Haploinsufficiency of NKX2-1 in Brain-Lung-Thyroid Syndrome with Additional Multiple Pituitary Dysfunction.

INTRODUCTION: Heterozygous mutations or haploinsufficiency of NKX2-1 are associated with the brain-lung-thyroid syndrome incorporating primary hypothyroidism, respiratory distress, and neurological disturbances. CASE PRESENTATION: We report a patient presenting in the neonatal period with multiple pituitary hormone deficiency including central hypothyroidism and hypoadrenalism, growth hormone deficiency, undetectable gonadotrophins, and a small anterior pituitary on MRI. CGH microarray revealed haploinsufficiency for NKX2.1 and during subsequent follow-up, she has exhibited the classic triad of brain-lung-thyroid syndrome with undetectable tissue on thyroid ultrasonography. Whilst the role of NKX2-1 is well described in murine pituitary development, this report constitutes the first description of multiple pituitary dysfunction in humans associated with the syndrome and haploinsufficiency NKX2-1. CONCLUSION: The report highlights a potential need for pituitary screening in patients with established brain-lung-thyroid syndrome and implicates NKX2.1 in human pituitary disease.

High-resolution computed tomography findings of thyroid transcription factor 1 deficiency (NKX2-1 mutations).

BACKGROUND: The expression of the NKX2-1 gene and its encoded protein, thyroid transcription factor 1 (TTF-1), plays a role in pulmonary surfactant homeostasis and lung development. NKX2-1 mutations have been associated with neonatal respiratory distress, hypotonia, choreoathetosis and congenital hypothyroidism. These clinical findings have been coined brain-lung-thyroid syndrome, although not all three organs are always involved. While many of these children develop interstitial lung disease, no systematic review of chest high-resolution CT (HRCT) findings has been reported. OBJECTIVE: To summarize the clinical presentations, pathology and HRCT imaging findings of children with NKX2-1 mutations. MATERIALS AND METHODS: We identified six children with NKX2-1 mutations, deletions or duplications confirmed via genetic testing at our institution. Three pediatric radiologists reviewed the children's HRCT imaging findings and ranked the dominant findings in order of prevalence via consensus. We then correlated the imaging findings with histopathology and clinical course. RESULTS: All children in the study were heterozygous for NKX2-1 mutations, deletions or duplications. Ground-glass opacities were the most common imaging feature, present in all but one child. Consolidation was also a prevalent finding in 4/6 of the children. Architectural distortion was less common. CONCLUSION: HRCT findings of TTF-1 deficiency are heterogeneous and evolve over time. There is significant overlap between the HRCT findings of TTF-1 deficiency, other surfactant dysfunction mutations, and pulmonary interstitial glycogenosis. TTF-1 deficiency should be considered in term infants presenting with interstitial lung disease, especially if hypotonia or hypothyroidism is present.

Perfusion abnormality of the caudate nucleus in patients with paroxysmal kinesigenic choreoathetosis.

PURPOSE: Previous cerebral blood flow and glucose metabolism studies suggest that the basal ganglia or thalamus is involved in the pathogenesis of paroxysmal kinesigenic choreoathetosis (PKC). However, the underlying cerebral abnormalities in idiopathic PKC have not been elucidated. To localise cerebral perfusion abnormalities in PKC, we performed interictal brain perfusion 99mTc-ethylcysteinate dimer (ECD) single-photon emission computed tomography (SPECT) in PKC patients and in normal controls. METHODS: Sixteen patients with idiopathic PKC and 18 age- and sex-matched normal controls were included. The patients were de novo diagnosed as having PKC, or had not taken medication for at least 3 months; none of them had structural abnormalities on MRI. Patients had a history of PKC attacks of a duration not exceeding 5 min and starting either on one side or on both sides of the body. These attacks were always induced by a sudden initiation of voluntary movement. PKC attacks were recorded in a hospital after being induced by neurology staff in 13 of the 16 patients. Interictal brain perfusion 99mTc-ECD SPECT was performed in all 16 patients and 18 normal controls. Differences between the cerebral perfusion in the PKC group and the normal control group were tested by statistical parametric mapping. Student's t test was used for inter-group comparisons. RESULTS: Compared with normal controls, patients with idiopathic PKC showed interictal hypoperfusion in the posterior regions of the bilateral caudate nuclei (false discovery rate-corrected P<0.001 with a small volume correction). CONCLUSION: This study showed that cerebral perfusion abnormality of bilateral caudate nuclei is present in idiopathic PKC.

[Ictal SPECT and paired stimulation SEP recovery curve in a patient with paroxysmal kinesigenic choreoathetosis].

Paroxysmal kinesigenic choreoathetosis (PKC) is a rare and benign disorder with its onset in childhood. PKC generally improves with age, and its pathophysiology has not been revealed. We recorded both ictal and interictal SPECT in a 14-year-old girl with PKC. Ictal SPECT showed a significant decrease in blood flow in the caudate nucleus contralateral to the limb showing an involuntary movement. We also examined paired-pulse stimuli somatosensory evoked potential (SEP) of the same patient. Recovery pattern of P25 and N33 components was normal and comparable to 5 healthy volunteers, suggesting the absence of cortical hyperexcitability. These results suggest dysfunction or immaturity of the indirect pathway of basal ganglia in PKC, as well as the hyperexcitability of the descending pathway.

[Kinesigenic paroxysmal choreoathetosis: contribution of SPECT]. / Coreoatetosis paroxística cinesigénica: aportación de la SPECT.

We report two unrelated patients affected of kinesigenic paroxysmal choreoathetosis (CPC), during a symptomatic period. Routine complementary exams were normal. The 99mTc-HMPAO cerebral SPECT showed hyperactivation in the basal ganglia opposite to the choreoathetosic symptoms and reduced untake in the near parietal and subcortical zones in one case. These observations suggest that abnormal hyperactivity of contralateral basal ganglia may cause choreathetotic movements in patients with CPC.

Ictal (99m)Tc ECD SPECT in paroxysmal kinesigenic choreoathetosis.

Paroxysmal kinesigenic choreoathetosis is a rare neurologic disorder characterized by sudden attacks of brief involuntary dyskinetic movement that are precipitated by voluntary movement. A 14-year-old male who presented with frequent brief attacks of hemidystonia triggered by sudden movement is reported. Investigations, including video electroencephalogram and magnetic resonance imaging of brain, were normal. There was excellent and sustained response to carbamazepine. Ictal single-photon emission computed tomography using (99m)Tc ethyl cysteinate dimer revealed increased perfusion of the contralateral basal ganglia, which is associated with onset of choreoathetosis attacks. Our findings provide evidence that hyperactivity of the basal ganglia is associated with the dyskinetic attacks in paroxysmal kinesigenic choreoathetosis.

(+)-alpha-[11C]Dihydrotetrabenazine PET imaging in familial paroxysmal dystonic choreoathetosis.

Clinical observations suggest a disturbance of striatal dopaminergic function in familial paroxysmal dystonic choreoathetosis (PDC). The authors used PET with [11C]dihydrotetrabenazine (DTBZ) to study striatal dopaminergic innervation in PDC. The results did not reveal abnormal DTBZ binding potential in PDC striatum. This suggests that dopaminergic abnormalities, if present, may be due to altered regulation of dopamine release or to postsynaptic mechanisms, rather than to an altered density of nigrostriatal innervation.

[Ictal 99mTC-HMPAO-SPECT in a case of paroxysmal kinesigenic choreoathetosis].

A case of paroxysmal kinesigenic choreoathetosis (PKC) was described. The patient had attacks of paroxysmal choreoathetotic movements lasting 20-30 seconds. The attacks were regularly precipitated by sudden and unintentional movements. There were no metabolic abnormalities. EEG showed no epileptiform discharges. The attacks were subsided after administration of carbamazepine. We studied this patient with single photon emission computed tomography (SPECT) using 99mTc-HMPAO. Ictal SPECT revealed decrease of cerebral blood flow in the basal ganglia on the contralateral side of choreothetotic movements. Although the pathophysiology of PKC is still uncertain, it is hypothesized that motor activities are influenced by the direct pathway (positive feedback) and the indirect pathway (negative feedback) from the basal ganglia to the motor cortecis. Dysfunction of negative feedback is considered to be common underlying mechanisms of hyperkinetic disorders. Our findings support this hypothesis. Dysfunction of basal ganglia is likely relevant to the genesis of choreoathetosis.

The right brain hemisphere is dominant in human infants.

The development of functional brain asymmetry during childhood is confirmed by changes in cerebral blood flow measured at rest using dynamic single photon emission computed tomography. Between 1 and 3 years of age, the blood flow shows a right hemispheric predominance, mainly due to the activity in the posterior associative area. Asymmetry shifts to the left after 3 years. The subsequent time course of changes appear to follow the emergence of functions localized initially on the right, but later on the left hemisphere (i.e. visuospatial and later language abilities). These findings support the hypothesis that, in man, the right hemisphere develops its functions earlier than the left.

The cervical spine in athetoid cerebral palsy. A radiological study of 180 patients.

We have reviewed the cervical spine radiographs of 180 patients with athetoid cerebral palsy and compared them with those of 417 control subjects. Disc degeneration occurred earlier and progressed more rapidly in the patients, with advanced disc degeneration in 51%, eight times the frequency in normal subjects. At the C3/4 and C4/5 levels, there was listhetic instability in 17% and 27% of the patients, respectively, again six and eight times more frequently than in the control subjects. Angular instability was seen, particularly at the C3/4, C4/5 and C5/6 levels. We found a significantly higher incidence of narrowing of the cervical canal in the patients, notably at the C4 and C5 levels, where the average was 14.4 mm in the patients and 16.4 mm in normal subjects. The combination of disc degeneration and listhetic instability with a narrow canal predisposes these patients to relatively rapid progression to a devastating neurological deficit.

Regional cerebral glucose metabolism in clinical subtypes of cerebral palsy.

Twenty-three children with 4 clinical subtypes of cerebral palsy were studied using 2-deoxy-2(18F)fluoro-D-glucose (FDG) and positron emission tomography (PET). Subtypes included spastic quadriparesis (N = 6), spastic diplegia (N = 4), infantile hemiplegia (N = 8), and choreoathetosis (N = 5). FDG-PET images were correlated with magnetic resonance imaging or computed tomography. Although the location of glucose metabolic abnormalities corresponded, in general, to abnormalities of brain structure demonstrated by structural imaging studies, the distribution of metabolic impairment almost invariably extended beyond the region of anatomic involvement. The following observations in specific subtypes of cerebral palsy were determined with FDG-PET: (1) In spastic diplegic patients, PET revealed focal areas of cortical hypometabolism in the absence of apparent structural abnormality; (2) A relatively normal pattern of cortical metabolism was observed in most patients with choreoathetoid cerebral palsy, despite marked hypometabolism in the thalamus and lenticular nuclei; and (3) In patients with infantile hemiplegia, FDG-PET disclosed symmetric cerebellar glucose metabolism with absence of crossed cerebellar hypometabolism (diaschisis). This finding is contrary to the typical persistence of crossed cerebellar diaschisis in adult patients with acquired cerebral lesions and suggests metabolic recovery due to developmental plasticity. The possibility that FDG-PET may be clinically useful in identifying the cerebral palsy patient with potential learning handicap and in the study of functional recovery or sparing following brain injury should be explored further.

Unstable cervical spine in athetoid cerebral palsy.

The manifestations and pathomechanism of cervical instability of the athetoid neck in cerebral palsy (CP) patients was clarified in this study by means of static and dynamic x-ray analysis. Instability was defined as follows: 1) listhesis indicating anterior or posterior slip of more than 3 mm and/or 2) sagittal rotation between two vertebrae beyond the normal range measured by Penning. Cervical instability fitting this definition mainly took place in the upper and middle cervical disc levels, such as C3-4, C4-5, and/or occasionally C5-6. These coincide with the disc levels adjacent to the apex of the lordotic curve and/or those around the transitional vertebrae between the two reversed curves that render the cervical spine S-shaped in athetoid CP. A large facet angle at the apex vertebra facilitated anterior and/or posterior listhesis of the vertebrae. Conversely, a sudden decrease in the facet angle around the transitional vertebra in S-shaped curves precipitated deflection of the spine and increased sagittal rotation at this level. In addition to these structural abnormalities, rapid and repetitious neck movements seemed to accelerate the progression of cervical instability in athetoid CP patients.

Unilateral involuntary movements of acute onset in the adult, nine case reports and an alternative pathophysiological hypothesis.

During the last decade nine adult patients were seen with an unilateral choreoathetosis or choreoballism of acute onset. In seven a hemodynamically significant lesion in a carotid artery has been detected; in four the artery was completely occluded. In one there was a subclavian steal syndrome, and in another the etiology remained unclear. Three patients had their dyskinesia at the same side as the carotid artery lesion, and four at the controlateral side.

Abnormal computed tomograms in paroxysmal kinesigenic choreoathetosis.

In a case of paroxysmal kinesigenic choreoathetosis (PKC), an abnormality was found in the right hemisphere by computed tomography. It was not possible to define the pathological condition or the extent of the abnormality, and it is not known whether there was involvement of the basal ganglia. Nevertheless, this finding supports the concept that PKC results from an abnormality at the level of the cerebral hemisphere.