Publications by authors named "Anne Ronan"

21 Publications

  • Page 1 of 1

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

J Clin Endocrinol Metab 2021 Jan;106(2):e660-e674

Department of Child Neurology, University Children's Hospital Tübingen, Tübingen, Germany.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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http://dx.doi.org/10.1210/clinem/dgaa700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823228PMC
January 2021

An Activating Variant in CTNNB1 is Associated with a Sclerosing Bone Dysplasia and Adrenocortical Neoplasia.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

Context: The WNT/β-catenin pathway is central to the pathogenesis of various human diseases including those affecting bone development and tumor progression.

Objective: To evaluate the role of a gain-of-function variant in CTNNB1 in a child with a sclerosing bone dysplasia and an adrenocortical adenoma.

Design: Whole exome sequencing with corroborative biochemical analyses.

Patients: We recruited a child with a sclerosing bone dysplasia and an adrenocortical adenoma together with her unaffected parents.

Intervention: Whole exome sequencing and performance of immunoblotting and luciferase-based assays to assess the cellular consequences of a de novo variant in CTNNB1.

Main Outcome Measure(s)/result: A de novo variant in CTNNB1 (c.131C>T; p.[Pro44Leu]) was identified in a patient with a sclerosing bone dysplasia and an adrenocortical adenoma. A luciferase-based transcriptional assay of WNT signaling activity verified that the activity of β-catenin was increased in the cells transfected with a CTNNB1p.Pro44Leu construct (P = 4.00 × 10-5). The β-catenin p.Pro44Leu variant was also associated with a decrease in phosphorylation at Ser45 and Ser33/Ser37/Thr41 in comparison to a wild-type (WT) CTNNB1 construct (P = 2.16 × 10-3, P = 9.34 × 10-8 respectively).

Conclusion: Increased β-catenin activity associated with a de novo gain-of-function CTNNB1 variant is associated with osteosclerotic phenotype and adrenocortical neoplasia.
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http://dx.doi.org/10.1210/clinem/dgaa034DOI Listing
March 2020

Biallelic Mutations in MTPAP Associated with a Lethal Encephalopathy.

Neuropediatrics 2020 06 28;51(3):178-184. Epub 2019 Nov 28.

Laboratory of Neurogenetics and Neuroinflammation, Sorbonne-Paris-Cité, Institut Imagine, Paris Descartes University, Paris, France.

Background: A homozygous founder mutation in /, encoding mitochondrial poly(A) polymerase (MTPAP), was first reported in six individuals of Old Order Amish descent demonstrating an early-onset, progressive spastic ataxia with optic atrophy and learning difficulties. MTPAP contributes to the regulation of mitochondrial gene expression through the polyadenylation of mitochondrially encoded mRNAs. Mitochondrial mRNAs with severely truncated poly(A) tails were observed in affected individuals, and mitochondrial protein expression was altered.

Objective: To determine the genetic basis of a perinatal encephalopathy associated with stereotyped neuroimaging and infantile death in three patients from two unrelated families.

Methods: Whole-exome sequencing was performed in two unrelated patients and the unaffected parents of one of these individuals. Variants and familial segregation were confirmed by Sanger sequencing. Polyadenylation of mitochondrial transcripts and de novo synthesis of mitochondrial proteins were assessed in patient's fibroblasts.

Results: Compound heterozygous p.Ile428Thr and p.Arg523Trp substitutions in MTPAP were recorded in two affected siblings from one family, and a homozygous p.Ile385Phe missense variant identified in a further affected child from a second sibship. Mitochondrial poly(A) tail analysis demonstrated shorter posttranscriptional additions to the mitochondrial transcripts, as well as an altered expression of mitochondrial proteins in the fibroblasts of the two siblings compared with healthy controls.

Conclusion: Mutations in MTPAP likely cause an autosomal recessive perinatal encephalopathy with lethality in the first year of life.
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http://dx.doi.org/10.1055/s-0039-3400979DOI Listing
June 2020

Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy.

J Am Coll Cardiol 2018 07;72(4):419-429

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. Electronic address:

Background: Whole genome sequencing (WGS) is a comprehensive genetic testing approach that reports most types of nucleotide variants.

Objectives: This study sought to assess WGS for hypertrophic cardiomyopathy (HCM) in which prior genetic testing did not establish a molecular diagnosis, and as a first-line genetic test.

Methods: WGS was performed on 58 unrelated patients with HCM, 14 affected family members, and 2 unaffected parents of a severely affected proband. The authors searched for nucleotide variants in coding regions of 184 candidate cardiac hypertrophy genes. They also searched for nucleotide variants in deep intronic regions that alter RNA splicing, large genomic rearrangements, and mitochondrial genome variants. RNA analysis was performed to validate splice-altering variants.

Results: The authors found a pathogenic or likely pathogenic variant in 9 of 46 families (20%) for which prior genetic testing was inconclusive. Three families had variants in genes not included in prior genetic testing. One family had a pathogenic variant that was filtered out with prior exome sequencing. Five families had pathogenic variants in noncoding regions, including 4 with deep intronic variants that activate novel splicing, and 1 mitochondrial genome variant. As a first-line genetic test, WGS identified a pathogenic variant in 5 of 12 families (42%) that had never received prior genetic testing.

Conclusions: WGS identified additional genetic causes of HCM over targeted gene sequencing approaches. Extending genetic screening to deep intronic regions identified pathogenic variants in 9% of gene-elusive HCM. These findings translate to more accurate diagnosis and management in HCM families.
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http://dx.doi.org/10.1016/j.jacc.2018.04.078DOI Listing
July 2018

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing.

Mol Syndromol 2018 Feb 25;9(2):70-82. Epub 2018 Jan 25.

School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, NSW, Australia.

The overgrowth syndromes are important to diagnose, not just for accurate genetic counseling, but also for knowledge surrounding cancer surveillance and prognosis. There has been a recent expansion in the number of genes associated with a mendelian overgrowth phenotype, so this review updates previous classifications of overgrowth syndromes. We also describe a clinical and molecular approach to the investigation of individuals presenting with overgrowth. This review aims to assist the clinical diagnosis of generalized overgrowth syndromes by outlining the salient features of well-known overgrowth syndromes alongside the many syndromes that have been discovered and classified more recently. We provide key clinical "handles" to aid clinical diagnosis and a list of genes to aid with panel design when using next generation sequencing, which we believe is frequently needed due to the overlapping phenotypic features seen between overgrowth syndromes.
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http://dx.doi.org/10.1159/000484532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836217PMC
February 2018

Chromosome microarray analysis: A soothing guide.

Authors:
Anne Ronan

J Paediatr Child Health 2018 Jun 24;54(6):599-601. Epub 2018 Mar 24.

Hunter Genetics Unit, Hunter New England Local Health District, Newcastle, New South Wales, Australia.

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http://dx.doi.org/10.1111/jpc.13869DOI Listing
June 2018

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

Am J Hum Genet 2017 Jun;100(6):907-925

Laboratory of Cytogenetics, Rouen University Hospital, 76031 Rouen, France.

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.
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http://dx.doi.org/10.1016/j.ajhg.2017.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473733PMC
June 2017

Recurrent ATP2A2 p.(Pro602Leu) mutation differentiates Acrokeratosis verruciformis of Hopf from the allelic condition Darier disease.

Am J Med Genet A 2017 Jul 12;173(7):1975-1978. Epub 2017 May 12.

University of Newcastle, NSW, Australia.

Darier disease and Acrokeratosis Verruciformis of Hopf (AKV) are rare disorders of keratinization with autosomal dominant inheritance and very distinct clinical pictures. Both have been shown to be caused by mutations in ATP2A2 (ATPase, Ca transporting, cardiac muscle, slow-twitch) a gene encoding one of the SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase2) intracellular pumps with a crucial role in cell-to-cell adhesion in both skin and heart. While hundreds of different missense and nonsense mutations cause Darier disease, only one missense mutation, p.(Pro602Leu), has been identified in families with AKV. We report a family with AKV due to the p.(Pro602Leu) mutation and discuss implications for this recurrent mutation on knowledge of ATP2A2 structure and function.
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http://dx.doi.org/10.1002/ajmg.a.38268DOI Listing
July 2017

The spectrum of infantile myofibromatosis includes both non-penetrance and adult recurrence.

Eur J Med Genet 2017 Jul 9;60(7):353-358. Epub 2017 Mar 9.

Hunter Genetics, Hunter New England Local Health District, PO Box 84, Waratah, NSW, Australia 2298. Electronic address:

Infantile myofibromatosis is characterized by benign myofibroblastic tumors within skin, muscle, bone or viscera which have a characteristic staining pattern on immunohistochemistry. The condition typically presents in infancy and the tumors often disappear by the third year of life. Mutations in the PDGFRB gene and NOTCH3 genes have been identified in familial forms of the condition. We present two families with molecularly confirmed germline mutations in the PDGFRB gene, one demonstrating a phenotype ranging from complete non-penetrance to neonatal lethality; and the other illustrating adult recurrence of the tumors.
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http://dx.doi.org/10.1016/j.ejmg.2017.02.005DOI Listing
July 2017

Somatic-gonadal mosaicism causing Sotos syndrome.

Am J Med Genet A 2016 Dec 8;170(12):3360-3362. Epub 2016 Sep 8.

Department of Diagnostic Genomics, PathWest Laboratory Medicine Western Australia, Perth, Western Australia, Australia.

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http://dx.doi.org/10.1002/ajmg.a.37867DOI Listing
December 2016

Diagnosis of pneumonia in children with dehydrating diarrhoea.

J Health Popul Nutr 2014 Mar;32(1):14-8

The World Health Organization (WHO) guidelines for diagnosis of pneumonia are based on the history of cough or difficult breathing and age-adjusted respiration rates. Metabolic acidosis associated with dehydrating diarrhoea also influences the respiration rate. Two hundred and four children, aged 2 to 59 months, with dehydrating diarrhoea and a history of cough and/or fast breathing, were enrolled in a prospective study. Pneumonia diagnoses were made on enrollment and again 6 hours post-enrollment (after initial rehydration), using the WHO guidelines. These were compared with investigators' clinical diagnosis based on history and findings of physical examination and a chest x-ray at the same time points. Using the WHO guidelines, 149/152 (98%) infants in the 2-11 months age-group and 38/40 (95%) children in the 12-59 months age-group were diagnosed to have pneumonia on enrollment, which dropped to 107 (70%) and 30 (75%) respectively at 6 hours post-enrollment. The specificity of the WHO guidelines for diagnosis of pneumonia was very low (6.9%) at enrollment but increased to 65.5% at 6 hours post-enrollment, after initial rehydration. The specificity of the WHO guidelines for diagnosis of pneumonia in young children is significantly reduced in dehydrating diarrhoea. For young children with dehydrating diarrhoea, rehydration, clinical and radiological assessments are useful in identifying those with true pneumonia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089067PMC
March 2014

BDNF and DYRK1A are variable and inversely correlated in lymphoblastoid cell lines from Down syndrome patients.

Mol Neurobiol 2012 Oct 5;46(2):297-303. Epub 2012 Jun 5.

Unit of Functional and Adaptive Biology, Sorbonne Paris Cité, Univ. Paris Diderot, EAC-CNRS 4413, 75013 Paris, France.

Down syndrome or trisomy 21 is the most common genetic disorder leading to mental retardation. One feature is impaired short- and long-term spatial memory, which has been linked to altered brain-derived neurotrophic factor (BDNF) levels. Mouse models of Down syndrome have been used to assess neurotrophin levels, and reduced BDNF has been demonstrated in brains of adult transgenic mice overexpressing Dyrk1a, a candidate gene for Down syndrome phenotypes. Given the link between DYRK1A overexpression and BDNF reduction in mice, we sought to assess a similar association in humans with Down syndrome. To determine the effect of DYRK1A overexpression on BDNF in the genomic context of both complete trisomy 21 and partial trisomy 21, we used lymphoblastoid cell lines from patients with complete aneuploidy of human chromosome 21 (three copies of DYRK1A) and from patients with partial aneuploidy having either two or three copies of DYRK1A. Decreased BDNF levels were found in lymphoblastoid cell lines from individuals with complete aneuploidy as well as those with partial aneuploidies conferring three DYRK1A alleles. In contrast, lymphoblastoid cell lines from individuals with partial trisomy 21 having only two DYRK1A copies displayed increased BDNF levels. A negative correlation was also detected between BDNF and DYRK1A levels in lymphoblastoid cell lines with complete aneuploidy of human chromosome 21. This finding indicates an upward regulatory role of DYRK1A expression on BDNF levels in lymphoblastoid cell lines and emphasizes the role of genetic variants associated with psychiatric disorders.
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http://dx.doi.org/10.1007/s12035-012-8284-7DOI Listing
October 2012

Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures.

J Med Genet 2012 Feb;49(2):126-37

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington 98195-6320, USA.

Background: Joubert syndrome (JS) is a ciliopathy characterised by a distinctive brain malformation (the 'molar tooth sign'), developmental delay, abnormal eye movements and abnormal breathing pattern. Retinal dystrophy, cystic kidney disease, liver fibrosis and polydactyly are variably present, resulting in significant phenotypic heterogeneity and overlap with other ciliopathies. JS is also genetically heterogeneous, resulting from mutations in 13 genes. These factors render clinical/molecular diagnosis and management challenging. CC2D2A mutations are a relatively common cause of JS and also cause Meckel syndrome. The clinical consequences of CC2D2A mutations in patients with JS have been incompletely reported.

Methods: Subjects with JS from 209 families were evaluated to identify mutations in CC2D2A. Clinical and imaging features in subjects with CC2D2A mutations were compared with those in subjects without CC2D2A mutations and reports in the literature.

Results: 10 novel CC2D2A mutations in 20 subjects were identified; a summary is provided of all published CC2D2A mutations. Subjects with CC2D2A-related JS were more likely to have ventriculomegaly (p<0.0001) and seizures (p=0.024) than subjects without CC2D2A mutations. No mutation-specific genotype-phenotype correlations could be identified, but the findings confirm the observation that mutations that cause CC2D2A-related JS are predicted to be less deleterious than mutations that cause CC2D2A-related Meckel syndrome. Missense variants in the coiled-coil and C2 domains, as well as the C-terminal region, identify these regions as important for the biological mechanisms underlying JS.

Conclusions: CC2D2A testing should be prioritised in patients with JS and ventriculomegaly and/or seizures. Patients with CC2D2A-related JS should be monitored for hydrocephalus and seizures.
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http://dx.doi.org/10.1136/jmedgenet-2011-100552DOI Listing
February 2012

Two new cases with microdeletion of 17q23.2 suggest presence of a candidate gene for sensorineural hearing loss within this region.

Am J Med Genet A 2011 Dec 3;155A(12):2964-9. Epub 2011 Nov 3.

Genetic Counselling Clinic, Kennedy Center, Glostrup, Denmark.

Microdeletion of the 17q23.2 region has very recently been suggested as a new emerging syndrome based on the finding of 8 cases with common phenotypes including mild-to-moderate developmental delay, heart defects, microcephaly, postnatal growth retardation, and hand, foot, and limb abnormalities. In this report, we describe two new 17q23.2 deletion patients with mild intellectual disability and sensorineural hearing loss. They both had submicroscopic deletions smaller than the common deleted region for the 8 previously described 17q23.2 microdeletion cases. TBX4 was previously suggested as the responsible gene for the heart or limb defects observed in 17q23.2 deletion patients, but the present cases do not have these features despite deletion of this gene. The finding of sensorineural hearing loss in 5 of the 10 cases, including the present cases, with a microdeletion at17q23.2, strongly suggests the presence of a candidate gene for hearing loss within this region. We screened 41 patients with profound sensorineural hearing loss for mutations of TBX2 and detected no mutations.
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http://dx.doi.org/10.1002/ajmg.a.34302DOI Listing
December 2011

Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib.

J Med Genet 2011 Jan 23;48(1):55-63. Epub 2010 Oct 23.

INSERM, Université Paris Descartes, Hôpital Saint Vincent de Paul, France.

Background: Pseudohypoparathyroidism type Ib (PHP-Ib) is due to epigenetic changes at the imprinted GNAS locus, including loss of methylation at the A/B differentially methylated region (DMR) and sometimes at the XL and AS DMRs and gain of methylation at the NESP DMR.

Objective: To investigate if quantitative measurement of the methylation at the GNAS DMRs identifies subtypes of PHP-Ib.

Design And Methods: In 19 patients with PHP-Ib and 7 controls, methylation was characterised at the four GNAS DMRs through combined bisulfite restriction analysis and quantified through cytosine specific real-time PCR in blood lymphocyte DNA.

Results: A principal component analysis using the per cent of methylation at seven cytosines of the GNAS locus provided three clusters of subjects (controls n=7, autosomal dominant PHP-Ib with loss of methylation restricted to the A/B DMR n=3, and sporadic PHP-Ib with broad GNAS methylation changes n=16) that matched perfectly the combined bisulfite restriction analysis classification. Furthermore, three sub-clusters of patients with sporadic PHP-Ib, that displayed different patterns of methylation, were identified: incomplete changes at all DMRs compatible with somatic mosaicism (n=5), profound epigenetic changes at all DMRs (n=8), and unmodified methylation at XL in contrast with the other DMRs (n=3). Interestingly, parathyroid hormone concentration at the time of diagnosis correlated with the per cent of methylation at the A/B DMR.

Conclusion: Quantitative assessment of the methylation in blood lymphocyte DNA is of clinical relevance, allows the diagnosis of PHP-Ib, and identifies subtypes of PHP-Ib. These epigenetic findings suggest mosaicism at least in some patients.
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http://dx.doi.org/10.1136/jmg.2010.081356DOI Listing
January 2011

Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region.

BMJ Case Rep 2009 4;2009. Epub 2009 Jun 4.

Hunter Genetics Unit, Waratah, New South Wales, Australia.

A 4.3 Mb duplication of chromosome 21 bands q22.13-q22.2 was diagnosed by interphase fluorescent in situ hybridisation (FISH) in a 31 week gestational age baby with cystic hygroma and hydrops; the duplication was later found in the mother and in her 8-year-old daughter. All had the facial gestalt of Down syndrome (DS). This is the smallest accurately defined duplication of chromosome 21 reported with a DS phenotype. The duplication encompasses the gene DYRK1 but not DSCR1 or DSCAM. Previous karyotype analysis and telomere screening of the mother, and karyotype analysis and metaphase FISH of a chorionic villus sample, had all failed to reveal the duplication. The findings in this family add to the identification and delineation of a "critical region" for the DS phenotype on chromosome 21.
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http://dx.doi.org/10.1136/bcr.05.2009.1914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027932PMC
November 2011

Atypical Angelman syndrome with macrocephaly due to a familial imprinting center deletion.

Am J Med Genet A 2008 Jan;146A(1):78-82

Hunter Genetics Unit, Waratah, NSW, Australia.

Two elderly brothers with severe intellectual disability were diagnosed with Angelman syndrome after a once-removed, 15-year-old cousin was found to have the syndrome due to a deletion of the imprinting center. For many years it was believed the brothers, who both have macrocephaly, were affected by nonsyndromic X-linked mental retardation. This was because, apart from absent speech and intellectual disability, the phenotype of the two men was not characteristic of Angelman syndrome. Conversely, the cousin, in addition to severe intellectual disability, language impairment, and ataxic gait, has microcephaly. None of the three have seizures, and so in the presence of the brothers' macrocephaly, Angelman syndrome was not considered until a diagnosis was made in the younger distant cousin. We report on a familial imprinting center deletion and the importance of considering the mild and atypical Angelman syndrome phenotypes within the differential diagnosis of intellectual handicap, particularly in clarifying the genetic risk to other family members.
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http://dx.doi.org/10.1002/ajmg.a.31952DOI Listing
January 2008

Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region.

J Med Genet 2007 Jul 19;44(7):448-51. Epub 2007 Jan 19.

A 4.3 Mb duplication of chromosome 21 bands q22.13-q22.2 was diagnosed by interphase fluorescent in-situ hybridisation (FISH) in a 31-week gestational age baby with cystic hygroma and hydrops; the duplication was later found in the mother and in her 8-year-old daughter by the same method and confirmed by array comparative genomic hybridisation (aCGH). All had the facial gestalt of Down syndrome (DS). This is the smallest accurately defined duplication of chromosome 21 reported with a DS phenotype. The duplication encompasses the gene DYRK1 but not DSCR1 or DSCAM, all of which have previously been implicated in the causation of DS. Previous karyotype analysis and telomere screening of the mother, and karyotype analysis and metaphase FISH of a chorionic villus sample, had all failed to reveal the duplication. The findings in this family add to the identification and delineation of a "critical region" for the DS phenotype on chromosome 21. Cryptic chromosomal abnormalities can be missed on a routine karyotype for investigation of abnormal prenatal ultrasound findings, lending support to the use of aCGH analysis in this setting.
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http://dx.doi.org/10.1136/jmg.2006.047373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2598003PMC
July 2007

Elevated atopy in healthy obese women.

Am J Clin Nutr 2005 Sep;82(3):504-9

Department of Animal and Nutritional Sciences, University of New Hampshire, Durham, NH 03824, USA.

Background: Allergic disorders, including asthma, have increased dramatically in the United States in the past 20 y. Epidemiologic studies have found body mass index (body weight in kg/height squared in m) to be a positive independent correlate of atopy in women but not in men.

Objective: We investigated the prevalence of atopy among healthy obese and nonobese women and its relation to fat mass (FM), insulin resistance, and plasma concentrations of 17beta-estradiol, interleukin 4 (IL-4), and leptin.

Design: A cross-sectional study of 21 obese (> or = 30% body fat) and 22 nonobese (< 30% body fat) women (18-41 y of age) was performed. The following measurements were taken: FM by plethysmography, total and specific immunoglobulin E (IgE) by automated immunosorbent analysis, and blood glucose, insulin, C-peptide, 17beta-estradiol, sex hormone-binding globulin, and IL-4. Insulin sensitivity was determined on the basis of the fasting insulin resistance index and with an oral-glucose-tolerance test.

Results: The frequency of specific IgE in the obese group was almost 3 times that in the nonobese group (P = 0.008). The total IgE concentration was not significantly different between groups. Plasma concentrations of 17beta-estradiol, the ratio of 17beta-estradiol to sex hormone-binding globulin, the fasting insulin resistance index, and C-peptide and leptin concentrations were higher in the obese than in the nonobese group (P < 0.05) after adjustment for oral contraceptive use. All factors correlated positively with FM. Logistic regression showed FM to be the only positive predictor of specific IgE (P = 0.01).

Conclusion: The findings confirm a direct relation between obesity and a T helper 2 cell immune response in women.
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http://dx.doi.org/10.1093/ajcn.82.3.504DOI Listing
September 2005

Bioterrorism and the epidemiology of fear.

Lancet Infect Dis 2002 Jun;2(6):326

University of Pittsburgh, Pittsburgh, PA 15261, USA.

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http://dx.doi.org/10.1016/s1473-3099(02)00286-4DOI Listing
June 2002

Effects of ketamine-xylazine and isoflurane on insulin sensitivity in dehydroepiandrosterone sulfate-treated minipigs (Sus scrofa domestica).

Comp Med 2002 Jun;52(3):233-7

Department of Animal and Nutritional Sciences, University of New Hampshire, Durham 03824-3505, USA.

Isoflurane and ketamine-xylazine (KX) combinations are widely used veterinary anesthetics, KX being the particularly common agent for immobilizing swine. Results of previous studies indicate that KX and xylazine suppress insulin release. The steroid hormones, dehydroepiandrosterone (DHEA) and its sulfated form, dehydroepiandrosterone-sulfate (DHEAS), have variable effects on insulin sensitivity in animals. We evaluated the effect of DHEAS on plasma glucose and insulin concentrations in female Yucatan swine under KX and isoflurane anesthesia. A 2 x 2 factorial design was used. Twenty-four 17-week-old gilts were randomly assigned to receive vehicle (placebo) or DHEAS as part of an ongoing study. The KX was given intramuscularly to all animals prior to blood sample collection at weeks two and four. At week three, all animals received isoflurane by inhalation. During KX anesthesia, mean insulin concentration in DHEAS-treated and control groups approximated half the postisoflurane values (P < 0.001). While under isoflurane, the DHEAS group had significantly higher mean plasma insulin concentration and mean insulin-to-glucose ratio, compared with values for controls (P < 0.05). These findings are consistent with changes in insulin values following DHEAS treatment observed previously in nonanesthetized swine. The effect of DHEAS treatment was absent in animals under KX anesthesia. These results suggest that KX significantly decreases plasma insulin concentration and blunts DHEAS-associated insulin resistance in female minipigs.
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June 2002