Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association.

At the recent Tuberous Sclerosis Consensus Conference, a subcommittee proposed recommendations to guide the rational use of diagnostic studies in patients with tuberous sclerosis complex. Recommendations were made for diagnostic evaluation at the time of diagnosis, when testing helps both to establish the diagnosis and to identify potential complications. Additional guidelines were proposed for the ongoing surveillance of established patients to detect later complications of tuberous sclerosis complex. In the absence of comprehensive population studies to govern the use of diagnostic studies in individuals with tuberous sclerosis complex, the panel developed guidelines based on the disorder's natural history, concentrating on complications that are common, clinically significant, and more easily managed when found early. Finally, the group made suggestions for the use of diagnostic tests to identify family members who have tuberous sclerosis complex. Although these recommendations should standardize and improve our use of diagnostic studies in individuals with tuberous sclerosis complex, the clinical approach in a given patient must remain flexible enough to meet the needs of individual patients and families.

Mutation analysis of the TSC2 gene in an African-American family.

Tuberous sclerosis complex is an autosomal dominant disorder with loci on chromosome 9q34 (TSC1) and chromosome 16p13.3 (TSC2). The TSC2 gene has been isolated. To date, only a small number of intragenic deletional and point mutations have been detected, almost exclusively in sporadic (no family history) cases. With the exception of a single parent/offspring pair, there have been no published reports of mutations in extended multigenerational chromosome 16-linked TSC2 families. For our TSC studies we ascertained and sampled a four-generation African-American TSC family that shows a high likelihood for linkage to chromosome 16 (z=1.53). Using single-strand conformation polymorphism analysis we identified a 4590/4591delC mutation in exon 34. The 4590/4591delC causes a frameshift mutation resulting in the creation of a premature stop codon. In addition, we have detected a 542del4 polymorphism in the two partially overlapping polyadenylation signals in exon 40 that segregates in the family. The polymorphism has been detected in six of 72 African-American control chromosomes examined, and has not been detected in 80 Caucasian control chromosomes examined.

18-Fluorodeoxyglucose positron emission tomography in children and adolescents with traumatic brain injury.

Twenty-two previously normal children and adolescents who suffered a severe, non-penetrating traumatic brain injury had PET during rehabilitation at a median of 1.5 months after the injury. Outcome was assessed at a median of 25 months after brain injury. 16 subjects had CT or MRI within 24 days of PET and 11 subjects had a second PET at the point of outcome (median 28 months after first PET). The PET score (obtained by adding the score of 15 brain regions: normal metabolism = 1; reduced = 0) was significantly associated with the clinical outcome measure. PET earlier than 12 weeks after head trauma correlated with outcome, but later PET did not. PET scores improved significantly between rehabilitation and outcome for the 11 subjects who had two PETs, but improvement was not associated with improvement in clinical condition. PET score did not add to the amount of variance explained in the last regression model for prediction of outcome when the results of contemporaneous CT/MRI and clinical condition were taken into account. The data suggest that routine PET during rehabilitation is no more useful than contemporaneous CT or MRI for prediction of outcome.

Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder of unknown aetiology that affects numerous body systems including skin, brain and kidneys. Some TSC has been linked to chromosome 9, additional TSC genes on chromosomes 11 and 12 have been proposed, but the majority of TSC families remain unlinked. Using TSC families in which data had excluded linkage to chromosome 9, we failed to detect linkage with loci on chromosomes 11, 12 and others. One marker examined was D16S283, the closest locus on the proximal side of the polycystic kidney disease type 1 (PKD1) gene. Linkage between TSC and D16S283 demonstrated a lod score of 9.50 at theta = 0.02 with one family independently presenting a lod score of 4.44 at theta = 0.05. These data reveal an important TSC locus near the region of PKD1 on chromosome 16p13.

Chronic inflammatory demyelinating polyradiculoneuropathy of childhood: treatment with high-dose intravenous immunoglobulin.

We treated four children with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with high-dose intravenous immunoglobulin (IVIG). All patients received 400 mg/kg of IVIG a day for 5 days during relapses, and one patient received additional periodic infusions of 400 mg/kg. All patients showed excellent recovery of motor strength following each relapse that was treated with IVIG. Compared with plasmapheresis (which was used to treat relapses earlier), recovery of function with IVIG treatments was similar, and in two patients it was superior, to plasmapheresis. There were no side effects with IVIG treatments as compared with plasmapheresis with which two children had infection of central lines with Staphylococcus epidermidis, one had profuse bleeding from accidental extrusion of a central line, and one had multiple episodes of major venous thromboses. High-dose IVIG was a safe and effective adjunctive therapy for childhood CIDP in these four patients.

Linkage studies in tuberous sclerosis. Chromosome 9?, 11?, or maybe 14!

Published reports show linkage of tuberous sclerosis (TSC) to either chromosome 9 in some families or chromosome 11 in other families. We studied 243 individuals (82 with TSC) from 16 multigenerational TSC families. The diagnosis of TSC conformed to the criteria of Gomez. Penetrance was estimated at 0.90. DNA markers were analyzed using Southern blotting, probe hybridization, autoradiography, and genetic linkage analysis. Two-point lod scores for TSC were calculated for 43 genetic markers distributed over 11 chromosomes. Tests for homogeneity rejected the null hypothesis of homogeneity. Linkage to TSC was excluded (z less than or equal to -2, theta greater than or equal to 0.05) for 23 of these markers including 9q34 and 11q markers. One family gave z(theta max) = 1.8, theta max = 0.001 with ABO (on 9q34), and two other families attained lod scores greater than 1 for 9q34-region markers. The lod score for TSC versus chromosome 14 marker pAW101 (D14S1) was z(theta max) = 1.98, theta max = 0.15. A single large family has overall negative lod scores for markers localized to both chromosome 9 and chromosome 11. These data confirm genetic heterogeneity in TSC and suggest linkage of some families to 9q34. Furthermore, the data suggest that 14q may be an interesting area.

Absence of linkage of ABO blood group locus to familial tuberous sclerosis.

A mutation leading to tuberous sclerosis was linked to the ABO blood group locus (9q34) on the long arm of chromosome 9. In an effort to confirm this assignment, nine multigenerational families with tuberous sclerosis, comprising 126 sampled individuals, were assessed for linkage of the ABO locus to tuberous sclerosis. Two-point linkage analysis and multilocus linkage analysis were used to evaluate linkage between tuberous sclerosis and the markers ABO, MCT136, and AblK2. Linkage of ABO to tuberous sclerosis was excluded for a distance of 20 centimorgans (cM) encompassing the region of the ABO locus. There was no evidence for genetic heterogeneity within this data set. Using 23 polymorphic markers, exclusion mapping demonstrated only a 1% probability that the tuberous sclerosis locus was on the distal short arm of chromosome 9 and provided no evidence in support of a tuberous sclerosis locus on the remainder of chromosome 9 including the area of the ABO locus.

Intracranial pressure (ICP) monitoring as a guide to prognosis in a lightning-injured, comatose child.

Every year there are many deaths due to lightning injuries in the United States. A case is presented of a young child who suffered cardiopulmonary arrest following being struck by lightning strike and in whom ICP monitoring was utilized. We postulate that ICP and CPP measurements may be useful as prognostic indicators for comatose lightning victims and, therefore, may help in the management of the patient.

Hysterical conversion reactions mimicking neurological disease.

Seven children with illnesses diagnosed as hysterical conversion reactions (HCRs) were treated at our institution over a period of nine months. They all had neurological symptoms that included one or more of the following: paralysis, headache, seizures, and episodic blindness. All patients but one were misdiagnosed as having an organic disease prior to our final diagnosis. Five children were treated with medications for presumed organic illnesses. In all of these children a diagnosis of HCR was made on the basis of their history and neurological examination findings. They all recovered or began recovery within a few days of having HCR diagnosed, and none of them had had a relapse three to 11 months after the diagnosis of HCR was made. We believe, and there is ample evidence in the literature, that a positive diagnosis of HCR in childhood can be made when neurological manifestations cannot be explained on an anatomic and physiological basis. Although absence of an obvious organic cause is a helpful clue, exhaustive exclusion of all possible organic causes is not necessary for the diagnosis of HCR.

Hyperdensity on CT after seizure: a pitfall.

A 12-year-old boy had a hyperdense area corresponding to a gyral pattern on an enhanced CT brain scan within 12 hours of his last seizure. The hyperdense area disappeared on a subsequent enhanced CT scan after he was seizure free for about 48 hours. The hyperdense area was in a location (mesial frontal lobe) predicted by the interictal physical exam findings and the seizure type recorded on video-EEG monitoring. We postulate that the CT abnormality was due to transitory increase of regional cerebral blood flow and vascular permeability.

Birth injury-induced glossolaryngeal paresis.

Glossolaryngeal paresis followed a difficult delivery and forceps manipulation and was due to a single extracranial traumatic lesion. Although the laryngeal palsy was suspected, hypoglossal involvement was not initially apparent. Search for additional neurologic insult is warranted when a single birth injury is identified. The glossolaryngeal paresis disappeared by age 6 months.

Headache and acute illness in children.

Thirty-seven children with headaches who were seen in a walk-in clinic were matched to 37 headache-free controls. Thirty percent of the headache group and 11% of the headache-free control group had a body temperature above 38 degrees C (p less than 0.05). Nonrhythmic pain was more commonly associated with fever than was rhythmic pain (p less than 0.05). Of 34 headache subjects who completed questionnaires, those with more intense headaches reported a greater number of headache-exacerbating factors (p less than 0.01). Bilateral headaches were more painful than unilateral headaches, and in two thirds of the subjects, the intensity of pain paralleled the course of the underlying illness. A family history of migraine was more common in the headache group as compared to the headache-free control group (p less than 0.05). Headaches associated with acute illnesses may be a precursor to later migraine.