrams and images
The cranial nerves (CN) are twelve pairs of nerves that, with the exception of the spinal accessory nerve (CN XI), originate in the brain and contribute to the peripheral nervous system (PNS), supplying the head and neck.
These 12 paired nerves, and their main branches, include:
- The olfactory nerve (CN I)
- The optic nerve (CN II)
- The oculomotor nerve (CN III)
- The trochlear nerve (CN IV)
- The trigeminal nerve (CN V)
- The abducens nerve (CN VI)
- The facial nerve (CN VII)
- Temporal branch
- Zygomatic branch
- Buccal branch
- Mandibular branch
- Cervical branch
- The vestibulocochlear nerve (CN VIII)
- The glossopharyngeal nerve (CN IX)
- The vagus nerve (CN X)
- The spinal accessory nerve (CN XI)
- The hypoglossal nerve (CN XII)
Of these nerves, some have special sensory functions, some have somatic sensory functions, some have autonomic functions, some have somatic motor functions, and some have a combination of the aforementioned functions. The olfactory nerve, the optic nerve, the facial nerve, the vestibulocochlear nerve, the glossopharyngeal nerve, and the vagus nerve each play roles in special sensory functions (i.e. olfaction, vision, gustation, audition, and balance).
The trigeminal nerve (all three branches: the ophthalmic, maxillary, and mandibular) and the glossopharyngeal nerve play roles in somatic sensory functions.
The oculomotor nerve, the facial nerve, the glossopharyngeal nerve, and the vagus nerve have important autonomic functions.
Finally, the oculomotor nerve, the trochlear nerve, the mandibular branch of the trigeminal nerve (V3), the abducens nerve, the facial nerve, the glossopharyngeal nerve, the vagus nerve, the spinal accessory nerve, and the hypoglossal nerve are responsible for motor functions.
One way to simplify efforts to understand each nerve and each of its separate functions is to separate the 12 cranial nerves into smaller groups. This can be done by first dividing the overarching group of 12 nerves into nerves which are considered to have primarily motor functions; nerves which are considered to have primarily sensory functions; and nerves which have a combination of both motor and sensory components.
This article will provide an introduction to the cranial nerves which are considered primarily sensory nerves, which includes the olfactory nerve, the optic nerve, and the vestibulocochlear nerve. The terminal nerve (CN 0, or CN N), although not conventionally included in the list of cranial nerves, will also be discussed among this group.
Even at very low concentrations, humans can detect odors chemically. These chemicals stimulate chemoreceptors attached to cell bodies in the olfactory mucosa, a region of specialized epithelium in the nasal cavity located just below a sheet of bone in the skull called the cribriform plate. These bipolar sensory receptor neurons each give off single dendrites at one end that terminate as olfactory knobs in the olfactory mucosa, and single unmyelinated special visceral afferent axonal fibers which transmit olfactory information to the brain for interpretation at the other end.
Rather than coalescing into a single structure, it is small bundles of these individual axons which make up the olfactory nerve (CN I). These olfactory nerve bundles enter the brain via the cribriform plate of the ethmoid bone and transmit information to neurons in the olfactory bulb on the ipsilateral (same) side.
The olfactory bulb lies on the inferior (ventral) surface of the prefrontal cortex of the forebrain bilaterally. It receives signals from the olfactory nerve and is the first part of the central nervous system in which these signals are processed. The axons of the olfactory sensory neurons spread themselves over the surface of the bulbs, forming an olfactory nerve layer. The glomerular layer, located near the surface of the bulb, contains clusters of nerve terminals of the olfactory sensory neurons as well as dendrites of various other cell types. Mitral and tufted cells in particular are excited by the olfactory sensory neurons, and transmit the signals they receive from the olfactory bulbs to forebrain structures for continued processing. They do this via axonal bundles referred to as the olfactory tracts. There are two olfactory tracts or branches on each side: the medial and lateral olfactory striae.
The lateral pathway sends olfactory information to the temporal lobe and nearby limbic structures: these axons project to the primary olfactory cortex (piriform cortex), amygdala, and entorhinal cortex located in the temporal lobe. Neurons in the piriform cortex, amygdala, and entorhinal cortex project to the prefrontal cortex. Neurons in the entorhinal cortex, via the perforant fiber pathway, also project to and modulate the functions of the hippocampus, a structure located in the medial temporal lobe associated with memory formation. Although some olfactory projections reach the prefrontal cortex without passing through and synapsing in the thalamus, the piriform cortex does send some axons to the the mediodorsal thalamic nucleus which in turn projects to a number of regions in the frontal lobe, including the prefrontal cortex.
The medial pathway contains axonal fibers of some mitral and tufted cells which project to a number of medial limbic structures, including the substantia innominata, medial septal nucleus, and bed nucleus of the stria terminalis. Some mitral and tufted cell axons also project to the anterior olfactory nucleus, a region of cell bodies within the posterior part of each olfactory bulb. Neurons in the anterior olfactory nucleus subsequently gives off axons which also travel via the medial olfactory pathway; but instead of remaining on the ipsilateral side, these fibers cross to the opposite cerebral cortex via the anterior commissure (a fiber bundle rostral to the descending column of the fornix) and synapse on the contralateral olfactory bulb.
Olfactory projections to the limbic system mediate affective (emotional) aspects of olfactory sensation; whereas descending projections to the hypothalamus, midbrain periaqueductal gray, and autonomic centers of the brainstem and spinal cord mediate autonomic responses to olfactory stimuli.
Pathway and parts
The optic nerve (CN II) is the cranial nerve that carries visual information, allowing us to see the world around us. It is made up of special sensory afferent fibers which transmit visual information from the retina, the innermost layer of the eye, to the brain. The signals transmitted by this nerve are first received by specialized receptors in the retina called photoreceptors, of which there are two types: rods, which respond to light, and cones, which detect color.
The retina represents a map of the visual field in which everything is reversed and upside down due to the angles at which light enters the eyes. As a result, the left visual field falls on the right side of the retina, the right visual field falls on the left side of the retina, the upper visual field falls on the lower side of the retina, and the lower visual field falls on the upper side of the retina. As such, the inferior, inner (nasal) quadrant of the retina corresponds to the upper, outer quadrant of the visual field, etc.
The axonal processes of rods and cones synapse in the retina with other cells known as horizontal cells and bipolar cells, which process signals from the photoreceptors. Ganglion cells are the only retinal cells able to fire action potentials, and it is their axons which travel toward the posterior pole of the eye and coalesce, preparing to exit the eye at the optic disc.
The optic disc is a pale circular region in the retina, colloquially known as the blind spot because it has no photoreceptors and thus is incapable of picking up visual stimuli. Despite this, we do not have an obvious hole in our visual fields because our brain essentially fills in the blank (although the blind spot can be demonstrated by looking straight forward with one eye closed and holding up one’s pointed index finger on the hand on the opposite side as the closed eye approximately a foot from one’s open eye. Then, moving the index finger from the midline slowly into the periphery; when the top of the finger disappears, you have found your blind spot).
At the optic disc, the ganglionic axons become myelinated and exit each eye as the optic nerves. The optic nerves are additionally covered by extensions of the meninges which cover the brain. The optic nerves enter the cranial cavity via the optic canals, and enter the brain at the pre-optic region of the diencephalon. Upon entering the brain, the optic nerves join to form an “x”-shaped structure called the optic chiasm. It is here that the fibers extending from the inner (nasal) half of each retina cross to the contralateral side, whereas fibers extending from the outer (temporal) half of each retina remain ipsilateral and uncrossed. This ultimately means that each cerebral hemisphere receives information on the opposite visual field, and does so by receiving some information from both eyes.
The fibers then depart the optic chiasm as optic tracts, with the left optic tract containing axons from the temporal hemiretina of the left eye and nasal hemiretina of the right eye, and the right optic tract containing axons from the temporal hemiretina of the right eye and nasal hemiretina of the left eye.
These tracts project to the lateral geniculate nuclei (LGN) of the thalamus on their corresponding sides, where they synapse on layers of cell types finely attuned to detect different types of visual stimuli. The ventral magnocellular layers contains large cells focused on movement and location, while the dorsal parvocellular layers contains smaller cells focused on detail, color, etc. Axons of cells in the magnocellular layers project to more dorsal (superficial) regions of the primary visual cortex (the “where” pathway), whereas axons of cells in the parvocellular layers project to more ventral (deep) regions of the primary visual cortex (the “what” pathway).
The primary visual cortex (Brodmann’s area 17) is the cortical region ultimately dedicated to the perception of the visual stimuli transmitted by the optic nerve.
Optic Nerve: Pupillary light reflex
The pupillary light reflex is the reflexive constriction of the pupils in response to light. There are two main components of this reflex: an afferent (sensory) component involving the optic nerve and an efferent component involving the oculomotor nerve. The reflex is triggered when cells in the retina are activated by light, sending signals down the optic nerve (the afferent component of the reflex). Optic nerve fibers project and synapse in the pretectal region of the midbrain, which contributes to the circuit for the pupillary light reflex.
Neurons from the pretectal region then project and synapse in the oculomotor nucleus. From here, preganglionic parasympathetic neurons from the Edinger-Westphal nucleus send axons via the oculomotor nerve to synapse with postganglionic neurons in the ciliary ganglion, which sends signals to the sphincter pupillae muscle to contract and leads to constriction of the pupil (the efferent component of the reflex).
The vestibulocochlear nerve (CN VIII) transmits information regarding two very important senses: audition and balance. Auditory information is transmitted by the cochlear part of the vestibulocochlear nerve, and information on balance is transmitted by the vestibular part of the vestibulocochlear nerve.
Auditory Signals and the cochlear component
Our ability to perceive sound begins with specialized receptors called hair cells, located in a structure called the Organ of Corti in the inner ear. These cells are triggered when air pressure waves incite vibrations in the tympanic membrane, which subsequently oscillate the stapes bone against the oval window of a structure called the cochlea.
The cochlea is filled with fluid called perilymph that is non-compressible, so movement of the stapes against the oval window by air pressure waves transmits those pressure waves into the cochlea, leading to oscillatory movement of the perilymph. This leads to vibration of a membrane within the cochlea called the basilar membrane, which contains the Organ of Corti.
There are two types of hair cells in the Organ of Corti: outer hair cells, and inner hair cells. The outer hair cells are called stereocilia and lie between two membranes: their tips are situated within a membrane called the tectorial membrane, and their bodies lie on the basilar membrane. When the basilar membrane is displaced upward by pressure waves, the stereocilia are displaced.
Lateral displacement depolarizes the cell, triggering the generation of a signal; whereas medial displacement hyperpolarizes the cell, preventing the generation of a signal. The frequency triggering signal generation by a hair cell depends on the hair cell’s location in the basilar membrane. This is referred to as a tonotopic distribution: hair cells located in the basal portion respond to high frequencies, whereas those located in the apical portion respond to low frequencies.
Once signals are generated by stereocilia in the Organ of Corti, they are transmitted to the peripheral processes of bipolar neurons that form a structure called the spiral ganglion. Projections from these bipolar neurons form the cochlear nerve.
Balance/movement and the vestibular component
The anatomical components of the vestibular system are the otolith organs (the saccule and utricle) which detect linear acceleration, and three semicircular canals, which detect angular acceleration.
Like the cochlea of the auditory system, these organs are filled with endolymph; and like the receptors of the auditory system, the receptors of the vestibular system are hair cells. These hair cells also come in two types: type I hair cells, which are goblet shaped; and type II hair cells, which are cylindrical; but in the vestibular system, stereocilia project from the apical part of all types of hair cells, with small kinocilium extending slightly above each stereocilium. The bodies of these hair cells are surrounded by supporting cells connected by tight junctions, separating the hair cell from the endolymph surrounding the cilia while the apical stereocilia project into a gelatinous matrix.
Displacement of the cilia occurs when the endolymph moves in a particular direction, i.e. when there is a change in position or motion of the head. Displacement of the stereocilia toward the kinocilia results in excitation of the hair cells; whereas displacement of the stereocilia away from the kinocilia results in inhibition of the hair cells.
The hair cells are innervated by peripheral processes of vestibular (Scarpa’s) ganglia within the vestibular labyrinth (the maculae of the utricle and saccule, and the ampullae of the semicircular canals). The central processes of these bipolar neurons in the vestibular ganglia make up the vestibular part of the vestibulocochlear nerve.
Pathway of the vestibulocochlear nerve
The vestibular and cochlear components of the vestibulocochlear nerve travel as separate nerves through the internal auditory meatus, along with the facial nerve and labyrinthine artery.
They then cross the posterior cranial fossa. It is in the posterior cranial fossa, within the petrous part of the temporal bone, that the cochlear nerve and the vestibular nerve join to form a unified vestibulocochlear nerve.
This unified nerve reaches the lateral surface of the brainstem at the medullopontine angle. At this point, the vestibulocochlear nerve re-divides into vestibular and cochlear branches where they enter the brainstem at the rostral medulla.
The axons making up the cochlear nerve project to cochlear nuclei in the rostral medulla in a tonotopic manner similar to that observed in the basilar membrane. Axons carrying high-frequency sound signals from the basal part of the basilar membrane project deep into the nuclei, while axons carrying low-frequency sound signals from the apical part of the basilar membrane project into more superficial regions of the nuclei.
From here, signals are transmitted through various pathways to a number of brain areas, including:
- the superior olivary nucleus
- the inferior colliculi in the midbrain
- the medial geniculate nucleus of the thalamus
- the primary auditory cortex (in the transverse temporal gyri of Heschl in the medial superior temporal gyrus)
The axons extending from afferent neurons in the vestibular ganglia in the labyrinth project to various vestibular nuclei in the rostral medulla and caudal pons in the brainstem. The nuclei to which they project depends on the vestibular structures from whence they originate.
Axons of afferent neurons from the ampullae of the semicircular canals project to the superior vestibular nucleus (SVN) and rostral portion of the medial vestibular nucleus (MVN).
Many axons of afferent neurons from the maculae of the utricle and saccule project to the lateral vestibular nucleus (LVN), but some axons from the macula of the saccule project to the inferior vestibular nucleus (IVN) as well. Axons originating in these nuclei provide input to various regions of the brain, including:
- the trochlear nuclei
- oculomotor nuclei
- abducens nuclei
- parts of the cerebral cortex
Vestibulocochlear nerve and the vestibulo-oculomotor reflex
Signals received and transmitted by the vestibular branches of the vestibulocochlear nerve influence eye movements by way of the vestibular nuclei, which in turn project axons to the oculomotor, trochlear, and abducens nuclei which influence movement of the extraocular muscles. This works such that when the head moves in one direction, the eyes move in the opposite direction, staying fixed on an object until the object leaves the visual field. The eyes then move rapidly with the movement until fixing on another object until that new object is out of vision. This rapid eye movement between fixations is called a saccade.
This sequence of slower eye movement in the opposite direction to head movement with fixation followed by rapid eye movement in the same direction as head movement until fixation is again achieved is called nystagmus or the vestibulo-ocular reflex. The slower eye movement in the direction opposite to head movement is controlled by vestibular input from the vestibular nuclei, and involves the medial longitudinal fasciculus (MLF). The rapid saccadic eye movement is controlled by the paramedian pontine reticular formation (PPRF).
Although not typically taught in most medical programs, some consider the terminal nerve (CN 0, or CN N) as a thirteenth cranial nerve. Its sensory endings are located in the nasal mucosa. It has three main filaments in the nasal cavity, located just posterior to the antero-superior border of the nasal septum, and its branches have a similar distribution as the olfactory nerves. Also like the branches of the olfactory nerve, branches of the terminal nerve pass through the foramina of the cribriform plate as well. The nerve fibers course posteriorly along the medial surface of the olfactory tract to the surface of the brain near the olfactory trigone, between the olfactory peduncles and rostral to the optic chiasm.
There are a number of theories regarding the function of the terminal nerve, but it is believed that it plays a role in reproductive behavior. It has been speculated that it is used to detect pheromones, contributing to mate selection, and that it enhances olfaction to influence reproductive behavior (i.e. based on findings such as a woman’s sense of smell is most acute when she is ovulating, women rating smell as a man’s most attractive feature, and traumatic loss of olfactory nerves is often accompanied by a reduction in libido).
Anosmia or hyposmia
When the skull sustains trauma, axons projecting from sensory neurons in the olfactory mucosa can be damaged if there is trauma-induced movement of the olfactory bulb. If the damage is significant, the result may be anosmia (loss), hyposmia (reduction), or dysosmia (distortion) of olfactory function, i.e. sense of smell.
Infections can also damage the olfactory mucosa for the same outcome; and loss, reduction, or alteration of sense of smell have also been noted to occur in neurodegenerative conditions such as Alzheimer’s or Parkinson’s diseases. Lesions to olfactory nerve or tract resulting in anosmia, hyposmia, and/or dysosmia have also been observed to affect taste perception, in a way comparable to when one has a head cold and is highly congested.
An uncinate fit describes a seizure involving parts of the temporal lobe which induces cacosmia, hallucinations of experiencing unpleasant smells. The structures associated with this type of seizure condition are the:
- parahippocampal gyrus
- piriform cortex
- entorhinal cortex
Lesions in the optic nerve and visual pathway
Optic nerve damage
When the optic nerve of one eye is lesioned, an affected individual presents with Marcus-Gunn pupil. This means that shining a light into the unaffected eye will result in bilateral pupillary constriction; but shining a light into the affected eye with the damaged optic nerve will result in dilation of both pupils rather than constriction. This is because the signals received by the eye with the damaged nerve cannot be effectively transmitted to the Edinger-Westphal nucleus, so the reduction in signal is interpreted as lower light intensity. The natural response to low light intensity is to shut off parasympathetic response, so the eyes dilate rather than constrict. Marcus-Gunn pupil can be demonstrated via the swinging flashlight test in which the patient sits in a dimly lit room, a light source is moved back and forth from one eye to the other, and pupillary reactions are observed.
Optic chiasm damage
Damage to the optic chiasm interrupts axonal fibers transmitting information from the nasal hemiretinae of both eyes as they cross to the contralateral side. Because the nasal hemiretinae transmit signals corresponding to the temporal visual fields, affected individuals present with a condition called non-homonymous bitemporal hemianopia: this is defined by loss of vision in the right side of the right visual field, and of the left side of the left visual field.
This condition is frequently associated with the presence of a large pituitary adenoma, which compresses the optic chiasm. Most pituitary adenomas are prolactin-secreting, so affected individuals may also present with high prolactin levels, with amenorrhea in women and reduction of sperm count in men. This is due to prolactin’s inhibitory action on gonadotropin-releasing hormone (GnRH) production. If a pituitary adenoma is the underlying etiology of the visual deficit, microsurgery to remove the adenoma can correct the visual deficit.
Optic tract damage
Damage to the optic tract interrupts axonal fibers transmitting information from the temporal retina on the ipsilateral side and the nasal retina on the contralateral side. The resulting condition is called contralateral homonymous hemianopia because the same half of the visual field is lost in both eyes.
Other lesions along the visual pathway after the optic nerve terminates are associated with their own specific visual deficits, including, for example: superior homonymous quadrantanopia in the visual field of the eye contralateral to a damaged temporal lobe; inferior homonymous quadrantanopia in the visual field of the eye contralateral to a damaged parietal lobe; and inferior, superior, or full contralateral homonymous hemianopia with sparing of central vision (macular sparing) if the superior, inferior, or both superior and inferior banks (respectively) of the calcarine fissure in the primary visual cortex are damaged.
There are two general types of deafness, and these must be distinguished from one another in a patient presenting with difficulty hearing. Deafness resulting from lesions of the cochlea, cochlear nerve, or central auditory pathways is referred to as sensorineural deafness, and presents with deafness in the ear on the ipsilateral side as the damaged structure. If the lesion is in a higher auditory nucleus, hearing may be attenuated but is not completely lost, since the auditory pathways are highly complex, crossing and synapsing many times in multiple locations.
This must be distinguished from conduction deafness, which can result from a number of processes which reduce movement of the middle ear ossicles, thereby inhibiting the transmission of pressure waves into the inner ear. Such conditions include:
- otosclerosis, a bony outgrowth of the stapes;
- hydroxyapatite (a calcium phosphate ceramic) replacement of the malleus and incus;
- otitis media, chronic infection of the middle ear with fluid accumulation; or
- untreated cholesteatoma, an expanding growth of keratinizing squamous epithelium in the mastoid process or middle ear).
Two simple hearing tests, Weber’s test and Rinne’s test, can help to distinguish the type of deafness with which a patient is presenting.
In Weber’s test, the base of a vibrating tuning fork is placed on top of the person’s head at the midline. If a patient has conduction deafness, he or she will report the sound as louder in the affected ear. If the patient has sensorineural deafness, the patient will report the sound as louder in the unaffected ear.
In Rinne’s test, a vibrating tuning fork is held in front of the person’s affected ear (without touching it to the person) to evaluate air conduction; and then held with the base of the vibrating tuning fork resting on the mastoid process to evaluate bone conduction. Perception of the sound as louder in the air indicates the hearing loss is sensorineural in nature, whereas perception of the sound as louder when the fork is placed on the mastoid process indicates conductive hearing loss.
Tinnitus describes a condition in which one hears “ringing” in the ears. Its pathophysiology is unclear, but it may result from damage to the cochlear and vestibular end-organs. It can also be caused by toxic doses of salicylates; or appear as part of a condition called cinchonism, along with dizziness and potentially a mild thrombocytopenia, due to treatment with the Class IA antiarrhythmic quinidine (even at therapeutic levels).
Acoustic neuroma, also known as vestibular Schwannoma, is a rare, benign (non-cancerous), slow-growing tumor of Schwann cells, the cells responsible for myelinating peripheral nerves and peripheral parts of cranial nerves. As the name suggests, acoustic neuromas develop from Schwann cells surrounding the peripheral part of the vestibulocochlear nerve. As the tumor grows, it compresses surrounding structures including the nearby nerves, blood vessels, and even the cerebellum and brainstem.
The first symptoms, however, are typically related to auditory and vestibular function, i.e. tinnitus, hearing disturbance or deafness on the affected side. If it occurs, compression of the brainstem can be life-threatening as the brainstem controls vital areas such as the respiratory center. Development of bilateral acoustic neuromas is associated with the very rare (occurring in only 1 in 30,000 to 1 in 50,000 births) hereditary condition neurofibromatosis type 2 (NF-2). If this condition remains untreated, complete deafness can potentially occur.
The term vertigo refers to the sensation that one is turning or rotating when there is, in fact, no actual motion. This typically occurs due to increased sensitivity of the cupula to angular movement, caused by accumulation and adherence of debris from the otolithic membrane of the saccule and utricle in the posterior semicircular canal to the cupula. However, it can also be caused by lesions affecting the vestibular division of the vestibulocochlear nerve, peripheral lesions affecting the vestibular labyrinth in the inner ear, or central lesions affecting the vestibular nuclei in the brainstem or their projections and associations.
Associated symptoms include nausea, vomiting, and gait ataxia, and peripheral lesions are also accompanied by unidirectional nystagmus. Vertigo can also occur due to vestibular neuritis, inflammation of the vestibular labyrinth: additional symptoms include postural imbalance, nystagmus, and nausea.
Vertigo can be treated with H1 (histamine) receptor antagonists or promethazine, which has the added bonus of treating vertigo-associated vomiting.
Ménière’s disease is a complex, poorly understood disorder affecting the vestibular and auditory systems: those affected present with intermittent and relapsing vertigo, which may be accompanied by tinnitus or distorted hearing. Vertigo can be mild, or it can be very severe to the point of being debilitating; and it can last anywhere from minutes to hours. Accumulation of endolymph, edema of the endolymph-containing spaces, and hair-cell damage are observed on histopathological examination - as such, it is suspected that poor drainage of endolymph fluid from the labyrinth may be the cause.
Treatment is difficult, but some patients respond to steroids or diuretics, which may relieve symptoms by reducing the edema; and H1 receptor antagonists have also shown some efficacy. If vertigo is severe, the ototoxic aminoglycoside antibiotic streptomycin may be utilized to destroy hair cells, or surgery can be performed to remove the labyrinth.
A mother walks into your office with her son, a slim, rather small boy who looks somewhat pink in the face, embarrassed to have his mother pulling him at her side. Although she has no major worries regarding his health, she expresses concern that he doesn’t appear to be keeping up developmentally with other boys his age. “For a while,” she said, “I thought maybe he was just a late bloomer… but all of the other boys in his class have gotten bigger and taller by now, and he just hasn’t seemed to change all that much over the last few years. Not that I’m complaining,” she notes, “I love him just as he is”—the boy grimaces—“but I just have a feeling something’s not right, that a little more should have changed by now. I mean he’s 16, and his older brother hit puberty before then…” She takes a moment, before adding “He’s also a bit spacey, too; honestly, I can’t ever ask him to keep an eye on the cooking, he burns absolutely everything; I don’t know how, either, I can smell it all over the house!” Further questioning of the mother and son regarding his medical background was unrevealing, excepting that the boy had bilateral orchiopexy (undescended testicle repair surgery) shortly after his first birthday.
Kallmann syndrome, which may result from a number of different gene mutations, is characterized by delayed or absent puberty and impaired sense of smell. It is a type of hypogonadotropic hypogonadism resulting from lack of production of hypothalamic hormones directing sexual development. Anosmia or hyposmia is a characteristic feature of Kallmann syndrome, and distinguishes Kallmann syndrome from most other types of hypogonadotropic hypogonadism.
Olfactory sensation is impaired to due to failure of migration of the olfactory neurons from their point of origination in the developing nose to the olfactory bulb in the brain: without this neuronal migration and appropriate formation of the olfactory nerve, olfactory signals cannot be transmitted to the brain for further processing. Failure of neuronal migration is also believed to be the reason behind hypogonadotropic hypogonadism: in normal development, neurons producing GnRH also migrate from the developing nose to the hypothalamus in the brain. GnRH, normally released from the hypothalamus, is responsible for stimulating the production of other sex hormones vital to normal sexual development. If the GnRH-releasing neurons are misplaced, other sex hormones that depend on the presence GnRH will not be produced.
Males with Kallmann syndrome present with a small penis and undescended testes (cryptorchidism). At puberty, affected males and females do not develop secondary sex characteristics: this means men do not develop facial hair or deepening of the voice; and women do not undergo menarche (the commencement of ovulation and menstrual periods) or normal breast development. Without treatment, most individuals with Kallmann syndrome are infertile.
Other features that may appear in patients with Kallmann syndrome include:
- unilateral renal agenesis (failure of one kidney to develop)
- bony abnormalities of the fingers and toes
- cleft lip with or without cleft palate
- abnormal eye movements
- hearing loss
- abnormal development of the teeth