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ABSTRACT: We report on a full-term male infant with hypoplastic male genitalia and bilateral impalpable testes noted at birth, who over the following months developed increasing hypotonia, apneic episodes, and seizures resulting in his death at age 24 weeks. During this period regression of penile corporeal tissue was observed. An endocrinological diagnosis of primary hypogonadism was made and cerebral imaging at 19 weeks showed reduced periventricular white matter with marked pontocerebellar hypoplasia (PCH)/atrophy, but a well-developed posterior fossa. We propose that this condition constitutes a new form of severe PCH/atrophy with testicular regression that has onset in the fetal period.
American Journal of Medical Genetics Part A 04/2011; 155A(4):667-72. · 2.39 Impact Factor
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Sally Ann Lynch, Nicola Foulds,
Ann-Charlotte Thuresson,
Amanda L Collins,
Göran Annerén,
Bernt-Oves Hedberg,
Carol A Delaney,
James Iremonger,
Caroline M Murray,
John A Crolla,
Colm Costigan,
Wayne Lam,
David R Fitzpatrick,
Regina Regan,
Sean Ennis,
Freddie Sharkey
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ABSTRACT: We report six patients with array deletions encompassing 12q14. Out of a total of 2538 array investigations carried out on children with developmental delay and dysmorphism in three diagnostic testing centres, six positive cases yielded a frequency of 1 in 423 for this deletion syndrome. The deleted region in each of the six cases overlaps significantly with previously reported cases with microdeletions of this region. The chromosomal range of the deletions extends from 12q13.3q15. In the current study, we report overlapping deletions of variable extent and size but primarily comprising chromosomal bands 12q13.3q14.1. Four of the six deletions were confirmed as de novo events. Two cases had deletions that included HMGA2, and both children had significant short stature. Neither case had osteopoikilosis despite both being deleted for LEMD3. Four cases had deletions that ended proximal to HMGA2 and all of these had much better growth. Five cases had congenital heart defects, including two with atrial septal defects, one each with pulmonary stenosis, sub-aortic stenosis and a patent ductus. Four cases had moderate delay, two had severe developmental delay and a further two had a diagnosis of autism. All six cases had significant speech delay with subtle facial dysmorphism.
European journal of human genetics: EJHG 01/2011; 19(5):534-9. · 3.56 Impact Factor
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T Kleefstra,
W A van Zelst-Stams,
W M Nillesen,
V Cormier-Daire,
G Houge, N Foulds,
M van Dooren,
M H Willemsen,
R Pfundt,
A Turner, [......],
R Casalone,
A Weber,
L A Brueton,
A Delicado Navarro,
M Palomares Bralo,
H Venselaar,
S P A Stegmann,
H G Yntema,
H van Bokhoven,
H G Brunner
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ABSTRACT: The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far.
By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein.
The data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.
Journal of Medical Genetics 04/2009; 46(9):598-606. · 6.36 Impact Factor
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ABSTRACT: We present a patient with a novel heterozygous deletion of 7q11.22-q11.23. Standard cytogenetic analysis using the ELN cosmid 82C and the ELN/ LIMK1 cosmid 34B FISH probes suggested a diagnosis of Williams syndrome. Although he has supravalvular aortic stenosis and peripheral pulmonary artery stenosis, which are common in this condition, he does not have the clinical gestalt of Williams syndrome. 44k oligo array CGH analysis showed a 2.43 Mb deletion, encompassing the proximal 1.43 kb of the Williams syndrome critical region and extending approximately 1 Mb beyond it. The deletion of further genes outside the Williams syndrome critical region does not appear to be having a phenotypic effect at present.
American Journal of Medical Genetics Part A 12/2008; 146A(24):3206-10. · 2.39 Impact Factor
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ABSTRACT: Marfan syndrome is an autosomal dominant condition, with manifestations mainly in the skeletal, ocular, and cardiovascular systems. The disorder is caused by mutations in fibrillin-1 gene (FBN1). The majority of these are family-specific point mutations, with a small number being predicted to cause exon-skipping. To date, there have only been five reports of in-frame exon deletions in FBN1, with the largest of these spanning three exons. Mosaicism is rarely recorded and has only been reported in the unaffected, or mildly affected, parents of probands. Here, we report on the clinical histories of two children with exon deletions in FBN1. Both have severe Marfan syndrome with significant signs in infancy. One patient has a deletion of exon 33, which has not previously been reported. The other has the largest reported deletion, which spans 37 exons, and also represents the first reported case of mosaicism in a patient with Marfan syndrome.
American Journal of Medical Genetics Part A 06/2008; 146A(10):1320-4. · 2.39 Impact Factor
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Clinical Dysmorphology 11/2006; 15(4):211-2. · 0.54 Impact Factor
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ABSTRACT: Carbimazole embryopathy is a recently recognized and defined phenotype. Choanal atresia; gastrointestinal anomalies, particularly esophageal atresia; athelia or hypothelia; developmental delay; hearing loss; aplasia cutis; and dysmorphic facial features all can occur after exposure to the antithyroid drugs carbimazole or methimazole during gestation. Although full expression of this phenotype appears to be an uncommon sequelae of antenatal carbimazole exposure, infants with less overt manifestations may remain with the condition undiagnosed. It is clearly important when an infant with choanal atresia is assessed to take an adequate drug history and consider this embryopathy as a potential causative factor.
Archives of Otolaryngology - Head and Neck Surgery 10/2006; 132(9):1009-11. · 1.63 Impact Factor
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ABSTRACT: Concerns about the safety of carbimazole in pregnancy were raised in 1985. Since this time many reports of children believed to have been affected by carbimazole in utero have appeared in the medical literature. Initial reports were of an increased incidence of scalp defects in the infants of treated mothers, but many other anomalies have now been described. Choanal atresia, gastrointestinal anomalies-particularly esophageal atresia, athelia/hypothelia, developmental delay, hearing loss, and dysmorphic facial features have all been reported. The phenotype associated with exposure to carbimazole appears to be rare but specific with distinctive facial features. We report on two new cases of carbimazole embryopathy with strikingly similar facial features.
American Journal of Medical Genetics Part A 02/2005; 132A(2):130-5. · 2.39 Impact Factor
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ABSTRACT: Sedaghatian type spondylometaphyseal dysplasia is a rare osteochondrodysplasia first described in 1980. The original report describes an Iranian infant with mild rhizomelic limb shortening, severe metaphyseal cupping and irregularity and platyspondyly who died shortly after birth. The baby was born to a consanguineous couple who had reportedly had two similarly affected infants, one male and one female. No documented radiology is available on the female infant. Since this publication, 10 further case reports of male infants with this condition have appeared in the literature all of whom have died shortly after birth. We report a fully documented female case of Sedaghatian type spondylometaphyseal dysplasia providing further evidence to support an autosomal recessive mechanism of inheritance.
American Journal of Medical Genetics Part A 06/2003; 118A(4):377-81. · 2.39 Impact Factor
