Hemimegalencephaly is a rare central nervous system disorder of neuronal cell lineage, proliferation, maturation, and migration characterized by in utero
Aug. 24, 2021
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In this article, the clinical, imaging, and neuropathological features and proposed pathogeneses of septo-optic-pituitary dysplasia complex are reviewed, including an extensive discussion of the genetic and acquired factors appearing to contribute to this disorder. Although relatively rare, septo-optic-pituitary dysplasia complex is a highly relevant topic for pediatric neurologists, ophthalmologists, and pediatricians as the identification of visual impairment due to optic nerve hypoplasia requires the physician to consider the possibility of congenital hypopituitarism, a disorder that may be life-threatening if undetected and untreated. This update includes a review of a study in which intraperitoneal injections of ethanol to pregnant mice heterozygous for a Sonic hedgehog-related gene at embryonic day 8 resulted in the development of optic nerve hypoplasia in the offspring. The results of this work lend support to the notion that ethanol consumption during the first trimester in humans may play a direct role in the pathogenesis of some cases of septo-optic-pituitary dysplasia complex rather than simply representing a casual associative phenomenon. A few genetic mutations are now recognized, but they represent a tiny minority of patients studied genetically. The rare preoptic-septal form of holoprosencephaly represents an overlap between these 2 developmental midline malformations of the brain.
• Any of the 3 key components of septo-optic-pituitary dysplasia (absence of the septum pellucidum, optic nerve hypoplasia, hypopituitarism) may occur alone or in combination.
• There are a wide variety of developmental brain anomalies that may occur in association with septo-optic-pituitary dysplasia, the most important of which are agenesis of the corpus callosum, lobar holoprosencephaly, schizencephaly, olfactory bulb hypoplasia, and focal cortical dysplasias.
• When encountering a patient (including a fetus) with optic nerve hypoplasia or midline brain developmental defects, the clinician must consider the possibility that the patient may also have – or eventually develop – hypopituitarism.
• Although mutations in many different genes have been associated with septo-optic-pituitary dysplasia complex, most cases of this disorder are sporadic and may result from a combination of 1 or more genetic polymorphisms and an early pregnancy vascular disruption phenomenon in the basal forebrain.
• An association with 1st trimester alcohol ingestion is recognized and, in some cases, may induce as an epigenetic teratogenesis.
The combination of bilateral optic nerve hypoplasia and congenital absence of the septum pellucidum was first described by Reeves in 1941 (108). Fifteen years later, in a landmark paper, de Morsier collated 36 published cases of absence of the septum pellucidum: 12 pathological studies (including a new one of his own) and 24 cases detected by pneumoencephalography (32). Among the 36 cases, de Morsier found 9 having a combination of absent septum pellucidum and a variety of congenital ocular anomalies that included anophthalmia, optic nerve “atrophy,” and optic tract malrotation. Believing that the combined presence of these 2 locations of basal forebrain anomaly was more than coincidental, de Morsier coined the term "septo-optic dysplasia" to describe the phenomenon (32).
As Garcia-Filion and Borchert pointed out, de Morsier did not actually report a case having both septal agenesis and clearly described optic nerve hypoplasia (although he did mention Reeves’ earlier report) (45). Nevertheless, with the passage of time, de Morsier’s original conception of a combination of septal agenesis with any type of congenital ocular anomaly has been gradually converted into the more restricted connotation of septal agenesis with bilateral or unilateral optic nerve hypoplasia. As a somewhat ironic consequence of this migration in terminology, the eponym “de Morsier syndrome” (for “septo-optic dysplasia”) has been employed to describe a phenomenon that de Morsier himself never described.
In 1970, Hoyt and colleagues observed that some cases of septo-optic dysplasia also had hypopituitary dwarfism; hence, the evolution of the expanded term "septo-optic-pituitary dysplasia," the descriptor most often used now (59). In this article, the term "septo-optic dysplasia" will be used only for the combination of optic nerve hypoplasia and absent septum pellucidum without hypopituitarism, whereas “septo-optic-pituitary dysplasia” refers to the additional presence of hypopituitarism. This neuroendocrine association with the typical cerebral malformations were confirmed by other authors (91) but the cerebral anomalies do not predict the development of pituitary endocrinopathies (44).
With the advent of improved imaging techniques (CT scanning, MRI), as well as a number of pathological studies (112), it has become clear that the 3 cardinal manifestations of the syndrome may each occur alone, or they may occur in several different combinations. Bilateral optic nerve hypoplasia and hypopituitarism may occur without absence of the septum pellucidum (25; 19; 110; 28); optic nerve hypoplasia and absent septum pellucidum occur without pituitary dysfunction (108; 19); and all 3 manifestations occur together (59). To date, hypopituitarism in combination with absence of the septum pellucidum, unless accompanied by corpus callosum dysgenesis, has not been reported. A retrospective MRI review of 17 patients with septo-optic dysplasia, ranging in age from 2 months to 17 years with equal gender ratio, demonstrated partial agenesis of the corpus callosum in 15, agenesis of the septum pellucidum in 11, bilateral optic nerve hypoplasia in 16, hypoplastic anterior pituitary in 5, ectopic neurohypophysis in 8, absent olfactory bulbs in 4 (present but hypoplastic bulbs not noted), and a variety of cortical dysgeneses in 13 (05). In our experience, olfactory aplasia also is infrequent but hypoplasia of the olfactory bulbs is seen in the majority and does not correlate with normal or abnormal pituitary function (118).
Furthermore, septo-optic-pituitary dysplasia may be associated with a broad spectrum of other cerebral anomalies. The most frequent association is with schizencephaly (03; 11; 69; 17). In a retrospective study of 734 patients with schizencephaly, septo-optic-pituitary dysplasia coexisted in 69.1% (17). Others include lobar holoprosencephaly (112; 104), preoptic-septal variant of holoprosencephaly (54), olfactory tract and bulb hypoplasia, (73; 118; 117), basal encephalocele (101), partial or complete absence of the corpus callosum (136; 124), gray matter heterotopia (19), a variety of unilateral or bilateral focal cortical dysplasias (94; 88; 124), porencephaly (03; 69), hippocampal hypoplasia (110), absence of the epithalamic structures including the pituitary gland (120), periventricular leukomalacia (19), fusion of the cerebellar hemispheres (86), and partial absence of the falx cerebri (110).
There is increasing evidence to show that the borders of the syndrome of septo-optic-pituitary dysplasia are, at best, indistinct, and are a spectrum (60; 24; 05; 92). For example, major midline developmental brain anomalies (ie, lobar and semilobar holoprosencephaly, agenesis of the corpus callosum) may be accompanied by pituitary insufficiency in the absence of any ocular pathology (21). Optic nerve hypoplasia occurs in 75% to 96% of patients with agenesis of the septum pellucidum (115; 24). Hahn and colleagues reported a case of so-called septopreoptic holoprosencephaly (midline fusion restricted to the septal and preoptic areas, sparing the orbital frontal lobes) associated with hypopituitarism but with no apparent visual impairment (54). Cases of isolated pituitary insufficiency and posterior pituitary lobe ectopia, without ocular or septal anomalies, have been associated with periventricular gray matter heterotopia (89). In young children with optic nerve hypoplasia with or without other CNS components of septo-optic dysplasia, the brain malformations do not predict hypopituitarism (44).
Ocular anomalies in addition to optic nerve hypoplasia also occur in septo-optic-pituitary dysplasia (42). The funduscopic optic disc macular distance is altered (71). Bilateral exudative retinal detachment is reported (02). Increased intraocular pressure (glaucoma) may occur rarely (129). Unilateral ptosis, oculomotor palsy, and nystagmus are reported (138). Gunduz and colleagues reported a child with anterior segment dysgenesis in 1 eye and a cataract in the other. The presence of bilateral optic nerve hypoplasia, absence of the septum pellucidum, and thinning of the corpus callosum were only recognized on MRI (52).
Given the seemingly endless reported variations of the septo-optic-pituitary dysplasia syndrome, it is not surprising that there is considerable debate in the literature concerning the most appropriate name for this disorder. Many publications have adopted an alternative definition of “septo-optic dysplasia” put forward by Kelberman and Dattani: i) optic nerve hypoplasia, ii) pituitary hormone abnormalities, and iii) midline brain defects, including agenesis of the septum pellucidum and/or corpus callosum (66). Although this definition has the merit of including callosal agenesis as a major diagnostic criterion, it also permits the awkward situation in which a patient with septal-pituitary dysplasia but normal eyes is deemed to have “septo-optic dysplasia” – a terminological contradiction that could easily lead to diagnostic confusion. A minority of patients with additional neurologic deficits has led some authors to term an expanded phenotype as “septo-optic dysplasia plus syndrome.” Some of these additional inconstant features include seizures, which can occur in infancy or can be a late complication appearing in adolescence or adult life (53; 40), hearing loss of the neurosensory type (57), and prominent mirror movements of the hands (35).
In recognition of the remarkable variety of central nervous system anomalies that are associated with septo-optic-pituitary dysplasia, Polizzi and colleagues suggested the use of an umbrella term that would cover most eventualities: “septo-optic dysplasia complex” (104). In order to emphasize the clinical importance of pituitary insufficiency in this disorder, as well as to acknowledge the contribution of Hoyt and colleagues (59), it seems reasonable to modify the terminology of Polizzi and colleagues to “septo-optic-pituitary dysplasia complex.”
In light of the enormous variability in anatomical and clinical manifestations just described, it has been suggested that septo-optic-pituitary dysplasia complex is really nothing but a hodgepodge of congenital brain anomalies whose apparent association is the result of ascertainment biases (eg, optic nerve hypoplasia, pituitary dwarfism). Although this conclusion has much to recommend it, the so-called syndrome of septo-optic-pituitary dysplasia complex has continued to merit attention because its most obvious clinical feature, optic nerve hypoplasia with early visual impairment or blindness, has required the physician to consider the possibility of congenital hypopituitarism, a disorder that may be life-threatening if undetected and untreated.
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