Vein of Galen malformations
Vein of Galen malformations are congenital arteriovenous malformations involving the deep venous system of the brain that were first described in 1895
Sep. 24, 2021
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This article includes discussion of Potter sequence, oligohydramnios sequence, Potter syndrome, Potter’s sequence, Potters sequence, congenital anomalies of the kidney and urinary tract, and CAKUT. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Potter syndrome, also known as oligohydramnios sequence, covers a phenotypically and genetically heterogeneous group of familial or sporadic conditions that may stem from different origins. Affected newborns have characteristic facial and limb deformities and pulmonary hypoplasia resulting from oligohydramnios, primarily consequent to severe renal pathologies or occasional nonurinary mechanisms. The author highlights new developments in the treatment of oligohydramnios and reviews CNS anomalies associated with some cases of Potter syndrome.
• In classic Potter syndrome, bilateral renal agenesis and consequent anhydramnios lead to a constellation of findings characterized by congenital deformations (flattened “Potter” facies and limb deformities).
• Potter “sequence” enlarges the pathogenetic spectrum by including other renal or urinary anomalies that also lead to oligo/anhydramnios either by failure of urine production or obstruction to urine outflow.
• Oligo/anhydramnios can also stem from nonrenal causes (eg, chronic leakage of amniotic fluid or placental pathology), but a major complication arising from all causes is pulmonary hypoplasia, with subsequent death in the newborn period from respiratory insufficiency.
• Some cases are associated with gene mutations, most recently integrin alpha 8; inheritance in familial cases has been described as autosomal dominant, recessive, or multifactorial.
Edith Potter first described a syndrome in infants characterized by bilateral renal agenesis and associated deformities, such as flattening of facies (68). Potter later extended the syndrome to include other severe cystic kidney conditions. Subsequently, the term “sequence” replaced “syndrome” because the characteristic phenotype of these infants is independent of the kidney pathology and is related to the ensuing oligohydramnios. Consequently, “oligohydramnios sequence” and “Potter sequence” are used interchangeably (16; 53).
Involvement of the CNS in oligohydramnios sequence has sometimes been mentioned in the literature; however, only exceptionally has a detailed neuropathologic study of these defects been conducted (43).
Infants with Potter sequence have characteristic facial and limb deformities and pulmonary hypoplasia. Severe renal or obstructive urinary malformations are usually the cause of oligohydramnios. It is the latter that gives rise to the facial and limb deformities and impairs normal development of the lungs. In others, however, nonurinary causes such as amniotic fluid leakage and placental pathology could provoke oligohydramnios with the same consequences (21; 63). The umbilical cord is often shorter than expected in fetuses, most probably the result of oligohydramnios, fetal constraint, and reduced movement in utero (37).
In the typical liveborn infant with renal agenesis or dysplasia, death occurs within several hours of birth, mainly due to pulmonary hypoplasia and consequent respiratory failure. The severity of respiratory insufficiency depends in part on the duration of oligohydramnios (44). In rare instances of less severe renal and nonurinary cases, longer survival is possible. Body weight and amniotic fluid index are important prognostic indicators (27). Potter sequence may occur with associated multiple congenital abnormalities that are not directly related to the Potter anomaly (syndromic cases), or without them (nonsyndromic cases). Among the associated multiple congenital abnormalities, CNS involvement has only occasionally been reported. This consisted mostly of gross cerebral malformations and included such diverse findings as hydrocephalus, occipital encephalocele, microcephaly, porencephalic cysts, absent corpus callosum, polymicrogyria, subependymal cysts, cerebellar dysgenesis, optic nerve hypoplasia or megalopapilla, and cerebral bleedings (16; 84).
Studies of a series of cases with oligohydramnios sequence, however, revealed in all cases examined, the presence of a variety of cerebrocortical cytoarchitectural abnormalities that are directly and consistently related to defects in neuroblast migration during the period of cerebral cortical histogenesis (43). Similar systematic defects in neuroblast migration have been reported in another series of Potter cases (30). Thus far, detailed neuropathologic investigation has been carried out only in these 2 series.
Most of the cases of oligohydramnios sequence that result from severe renal pathology are incompatible with postnatal life. These infants are either stillborn or die within hours or days of delivery, mainly because of pulmonary hypoplasia and respiratory failure. Renal prognosis in infants born with unilateral renal agenesis depends in part upon the compensatory growth of the remaining kidney (66). Adverse effects in newborns with other causes of oligohydramnios (eg, abruption, premature rupture of membranes) include low birth weight, chronic lung disease, and neonatal mortality (46). A few cases with no primary defect in the urinary system may result in a viable infant with some signs of oligohydramnios sequence. Such infants usually present with the “dry lung syndrome,” which could respond to resuscitation and assisted ventilation. One study suggests that increased urinary MCP-1 (monocyte chemotactic protein-1) is an indicator for renal damage and that ongoing renal inflammation mediated by local monocytes may be responsible for progressive renal damage (04). Discordance for renal agenesis has been reported in both dichorionic diamniotic and monozygotic twins (40; 47).
The neurologic outcome in these rare viable infants would conceivably depend on the nature and severity of any underlying neuropathologic deficit. No such clinicopathological correlation studies are currently available.
A midgestational fetus was born at 21 weeks and survived less than 1 hour.
Death was due to extreme prematurity and severe pulmonary hypoplasia, the latter a consequence of bilateral renal agenesis with anhydramnios. Limb deformations, including talipes equinovarus, and a small mandible were noted. Karyotyping was not successful.
The term “Potter sequence” covers a group of diseases that are phenotypically similar but of different origins (76).
Many cases are syndromic and chromosomal; others are Mendelian. Mutations in RET, GDNF, UPK3A, PAX2, PAX8, and GREB1L have been noted in some cases of renal hypoplasia/adysplasia (79; 84; 78; 10; 17; 74; 09). Some of these are rare, and thus, pathogenesis remains under investigation (38). Abnormal expression in WT1 has been identified in affected patients as well (54; 55). Mutations in integrin alpha 8 (specifically the integrin alpha 8 encoding gene ITGA8) have been identified in familial cases of bilateral renal agenesis (36). Studies of monozygotic twins discordant for renal agenesis suggest that nongenetic factors may also be involved in pathogenesis (40). Bilateral renal agenesis or dysgenesis is, for example, found in about 6% of infants of insulin-dependent diabetic mothers (59). Of additional interest is the fact that integrin alpha 8-null mice manifest abnormalities in lung morphogenesis (05). As more is learned about the effect of these mutations, this observation may alter the widely held view that oligohydramnios resulting from renal agenesis is a primary cause of pulmonary hypoplasia.
Potter sequence manifests phenotypic and genetic heterogeneity; environmental (eg, pregestational maternal diabetes) and epigenetic factors have been implicated as well (60). Exposure to certain teratogens during pregnancy has sometimes been implicated as a causal factor (15). For a full list of identifiable syndromes in which the Potter sequence has been seen, see Table 4 of Curry (16). The presence of additional anomalies that do not appear to be related to oligohydramnios complicates the understanding, and sometimes primary diagnosis, of this condition (24).
The initiating event in Potter sequence is oligohydramnios (or anhydramnios) of any cause. The extrarenal features of Potter sequence are believed to result from prolonged fetal compression. Underlying renal or urinary malformations are heterogeneous and could be developmental malformations or genetically based.
The causal and pathogenic diversity of the Potter sequence is, therefore, evident. This etiologic diversity may explain the heterogeneity of the occasional “oligohydramnios sequence unrelated” cerebral malformations of nonmigrational origin that have been reported in this syndrome. Among the 4 major categories of renal cystic disease, type I was mostly correlated with CNS, skull, and spine abnormalities (11).
The neuroblast migration defects, however, seem to be yet another “constant” consequence of oligohydramnios and prolonged fetal compression in this syndrome. These “fixed oligohydramnios sequence-related” cerebral abnormalities are thought to result from a defect in the guiding radial glial fibers needed by migrating neuroblasts during the period of cerebral histogenesis (43).
Some fetuses or infants with oligohydramnios have shown anomalies of the central nervous system. The familial occurrence of 2 cases of agenesis of the corpus callosum was reported in infants with multicystic dysplastic kidney (87). The mother was exposed to increased electromagnetic radiation during both pregnancies. Familial renal adysplasia has also been associated with schizophrenia (56).
Defects of neuroblast migration have been detected in the developing brain of oligohydramnios sequence cases (49; 43). These consisted of abnormal lamination of cerebral cortex, white matter heterotopias, and meningeal and molecular zone neuronal-glial heterotopia.
In addition, 1 or more of the following brain anomalies were sometimes found: abnormal gyration patterns, brainstem heterotopia, adysplasia of basal ganglia, olivary anomalies, hydrocephalus, and ependymal desquamation. Cerebrocortical nerve cell bodies were often grouped in columnar blocks separated from 1 another by acellular strips composed of bundles of nerve fibers. This columnar pattern prevails in upper neocortical levels. The white matter beneath these neuron-deficient cortical strips contains many neurons trapped in a pattern corresponding to the overlying cell-sparse spaces. Foci of gliosis and, occasionally, of mineralization could be found in the white matter and basal ganglia.
In many cases, defects related to neuroblast migration were also found in other zones of gliophilic neuroblast migration, such as the hippocampus and cerebellum. The dentate gyrus may have an immature aspect with incomplete rotation, and its cortical plate may be abnormally wide and thickened. Cerebellar Purkinje and granular cell heterotopia could also be found as well as cerebellar polymicrogyria. These neuroblast migrational defects were detected in oligohydramnios sequence groups with various renal pathologies (43).
The migration of young neuroblasts during the ontogenetic period of the mammalian brain is guided by a system of immature glial cells known as radial glial fibers (42; 19; 23; 28). These fibers span the pallial wall from the periventricular zone, where young neurons are generated, to the pial surface and serve as specialized substrates along whose surfaces migrating neuroblasts slide (14). In the human fetal telencephalon, this process takes place primarily between 7 weeks and 16 weeks of gestation (51; 03); however, data suggest that at least residual neuroblast migration continues well into the second half of gestation (75; 42; 20). Specialized neuropathologic studies that were applied in oligohydramnios sequence cases show that this late neuroblast migration is deranged. This defective neuroblast migration seems to result from an abnormality in the radial glial fibers during the period of cortical histogenesis. In these oligohydramnios sequence cases, the late contingent of radial glial fibers was found to present remarkable ultrastructural alterations consisting of autophagic vacuoles and primary and secondary lysosomal proliferation, changes that underlie a precocious transformation of radial glial fibers into astrocytes; therefore, it was hypothesized that this abnormally induced radial glial fibers transformation is the pathogenic mechanism responsible for the defects in neuroblast migration, because this precocious transformation of radial glial fibers would eliminate the guiding substrates needed by young neuroblasts for their migration. These young neuroblasts would, thus, end heterotopically (43).
It has been suggested that a mechanical factor precipitates such abnormal glial transformation in the brains of cases with Potter sequence. The consequence of oligohydramnios and prolonged fetal compression seems to be that intrauterine steric hindrance might physically “break” the slender and long radial glial fibers by applying abnormal strain to these delicate structures. If this hypothesis is maintained, it would imply that migrational defects resulting from strained radial glial fibers could be an integral part of the oligohydramnios sequence; however, other adverse factors that could have damaging effects on the radial glial fibers have not been totally ruled out. These include intrauterine infections, metabolic abnormalities, and ischemic-anoxic conditions. Some of these adverse factors might themselves result from, or be favored by, prolonged compression in cases of oligohydramnios.
In general, the prevalence of congenital anomalies of the kidney and urinary tract is about 0.5% to 1% and represents the most common form of birth defect (08; 73). More specifically, the epidemiology of neuroblast migration defects and other cerebral malformations in oligohydramnios sequence reflects that of the underlying disease. The incidence of Potter sequence is probably best estimated by combining the incidences of the individual conditions underlying oligohydramnios sequence. The yearly combined rate for the major variants was found in 1 study to be between 0.16 and 0.34 per 1000 births (69).
No specific or uniformly successful methods of prevention are known. Serial amnioinfusion as a means of preventing pulmonary hypoplasia and compression effects is in early stages of development, carries risks, and, if attempted, needs to be accompanied by thorough counseling (86; 81).
Recurrence risk counseling for the family of a child with Potter sequence is a complex issue—one that will be clarified as genetic, or other factors are recognized. Each case must be shown not to be part of a more extensive disease, syndrome, or teratologic sequence that could result in this phenotype. Prenatal ultrasound testing for renal and urinary tract abnormalities that lead to oligohydramnios sequence should be offered to all at-risk families beginning at 16 weeks gestation to monitor for recurrence (16).
Certain conditions and drugs were found to have a teratogenic effect during pregnancy. These include gestational diabetes, diabetes mellitus, thalidomide, severe hypoxia, x-rays, maternal rubella, and probably other infections as well as many of the angiotensin-converting enzyme inhibitors, particularly enalapril (16; 69; 15; 82). However, siblings and parents of infants with lethal renal agenesis and renal dysgenesis have “silent” genitourinary anomalies at an incidence of more than 30 times that of the general population; therefore, first-degree relatives should undergo ultrasound examination to screen for silent anomalies.
The heterogeneity of the “oligohydramnios sequence unrelated” CNS malformations that are occasionally encountered in Potter sequence presumably reflects the broad range of origins of the various conditions that give rise to oligohydramnios sequence and the Potter phenotype. Careful clinical examination, record of family histories, chromosomal analysis of infants and parents, and complete autopsies including meticulous neuropathologic examination are necessary to recognize and classify these conditions. The great majority of cases of oligohydramnios that can give rise to the Potter sequence are caused by renal and urinary tract conditions of various origins. These different types of renal cystic diseases were reviewed by Curry (16) and by Zerres (89) and include a variety of sporadic, genetic, and Mendelian kidney conditions (83; 01). Renal tubular dysgenesis predisposes to Potter sequence as well (32) and can occur on an autosomal recessive basis (29). Occasional nonrenal causes of oligohydramnios have been reported, including chronic amniotic fluid leakage and placental pathology (33; 63).
About 20% of cases with the Potter phenotype are part of a more extensive disease with many multiple congenital abnormalities. It is in this group of syndromic cases that cerebral malformations are often reported (16).
The “fixed oligohydramnios sequence-related” cerebral abnormalities, resulting from defects in neuroblast migration, however, have apparently been encountered in every case of oligohydramnios sequence irrespective of its etiology.
A host of clinical signs indicate further workup of the urinary system, including polyuria or nocturia, infection of the urinary tract, hypertension, difficulties in urination, bladder distention or other dysfunction, abnormal bowel physiology, and failure to thrive (61). Imaging may include pre- or postnatal ultrasonography, CT scan, and MRI (70). Color Doppler ultrasound is helpful in identifying renal arteries and can be especially beneficial where visualization of the kidneys is suboptimal; examination is possible as early as the first trimester (35). MRI can add diagnostic information to the more preliminary findings of fetal ultrasound, to the point of altering diagnoses or parental decision-making (39). The technique of fetal diffusion-weighted MRI with apparent diffusion coefficient determination provides for the noninvasive evaluation and prediction of renal function in fetuses with renal anomalies and/or oligohydramnios (22).
Many of the syndromic cases of Potter sequence are associated with multiple congenital abnormalities, including reduced stature with skeletal, heart, cleft palate, and other oropharyngeal anomalies; heterotaxy defects have been reported in several studies (90; 64; 12; 65; 73). Unilateral renal agenesis may be associated with a variety of anomalies involving the contralateral kidney (15%) or, in a third of cases, extra-renal tissues (52). An infrequent association is retrocaval course of the contralateral ureter (13). Malformations of the CNS and skull are recognized as well (29). The diversity of CNS anomalies probably reflects, at least in part, the heterogeneity of the underlying oligohydramnios sequence cases with which they are sometimes associated.
The marked clinical and pathologic heterogeneity of the conditions that could give rise to the Potter phenotype necessitates thorough diagnostic approaches and classification in order to obtain a framework on which to assess recurrence risk and plan prenatal diagnosis in subsequent pregnancies.
In addition to a careful clinical examination and a family history, each infant who dies of Potter sequence should undergo complete autopsy with special attention given to the urinary, pulmonary, and nervous systems (48). Studies continue to demonstrate the utility of autopsy in identifying renal lesions or associated syndromes that were undiagnosed by prenatal ultrasound (67; 26). When autopsy is not permitted, postmortem imaging (ie, ultrasonography, MRI, CT scan) may – with consent, of course – be of help in identifying anatomic changes. Chromosome analysis of blood, skin, and other tissues in affected infants is also necessary (07). Karyotypic abnormalities, including uncommon ones such as 4p- (Wolf-Hirschhorn) syndrome or 47,XXY (Klinefelter syndrome), have been associated with oligohydramnios sequence (80; 02; 62). Trisomy 12, which is usually lethal, may be encountered in survivors when mosaic (72). Karyotyping should be considered in parents, especially if the infant had multisystem involvement including CNS malformations. Renal ultrasound or urologic examination of the parents is indicated in patients with renal agenesis, cystic dysplasia, or renal tubular dysgenesis (31). Investigation of more distant relatives is indicated if a family history of genitourinary anomalies exists or if either parent has an abnormality on ultrasound. Functional urologic evaluation of parents and siblings of infants with obstructive uropathy should be considered. As a result of the risk of recurrence, prenatal high-resolution ultrasound monitoring of subsequent pregnancies and testing of alpha-fetoprotein levels in maternal serum should be offered to all women who have had a child with this phenotype.
Antepartum diagnosis is possible in most cases by means of ultrasound scanning, which should be performed in the second trimester (77). The ultrasonographer should exercise care to examine the entire urinary tract as well as other systems, in order to identify or exclude other conditions (18). Both amnioinfusion and maternal hydration (2 liters of 5% dextrose administered over 2 hours) have been of some success in increasing amniotic fluid volumes in cases of oligohydramnios (34; 88). Parents should be counseled regarding the potential genetic ramifications and offered renal ultrasound examination (58).
In viable infants, the “dry lung syndrome after oligohydramnios” was suggested to respond to positive high-pressure ventilation to overcome lung collapse. Inhaled nitric oxide was also reported to have dramatic role in pulmonary disease after prolonged oligohydramnios (25). Renal agenesis, whether unilateral or bilateral, may be associated with anomalies of the seminal vesicle and vas deferens (hypoplasia, absence); in cases of unilateral renal agenesis, changes may be ipsilateral or contralateral to the absent kidney (71). The vas may be absent bilaterally in cases of unilateral renal agenesis (50). Survival in premature infants depends upon the severity of renal and pulmonary disease and the availability of peritoneal or hemodialysis, cardiorespiratory support, and eventual renal transplantation (57).
Management of neurologic disorders in any surviving infant would be determined by the nature of that deficit. Some of the “minor cortical dysgeneses” resulting from minimal defects in neuroblast migration could, perhaps, be compatible with “near normal life” with only minor cognitive deficits if not associated with other neurologic or non-neurologic afflictions. Follow-up studies of any such cases would provide definitive information.
Women with unilateral renal agenesis may be at risk for adverse outcomes, including preterm delivery, pre-eclampsia, and a need for cesarian section (45).
In certain cases of oligohydramnios, infused fluid could be successful in decreasing pulmonary hypoplasia. Even in cases of bilateral renal agenesis, serial amnioinfusion has been used successfully with the assistance postnatally of peritoneal dialysis (06). However, the procedure is not routine, may be associated with complications such as chorioamnionitis (85; 41), and requires counseling (81).
Oligohydramnios sequence is usually associated with breech presentation and premature delivery; thus, many nonviable neonates are delivered by cesarean section. Given the lethality of this anomaly, some families elect therapeutic termination of pregnancy when ultrasound diagnosis is obtained prenatally.
Joseph R Siebert PhD
Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.See Profile
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