Duplication within two regions distal to MECP2: clinical similarity with MECP2 duplication syndrome.

BACKGROUND: X-linked methyl-CpG-binding protein 2 (MECP2) duplication syndrome is prevalent in approximately 1% of X-linked intellectual disabilities. Accumulating evidence has suggested that MECP2 is the causative gene of MECP2 duplication syndrome. We report a case of a 17-year-old boy with a 1.2 Mb duplication distal to MECP2 on chromosome Xq28. Although this region does not contain MECP2, the clinical features and course of the boy are remarkably similar to those observed in MECP2 duplication syndrome. Recently, case reports have described duplication in the region distal to, and not containing, MECP2. These regions have been classified as the K/L-mediated Xq28 duplication region and int22h1/int22h2-mediated Xq28 duplication region. The case reports also described signs similar to those of MECP2 duplication syndrome. To the best of our knowledge, ours is the first case to include these two regions. CASE PRESENTATION: The boy presented with a mild to moderate regressive intellectual disability and progressive neurological disorder. He developed epilepsy at the age of 6 years and underwent a bilateral equinus foot surgery at 14 years of age because of the increasing spasticity in lower extremities since the age of 11. Intracranial findings showed hypoplasia of the corpus callosum, cerebellum, and brain stem; linear hyperintensity in the deep white matter; and decreased white matter capacity. During his childhood, he suffered from recurrent infection. However, genital problems, skin abnormalities and gastrointestinal manifestations (gastroesophageal reflux) were not observed. CONCLUSIONS: Cases in which duplication was observed in the region of Xq28 that does not include MECP2 also showed symptoms similar to those of MECP2 duplication syndrome. We compared four pathologies: MECP2 duplication syndrome with minimal regions, duplication within the two distal regions without MECP2, and our case including both regions. Our results suggest that MECP2 alone may not explain all symptoms of duplication in the distal part of Xq28.

[The effect of noninvasive positive pressure ventilation in children with severe motor and intellectual disabilities with respiratory insufficiency].

We investigated the clinical course of 20 children (persons) with severe motor and intellectual disabilities (SMID) who were treated with noninvasive positive pressure ventilation (NPPV) for respiratory insufficiency. NPPV was effective in 10 of 11 patients treated for acute respiratory failure, and in 7 of 9 patients treated for chronic respiratory failure. Twelve patients were treated with NPPV for more than one year. There were no complications associated with NPPV in any of the patients. NPPV improved ventilation impairment soon after ventilation was started, and avoided the need for the endtracheal intubation by adjusting airway management and the choice of mask in all but one of the patients with acute respiratory failure. NPPV in combination with wearing a chin strap was highly effective in patients with open state or upper airway obstruction. Five patients were successfully weaned off the ventilator soon after recovery from acute respiratory failure using NPPV, whereas 5 patients who continued NPPV during the chronic phase after recovery did not experience recurrent episodes of acute respiratory failure. We conclude that NPPV may be an effective treatment for SMID with respiratory insufficiency.

Interstitial deletion within 7q31.1q31.3 in a woman with mild intellectual disability and schizophrenia.

We report the case of a Japanese woman with an interstitial deletion within the 7q31.1q31.3 region, she presented with mild intellectual disability since infancy, and later developed characteristic psychiatric manifestations, including abnormal behavior, delusions, and hallucinations. She was diagnosed with paranoid schizophrenia (F20.0, International Statistical Classification of Diseases and Related Health Problems 10th Revision). Array comparative genomic hybridization examination revealed the deletion involving several important genes for neurodevelopment. Particularly, FOXP2, DOCK4, MET, and WNT2 in this region are suggested to be related to language impairment, autistic disorders, and cognitive disorders, via the WNT pathway. In addition, the WNT signal pathway has been suggested to be implicated in the pathogenesis of psychiatric disorders such as schizophrenia and bipolar disorder. However, there is no case report regarding schizophrenia associated with a 7q31 microdeletion. We suspect that the disruptions of these one or plural genes among the interstitial deletion of 7q31.1q31.3 may be involved in the development of schizophrenia in this woman. This is the first report on schizophrenia associated with a 7q31 microdeletion.

Acute neuropsychiatric disorders in adolescents and young adults with Down syndrome: Japanese case reports.

BACKGROUND: The aim of this study was to evaluate acute neuropsychiatric disorders in adolescents and young adults with Down syndrome. We report 13 Japanese adolescents or young adults with Down syndrome who developed acute neuropsychiatric disorders including withdrawal, depression, obsessive-compulsive behaviors, and occasional delusions or hallucinations. METHODS: THE FOLLOWING INFORMATION WAS COLLECTED FROM EACH PATIENT: age at onset of acute neuropsychiatric disorder, complications, signs and symptoms, personality traits before the onset of the acute neuropsychiatric disorder, prescribed medications with their respective doses and the response to treatment, and senile changes observed on magnetic resonance imaging or computed tomography. RESULTS: The mean age at onset of these disorders was 21.2 years. Brain imaging showed almost senile changes; patients responded well to low-dose psychotropic therapy. Patients had an onset at a young age and presented with treatable conditions, although the average age of the onset of Alzheimer's disease is generally over 40 years of age in patients with Down syndrome. CONCLUSION: These findings suggest that the pathology of acute neuropsychiatric disorder in patients with Down syndrome may be related to presenile changes; however, these disorders present features and a clinical course that is different from those presented in typical Alzheimer's disease with Down syndrome.

A woman with 46,XX,dup(16)(p13.11 p13.3) and the ATR-X phenotype.

We report a Japanese woman with 46,XX,dup(16)(p13.11p13.3), who closely resembled the phenotype of X-linked alpha-thalassemia/mental retardation syndrome (ATR-X, MIM # 301040). Although she never had alpha-thalassemia, she showed characteristic clinical features including severe mental retardation, characteristic facies and behavior. ATR-X is caused by mutations of the ATRX gene. Although the function of ATRX protein has remained unclarified, it is thought to be involved in the regulation of several genes. The only target gene identified so far is the alpha-globin gene at 16p13.3. Clinical similarity among patients with ATR-X and dup(16)(p13.11p13) may indicate that some target genes regulated by ATRX reside in the duplicated region between 16p13.11 and 16p13.3, and that these genes are abnormally upregulated in ATR-X differently from the alpha-globin gene.

Mosaic supernumerary inv dup(15) chromosome with four copies of the P gene in a boy with pigmentary dysplasia.

Association of the pink-eye-dilution gene (P) with hypopigmentation is seen in patients who have oculocutaneous albinism type 2 (OCA2) and Prader-Willi syndrome (PWS) or Angelman syndrome (AS). However, it remains unknown whether duplication or amplification of the P gene causes hyperpigmentation. We previously reported a woman who had hyperpigmentation with a duplication of the proximal part of 15q, including the P gene. Here, we describe an additional patient with mosaicism of inv dup(15) and clinical manifestations of severe psychmoter retardation, epilepsy, and pigmentary dysplasia showing mottled and linear patterns of hyperpigmentation. His karyotype was 47,XY,+idic(15)(pter-->q14::q14-->pter)[38]/46,XY[12] de novo. Chromosomal fluorescence in situ hybridization (FISH) showed six copies of the P gene. Therefore, his cutaneous mosaicism might be caused by the presence of both normal and hyperpigmented skin due to multicopies of the P gene.

EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma.

Lines of evidence have recently indicated a relationship between mutations in the P63 gene and ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome type 3 (EEC3). The p63 gene (P63) has homology to P53 known as a tumor-suppressor gene, but biological function of its protein has not yet been known well. There have been two reported patients who had EEC syndrome associated with malignant lymphoma. However, they did not undergo sequencing analysis of P63. Here, we present with a Japanese girl who had EEC3 and developed diffuse large B-cell type non-Hodgkin lymphoma. In this patient, we documented a heterozygous germline mutation, Asp312Gly, in P63. We speculated that p63 may exert a biological function as a tumor suppressor. Malignant lymphoma should be considered as an important complication of EEC3.