MECP2 duplications in six patients with complex sex chromosome rearrangements.

Duplications of the Xq28 chromosome region resulting in functional disomy are associated with a distinct clinical phenotype characterized by infantile hypotonia, severe developmental delay, progressive neurological impairment, absent speech, and proneness to infections. Increased expression of the dosage-sensitive MECP2 gene is considered responsible for the severe neurological impairments observed in affected individuals. Although cytogenetically visible duplications of Xq28 are well documented in the published literature, recent advances using array comparative genomic hybridization (CGH) led to the detection of an increasing number of microduplications spanning MECP2. In rare cases, duplication results from intrachromosomal rearrangement between the X and Y chromosomes. We report six cases with sex chromosome rearrangements involving duplication of MECP2. Cases 1-4 are unbalanced rearrangements between X and Y, resulting in MECP2 duplication. The additional Xq material was translocated to Yp in three cases (cases 1-3), and to the heterochromatic region of Yq12 in one case (case 4). Cases 5 and 6 were identified by array CGH to have a loss in copy number at Xp and a gain in copy number at Xq28 involving the MECP2 gene. In both cases, fluorescent in situ hybridization (FISH) analysis revealed a recombinant X chromosome containing the duplicated material from Xq28 on Xp, resulting from a maternal pericentric inversion. These cases add to a growing number of MECP2 duplications that have been detected by array CGH, while demonstrating the value of confirmatory chromosome and FISH studies for the localization of the duplicated material and the identification of complex rearrangements.

Incidence of pediatric Horner syndrome and the risk of neuroblastoma: a population-based study.

OBJECTIVE: To describe the incidence of pediatric Horner syndrome and the risk of occult malignancy in a population-based cohort. METHODS: The medical records of all pediatric patients (aged <19 years) residing in Olmsted County, Minnesota, who received diagnoses of Horner syndrome from January 1, 1969, through December 31, 2008, were retrospectively reviewed. RESULTS: Horner syndrome was diagnosed in 20 pediatric patients during the 40-year period, yielding an age- and sex-adjusted incidence of 1.42 per 100 000 patients younger than 19 years of age (95% confidence interval [CI], 0.80-2.04). Eleven of the 20 patients (55%) had a congenital onset, for a birth prevalence of 1 in 6250 (95% CI, 3333-10 000), while the remaining 9 (45%) had acquired syndromes. Seven of the 11 (63.6%) patients with congenital cases had a history of birth trauma, while the remaining 4 (36.4%) had no identifiable cause. Six of the 9 (66%) acquired cases occurred following surgery or trauma, while the remaining 3 (33%) had no known etiology. None of the 20 patients (95% CI, 0.0%-16.8%) were found to have a neuroblastoma or other malignancy during a mean follow-up of 56.5 months (range, 0-256.9 months). CONCLUSIONS: The incidence of pediatric Horner syndrome in this population was 1.42 per 100 000 patients younger than 19 years, with a birth prevalence of 1 in 6250 for those with a congenital onset. Birth, surgical, or other trauma occurred in 13 (65%) of the patients, while none were found to have an underlying mass lesion, suggesting a need for reappraising current recommendations for extensive evaluations in these patients.

Oculopharyngeal somatic myopathy in a patient with a novel large-scale 3,399 bp deletion and a homoplasmic T5814C transition of the mitochondrial DNA.

We report a 65-year-old woman with a sporadic form of progressive oculopharyngeal somatic myopathy due to a novel large-scale 3,399 base pair (bp) deletion of the mitochondrial DNA (mtDNA) and co-occurrence of a homoplasmic T5814C transition. The onset of myopathy began from chronic progressive external ophthalmoplegia (CPEO) at age of 20 years. Bulbar weakness, neck and proximal limb paralysis, slowly progressed to eventual respiratory failure. The plasma levels of pyruvate (1.5 mg/dL) and lactate (20.2 mg/dL) were elevated. Muscle biopsy showed decreased enzymatic activity of cytochrome c oxidase, but no ragged-red fibers. Electron microscopy showed "parking-lot" paracrystalline inclusions in the enlarged mitochondria suggestive for mitochondrial myopathy. Sequencing of the whole mitochondrial genome of the patient's muscle and leukocytes showed 3,399 bp deletion of the mtDNA from nucleotide position 8,024 to 11,423 and a homoplasmic thymidine to cytosine transition at nucleotide position 5,814 of the tRNA(Cys) gene of mtDNA (T5814C). T5814C was absent in the white blood cells of the patient's daughter and in 205 normal controls. We conclude that a large-scale deletion may coexist with T5814C transition in patients with sporadic form of mitochondrial cytopathy manifested by slowly progressive oculopharyngeal somatic myopathy.

Early detection of severe cholestatic hepatopathy in COACH syndrome.

COACH syndrome is a disorder with cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. Sixteen cases with certain COACH diagnosis have been reported so far. Neurologic abnormalities are the first symptoms in most cases. The majority of cases were diagnosed late in childhood or adolescence. Complications of the hepatopathy contribute extensively to the morbidity and lethality in the course of the disease. Major complications are portal hypertension, esophageal varices, and gastrointestinal bleeding. We report of a child with only mild neurologic symptoms, but severe hepatic fibrosis with cholangiopathy, and review the literature. This is the first description of profound cholestatic hepatopathy in a very young child with COACH syndrome. The patient was found to have cerebellar vermis hypoplasia, unilateral optical nerve coloboma, mild dysmorphic signs, and a ventricular septum defect. Routine laboratory investigations eventually revealed elevated liver enzymes. Prothrombin time was abnormal. Ultrasound scan of the liver was normal. Hepatotropic viral infections were excluded. We performed a liver biopsy at the age of 16 months, confirming an early stage of cirrhosis with septal fibrosis and pseudolobules, inflammatory infiltrates, signs of cholestasis, and reduced numbers of intrahepatic bile ducts. Early detection and differentiation of liver pathology are important in COACH syndrome. Progressive destructive cholangiopathy may contribute to hepatic fibrosis in COACH syndrome. Liver disease can be severe even in cases with mild neurologic deficits.

Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons.

Artemin (ARTN) is a member of the GDNF family of ligands and signals through the Ret/GFRalpha3 receptor complex. Characterization of ARTN- and GFRalpha3-deficient mice revealed similar abnormalities in the migration and axonal projection pattern of the entire sympathetic nervous system. This resulted in abnormal innervation of target tissues and consequent cell death due to deficiencies of target-derived neurotrophic support. ARTN is expressed along blood vessels and in cells nearby to sympathetic axonal projections. In the developing vasculature, ARTN is expressed in smooth muscle cells of the vessels, and it acts as a guidance factor that encourages sympathetic fibers to follow blood vessels as they project toward their final target tissues. The chemoattractive properties of ARTN were confirmed by the demonstration that sympathetic neuroblasts migrate and project axons toward ARTN-soaked beads implanted into mouse embryos.

Idiopathic Horner's syndrome in the golden retriever.

A prospective study was made of cases of idiopathic Horner's syndrome in dogs referred to the author. Over a six-year period the condition was recorded in 62 golden retrievers. Examination suggested that the lesions affected the preganglionic neuron.

A balanced autosomal translocation (3;9) associated with primary hypogonadism and dorsal spine stenosis.

A man with a balanced translocation between chromosomes 3 and 9 associated with primary hypogonadism and dorsal spine stenosis is reported. The possible significance of this chromosomal abnormality is discussed.

Autosomal dominant congenital Horner's syndrome in a Dutch family.

A Dutch family is reported with congenital Horner's syndrome in five cases spanning five generations, with symptoms of varying degree but mainly ptosis and meiosis. Heterochromia iridium, anhidrosis, and enophthalmos were not present. The site of the lesion may be in the region between Gasser's ganglion and the short vertical segment of the internal carotid artery near the siphon. There are only four previous reports showing autosomal dominant inheritance of congenital Horner's syndrome.