Olfactory bulb agenesis, hypoplasias, and dysplasias

Harvey B Sarnat MD FRCPC MS (Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.)
Originally released July 7, 1997; last updated January 22, 2017; expires January 22, 2020

This article includes discussion of olfactory bulb agenesis, hypoplasias, and dysplasias and olfactory hypoplasias and agenesis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

In this article, the author describes olfactory bulb agenesis and dysgenesis and also reviews the embryology, maturation, neuropathology, and clinical diagnosis and manifestations. The olfactory bulb is still immature but functional in the term neonate. It is a reservoir of progenitor “stem” cells capable of neuronal differentiation in the adult as well as in the fetus. Complete agenesis of the olfactory tract results in congenital anosmia. Olfactory reflexes in the neonate and preterm infant can be tested as early as 28 weeks gestation using a nonirritant aromatic substance, such as peppermint (infantile olfactory reflexes). Fetuses perceive odors in the amniotic fluid that circulates through the nasal passages in the late second and third trimesters. Agenesis of the olfactory bulbs (arrhinencephaly) is a constant feature in alobar and semilobar holoprosencephaly but also can occur as an isolated minor cerebral malformation without other dysgeneses. At times it is asymmetrical. In Kallmann syndrome, there is hypogonadism with delayed or absent puberty; associated neurologic findings may be present, such as ataxia, impaired hearing, eye movement disorders, or mental handicap. Diagnosis is confirmed by MRI, and molecular studies can reveal genetic mutations. Dysgenesis, rather than agenesis, of the histological architecture of the olfactory bulbs occurs in some genetic syndromes and particularly in postzygotic somatic mutations such as tuberous sclerosis complex and hemimegalencephaly. Multiple genetic factors are essential in normal olfactory bulb ontogenesis. Supernumerary olfactory bulbs are rarer than agenesis but documented and associated with impaired olfaction. Fusion of olfactory bulbs may occur in some cases in which the bulb appears unilaterally absent on gross examination.

Key points

 

• Agenesis of the olfactory bulbs (arrhinencephaly) may occur as an isolated defect, as a component of holoprosencephaly (regardless of the genetic etiology) associated with other cerebral malformations, or as a component of Kallmann syndrome with endocrinopathies.

 

• Agenesis or hypoplasia of 1 or both olfactory bulbs at times occurs in isolation without other CNS anomalies or with other focal defects such as hypoplasia of the ipsilateral optic nerve.

 

• The clinical feature is anosmia, but patients rarely complain of this because it is congenital rather than acquired after they had experienced a sense of smell; the deficit is nonprogressive.

 

• It can be diagnosed by MRI of the olfactory bulbs following clinical demonstration of absent olfaction bilaterally; neuropathological confirmation is demonstrated at autopsy, though olfactory agenesis is not a cause of death.

 

• Olfactory reflexes are present at birth (after 32 weeks gestation) and can be tested as part of the neurologic exam in neonates and young infants by using an aromatic, non-irritative test substance that does not stimulate the pain endings of the trigeminal nerve in the nasal mucosa; responses are sucking or arousal withdrawal.

 

• The principal well-documented olfactory dysplasias are the presence of a deep longitudinal sulcus on the inferior surface with synaptic glomeruli lining the neural tissue on either side (hemimegalencephaly), megalocytic and dysplastic neurons (tuberous sclerosis and hemimegalencephaly), fusion of the 2 olfactory bulbs, and delayed maturation of expression of neuronal proteins and synapse formation.

 

• Olfactory bulb agenesis should be distinguished from acquired causes of anosmia, such as fracture of the cribriform plate in head trauma, tumors, granulomas and other lesions of the olfactory bulbs or tracts, olfactory groove meningioma, vascular anomalies associated with a persistent fetal olfactory artery, and olfactory impairment due to chemotherapy or other drugs.

 

• Multiple genetic mutations and deficiencies of transcription factors and cell adhesion molecules are associated with olfactory agenesis, but usually with other CNS anomalies.

 

• Supernumerary olfactory bulbs occur rarely.

 

• Some olfactory auras in focal epilepsy may originate in the olfactory bulb and can only be mediated by the amygdala, insula, or entorhinal cortex.

Historical note and terminology

Perception of odorous soluble molecules is the earliest special sense to develop both phylogenetically and ontogenetically. Even simple medusae (jellyfish) and polyps (hydra) that poses only a simple nerve net without a brain or even a ganglion can perceive and distinguish molecules in surrounding sea water as attractants (ie, food) or adversive elements (ie, potentially harmful) and react accordingly, as noted as early as 1849 by the famous English biologist of his era, Thomas Huxley (Huxley 1849). Human fetuses also perceive odors dissolved in amniotic fluid. Whether these primitive perceptions are best classified as olfactory or gustatory (taste) is a difficult distinction. Both fetuses and preterm neonates distinguish different types of both pleasant and unpleasant odors (Lipsitt et al 1963; Sarnat 1978; Schaal et al 1998; Marlier et al 2007).

The first report of anosmia associated with hypogonadism was in 1856 (Maestre de San Juan 1993). In 1918 Blakeslee described specific anosmia for either pale pink or red verbenas, but not for both, in a group of healthy people (Blakeslee 1918), and a few reports have since appeared describing familial congenital anosmia in otherwise mainly asymptomatic people (Mainland 1945; Lygonis 1968; Singh et al 1970). In addition, there have been occasional descriptions of "sporadic cases of Kallmann syndrome," in which isolated congenital anosmia is also present (Hermanussen and Sippell 1985). In a seminal paper on the genetic aspects of primary eunuchoidism, Fritz Kallmann and colleagues described 36 males and 12 females in whom the condition was associated with combinations of anosmia, color blindness, synkinesis, and mental handicap (Kallmann et al 1944). Subsequent clinical descriptions have permitted better delineation of the syndrome and its association with aplasia or hypoplasia of the olfactory bulbs and tracts (Sparkes et al 1968; Males et al 1973; White et al 1983; Hermanussen and Sippell 1985). A study that investigated isolated congenital anosmia without chromosomal disorders (Abolmaali et al 2002) compared the MRI appearances of the frontobasal structures of 16 patients with controls. In half the patients there was bilateral hypoplasia of the olfactory bulbs, and in the remainder there were combinations of hypoplasia and aplasia of the bulbs. Descriptions of anosmia and olfactory aplasia as 1 component of the holoprosencephalies represent the other extreme of the spectrum (Friede 1989; Louis et al 1992). Isolation of the Kallmann syndrome gene in X-linked Kallmann syndrome has expanded our insight into this syndrome of anosmia and hypogonadism (Lutz et al 1993; Prager and Braunstein 1993).

Olfaction and taste are functionally closely related despite the wide separation of their neuroanatomical receptive centers in the olfactory bulb and lower brainstem, respectively (Sarnat 2016). Even the simplest marine animals with only a primitive nerve network and no central nervous system, such as medusa (jellyfish) and polyps (hydra, sea anemones, etc.), perceive molecules dissolved in the water as either threatening, resulting in retraction of tentacles, or food, resulting in feeding behaviors. In humans, postnatal respiration is essential for smell, and retronasal olfaction is dependent on expiration and also refines perception of taste for chocolate and other flavors, even accompanied by EEG changes (Masaoka et al 2010). Olfaction is an important aspect of wine tasting and distinguishing foods.

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