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Neu-Laxova syndrome is a rare congenital disorder characterized by microcephaly, limb contactures, lissencephaly and ichthyosis. A case of Neu-Laxova syndrome is presented, with a discussion of clinical manifestations, complications, and therapeutic interventions.
We report clinical, neuroradiological and neuropathological findings of monozygotic twin sisters born at 30 weeks' gestation, with pontocerebellar hypoplasia (PCH) similar but not identical to type 2 PCH. They presented with hypertonia, jitteriness, spontaneous and provoked myoclonic jerks (hyperekplexia), apnoeic episodes, and progressive microcephaly. They died at 7 weeks of age from respiratory failure.
The International Aicardi-Goutières Syndrome Association (IAGSA) was founded in 2000, its aim being to collect and analyse all available information on this rare syndrome (whose true incidence is not known) in order to increase knowledge of the pathology and the number of reported cases. We analysed the clinical, neuroradiological and biological characteristics of 21 new Aicardi-Goutières syndrome subjects (seven observed directly and 14 on whom we gathered detailed clinical information) and compared our findings with data in the literature. The main clinical symptoms (pyramidal and extrapyramidal symptoms, psychomotor delay, microcephaly) and neuroradiological features (basal ganglia calcification, atrophy, white matter alterations) observed show a greater homogeneity in our subjects than in the literature cases, which indicates an improvement in the diagnostic accuracy of Aicardi-Goutières syndrome. Other symptoms, such as feeding difficulties and irritability are less frequent, but characteristic and present early (even at onset of the disease). In the literature, doubts are expressed as to whether lymphocytosis and/or raised interferon-alpha in cerebrospinal fluid are crucial for a diagnosis of Aicardi-Goutières syndrome. Our data suggest that they are, and in particular that an important role is played by raised interferon-alpha. The clinical course seems to show different stages: early onset, rapid progression, severe deterioration, stabilization. Our follow-up seems to indicate a trend not necessarily towards a worsening, but instead towards a stabilization or even a slight improvement of the clinical picture.
Serological tests were performed on 58 children with microcephalus and 223 children with cerebral damage but no microcephalus (all patients were living in the Munich region). In the microcephalus group 38% had antibodies against cytomegalovirus, while in healthy controls the incidence was only 18%. Mean titre levels were significantly higher in microcephalic children. Of eleven microcephalic children seven were cytomegalovirus excreters: all of the latter had severe cerebral defects. On the other hand, in patients with cerebral damage but no microcephaly there was no difference serologically or with regard to virus excretion from healthy controls. The authors suggest, in conformity with opinions expressed by others, that there is a definite connection between--usually unrecognised--cytometalovirus infection and certain forms of cerebral damage. They may be atypical and symptom-poor diseases in which CNS signs appear only in the course of time.
Purely cortical cerebral calcification without involvement of the cerebellum was observed radiologically in a 3-month old girl; the calcification was extensive and symmetrical. During a three year period of observation, she showed severe psychomotor retardation, spasticity, microcephaly, a secondary scoliosis, subluxation of the hips and fits. These changes have only been observed so far following pre-natal herpes encephalitis. Following this condition there may also be periventricular calcification. Therefore it is assumed that the extensive cortical calcification is due to a virus, but not necessarily a specific one and that it depends on the age of the foetus at the time of the infection.
Micro syndrome is a rare condition in which congenital cataracts, microphthalmia, and facial dysmorphism are associated with severe neurological disorders, namely: microcephaly and psychomotor retardation. We report on polymicrogyria and motor neuropathy in a patient with Micro syndrome. These findings provide new insights into developmental defects underlying motor and mental disabilities.
We report the case of a 7-year old girl with Høyeraal-Hreidarsson syndrome (HHS) and review other cases of HHS. In addition to the previously described important signs of HHS, i.e., prenatal growth retardation, microcephaly, psychomotor retardation, progressive pancytopenia, immunological abnormalities, and cerebellar hypoplasia and ataxia, we consider that delayed myelination of cerebral white matter and hypoplastic corpus callosum should be added to the list of important signs. However, it is not clear whether delayed myelination of white matter in HHS indicates dysmyelination or demyelination. Furthermore, we suggest that immunological abnormalities of both T and B cells are one of the important signs of HHS. We consider these new important signs to be valuable for the diagnosis of HHS.
We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome). Mutation analysis of the zinc finger homeo box 1 B (ZFHX1 B) gene revealed a de novo 7 bp deletion (TGGCCCC) at nucleotide 1773 (1773 delTGGCCCC) resulting in a frameshift and leading to a termination codon at amino acid residue 604 (604 X) in exon 8 C. The zinc finger homeo box 1 B (Smad interacting protein-1) is a transcription corepressor of Smad target genes with functions in the patterning of neural crest derived cells, CNS, and midline structures. Mutations in ZFHX1 B can lead to neurological disorders in addition to dysmorphic features, megacolon, and other malformations.
Serine deficiency disorders comprise a new group of inborn errors of serine metabolism. Patients affected with these disorders present with major neurological symptoms including congenital microcephaly, seizures, psychomotor retardation or polyneuropathy. The diagnosis of serine deficiency is based on the detection of low concentrations of the amino acids serine and glycine in fasted plasma and cerebrospinal fluid (CSF). Amino acid analysis of cerebrospinal fluid is preferable over plasma analysis, because the deficiencies are more pronounced in CSF. Because of the interference of amino acids absorbed from the diet, diagnostic procedures have to be performed in the fasted state. Although the disorders are probably rare and not many cases have been reported, recognition of serine deficiency is important, given the fact that the disorders are potentially treatable. The clinical symptoms respond well to amino acid replacement therapy. So far, three serine deficiency disorders have been reported; 3-phosphoglycerate dehydrogenase deficiency, 3-phosphoserine phosphatase deficiency and a still unexplained serine deficiency disorder. In this paper, we will discuss the various serine deficiency disorders, their biochemical abnormalities and the results of amino acid replacement therapy.
We report the neonatal courses, early postnatal development, and neuroimaging findings of 17 patients with marked microcephaly and simplified cerebral gyral patterns, a condition that we call microlissencephaly. Retrospective analyses of the clinicoradiologic features of these patients allowed segregation of the patients into 5 distinct groups with varying outcomes. The apparent discreteness of these groups suggests multiple etiologies of this malformation, although there appears to be a strong genetic component with probable autosomal recessive inheritance. Utilizing the neonatal course and neuroradiologic features of these infants allows classification of specific subsets, which may be useful to predict outcome.
Two infants are described, who, we suggest, represent a fourth subtype of carbohydrate-deficient glycoprotein (CDG) syndrome. Both patients showed microcephaly and severe epilepsy with absent psychomotor development and similar minor dysmorphic features. There were no signs of liver dysfunction. Several glycoproteins in blood, including transferrin, alpha 1-antitrypsin, antithrombin and thyroxine-binding globulin, demonstrated abnormal isoforms suggesting a partial deficiency of mainly one or two sialic acid residues. Both the clinical picture and the glycoprotein abnormalities were different from previously defined types of CDG syndrome.
Varicella-Zoster (V-Z) virus infection during pregnancy is uncommon. Nevertheless, it has importance due to the risk of vertical transmission of the infection and also because of a higher morbidity rate among pregnant women. The cases of varicella infection that occur in the first and second trimesters of pregnancy are occasionally associated to the development of congenital varicella syndrome. We studied 22 women whose pregnancy was complicated with varicella during the first 20 weeks of gestation. The average age of these patients was 20 +/- 3.6 years with a range of 16 to 20 years. None of the patients presented complications due to the V-Z virus infection. Two pregnancies finalized in preterm labor. None of the newborns had congenital anormalies; one presented microcephaly, and another low birth weight. There was no significant difference between the infants of women with varicella and those of the controls in birth weight, size, and head circumference. We concluded that varicella infection during the first 20 weeks of gestation was not associated with serious maternal morbidity, and has low repercussion in the pregnancy outcome and the fetus.
A familial cerebral malformation combined with chronic hypernatremia is reported. We found three children of a Moroccan family with microcephaly and hypoplasia of the frontal brain. The frontal parts of the lateral ventricles were absent. Two of the children had a defect of the midline structures with fusion of the lateral ventricles similar to holoprosencephaly. Further clinical symptoms were generalized spasticity, delay of mental development and hypodipsia.
HISTORY AND CLINICAL FINDINGS: Dizygotic twin sisters were born to a woman who, shortly before becoming pregnant, had developed Graves' disease with markedly elevated triiodothyronine (T3) levels and highly positive TSH receptor antibody titres (TRAb: 169 mU/ml). From the second week of life onwards they had a goitre and hyperexcitability, tachycardia and failure to thrive were noted. In addition, twin I had mild exophthalmos. As thyrostatic treatment of the mother was very difficult, intrauterine hypothyroidism or transitory hyperthyroidism had presumably occurred in the twins. INVESTIGATIONS: Twin I had maximal thyroxine (T4) concentration of 26.2 micrograms/dl, while it was 24.7 micrograms/dl in twin II with suppressed TSH. Both twins had high concentrations of TRAb and antibodies against thyroid peroxidase. DIAGNOSIS, TREATMENT AND COURSE: With the diagnosis of neonatal Graves' disease established, both twins were treated with propranolol (2 mg/kg.d) and phenobarbitone (2-4 mg/kg.d). Twin I, whose symptoms were more severe, also received propylthiouracil (5 mg/kg.d) until euthyroidism had been achieved. Although twin II became euthyroid spontaneously, she gained weight only slowly and microcephaly developed together with definite motor and mental retardation. It remains unclear whether these were consequences of intrauterine hypothyroidism or post-partum hyperthyroidism. CONCLUSION: Graves' disease during pregnancy demands interdisciplinary collaboration between gynaecologist, physician and paediatrician to prevent severe sequelae in the children. Early risk assessment is possible by measuring the TSH receptor antibody titre in umbilical blood.
A database which runs on an office microcomputer is being developed for the diagnosis of genetically determined neurological disorders. At present about 1100 conditions with their clinical features and 3000 references are stored in the database. We discuss a family with 3 sibs affected by a unique neurological disorder and show how the database is used. The 3 sibs, 4, 5 and 10 years old, show the same clinical course characterized by congenital cataracts, microcephaly, hypotonia, mental retardation, pyramidal signs and choreoathetoid movements starting in early childhood. The parents are first cousins of Bangladeshi origin. This condition does not appear in published report and is not listed in the database. It can therefore be concluded that the sibs have a unique autosomal recessive disorder.
To evaluate the risk of offspring of heavy drinking during pregnancy, we administered a questionnaire to 633 women at the first prenatal visit. Nutritional status, smoking, drug and alcohol use were determined. Women were classified into three groups: abstinent and rare drinkers; moderate drinkers; and heavy drinkers. After delivery, detailed pediatric, neurologic and developmental examinations were administered by a physician without prior knowledge of any history. Infants born to heavy drinkers had twice the risk of abnormality of those born to abstinent or moderate drinkers (P less than 0.001). Thirty-two per cent of infants born to heavy drinkers demonstrated congenital anomalies, as compared to 9 per cent in the abstinent and 14 per cent in the moderate group (P less than 0.001). Microcephaly and multiple congenital anomalies were much more frequent in this group (P less than 0.001). Heavy drinking during pregnancy increases the risk to offspring.
Since many women with phenylketonuria (PKU) will have children of their own, we were interested in ascertaining the effect of maternal PKU and hyperphenylalaninemia on the offspring of such women. We reviewed the literature on this subject and obtained additional unpublished data through an international survey. Data were collected on 524 pregnancies in 155 women; in 34 pregnancies a low-phenylalanine diet was begun after or shortly before pregnancy was established. Among untreated pregnancies, the frequencies of mental retardation, microcephaly, and congenital heart disease were greatly increased over those in the normal population, and these increases correlated with the mother's blood levels of phenylalanine. Ninety-five per cent of mothers with blood phenylalanine concentrations of 20 mg per deciliter or higher had at least one mentally retarded child. Bias introduced by case-finding methods cannot explain these results. It is not clear from our review whether dietary treatment begun after conception is helpful, but treatment begun before conception should be evaluated.
We studied the effects of maternal phenylketonuria and hyperphenylalaninemia on 53 offspring from untreated pregnancies in 22 mothers who were identified by routine screening of umbilical-cord blood. The IQ of the offspring was significantly correlated with both maternal IQ (r = 0.83, P less than 0.001) and maternal blood phenylalanine level (r = 0.82, P less than 0.001), but with one exception, mental retardation in offspring was present only when the maternal blood phenylalanine level exceeded 1100 mumol per liter (18 mg per deciliter). Microcephaly in offspring was consistently present only when the maternal blood phenylalanine level exceeded 1200 mumol per liter (20 mg per deciliter). Congenital heart disease and other congenital anomalies were rare among offspring. The data suggest that severe atypical or classic phenylketonuria (blood phenylalanine level, greater than 1100 mumol per liter) in the mother has a substantial cognitive effect on her offspring but that the effect of mild hyperphenylalaninemia may have been overstated in the past.