Vein of Galen malformations
Nov. 28, 2022
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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, rhombencephalosynapsis of the cerebellar vermis and dentate nuclei, 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.
• Prenatal diagnosis by ultrasound or MRI is confirmed postnatally in a minority of cases; hence, neonatal assessment is essential.
The combination of bilateral optic nerve hypoplasia and congenital absence of the septum pellucidum was first described by Reeves in 1941 (119). Fifteen years later, in a landmark paper, the Swiss neurologist 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 (35). 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 (35).
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) (49). 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 (63). 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 (96) but the cerebral anomalies do not predict the development of pituitary endocrinopathies (48).
With the advent of improved imaging techniques (CT scanning, MRI), as well as a number of pathological studies (124), 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 (28; 21; 121; 31); optic nerve hypoplasia and absent septum pellucidum occur without pituitary dysfunction (119; 21); and all 3 manifestations occur together (63). 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 (06). 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 (131).
Furthermore, septo-optic-pituitary dysplasia may be associated with a broad spectrum of other cerebral anomalies. The most frequent association is with schizencephaly (03; 12; 74; 19). In a retrospective study of 734 patients with schizencephaly, septo-optic-pituitary dysplasia coexisted in 69.1% (19). Others include lobar holoprosencephaly (124; 114), preoptic-septal variant of holoprosencephaly (58), olfactory tract and bulb hypoplasia, (78; 131; 130), basal encephalocele (111), partial or complete absence of the corpus callosum (153; 139), gray matter heterotopia (21), a variety of unilateral or bilateral focal cortical dysplasias (99; 93; 139), porencephaly (03; 74), hippocampal hypoplasia (121), absence of the epithalamic structures including the pituitary gland (133), periventricular leukomalacia (21), fusion of the cerebellar hemispheres (91), and partial absence of the falx cerebri (121).
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 (64; 26; 06; 97). 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 (23). Optic nerve hypoplasia occurs in 75% to 96% of patients with agenesis of the septum pellucidum (127; 26). 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 (58). Cases of isolated pituitary insufficiency and posterior pituitary lobe ectopia, without ocular or septal anomalies, have been associated with periventricular gray matter heterotopia (94). In young children with optic nerve hypoplasia with or without other CNS components of septo-optic dysplasia, the brain malformations do not predict hypopituitarism (48).
Ocular anomalies in addition to optic nerve hypoplasia also occur in septo-optic-pituitary dysplasia (46). The funduscopic optic disc macular distance is altered (76). Bilateral exudative retinal detachment is reported (02). Increased intraocular pressure (glaucoma) may occur rarely (144). Unilateral ptosis, oculomotor palsy, and nystagmus are reported (156). 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 (56). Rare cases of bilateral micro-ophthalmia are described in septo-optic dysplasia (137).
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 (70). 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 (57; 44), hearing loss of the neurosensory type (61), and prominent mirror movements of the hands (39).
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” (114). In order to emphasize the clinical importance of pituitary insufficiency in this disorder, as well as to acknowledge the contribution of Hoyt and colleagues (63), 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.
The cardinal features of septo-optic-pituitary dysplasia complex are early visual impairment (due to optic nerve hypoplasia) and hypopituitary dwarfism. Both features may occur together in some patients or separately in others.
Visual impairment in septo-optic-pituitary dysplasia complex varies from complete blindness in both eyes to a mild reduction in acuity in only 1 eye. Sometimes, a clinically apparent hypoplastic optic nerve may have no detectable deficit in acuity. Even if acuity is normal, further analysis typically reveals a visual field defect or narrowing of the peripheral fields (82; 60).
The characteristic finding in optic nerve hypoplasia is a small, pale optic nerve head, usually one third to one half normal diameter. Surrounding the nerve head there may be a yellowish halo edged on both sides by rings of pigment, producing the so-called "double ring sign." These changes may be bilateral, asymmetric, or unilateral. Some cases may also show signs of optic nerve atrophy. Eight of the 51 cases reported by Margalith and colleagues had both hypoplasia and atrophy (82).
A reduced optic nerve head diameter is not the only abnormality of the optic disc found to be associated with hypopituitarism. Horton and Barkovich reported a teenaged boy with pituitary insufficiency and posterior pituitary ectopia in combination with bilateral diminished vision due to optic disc pits at the temporal disc margins associated with a gap in the retinal nerve fiber layer extending from the optic pit to the fovea (62). The fovea plana is absence of a foveal pit in the central fovea (macula); this developmental anomaly occurs in some cases of septo-optic dysplasia but does not necessarily impair visual acuity (72). Nonperfusion due to impaired neovascularization consistent with familial exudative vitreoretinopathy (FEVR) is associated in some cases of septo-optic-pituitary dysplasia (154).
Depending on the series reported, 27% to 73% of children with optic nerve hypoplasia also have evidence of impaired pituitary function (28; 83; 84; 135; 93; 09; 26; 100). In general, hypopituitarism is encountered more often in patients with optic nerve hypoplasia in combination with septal agenesis or absent corpus callosum; it is much less likely to occur if the latter radiological abnormalities are not accompanied by optic nerve hypoplasia (26). Growth hormone deficiency and hypothyroidism are the most common features of hypopituitarism in this disorder. Less frequently, one may see hypothyroidism, corticotropin deficiency, sexual infantilism, hyperprolactinemia, and diabetes insipidus in various combinations, with some cases having fully expressed panhypopituitarism. At the other end of the scale, precocious puberty has also been reported (83; 100). A possible explanation for this unexpected finding is given in the Diagnostic workup section.
Clinical evidence of hypopituitarism may emerge anywhere between the neonatal period and 8 years of age (26). Some patients with hypopituitarism develop potentially life-threatening symptoms in the neonatal period, before optic nerve hypoplasia is clinically apparent (82; 23; 27; 106). Neonatal problems include recurrent hypoglycemia, jaundice, seizures, the need for resuscitation at birth, apneic spells, respiratory difficulties, and electrolyte disturbances such as hypernatremia (105). Over half of the children in the series of Margalith and colleagues for whom there was adequate information (25 of 44 cases) had significant neonatal symptomatology, primarily due to growth hormone deficiency (82). Even after the neonatal period, sudden death from corticotropin deficiency may still occur. Brodsky and colleagues reported 5 children, from 9 months to 7 years old, with septo-optic-pituitary dysplasia complex who died suddenly. All 5 had corticotropin deficiency, compounded in 4 of the 5 by diabetes insipidus (20).
Epilepsy is an infrequent complication in septo-optic pituitary dysplasia and most patients do not have seizures though they may have EEG abnormalities as a risk factor. On the other hand, adults with septo-optic dysplasia are reported who showed pharmacologically refractory epilepsy (05). Sleep disturbances in children may be a clinical problem but unrelated to epilepsy (152).
Although an absent septum pellucidum forms an integral part of the syndrome, as described by de Morsier (35) and modified by Hoyt and colleagues (63), this feature is not found in half the reported cases of optic nerve hypoplasia with hypopituitarism (83; 21; 135). Absence of the septum pellucidum is frequently accompanied by modest enlargement and squaring of the frontal horns of the lateral ventricles, both on CT and MRI. In some cases, the septum is only partially absent (12). In others, the fornices and septal veins are displaced inferiorly in the ventricle, giving the false impression that the septum is partially present (74). Optic nerve hypoplasia and growth failure have also been reported in association with a wide cavum septum pellucidum (> 1 cm) (18).
Absence of the septum pellucidum as an isolated brain anomaly does not, in general, appear to produce any specific neurologic deficits. Septal area lesions induced in rats produce deficits in navigational ability (92); similar deficits have not been described in patients with septo-optic dysplasia. There is obviously an inherent difficulty in determining what cognitive or behavioral deficits, if any, are related to the septal area anomaly and what deficits are related to impaired vision or complications of pituitary insufficiency. Studies reported to date must be interpreted with caution because of their small patient numbers and largely retrospective nature.
In 2 studies of 7 and 6 children (respectively) with septo-optic dysplasia, no significant cognitive impairment was identified (151; 55). In a follow-up study of 14 children with isolated septal agenesis identified in utero, Damaj and colleagues found that 11 were normal, whereas 3 had mild delays in language acquisition or behavioral difficulties, which are problems that are also commonly seen in typical children (32). In contrast, Belhocine and colleagues reported a variety of motor and mental deficits in 3 patients with isolated agenesis of the septum pellucidum, whereas 3 other radiologically similar patients were asymptomatic (15).
Neuroimaging. There is a large body of radiological (CT and MRI) and pathological evidence for a wide variety of neuropathologic abnormalities that may occur in association with septo-optic-pituitary dysplasia complex (03; 91; 82; 136; 124; 12; 74; 36; 153; 21; 75; 42; 65; 99; 135; 78; 139; 121; 133; 147; 148; 04). Reported anatomical abnormalities include lobar holoprosencephaly, olfactory tract and bulb hypoplasia, schizencephaly, bilateral rolandic cortical dysplasia, partial or complete absence of the corpus callosum, gray matter heterotopia, hippocampal hypoplasia, absence of the epithalamus, temporal lobe arachnoid cyst, porencephaly, hydrocephalus, periventricular leukomalacia, hypoplasia of the falx cerebri, and absence of the cerebellar vermis with fusion in the midline of the cerebellar hemispheres and dentate nuclei ("rhombencephalosynapsis"). Agenesis of one cerebellar hemisphere also is reported in septo-optic dysplasia by neuroimaging, but without neuropathological confirmation (108). Abnormal hypoplastic midbrain and hindbrain (pons and medulla oblongata) are reported by MRI in rare cases, suggestive of a disorder of neural tube segmentation (133; 147).
Schizencephaly is especially common: it was present in 4 out of 9 cases in the series reported by Kuban and colleagues (74), and in 5 out of 11 cases in the MRI study of Barkovich and colleagues (12). The latter authors suggest that septo-optic dysplasia with schizencephaly is a disorder distinct from those cases without schizencephaly, because hypopituitary dwarfism was not present in their schizencephalic group. It also is reported sporadically as isolated case reports (38).
The olfactory bulbs are often bilaterally hypoplastic but rarely absent in septo-optic hypoplasia (131; 16). Functional olfactory perception is preserved, however, but acuity in distinguishing identity and intensity of odors may be diminished; patients with agenesis of the olfactory bulbs are anosmic. Olfactory reflexes are reliably tested in the neonatal period after 30 weeks’ gestation (131).
As might be expected, the neurologic symptoms and signs produced by these associated anomalies vary according to the type(s) of pathology in individual patients. The most common features include mental subnormality, learning disorders, epilepsy (including infantile spasms), hypotonia, hemiparesis (particularly in cases with schizencephaly or porencephaly), spastic diparesis (eg, especially those cases with periventricular leukomalacia), and neurosensory hearing loss. Social communication difficulties, at times evolving into a frank autism spectrum disorder, are frequently observed in children with septo-optic-pituitary dysplasia complex, as well as in children with isolated bilateral optic nerve hypoplasia and blindness (107). In a study in which the authors employed the Social Communication Questionnaire, Jutley-Neilson and colleagues found that in a cohort of 28 children with “septo-optic dysplasia” and 14 with isolated optic nerve hypoplasia, 23 out of 42 met the cutoff point for further investigation of the diagnosis of autism spectrum disorder; 9 of these met the criteria for consideration of the diagnosis of classical autism (66).
Like children with other causes of visual impairment, children with septo-optic-pituitary dysplasia complex may have disordered sleep regulation, varying from the presence of sustained periods of wakefulness during the night (fragmented sleep) to complete absence of a diurnal sleep cycle (arrhythmic sleep) (150). The mechanism of these sleep disturbances is complex, and not simply a matter of a failure to produce melatonin during the night. Webb and colleagues correlated sleep patterns and melatonin production in 6 children with optic-pituitary dysplasia, 2 of whom also had septal agenesis. Five of the 6 children had sleep fragmentation and 1 had a completely arrhythmic sleep pattern. Four of the 6 children had relatively normal melatonin production profiles; the 2 who did not also had other major brain anomalies and severe global developmental delay. Sleep disturbances are frequent in children with a wide variety of congenital brain malformations including septo-optic-pituitary dysplasia (152).
Systemic anomalies outside the CNS and eyes are rare, but amniotic band sequence involving the extremities and bilateral talipes equinovarus have been reported (07).
Neuropathology. Postmortem studies of septo-optic-pituitary dysplasia, in addition to demonstrating absence of the septum pellucidum, optic nerve/chiasm hypoplasia, and sometimes rhombencephalosynapsis or other cerebellar anomalies, also can demonstrate focal dysplasias of cortical lamination that were not anticipated from neuroimaging studies during life (17). Other rare cerebral anomalies of posterior fossa structures in particular, which are reported by MRI, require neuropathological confirmation; hence, it is important to perform autopsies in fetuses and children who do not survive with septo-optic-pituitary dysplasia.
The prognosis of septo-optic-pituitary dysplasia complex is largely determined by the extent of the basal forebrain abnormalities and associated anomalies. Visual impairment tends to remain stable throughout life, although some patients show a modest improvement in visual function with brain maturation (104). Provided that pituitary hypofunction, if present, is detected early and appropriate replacement therapy is introduced, the prognosis for growth and secondary sexual development is good (28). Precocious sexual maturation is sometimes observed (83; 100). Accelerated pubertal maturation can also occur with growth hormone replacement therapy (45). The neurologic outcome is excellent if the only central nervous system anomaly is absence of the septum pellucidum (151). If other brain anomalies are present, significant neurologic handicaps are likely, such as mental subnormality (holoprosencephaly, schizencephaly), learning and behavioral problems (any major brain anomaly), epilepsy (schizencephaly, focal cortical dysplasia, cortical heterotopia, porencephaly, periventricular leukomalacia), and cerebral palsy (schizencephaly, porencephaly, periventricular leukomalacia). In the series of optic nerve hypoplasia cases reported by Brodsky and Glasier, nearly all the patients with neuroradiologic abnormalities other than absent septum pellucidum, including those with posterior pituitary ectopia, had significant neurologic handicaps (21).
Septo-optic-pituitary dysplasia complex has no specific complications. Complications are those associated with the component phenomena (eg, brain injury secondary to hypoglycemia).
The following clinical vignettes illustrate the clinical spectrum seen in septo-optic-pituitary dysplasia complex. Case A has pituitary-optic dysplasia, and Case B has septo-optic dysplasia.
Case A. This 10-year-old girl was the product of a 42-week gestation, weighing 4.3 kg at birth. At approximately 12 weeks' gestation, the mother took 60 acetaminophen capsules in a failed suicide attempt. At birth, the infant was noted to have an abnormally large head and bilateral club feet. A cranial CT showed marked enlargement of the lateral and third ventricles, and an intact septum pellucidum. A ventriculoperitoneal shunt was inserted in the neonatal period, with successful correction of the hydrocephalus. The shunt has only required a single revision, at the age of 9 years.
By the age of 3 months, it was clear that the baby had poor vision. An ophthalmologic examination revealed that she had marked bilateral optic nerve hypoplasia.
She has never developed functional vision and attends a school for the blind.
The patient was noted to be abnormally short at the age of 3 years. An L-dopa and propranolol provocative test revealed an inadequate growth hormone response. Extensive endocrinologic investigation showed no evidence of thyroid or adrenal insufficiency. Careful endocrinologic follow-up detected hypothyroidism at the age of 5 and depressed cortisol levels by the age of 6. The patient has been treated with daily injections of synthetic growth hormone and with oral supplementation with L-thyroxine and Cortef. By the age of 9.5, she had demonstrated a marked acceleration of somatic growth, with height at the 50th percentile and a bone age of 11. She also showed clear signs of precocious puberty, with Tanner IV breasts and Tanner II pubic hair. In consequence, she has been given monthly injections of Depo-Lupron, which have thus far arrested further sexual development.
The patient has been consistently slow in motor, language, and cognitive development and has significant learning and behavioral difficulties. Follow-up CT scans have consistently demonstrated an abnormal gyral pattern in the right hemisphere with an aberrant sylvian fissure.
Case B. This 4-year-old girl was the product of a 37-week gestational period in an 18-year-old mother. The father was consuming cocaine regularly at the time of conception, but the mother was drug-free throughout the pregnancy. There was mild intrauterine growth retardation, and birth weight was only 2.3 kg. Despite this, the child has been in good health. She had left esotropia from an early age, but it was not until the age of 4 that a formal ophthalmologic exam revealed the presence of left optic nerve hypoplasia. A subsequent MRI study showed absence of the septum pellucidum and confirmed the left optic nerve abnormality.
An endocrinology workup showed normal levels of thyroid-stimulating hormone, cortisol, and follicle-stimulating hormone. Her height is in the 90th percentile for age.
As with many other malformations of the brain (such as absence of the corpus callosum), septo-optic-pituitary dysplasia complex is, at best, a syndrome and not a discrete diagnosis. Many possible etiologic factors have been suggested; overall, the timing of any acquired insult may be more important than its nature. Although, in most cases, no apparent etiology can be identified, the available evidence suggests that septo-optic-pituitary dysplasia complex most often results from a combination of environmental and genetic factors that are at play during the mid-first trimester of pregnancy.
Environmental factors or associations. Congenital optic nerve hypoplasia has been associated with maternal diabetes mellitus, intrauterine cytomegalovirus infection, and maternal ingestion of quinine and anticonvulsant drugs (104). Septo-optic dysplasia has been reported following therapeutic use of valproic acid during pregnancy (89) and maternal ingestion of phencyclidine (91), ethanol, marijuana (82; 29), cocaine, amphetamine, and phenylpropanolamine (36). Abuse of the last 3 drugs has also been associated with schizencephaly and porencephaly (36).
In a review of potential antecedents to optic nerve hypoplasia, Garcia-Filion and Borchert appropriately noted that most of the numerous studies cited above lacked a comparison with control populations; in consequence, their findings may reflect an ascertainment bias. At best, cases of septo-optic-pituitary dysplasia complex directly related to individual prenatal drug exposures and viral infections are probably rare (50).
There are more robust data to link septo-optic-pituitary dysplasia complex to young maternal age and primiparity (82; 142; 110; 90; 51; 09); all of these studies utilized either control populations or population norms for the region from which the patient cohort was derived. Young maternal age and primiparity appear to be independent precursors, at least for optic nerve hypoplasia (51). In the most recent of these studies, the average maternal age for the 88 reported cases of septo-optic dysplasia was 21 years, as against an average maternal age in the West Midlands area of the United Kingdom (the source of the 88 cases) of 29.3 years (09). Whether this correlation reflects the generally increased risk of congenital anomalies in the children of young mothers, the increased probability of drug ingestion during pregnancy in this age group, or the presence of some other still unrecognized factor remains open to speculation.
Embryological considerations. Optic nerve hypoplasia is thought to result from a failure of growth of retinal ganglion cells, with their central axonal projections, during embryonic life (ie, at approximately 4 to 6 weeks’ gestational age) (82; 104). More precisely, it appears that the axonal growth cones of the retinal ganglion cells, having not encountered a necessary molecular signal, fail to pierce the optic nerve head and, instead, grow aimlessly within the retina (102). An alternative hypothesis is that optic nerve hypoplasia may result from transsynaptic degeneration in the optic pathway following an encephaloclastic process later in pregnancy (eg, schizencephaly, porencephaly). The fact that some cases have concomitant evidence of optic atrophy has been advanced to support the idea of a persistent intrauterine insult occurring off and on throughout the pregnancy (83).
Agenesis of the septum pellucidum is believed to result from a defect in ventral induction of basal forebrain structures, normally occurring at about 6 weeks’ gestation (118; 22). The fact that absent septum pellucidum may be associated with optic nerve hypoplasia, olfactory tract hypoplasia, arrhinencephaly, lobar holoprosencephaly (124), and agenesis of the anterior corpus callosum lends support to this hypothesis. Embryologically, the septum is the ventromedial quadrant of the rostral part of the primitive fetal telencephalic hemisphere shortly after cleavage of the prosencephalon. It is a neural structure with neurons and glial cells but undergoes atrophy in humans, so that only a thin gliotic membrane, the septum pellucidum, is left by midgestation as a vestige (128). The vertical membranes or leaves of the 2 sides of the former septum enclose a glial (not ependymal)-lined cavity, the cavum septi pellucidi, which is prominent in fetal ultrasound and MRI studies, but the 2 leaves fuse postnatally in most cases, abolishing the cavum.
As far as congenital hypopituitarism is concerned, there is now convincing evidence that this usually results from failure of normal formation of the infundibulum and posterior pituitary, a process that also occurs at around 6 weeks’ gestation. In cases of septo-optic dysplasia where pituitary dysfunction is also identified, MRI typically shows absence or hypoplasia of the pituitary stalk, with ectopic, residual posterior pituitary tissue located just anterior to the mammillary bodies rather than in the sella turcica (69; 21). Identical MRI findings have been noted in the majority of patients with isolated pituitary dwarfism (143; 94). The anterior pituitary can usually be identified on MRI in the sella turcica. Pathological studies of the pituitary region in septo-optic-pituitary dysplasia complex have confirmed the residual anterior pituitary tissue and have demonstrated hypothalamic dysplasia, with absence of the pituitary stalk and of crucial hypothalamic nuclei (eg, the supra-optic and paraventricular nuclei) (124).
For the most part, the other brain anomalies sometimes associated with septo-optic-pituitary dysplasia complex also appear to date from early in the pregnancy. Schizencephaly and callosal agenesis are thought to be produced at around 2 months’ gestation, during the early phases of neuronal proliferation and migration (13). Porencephaly may develop at almost any time during the second and third trimesters, whereas periventricular leukomalacia usually dates from early in the third trimester (11). Schizencephaly (especially when unilateral), porencephaly, and periventricular leukomalacia all appear to result from focal or generalized vascular insults, whether ischemic (eg, schizencephaly) or hemorrhagic (eg, porencephaly). Thus, in cases where septo-optic-pituitary dysplasia complex is associated with 1 or more of these specific pathologic entities, one can postulate a vascular etiology for the entire collection of brain anomalies (eg, in the cases of maternal cocaine ingestion reported by Dominguez and colleagues) (36).
Support for a vascular cause of septo-optic-pituitary dysplasia complex has been advanced by Lubinsky (79). Noting that the disorder involves a number of disparate tissues and developmental processes occurring at different times of development, and that the disorder is often associated with brain anomalies strongly suspected to be of vascular origin (ie, schizencephaly, porencephaly), Lubinsky hypothesized a vascular disruption sequence, perhaps involving the proximal trunk of the anterior cerebral artery. Prior to the origin of the anterior communicating artery, the anterior cerebral artery travels over the optic nerves and chiasm, sending branches to those structures as well as to the anterior hypothalamus and the septum pellucidum. In a companion paper, Lubinsky also noted that previously identified prenatal vascular disruption sequences are strongly related to decreased maternal age (eg, hydranencephaly, gastroschisis) and suggested that septo-optic-pituitary dysplasia complex falls into the same category (80).
Several clinical cases with relevant overlap syndromes have been reported in support of Lubinsky’s vascular hypothesis. Stevens and Dobyns reported a patient, born to a 14-year-old mother, with septo-optic-pituitary dysplasia complex, bilateral perisylvian cortical dysplasia, periventricular nodular heterotopia, agenesis of the corpus callosum, multiple digit amputations, and constriction rings. The latter 2 abnormalities were presumed to be secondary to amniotic bands. Noting that amniotic bands appear to result from embryonic vascular disruption with bleeding into the amniotic sac, the authors proposed a vascular etiology for the various cerebral anomalies as well (139). Kamien and colleagues reported a boy with a combination of amyoplasia sequence and septo-optic dysplasia (68); amyoplasia is thought to result from a cervical spinal cord vascular disruption phenomenon in early gestation. In the same paper, the authors described a second patient who had with a combination of optic-pituitary dysplasia and gastroschisis. Finally, a case of gastroschisis associated with optic nerve hypoplasia, callosal hypoplasia, and hypopituitarism with posterior pituitary ectopia has been published (53).
Genetic factors. Reported cases of septo-optic-pituitary dysplasia complex on a clearcut genetic basis are relatively rare, but with the advent of whole exome sequencing, reports of patients with septo-optic-pituitary dysplasia complex and gene variants are steadily increasing. Novel mutations are being reported that generally were formerly associated only with neuroendocrine disturbances of pituitary insufficiency, including PROP1 (24) and FLNA splice site mutation (41). Nevertheless, of sporadic human cases of septo-optic-pituitary dysplasia that have undergone genetic studies to date, only about 1% are demonstrated to be associated with mutations in HESX1, SOX2, SOX3, or OXT2 genes (149; 85; 57).
The first relevant gene to be identified, and the 1 most extensively studied, is the homeobox gene Hesx1, which is expressed in developing forebrain tissue in mice. Absence of Hesx1 in the mouse is accompanied by a reduced prosencephalon, anophthalmia or microphthalmia, defective olfactory maturation, Rathke pouch bifurcations, as well as abnormalities in the corpus callosum, anterior and hippocampal commissures, and the septum pellucidum. In a study, Dattani and colleagues cloned human HESX1 and then identified a homozygous Arg53Cys missense mutation (or R160C in the open reading frame) in the HESX1 homeodomain in 2 siblings with septo-optic-pituitary dysplasia complex (33).
Subsequent research has identified many other HESX1 mutations associated with a range of phenotypic expression. Homozygous (R160H; R160C; 126T) and compound heterozygous (R159W/R160H) mutations in HESX1 have been reported with milder phenotypes involving only hypopituitarism with and without posterior pituitary ectopia (37; 40). For heterozygous HESX1 mutations, the described phenotypes fall into 2 major categories: (1) isolated pituitary deficiency with absent or ectopic pituitary gland on MR imaging and (2) pituitary insufficiency with unilateral optic nerve hypoplasia. Mutations reported to date include S170L, T181A, Q6H, I26T, E149K, and 306/307insAG (141; 25; 140; 90; 37).
Knock-in mouse models suggest that the phenotype produced by Hesx1 mutations is determined, at least in part, by the type of mutation and the transcription domain it disrupts. Embryos homozygous for the I26T mutation have pituitary defects and, sometimes, ocular abnormalities but no telencephalic malformations (125). In contrast, homozygous R160C knock-in mice have severe forebrain anomalies identical to those seen in the Hesx1 -/- knock-out mouse model. Thus, to a great extent, the I26T and R160C mouse mutations mimic, in terms of clinical severity, their human equivalents (33; 25).
It must be emphasized that septo-optic-pituitary-dysplasia complex due to HESX1 mutations is a rare finding. Dattani’s group have now screened 724 patients with septo-optic dysplasia (n=314) or isolated pituitary dysfunction, optic nerve hypoplasia or midline brain anomalies (n=410); only 6/724 subjects (less than 1%) had HESX1 mutations (90).
Since the discovery of HESX1 mutations as a cause of both familial and sporadic septo-optic-pituitary dysplasia complex, mutations in many other genes have been identified as factors in the pathogenesis of various elements of septo-optic-pituitary dysplasia complex as well as other overlapping syndromes, such as holoprosencephaly and Kallmann syndrome (hypogonadotropic hypogonadism and anosmia). Septo-optic-pituitary dysplasia complex has been related to mutations in the human SOX2, SOX3, OTX2, FGF8, PROKR2, FGFR1, KAL1, and TAX1BP3 genes (71; 85; 86; 117; 87; 120), and also, ARID1 and even SHH genes have been implicated (122). In the case of TAX1BP3, the 2 reported siblings also had a dilated cardiomyopathy (120). Septo-optic dysplasia has also been described in association with a heteroplasmic mitochondrial gene mutation leading to complex III deficiency; in addition, the patient had cerebellar hypoplasia, retinitis pigmentosa, cardiomyopathy, and acute rhabdomyolysis (132).
Hypothalamic dysgenesis and hypopituitarism have been found in cases of holoprosencephaly due to mutations in the SHH, SIX3, TGIF and ZIC2 genes (129) as well as the FGF8 gene (86). Of the genes thus far identified as factors in the pathogenesis of septo-optic-pituitary dysplasia complex, FGF8, FGFR1 and PROKR2 mutations have also been reported in cases of Kallmann syndrome (117). Conversely, heterozygous mutations in KAL1 have now been reported in 3 females with hypopituitarism and bilateral optic nerve hypoplasia (87). KAL1 codes for anosmin and was the first gene to be associated with Kallmann syndrome. One of the 3 patients also had reduced gonadotrophin releasing hormone levels whereas the other 2 (who were sisters) had no reported features of hypogonadism. Finally, patients with sporadic and familial isolated congenital pituitary insufficiency have been identified with mutations in FGF8 and PROKR2 (thus, overlapping with septo-optic-pituitary dysplasia complex) as well as, more specifically for this phenotype, PROP1, POU1F1, LHX3 and LHX4 (71; 117).
As mentioned above, evidence is beginning to emerge for a possible common pathogenetic pathway that may link together genetic and environmental influences in the production of septo-optic-pituitary dysplasia complex. First, Zhao and colleagues demonstrated in a mouse model that embryos engineered to lack expression of Sonic hedgehog protein (Shh) in the prospective hypothalamus developed pituitary hypoplasia and virtual absence of the optic nerve head, with retinal ganglion cell axons marooned in the retina (155). These authors further demonstrated that Sox2 and Sox3 in mice were dose-dependent regulators of Shh expression in the hypothalamus (recall that human SHH mutations are a cause of holoprosencephaly and SOX2/SOX3 mutations are known to cause septo-optic-pituitary dysplasia). SHH mutations can also be associated with septo-optic-pituitary dysplasia (122). Second, Aoto and colleagues showed that exposure of mouse embryos to ethanol resulted in holoprosencephaly associated with impaired Shh expression in precordial mesoderm (ie, prior to neural tube formation) (08). Third, Kahn and colleagues demonstrated that the offspring of pregnant mice given 2 intraperitoneal injections of ethanol (3.48 g/kg) at embryonic day 8 subsequently manifested bilateral optic nerve hypoplasia whereas the offspring of saline-injected mothers did not (67). The pregnant mothers were heterozygous for mutations in Cdon, a coreceptor for Shh. Homozygous Cdon -/- mice also had bilateral optic nerve hypoplasia to the same degree as ethanol-exposed mice – hypoplasia that was not made worse if they were also exposed to ethanol in utero. This latter result suggested that an intact Shh signaling pathway was necessary in order for ethanol to produce its teratogenic effects (67). In combination, these data suggest the possibility that the various teratogens known to be linked to septo-optic-pituitary dysplasia complex may produce their effects via a common pathway that involves impaired SHH expression in the developing hypothalamus (155).
Even though the concept of septo-optic-pituitary dysplasia complex as a putative diagnostic “entity” has been in medical literature for over 40 years, incidence figures for the disorder have only begun to emerge in the past decade. It has always been assumed that septo-optic-pituitary dysplasia complex is a rare disorder, but, with the advent of routine neuroradiological investigation of cases of optic nerve hypoplasia or congenital growth hormone deficiency, the incidence of cases having at least 2 of the 3 main components of the disorder is turning out to be higher than was originally suspected.
Patel and colleagues collected incidence figures for optic nerve hypoplasia and “septo-optic dysplasia” for a defined population in northwest England with what was believed to be nearly total case ascertainment (110). Their definition of septo-optic-pituitary dysplasia complex was any combination of 2 or more of the 3 cardinal features. They reported an age-specific incidence rate for the combined disorders of 10.9/100,000 persons aged 0 to 15 years; approximately 50% of the total fulfilled the criteria for “septo-optic dysplasia” for an approximate incidence of 5.5/100,000 children and youth. The European prevalence of septo-optic-pituitary dysplasia is 1.9 to 2.5 per 100,000 births, with highest prevalence in babies of mothers aged 20 to 24 years and higher in the United Kingdom than in the rest of continental Europe (52). In Canada, there is geographical clustering in northern (arctic and subarctic) communities, but whether this distribution is related to climate, to diet, or to genetic ethnicity of Inuit and other indigenous populations is uncertain (73).
In a study from the West Midlands region of the United Kingdom, Atapattu and colleagues were able to capture all cases referred to the Birmingham Children’s Hospital (the only tertiary pediatric facility in the geographic area) for possible septo-optic-pituitary dysplasia, optic nerve hypoplasia, multiple pituitary hormone deficiency, and isolated growth hormone deficiency (09). Two hundred and twenty-seven cases had at least 1 feature of the triad, 88 had 2 or more features (therefore “septo-optic dysplasia”), and 21 cases had all 3 criteria. The respective age-specific incidence figures for children younger than 16 years of age were 13.8/100.000, 8.3/100,000, and 1.98/100,000.
Patel and colleagues also found that the incidence of optic nerve hypoplasia and “septo-optic dysplasia” varied widely among the specific districts of their catchment area. The highest age-specific incidence figures were found in districts with overall lower socioeconomic levels. The authors concluded that social deprivation may be a significant factor in the pathogenesis of optic nerve hypoplasia (110). This hypothesis is indirectly supported by the finding of a relatively lower age-specific annual incidence rate for optic nerve hypoplasia in Olmsted County, Minnesota, the site of the Mayo Clinic, with 2.4/100,000 residents under age 19 (95). The average socioeconomic level of the citizens of Olmsted County is higher than in most large urban areas of the United States.
To put the matter of incidence in some perspective, in 2 large published case series, the percentages of children with isolated growth hormone deficiency who turned out to have 2 or more features of septo-optic-pituitary dysplasia complex were still very small. In a large American study, septo-optic dysplasia was found in 4% of 2331 children with growth hormone deficiency (10). From a large international database, Deal and colleagues reported that septo-optic dysplasia represented 2.1% of 9494 cases of growth hormone deficiency, and 19.0% of those with MRI evidence of abnormal pituitary development (n=1071)(34).
It is estimated that the incidence of septo-optic dysplasia is 1 out of 10,000 live births (04). Published series of septo-optic-pituitary dysplasia complex typically report no gender predilection (110; 09; 34). Most case series have also not noted any ethnic predilection. In the published series of Atapattu and colleagues, however, the incidence of the disorder among individuals of South Asian origin was much lower than it was for all other racial groups (09). In the predominantly Hispanic (Los Angeles area) clinic population studied by Garcia-Filion and colleagues, optic nerve hypoplasia was found significantly more frequently among whites, whereas the frequencies were lower among Hispanics and persons of Asian or Pacific Island origin (51).
Possibly avoidable risk factors for septo-optic-pituitary dysplasia complex are young maternal age and primiparity, maternal diabetes, and maternal drug ingestion or abuse (104; 36). Drugs that have been implicated to date include anticonvulsants, ethanol, phencyclidine, cocaine, amphetamine, and phenylpropanolamine. With the possible exception of ethanol, it is by no means clear, however, that avoidance or improved treatment of any of these factors would actually decrease the incidence of basal forebrain anomalies.
There is no evidence for any association between septo-optic-pituitary dysplasia complex and any type of cerebral pathology, other than the various developmental anomalies acquired in utero (eg, schizencephaly). Likewise, there are no associated disorders of organs outside the nervous system other than would be expected from hypothalamic-pituitary dysfunction.
Prenatal detection. Using obstetrical ultrasound and MRI techniques, it is possible to detect the presence of septo-optic dysplasia in the fetus but not usually early enough to allow for pregnancy termination. Lepinard and colleagues (77) detected absence of the septum pellucidum in 2 fetuses at 29 and 30 weeks’ gestational age, respectively. One was found to have optic chiasm hypoplasia and went on to develop hypopituitarism postnatally (77). Prenatal ultrasonographic studies are precise and predictive of postnatal MRI examinations in showing absence of the septum pellucidum and thus serving as a marker for the risk of optic nerve hypoplasia and pituitary insufficiency (113). However, one must exercise caution in diagnosing prenatal ultrasonographic and MRI diagnoses of absence of the septum pellucidum because only a quarter of such cases are confirmed postnatally as septo-optic-pituitary dysplasia (134).
Prenatal ultrasound assessment of the optic nerves is technically very difficult because the nerves are obscured by the developing sphenoid bones. But ocular and orbital abnormalities sometimes can be detected prenatally by ultrasonography (101) and ultrasonographic nomograms of fetal optic nerve sheath diameter are now described (59). On the other hand, Bault and colleagues have developed a technique for measuring the diameter of the optic tracts on obstetrical ultrasound studies performed between 21 and 36 weeks’ gestation and have derived normal reference ranges (14). In their study of 13 fetuses found to have septal agenesis and adequate long-term follow-up, 9 had normal optic tract diameters and normal vision at follow-up. Four fetuses had unilateral (n=1) or bilateral (n=3) optic tract hypoplasia; of these, 2 with bilateral involvement had pregnancy termination and optic nerve/tract hypoplasia on pathological examination. The other 2 were live-born, and the subject with bilateral optic tract hypoplasia on ultrasound was blind at birth.
Vinals and colleagues employed 2D ultrasound to evaluate optic chiasm size/width in the coronal plane between 21 and 30 weeks’ gestation (146). Eight out of one hundred and fifteen prospectively studied fetuses were found to have agenesis of the septum pellucidum. Of these, 5 had normal optic chiasm size; 4 of 5 had normal vision at birth, whereas notwithstanding the ultrasound chiasmatic measurement, 1 had bilateral optic nerve hypoplasia and unilateral schizencephaly. The other 3 had reduced chiasmatic width; of these, 1 had fetal growth retardation but normal vision, 1 had unilateral schizencephaly and bilateral optic nerve hypoplasia, and the third patient unilateral schizencephaly and nystagmus (146).
These data suggest that, using obstetrical ultrasound techniques, it is possible to detect optic pathway hypoplasia in utero and to predict later visual deficits. Nevertheless, as can be seen from the study by Vinals and colleagues, an apparently normal optic chiasm does not exclude the possibility that optic nerve hypoplasia is present.
The principal differential diagnoses for septo-optic-pituitary dysplasia complex are its main components occurring in isolation: optic nerve hypoplasia and congenital hypopituitarism, especially dwarfism. Turning this statement around, when confronted with a patient having optic nerve hypoplasia (even unilateral) or pituitary dwarfism, it is important to ensure that the patient does not have other features of septo-optic-pituitary dysplasia complex, including endocrine dysfunction, visual impairment, and important brain anomalies such as arrhinencephaly, callosal agenesis, schizencephaly, and porencephaly. For optic nerve hypoplasia, the main differential diagnosis is optic atrophy, which is often mistakenly diagnosed instead of optic nerve hypoplasia. In some cases, both diagnoses may coexist (82).
For hypopituitarism presenting in early life, the main differential diagnoses are idiopathic congenital hypopituitarism (ie, not associated with posterior pituitary ectopia), postnatal trauma, and craniopharyngioma (115).
Some cases of holoprosencephaly can be confused with septo-optic-pituitary dysplasia, and they indeed share some overlapping features. In particular, the mild septo-preoptic variant, which overlaps many features of the mild lobar holoprosencephaly, can be confusing in differential diagnosis (109). Neurons of the preoptic nucleus are associated with fever and appetite suppression during unwellness, but these symptoms are general (103).
The diagnosis of septo-optic-pituitary dysplasia complex should be considered in any child with partial or complete absence of the septum pellucidum, optic nerve hypoplasia, or pituitary dwarfism, whether or not neurologic symptoms are also present. The diagnosis often already is available at birth from routine fetal ultrasonography and is confirmed by postnatal MRI. In young infants with visual impairment, major cerebral malformations such as schizencephaly or porencephaly may not be apparent, with seizures, learning disabilities, hemiparesis, and other symptoms becoming manifest as the brain matures. Some authors have reported that patients with bilateral optic nerve hypoplasia and severe visual loss are more likely to have neuroradiological anomalies than those with good vision (136; 47), but the existence of exceptions means that routine imaging of all patients with optic nerve hypoplasia is required. In short, a high index of suspicion is mandatory, particularly if complications of endocrine dysfunction are to be prevented. Although this caveat is important considering the possible consequences of a missed diagnosis, one must remember that the vast majority of children with optic nerve hypoplasia or isolated pituitary dwarfism do not have septo-optic-pituitary dysplasia complex (104).
In general, in a patient with optic nerve hypoplasia, the presence of cerebral neuroradiological abnormalities – in particular absent septum pellucidum or callosal agenesis – increases the probability of the eventual development of hypopituitarism (121; 26).
Though the risk of epilepsy is low in septo-optic-pituitary dysplasia, relative to many other major cerebral dysgeneses, it is higher than in the control population and particularly if associated brain malformations such as schizencephaly, which is demonstrated by neuroimaging. For this reason, baseline EEG in early infancy is recommended even in patients who have not had clinical seizures observed to detect subclinical paroxysmal foci and to assess the maturation and symmetry of background rhythms. Repeat EEG at 2 years of age is useful for electrocerebral maturation and for epileptiform discharges that were not yet developed in earlier infancy.
Congenital optic nerve hypoplasia. The combination of severe visual impairment and a small optic nerve head, with or without a ring sign, usually makes the diagnosis straightforward. Milder forms of hypoplasia, with apparently intact vision, may require examination by red-free light, fundus photography, and precise visual field testing. Optic nerve hypoplasia may also be diagnosed and graded by optical coherence tomography (OCT), especially where the findings on funduscopic examination are equivocal (112). Interestingly, Pilat and colleagues also found that, in cases of apparently unilateral optic nerve hypoplasia, the average optic disc diameter, cup depth, and retinal nerve fiber layer thickness in the “normal” eye with intact visual acuity were smaller than in healthy controls, although not to a statistically significant degree (112). Precise MRI measurements of normal pediatric optic nerve diameter and length at various postnatal ages is feasible and is quantitatively diagnostic in documenting optic nerve hypoplasia (81).
With respect to other investigative techniques, plain skull roentgenograms may reveal small optic foramina, but the presence of small optic nerve(s) is best demonstrated by CT or MRI of the orbits (82; 21). Abnormalities in both the optic nerves and tracts were identified on diffusion tensor MRI in 2 children with septo-optic-pituitary dysplasia complex and optic-pituitary dysplasia, respectively; fractional anisotropy was diminished whereas mean diffusivity was increased (126).
Electroretinography is often normal in optic nerve hypoplasia, but visual evoked responses are typically either absent or delayed (30). N95 waveforms of pattern-evoked ERG have predictive value in diagnosis in optic nerve hypoplasia because congenital deficits of retinal ganglion cells are associated with diminished or nondetectable results, reflecting function of the inner layers of the central retina (88). Depending on the overall clinical picture, some children with optic nerve hypoplasia may need investigations for potentially treatable disorders such as intrauterine infections (cytomegalovirus, toxoplasmosis, syphilis) and abnormalities of peroxisomal function.
Hypopituitarism. Congenital pituitary insufficiency should be suspected in the neonatal period if there is recurrent hypoglycemia, prolonged jaundice, or seizures. Affected males may have micropenis. Progressive growth failure may not become apparent for several years, ostensibly because of growth hormone-like effects of prolactin, of which levels are frequently elevated in hypopituitarism of hypothalamic origin (28). Deficiency of individual pituitary hormones or hypothalamic-releasing factors may be detected as follows (83; 23; 54; 43; 145): (a) growth failure: reduced levels of serum insulin-like growth factor 1 and insulin-like binding protein 3; response of serum growth hormone levels to insulin-induced hypoglycemia, or to glucagon, arginine, or clonidine is usually impaired; (b) thyroid function: reduced free or total serum thyroxine; serum thyrotropin levels may be low, normal, or even high, depending on whether the problem is in the pituitary gland or the hypothalamus; response of the thyrotropin levels to thyrotropin-releasing hormone stimulation are usually reduced but may be normal or exaggerated; (c) adrenal function: reduced early-morning serum cortisol and serum corticotropin; reduced cortisol level responses to metyrapone stimulation, low-dose ACTH, glucagon, CRH, or insulin-induced hypoglycemia; (d) gonadal function: reduced levels of serum luteinizing and follicle-stimulating hormones, serum estradiol, and serum testosterone; response of luteinizing hormone and follicle-stimulating hormone levels to gonadotropin-releasing hormone may be normal or decreased; (e) prolactin: serum prolactin levels usually elevated; response to stimulation tests (eg, thyrotropin-releasing hormone) may be exaggerated; and (f) antidiuretic hormone: inability to concentrate urine with water deprivation; response of symptoms to arginine-vasopressin injection.
Nanduri and Stanhope have pointed out that, in their experience, preservation of gonadotrophic hormone secretion is common in septo-optic dysplasia, whereas gonadotrophin insufficiency is typical of all other types of pathology involving the hypothalamic-pituitary axis. They postulate that preservation of gonadotrophin secretion reflects the fact that GnRH neurons originate in the olfactory epithelium and migrate to the hypothalamus, arriving in the 13th week of gestation, long after the putative time window during which septo-optic-pituitary dysplasia complex is believed to develop (5 to 8 weeks’ gestation) (98). A prolactinoma was described in an adult woman with septo-optic dysplasia (116).
When hypopituitarism and optic nerve hypoplasia occur together, the endocrinologic work-up usually suggests impaired hypothalamic function, with fairly normal responses of pituitary hormone levels to exogenously administered releasing factors (83). Pituitary dysfunction is much more likely when optic nerve hypoplasia is bilateral rather than unilateral (136). Magnetic resonance imaging is of considerable help in the assessment of congenital pituitary dysfunction, the most characteristic findings being posterior pituitary ectopia and absence of the pituitary stalk (69; 143; 94). It is important to remember, however, that pituitary dysfunction may occur in patients with septo-optic dysplasia with a normal-appearing pituitary region on MRI (01).
Associated brain anomalies. Although CT scanning demonstrates many of the cerebral abnormalities seen in septo-optic-pituitary dysplasia complex, the preferred imaging technique is MR, particularly for visualization of callosal agenesis and gray matter heterotopia. The most frequent radiologic findings, other than posterior pituitary ectopia, are as follows: (a) absence of septum pellucidum; open communication between anterior horns of the lateral ventricles, squared-off look to anterior horns, inferiorly displaced fornices; (b) lobar holoprosencephaly; fusion of inferior frontal lobes, absence of anterior third ventricle; in severe cases, may have partial fusion of basal ganglia and monoventricle; (c) agenesis of corpus callosum; if complete, wide separation of lateral ventricles with high-riding third ventricle, parallel anterior horns, and dilated occipital horns (colpocephaly); absence of only the anterior portion may be accompanied by absent septum pellucidum; absence of only the posterior portion by colpocephaly; best seen in midline sagittal sections; (d) schizencephaly: cleft between lateral ventricle and pial surface of cerebral hemisphere, the cleft being lined with gray matter; best demonstrated on T1-weighted images; unilateral or bilateral; may be associated with gray matter heterotopia, pachygyria, polymicrogyria; (e) gray matter heterotopia: globules of gray matter lining the lateral ventricle or located in the central white matter; often associated with colpocephaly and callosal agenesis; best seen on T1-weighted images; (f) porencephaly: cystic cavity in central hemispheric white matter, openly communicating with lateral ventricle; (g) hippocampal hypoplasia: protruding into the temporal horn, the hippocampus is smaller than normal and in a vertical, rather than horizontal position; (h) septopreoptic holoprosencephaly: fusion of midline structures just anterior to the anterior commissure on axial sequences; azygous anterior cerebral artery; and (i) periventricular leukomalacia; effacement of central white matter, especially in trigonal area of lateral ventricles, often with dilation of the underlying portion of the ventricle; best seen on T2-weighted and fluid attenuated inversion recovery images (12; 74; 153; 42; 135; 121; 58).
Rarely, septo-optic dysplasia may be associated with hypoplasia of the midbrain neuromere and ophthalmoplegia due to oculomotor nerve deficiency (147). In addition to rhombencephalosynapsis with absence of the vermis that may accompany septo-optic-pituitary dysplasia, agenesis or hypoplasia of one cerebellar hemisphere is reported in rare cases (108).
Active medical intervention for septo-optic-pituitary dysplasia complex is possible only for those patients with pituitary dysfunction (eg, replacement therapy with growth hormone, thyroxine, estrogen, testosterone, adrenocorticoids, or vasopressin, as required). Readers interested in more detailed information on the management of pituitary insufficiency are referred to the review article by Geffner and the consensus article by Stanhope and associates (138; 54). For visual impairment, mental handicap, learning and behavioral problems, and cerebral palsy, treatment is largely supportive. Selected cases may benefit from ocular surgery, such as if increased intraocular pressure is detected (46). Hearing loss may also be partially improved if detected early (61). Patients developing recurrent epileptic seizures may require anticonvulsant medication.
Only 25% of fetuses with isolated septal agenesis suggestive of septo-optic dysplasia are confirmed with this diagnosis postnatally (134). Postnatal MRI can confirm with greater confidence optic nerve hypoplasia and ophthalmological examination in the first few months can ascertain if visual impairment accompanies it. Postnatal endocrinological studies should be performed to detect pituitary insufficiencies, a treatable component.
The diagnosis of septo-optic-pituitary dysplasia can be made or at least suspected prenatally from about 17 weeks’ gestation by fetal ultrasonography and MRI. It does not affect the course of the pregnancy.
Patients with growth hormone deficiency-related hypoglycemia or adrenal insufficiency may decompensate with the stress of anesthesia (104). Close supervision is also required for those patients with severe physical handicaps, where orthopedic surgery may be necessary. Death has been reported during anesthesia for MRI or surgery, including dental procedures in children, largely due to unrecognized pituitary insufficiency or inadequate hormonal replacement therapy (123). With these exceptions, there is no specific risk from anesthesia in children with septo-optic-pituitary dysplasia complex.
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Harvey B Sarnat MD FRCPC MS
Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.See Profile
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