Chromosome microarray analysis in a clinical environment: new perspective and new challenge.

The analysis of the human genome has largely been undertaken in a research environment, but recent developments in technology and associated workflow have allowed diagnostic laboratories to interrogate DNA at significantly improved levels of resolution. Principally, whole genome-based analysis of copy number changes using microarrays has led to this method replacing conventional karyotyping as a routine diagnostic workhorse. The resolution offered by microarrays is an improvement of at least an order of magnitude compared to karyotyping, but it comes at a cost in terms of the time spent in data interpretation. Overall, however, the die has been cast and cytogeneticists need to become familiar with the tools use by molecular geneticists and bioinformaticists. The following review provides a brief background to array technology, but uses a series of case studies to illustrate the usefulness and challenges of interpreting array data.

Phenotypic expansion and further characterisation of the 17q21.31 microdeletion syndrome.

BACKGROUND: The recognition of the 17q21.31 microdeletion syndrome has been facilitated by high resolution microarray technology. Recent clinical delineation of this condition emphasises a typical facial appearance, cardiac and renal defects, and speech delay in addition to intellectual disability, hypotonia and seizures. METHODS AND RESULTS: We describe 11 previously unreported patients expanding the phenotypic spectrum to include aortic root dilatation, recurrent joint subluxation, conductive hearing loss due to chronic otitis media, dental anomalies, and persistence of fetal fingertip pads. Molecular analysis of the deletions demonstrates a critical region spanning 440 kb involving either partially or wholly five genes, CRHR1, IMP5, MAPT, STH, and KIAA1267. CONCLUSION: These data have significant implications for the clinical diagnosis and management of other individuals with 17q21.31 deletions.

13q33.2 deletion: a rare cause of ambiguous genitalia in a male newborn with growth restriction.

UNLABELLED: 13q deletion is a rare cause of ambiguous genitalia in the male newborn, and can be associated with mental retardation of varying degree, retinoblastoma, and malformations of the brain, eye, genitourinary and gastrointestinal tract, depending on the level of the deletion. We present a male neonate with ambiguous genitalia and IUGR with a 13q33.2 deletion, and a paternal balanced translocation. Microarray analysis found the genes involved to be on chromosome 13 in the region 102989254bp-109214509bp. This deletion encompasses the EFNB2 gene, which has been implicated in genital malformations in 13q deletion cases. CONCLUSIONS: We find a link between haploinsufficiency of the EFNB2 gene and the presence of ambiguous genitalia and hypospadia in patients with a 13q.33 deletion. This work emphasizes the importance of early diagnosis of this condition due to the link with mental retardation and the need for follow up and management.

Molecular characterisation of a der(Y)t(Xp;Yp) with Xp functional disomy and sex reversal.

Sex reversal due to duplication of the Xp21 dosage-sensitive sex reversal locus results in XY females with gonadal dysgenesis. Pure Xp disomy (without a concurrent loss of genetic material) can occur by translocation or interstitial duplication. The case reported here is the rare form with a t(Xp;Yp). The combination of conventional clinical cytogenetic techniques, microsatellite analysis and high-density microarrays identified the X-chromosome breakpoint as centromeric of the NR0B1 gene and its control elements. Cytogenetics and array technology complemented each other in characterizing the translocation event and the extent of the dosage-sensitive sex reversal critical region on the derivative Y-chromosome. The implications of this analysis also lie in genetic counseling that highlight the likely de novo nature of a paternal meiotic event.

Toriello-Carey syndrome: case report with additional findings.

Toriello-Carey syndrome comprises agenesis of the corpus callosum, telecanthus, small palpebral fissures, Pierre Robin sequence, abnormal ears, nuchal laxity and cardiac defects. We report on a female patient who has some additional findings including an anteriorly placed anus. This anomaly adds to the list of other midline anomalies seen in this syndrome. We compare the findings to those seen in the Opitz BBBG syndrome, a well-defined syndrome of the midline developmental field. Our patient, having a severe manifestation of complicated congenital heart disease, died in the neonatal period, which argues against the likelihood that this is an X-linked disorder with more severe manifestations in males.

Cerebral infarction in Noonan syndrome.

We report on an infant with severe Noonan syndrome, chylothoraces, and hepatosplenomegaly who suffered two episodes of cerebral infarction before age 6 months. No underlying cause for these events was found. The presentation is discussed in relationship to other reports of stroke in Noonan syndrome which have previously been associated with underlying vascular malformations.

Trisomy of 3pter in a patient with apparent C (trigonocephaly) syndrome.

The C syndrome is a multiple congenital anomaly/mental retardation (MCA/MR) syndrome first described in sibs. The inheritance has been assumed to be autosomal recessive. Several authors have commented that the combination of anomalies found in the conditions suggest an underlying chromosomal anomaly and in a few apparent cases chromosome anomalies have been described. Our patient had findings consistent with the C syndrome and a duplication of 3p by use of subtelomere probes. This shows that new cytogenetic techniques continue to be important in defining the underlying cause of MCA/MR conditions.

X-linked dominant chondrodysplasia punctata: a peroxisomal disorder?

X-linked dominant chondrodysplasia punctata is characterised by resolving irregular punctate calcifications of epiphyses, variable ichthyosis and atrophoderma, short stature, and cataracts. We report on a patient with this syndrome who had transiently abnormal peroxisomal function tests. We review the literature and propose that X-linked dominant chondrodysplasia punctata is a peroxisomal disorder and that its phenotype can be explained by X chromosome lyonisation and the relative proliferation of cells expressing the normal X allele.

Report of two sibs with Knobloch syndrome (encephalocoele and viteroretinal degeneration) and other anomalies.

We report on two sibs with high myopia, vitreoretinal degeneration (VRD), and occipital encephalocoele or scalp lesion. We review the literature on Knobloch syndrome, discuss possible causes, and suggest a possible involvement of mesoderm in the morphogenesis. One case presents with very early onset of severe eye disease, whereas the other is notable for the very mild scalp defect. In addition, both appear to have an unusual pulmonary lymphatic condition.

A patient with VACTERL association, amelia and hemifacial microsomia.

We report on a girl with anal atresia, renal aplasia, vertebral and rib anomalies, amelia and hemifacial microsomia. The patient demonstrates the overlap between the VACTERL association and the oculoauriculovertebral dysplasia. We propose that amelia is a severe manifestation of the limb defects which occur in these developmental dysplasias.

Clinical phenotypes of nine cases of Kabuki syndrome from New Zealand.

Nine cases of Kabuki syndrome have been identified in Auckland and surrounding regions in the North Island, New Zealand since 1995. All have the characteristic facial dysmorphism and many of the well-described associated anomalies. Some of the abnormalities were unusual including a case with severe congenital mitral stenosis, two cases of eventration of the diaphragm, idiopathic thrombocytopaenic purpura and vitiligo. One child had an Arnold Chiari type 1 malformation and another had epibulbar dermoids, neither of which has previously been reported in this syndrome. There was a wide diversity of ethnic origin, with the syndrome being described in patients from the Pacific Islands for the first time. The cases described emphasize the broad range of associated anomalies found in Kabuki syndrome and further illustrate its presence in all ethnic groups.

Reflex neurovascular dystrophy in children.

Six children with reflex neurovascular dystrophy are described. The clinical characteristics are discussed, and the contrasting features between the adult and childhood syndrome are considered. The importance of early diagnosis and appropriate therapy is stressed.

Myofascial pain in children.

Five children with acute and chronic regional myofascial pain syndromes, involving the sternomastoid, the external oblique, the rectus abdominis and the biceps femoris, are described. The trigger points were treated initially by vapocoolant therapy followed by muscle stretching, and subsequently by moist heat applications and continuing muscle stretching. The pain resolved in all cases. Such syndromes received little attention in the medical literature, and consequently, affected patients have been given alternative diagnoses. The article seeks better recognition of such syndromes in order to provide adequate and appropriate management.

BCG osteitis: a case report.

Osteomyelitis of the left tibia of a two year old boy secondary to neonatal BCG immunisation is described. He made a good recovery following surgical debridement and anti-tuberculosis chemotherapy.

Developmental outcome at 18 months of children less than 1000 grams.

AIMS: Aims of this paper were to carry out an audit of 105 extremely low birth weight infants at 18 months of age, identifying problems, disseminating the resulting information and providing a basis for future work. METHODS: Children born in 1990-2 were classified in categories I to IV according to outcome, and selected perinatal variables were analysed for these groupings. RESULTS: The disability rate (categories I and II) within this cohort was 21% a similar finding to that reported in other literature. For the group with slow motor development and/or tonal abnormalities the percentage was 15. Despite the high risk nature of this group 64% of children were progressing well (category IV) at this age. No significant differences in outcome were found between small for gestational age and appropriate weight for gestational age infants. Significant results were demonstrated in the adverse effects of chronic lung disease and intraventricular haemorrhage on subsequent development. CONCLUSION: The information obtained from this study provides support for the use of this type of audit in Units with extremely low birth weight populations.

Interstitial deletion of 10q23.1 and confirmation of three 10qdel syndromes.

A five-year-old girl with global developmental delay and mild dysmorphic features was referred for karyotyping. Cytogenetic analysis identified an interstitial deletion in the approximate position of chromosome band 10q23.1. The patient's DNA was analysed using an Affymetrix SNP6.0 array, and a 7.46Mbp deletion was detected within the region 10q22.3-q23.32. The deletion encompasses the BMPR1A gene, but does not extend as far as the phosphatase and tensin homolog (PTEN) locus. The location and extent of the deletion is the first of a small group of 10q deletion patients, which has been characterised at the level of resolution afforded by a SNP6.0 chip. Essentially, this case confirms that patients with microdeletions in the 10q23 region can be further divided into three sub-classes, depending on whether the deletion encompasses the BMPR1A gene, the PTEN gene or both.