The fetal valproate syndrome

We evaluated seven children who had been exposed to sodium valproate (or valproic acid) in utero. A consistent facial phenotype was observed in all seven in addition to other birth defects in four. The facial changes consisted of epicanthal folds which continued inferiorly and laterally to form a crease or groove just under the orbit, flat nasal bridge, small upturned nose, long upper lip with a relatively shallow philtrum, a thin upper vermillion border, and downturned angles of the mouth. Hypospadias, strabismus, and psychomotor delay were found in two males; two children had nystagmus and two had low birth weight.     

The fetal valproate syndrome

We evaluated seven children who had been exposed to sodium valproate (or valproic acid) in utero. A consistent facial phenotype was observed in all seven in addition to other birth defects in four. The facial changes consisted of epicanthal folds which continued inferiorly and laterally to form a crease or groove just under the orbit, flat nasal bridge, small upturned nose, long upper lip with a relatively shallow philtrum, a thin upper vermillion border, and downturned angles of the mouth. Hypospadias, strabismus, and psychomotor delay were found in two males; two children had nystagmus and two had low birth weight.     

Severe acute hyperammonemia after brief exposure to valproate

The authors describe a case of acute hyperammonemia after the addition of valproate to the medication regimen of a patient on multiple psychotropic medications. The patient presented with acute mental-status changes consistent with delirium. With prompt intervention and supportive care, her delirium quickly cleared.     

Baller-Gerold syndrome Craniosynostosis-radial aplasia syndrome

A new case of the Baller-Gerold syndrome is described in a 6¹/₂-year-old, black male who presented at birth with bilateral synostoses of the coronal and lambdoidal sutures, bilateral radial aplasia, vertebral anomalies and genito-urinary malformations. The parents and siblings were unaffected, and there was no history of consanguinity. A review of the history and physical findings in our patient and in the four other patients previously reported in the literature is provided, with a discussion on pathogenesis, prognosis and the possible autosomal recessive mode of inheritance of the syndrome.     

The Baller-Gerold syndrome.

A case of severe craniosynostosis-radial aplasia (Baller-Gerold) syndrome is described in a newborn male, following a pregnancy complicated by polyhydramnios and intrauterine growth retardation. Death occurred after two hours owing to a prolonged apnoeic spell. Extensive agenesis of the frontal and parietal bones, resulting in a very large fontanelle, in addition to coronal bilateral craniosynostosis was observed at necropsy. There was also bilateral radial agenesis, oligodactyly of the hands and feet, a midline facial angioma, and a scrotally positioned anus, all of which have been described in some of the 10 previously reported cases. Microcephaly, erythroblastosis of the liver, and pancreatic islet cell hypertrophy were also noted.     

Verification of the fetal valproate syndrome phenotype

We have evaluated 19 children who were exposed to valproic acid (VPA) in utero to look for manifestations of a fetal valproate syndrome (FVS), as proposed by Di Liberti et al. [1984]. We found no consistent alterations of pre- or postnatal growth with exposure to VPA monotherapy. Postnatal growth deficiency and microcephaly were present however, in two thirds of children exposed to VPA in combination with other anticonvulsants. Developmental delay or neurologic abnormality was found in 71% of those exposed to VPA monotherapy, and in 90% of those exposed to VPA and other anticonvulsants. Craniofacial anomalies, which can be seen with other anticonvulsant exposures, including midface hypoplasia, short nose with a broad and/or flat bridge, epicanthal folds, minor abnormalities of the ear, philtrum or lip, and micrognathia were also found in infants whose mothers used VPA. Prominent metopic ridge and outer orbital ridge deficiency or bifrontal narrowing and certain major anomalies such as tracheomalacia, talipes equinovarus (with intact spine) and lumbosacral meningomyelocele seem to be peculiar to infants with VPA exposure. Other defects such as urogenital anomalies, inguinal or umbilical hernias, and minor digital anomalies that are common to other prenatal anticonvulsant exposures are also occasionally found in those exposed to VPA. Heart defects have been found in infants exposed to nearly every class of anticonvulsant although the types of defects associated with maternal VPA use may be clarified when classified by pathogenetic mechanism. Our findings overall are in agreement with the report of Di Liberti et al. [1984].     

Further delineation of the Baller-Gerold syndrome

Three new patients with the Baller-Gerold syndrome bring the number of reported cases to 20. In addition to craniosynostosis involving various sutures and preaxial reduction defects of variable severity, affected patients may have anal, urogenital, cardiac, central nervous system, and vertebral defects. Autosomal recessive inheritance is supported by the presence of affected sibs and parental consanguinity. © 1993 Wiley-Liss, Inc.     

Another TWIST on Baller-Gerold syndrome.

Baller-Gerold syndrome is characterized by craniosynostosis and preaxial upper limb malformations. Wide heterogeneity exists with regard to the presence of additional anomalies. Most of the 31 reported cases involve other malformations, including cardiac, Central Nervous System (CNS), and urogenital anomalies. Baller-Gerold syndrome is thought to have autosomal recessive inheritance. However, Gripp et al. [1999: Am. J. Med. Genet. 82:170-176] recently provided the first evidence for autosomal dominant inheritance with variable expressivity and severity. A nonsense mutation was found in TWIST, a gene associated with Saethre-Chotzen syndrome (SCS). Here we report on a male Caucasian patient of nonconsanguineous parents, with synostosis of the coronal, metopic, and sagittal sutures, and bilateral radial ray hypoplasia. The patient's small, round ears with prominent crus helices, and cervical anomalies are common features of SCS. The father had very mild features of SCS. We identify direct paternal transmission of a novel missense TWIST mutation in the highly conserved Helix II domain of this bHLH-family gene. This report lends further support to the recent findings by Gripp et al. [1999]. Future TWIST mutational analysis on patients with craniosynostosis and radial ray involvement will shed light on whether Baller-Gerold syndrome should be a distinct entity or some cases should be reclassified as a heterogeneous form of SCS.     

Baller-Gerold syndrome associated with congenital hydrocephalus

We present a new case of the Baller-Gerold syndrome (BGS) in an infant with prenatally apparent severe hydrocephalus, growth retardation, and cardiac and limb abnormalities detected by ultrasound at 26 weeks of gestational age. Subsequent survival to term and neonatal examination confirmed an unsuspected diagnosis of BGS.     

Anomalous right pulmonary artery origins in association with the fetal valproate syndrome

Two cases are reported of fetal valproate syndrome in association with anomalous right pulmonary artery origin. Both diagnoses were confirmed following cardiac catheterisation as echocardiography alone was inadequate to define the anatomy. Anomalous right pulmonary artery origin is extremely rare making a chance association with fetal valproate syndrome very unlikely. We recommend that anomalous pulmonary artery origin is borne in mind in patients with valproate syndrome undergoing cardiac assessment, particularly as this may be a difficult diagnosis to make on echocardiography.


Keywords: valproate syndrome; hemitruncus     

Baller-Gerold syndrome associated with congenital portal venous malformation.

We report a 4 year old boy in whom the clinical features of craniosynostosis and bilateral absent radii led to a diagnosis of Baller-Gerold syndrome. Additional congenital abnormalities included midface hypoplasia, atrial and ventricular septal defects, right hydronephrosis, partial sacral agenesis, and anterior ectopic anus. Evidence of portal venous hypertension was present from 8 months and a congenital portal venous malformation was discovered at 2 years. This is the first reported case of Baller-Gerold syndrome associated with a congenital portal venous malformation. We discuss the diagnostic confusion between this syndrome and other overlapping malformation syndromes and propose optimal evaluation strategies aimed at clarifying the nosology of these syndromes.     

Long first metacarpal in monozygotic twins with probable Baller-Gerold syndrome

We report on a pair of monozygotic twins with probable Baller-Gerold syndrome (BGS). Twin A had severe coronal craniosynostosis. Twin B had right radioulnar and ipsilateral first metacarpal hypoplasia. Both had bilateral fifth finger clinodactyly. Assuming that the twins were truly monozygotic, a single genetic disorder (i.e., BGS) could explain the variable expression. Together the twins have the typical anomalies of BGS. The diagnosis was supported by the metacarpophalangeal profile (MPP) which confirmed hypoplasia of the first right metacarpal in Twin A and bilateral fifth finger brachymesophalangy in both twins. Furthermore, the MPP showed an unexpected abnormal lengthening of the first metacarpal (unilateral in Twin A and bilateral in Twin B), a previously undetected radial ray defect in BGS. These findings suggest the possibility that the MPP may assist recognition of mild cases of BGS such as those with apparently isolated craniosynostosis or isolated upper limbs defects. Am. J. Med. Genet. 80:303–308, 1998. © 1998 Wiley-Liss, Inc.     

The Baller-Gerold syndrome: phenotypic and cytogenetic overlap with Roberts syndrome.

A case is reported where the major clinical features of craniostenosis and radial aplasia led to an initial diagnosis of Baller-Gerold syndrome. Mild fibular hypoplasia on skeletal survey led to review of the diagnosis and the similarity of the facial phenotype to that of Roberts syndrome was noted. Chromosome analysis showed the premature centromere separation characteristic of this condition. This case raises the question as to whether the Baller-Gerold syndrome can be considered as a distinct entity. It is suggested that cases diagnosed as having Baller-Gerold syndrome should have cytogenetic analysis and that known Roberts syndrome survivors are reviewed for signs of craniostenosis.     

Lung damage after long-term exposure of adult rats to sodium fluoride

Introduction

Fluorides, when taken in amounts exceeding the standard therapeutic dosage, are regarded as toxic substances. Chronic fluorosis causes marked destruction of lung tissues. The study aimed to determine whether the effect of a chronic toxic dose of sodium fluoride on the lung of an adult male albino rat is reversible or irreversible. This was done through light and electron microscopic studies. Morphometric study was also done.

Material and methods

Forty adult male rats were used. The animals were divided into 3 groups: control group; group I (chronic fluorosis group) in which sodium fluoride was given daily for 3 months; and group II (recovery group) in which sodium fluoride was given daily for 3 months and after that the rats survived for another month.

Results

The lung of group I was characterized by presence of blood and lymph congestion. Thickening of alveolar septa was also observed with rupture of septa and widening of the air spaces. The area % of collagen (1.13 ±0.5), septal wall thickness (13.47 ±6.1), and number of macrophages (5 ±2.5) increased in comparison to the control group (p ≤ 0.05). With discontinuation of sodium fluoride (group II), no much improvement was observed.

Conclusions

Chronic fluorosis has many pathological effects on the lung which are irreversible.