A case with a ring chromosome 13 in a cohort of 203 children with non-syndromic autism and review of the cytogenetic literature.

Autistic spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairments of social interaction, communication and restricted, repetitive and stereotyped patterns of behavior, interests and activities. Frequencies of chromosomal abnormalities in cohorts of individuals with ASD varying between 1.2 and 28.6% have been reported. In this study, we evaluated 203 Thai children who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), for autistic disorder or pervasive developmental disorder not otherwise specified (PDD-NOS), and who had neither major dysmorphic features nor CGG repeat expansions of the FMR1 gene. A routine G-banding chromosome analysis was performed at a minimum of ISCN 400-550 bands. A chromosomal abnormality was observed in one child (0.5%), a 41-month-old boy with a ring chromosome 13 detected by G-banding analysis and subsequently confirmed by FISH. SNP microarray analysis detected a 2.11-Mb deletion of chromosome 13q34, encompassing 23 genes. The MCF2L and UPF3A genes are among those genes that may explain the autistic features in our case. To the best of our knowledge, only one autistic case with a ring chromosome 13 has been previously reported. In this article, we also systemically reviewed 21 studies that utilized a conventional cytogenetic method to detect chromosomal abnormalities in patients with ASD. When we summed all cases with chromosomal abnormalities, including the case from our study, the frequency of chromosomal abnormalities detected by conventional cytogenetics in patients with ASD was 3.2% (118/3,712).

No Evidence of Abnormal Expression of Beta-Catenin and Bcl-2 Proteins in Pilomatricoma as One Clinical Feature of Tetrasomy 9p Syndrome.

BACKGROUND: Little is currently known about the genetics of pilomatricoma. A number of studies have reported some evidence that this disease may have a genetic association with mutations of CTNNB1 gene or expression of the beta-catenin protein. In this study, we reviewed literatures involving 30 patients with various genetic syndromes that have been linked to pilomatricoma and found that somatic mutations of the CTNNB1 gene were reported in 67% of patients. Pilomatricoma has been reported in patients with chromosome 9 rearrangements, including 4 patients with tetrasomy 9p syndrome and one patient with partial trisomy 9. In addition to beta-catenin, the expression of bcl2 was observed in pilomatricoma. OBJECTIVES: To report an additional case of tetrasomy 9p syndrome with concurrent pilomatricoma and to examine whether abnormal protein expressions of the CTNNB1 and/or BCL2 genes were present. METHODS: Cytogenetic analysis was carried out on peripheral blood, biopsied skin, and pilomatricoma tissue obtained from a patient with tetrasomy 9p syndrome. Immunohistochemical staining was performed on the pilomatricoma tissue, using beta-catenin and bcl2 monoclonal antibodies. RESULTS: SNP microarray revealed nonmosaic gain of the short arm of chromosome 9. A nonmosaic isodicentric chromosome 9 was identified in the peripheral blood but this rearranged chromosome was detected in only 8.3% of the skin fibroblasts. Chromosomal abnormalities were not detected in the pilomatricoma nor expression of beta-catenin or bcl2 proteins in our patient. CONCLUSION: Pilomatricoma could be a new clinical feature associated with tetrasomy 9p syndrome; however, we found no evidence of tetrasomy 9p or abnormal beta-catenin or bcl2 proteins of the CTNNB1 and BCL2 genes in our pilomatricoma patient.

Fragile X syndrome with anxiety disorder and exceptional verbal intelligence.

Fragile X syndrome (FXS) is often characterized by mental retardation. However, FXS is also associated with significant emotional and psychiatric problems, including anxiety, depression, attention difficulties, and learning disabilities in the presence of a normal IQ. This report describes a unique woman with the full mutation of FXS who has an exceptional profile of above-average intelligence combined with significant impairments due to anxiety and learning disability. Women with FXS can present primarily with learning and emotional problems, and clinicians should consider FXS in these women regardless of their IQ.

A girl with fragile X premutation from sperm donation.

We present a girl with the fragile X premutation who obtained the premutation allele from donated sperm. Our patient has clinical characteristics of fragile X syndrome including emotional problems and neuropsychological difficulties presenting as learning disabilities. She is also at high risk for premature ovarian failure and low risk for the fragile X-associated tremor ataxia (FXTAS). We suggest fragile X DNA screening in gamete donor candidates to decrease the chance of fragile X involvement in their offspring.

Common Clinical Characteristics and Rare Medical Problems of Fragile X Syndrome in Thai Patients and Review of the Literature.

Background. Clinical characteristics of fragile X syndrome (FXS) have been well documented in Caucasians, whereas in Asians they have rarely been described. Those that have been conducted used small cohorts that utilized DNA for diagnosis and larger cohorts that utilized cytogenetics for diagnosis. This study is to describe clinical characteristics of FXS in a large cohort of Thai patients diagnosed by standard molecular methods. Methods. Seventy-seven index cases and 46 affected relatives diagnosed with FXS were recruited into the study. To determine frequencies of common characteristics of FXS in prepubertal boys, we reviewed 56 unrelated cases aged between 18 and 146 months. To list rare medical problems, we reviewed 75 cases aged between 8 months to 71 years old, including 53 index cases and 22 affected relatives. In addition, we selected 16 clinical studies from various ethnicities for comparison with our findings. Results. In prepubertal boys with FXS, attention deficit and/or hyperactivity, prominent ears, macroorchidism, and elongated face were observed in 96%, 80%, 53%, and 48% of patients, respectively, whereas recognizable X-linked inheritance presented in 11% of patients. IQ scores ranged between 30 and 64 (mean ± SD = 43 ± 9, n = 25). We observed clinical findings that rarely or have never been reported, for example, medulloblastoma and tetralogy of Fallot. Conclusion. Attention deficit and/or hyperactivity and prominent ear are the most common behavioral and physical features in prepubertal boys with FXS, respectively. There are differences in frequencies of clinical characteristics observed between ethnicities; however, it is difficult to draw a solid conclusion due to different recruitment criteria and sample sizes within each study.

Mutation screening of the neurexin 1 gene in thai patients with intellectual disability and autism spectrum disorder.

AIM: Neurexin 1 has two major protein isoforms using alternative promoters, coding for the alpha-neurexin 1 (α-NRXN1) and beta-neurexin 1 (ß-NRXN1) genes. This study is to explore the possibility that variants of the NRXN1 gene predispose to intellectual disability (ID) and autism spectrum disorder (ASD). METHODS: The coding regions in 24 exons and exon-intron boundaries of the NRXN1 gene were investigated in 115 Thai patients with ID and ASD by direct DNA sequencing. RESULTS: Nine novel variants of the NRXN1 gene were identified. Four novel variants were found in the ß-NRXN1 gene, one variant of six GGC repeats in exon 1, and three variants at the 5'UTR. Five novel variants were identified in the α-NRXN1 gene, four intronic variants and one missense variant in exon 14 (c.2713T>A or p.F905I). CONCLUSION: Mutation screening of the NRXN1gene in patients with ID and ASD may be useful to identify potential variants predisposing to ID and ASD. However, further studies utilizing protein functional analysis of the novel variants are required for a more definite conclusion.

The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome.

STUDY OBJECTIVE: To determine the efficacy of melatonin on sleep problems in children with autistic spectrum disorder (ASD) and fragile X syndrome (FXS). METHODS: A 4-week, randomized, double blind, placebo-controlled, crossover design was conducted following a 1-week baseline period. Either melatonin, 3 mg, or placebo was given to participants for 2 weeks and then alternated for another 2 weeks. Sleep variables, including sleep duration, sleep-onset time, sleep-onset latency time, and the number of night awakenings, were recorded using an Actiwatch and from sleep diaries completed by parents. All participants had been thoroughly assessed for ASD and also had DNA testing for the diagnosis of FXS. RESULTS: Data were successfully obtained from the 12 of 18 subjects who completed the study (11 males, age range 2 to 15.25 years, mean 5.47, SD 3.6). Five participants met diagnostic criteria for ASD, 3 for FXS alone, 3 for FXS and ASD, and 1 for fragile X premutation. Eight out of 12 had melatonin first. The conclusions from a nonparametric repeated-measures technique indicate that mean night sleep duration was longer on melatonin than placebo by 21 minutes (p = .02), mean sleep-onset latency was shorter by 28 minutes (p = .0001), and mean sleep-onset time was earlier by 42 minutes (p = .02). CONCLUSION: The results of this study support the efficacy and tolerability of melatonin treatment for sleep problems in children with ASD and FXS.

Two boys with fragile x syndrome and hepatic tumors.

Hepatic tumors are rare childhood neoplasms with uncertain etiology. We report the cooccurrence of hepatic tumors in 2 boys with fragile X syndrome, one with hepatoblastoma and another with desmoplastic nested spindle cell tumor of liver. The pathogenesis of fragile X syndrome involves silencing of the fragile X mental retardation 1 gene and consequent loss of FMR1 protein. We speculate regarding molecular pathways that might explain the cooccurrence of the 2 conditions. Further examination of a possible functional link between hepatic neoplasia and loss of FMRP is warranted.

Testicular and pituitary inclusion formation in fragile X associated tremor/ataxia syndrome.

PURPOSE: We describe the medical course, neuropathology and testicular pathology in 2 men who died with fragile X associated tremor/ataxia syndrome. Fragile X associated tremor/ataxia syndrome, which is a recently described, late onset neurodegenerative disorder, affects up to a third of males and occasionally females older than age 50 years who are carriers of premutation alleles (55 to 200 CGG repeats) of the fragile X mental retardation 1 gene FMR1. Clinical manifestations of premutation status are distinct from those of the full mutation, which is the cause of the fragile X syndrome. MATERIALS AND METHODS: Standard pathological techniques were used to examine the brain, pituitary gland and testicular tissues of 2 males who had fragile X associated tremor/ataxia syndrome. RESULTS: The clinical course of the 2 cases included impotence before the onset of neurological symptoms of tremor and ataxia. Neuropathological findings included eosinophilic intranuclear inclusions in neurons and astrocytes throughout the central nervous system, and in the anterior and posterior pituitary gland of 1 of the 2 men. Inclusions were also seen in the Leydig and myoid cells in the testicles of these 2 men with fragile X associated tremor/ataxia syndrome. CONCLUSIONS: Fragile X associated tremor/ataxia syndrome inclusions are formed in tissues outside of the central nervous system. Involvement of the testicles and the pituitary gland may lead to neuroendocrine dysfunction, including testosterone deficiency. These noncentral nervous system components of fragile X associated tremor/ataxia syndrome require further study.