Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) robustly detects and distinguishes 11p15 abnormalities associated with overgrowth and growth retardation.

BACKGROUND: A variety of abnormalities have been demonstrated at chromosome 11p15 in individuals with overgrowth and growth retardation. The identification of these abnormalities is clinically important but often technically difficult. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a simple but effective technique able to identify and differentiate methylation and copy number abnormalities, and thus is potentially well suited to the analysis of 11p15. AIMS: To customize and test an MS-MLPA assay capable of detecting and distinguishing the full spectrum of known 11p15 epigenetic and copy number abnormalities associated with overgrowth and growth retardation and to assess its effectiveness as a first line investigation of these abnormalities. METHODS: Five synthetic probe pairs were designed to extend the range of abnormalities detectable with a commercially available MS-MLPA assay. To define the normal values, 75 normal control samples were analysed using the customized assay. The assay was then used to analyse a "test set" of 24 normal and 27 abnormal samples, with data analysed by two independent blinded observers. The status of all abnormal samples was confirmed by a second technique. RESULTS: The MS-MLPA assay gave reproducible, accurate methylation and copy number results in the 126 samples assayed. The blinded observers correctly identified and classified all 51 samples in the test set. CONCLUSIONS: MS-MLPA robustly and sensitively detects and distinguishes epigenetic and copy number abnormalities at 11p15 and is an effective first line investigation of 11p15 in individuals with overgrowth or growth retardation.

Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD).

Disorders of sex development (DSDs) are a diverse group of conditions where the chromosomal, gonadal or anatomical sex can be atypical. The highly heterogeneous nature of this group of conditions often makes determining a genetic diagnosis challenging. Prior to next generation sequencing (NGS) technologies, genetic diagnostic tests were only available for a few of the many DSD-associated genes, which consequently had to be tested sequentially. Genetic testing is key in establishing the diagnosis, allowing for personalised management of these patients. Pinpointing the molecular cause of a patient's DSD can significantly impact patient management by informing future development needs, altering management strategies and identifying correct inheritance pattern when counselling family members. We have developed a 30-gene NGS panel, designed to be used as a frontline test for all suspected cases of DSD (both 46,XX and 46,XY cases). We have confirmed a diagnosis in 25 of the 80 patients tested to date. Confirmed diagnoses were linked to mutations in AMH, AMHR2, AR, HSD17B3, HSD3B2, MAMLD1, NR5A1, SRD5A2 and WT1 which have resulted in changes to patient management. The minimum diagnostic yield for patients with 46,XY DSD is 25/73. In 34/80 patients, only benign or likely benign variants were identified, and in 21/80 patients only variants of uncertain significance (VOUS) were identified, resulting in a diagnosis not being confirmed in these individuals. Our data support previous studies that an NGS panel approach is a clinically useful and cost-effective frontline test for patients with DSDs.

Partial NSD1 deletions cause 5% of Sotos syndrome and are readily identifiable by multiplex ligation dependent probe amplification.

BACKGROUND: Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions. It is uncertain whether allelic or genetic heterogeneity underlies the residual cases and it has been proposed that other mechanisms, such as 11p15 defects, might be responsible for Sotos cases without NSD1 mutations or 5q35 microdeletions. OBJECTIVE: To develop a multiplex ligation dependent probe amplification (MLPA) assay to screen NSD1 for exonic deletions/duplications. METHODS: Analysis was undertaken of 18 classic Sotos syndrome cases in which NSD1 mutations and 5q35 microdeletions were excluded. Long range polymerase chain reaction (PCR) was used to characterise the mechanism of generation of the partial NSD1 deletions. RESULTS: Eight unique partial NSD1 deletions were identified: exons 1-2 (n = 4), exons 3-5, exons 9-13, exons 19-21, and exon 22. Using long range PCR six of the deletions were confirmed and the precise breakpoints in five cases characterised. This showed that three had arisen through Alu-Alu recombination and two from non-homologous end joining. CONCLUSIONS: MLPA is a robust, inexpensive, simple technique that reliably detects both 5q35 microdeletions and partial NSD1 deletions that together account for approximately 15% of Sotos syndrome.

Autosomal dominant macrocephaly: benign familial macrocephaly or a new syndrome?

During the course of a clinical study of Sotos syndrome, six out of 79 probands failed to fit the phenotype of Sotos syndrome but showed remarkable similarities to each other and to a further 11 first- and second-degree relatives. Clinical features in these index cases included macrocephaly, greater than +3.5 SD; normal or near normal birth weight and length with subsequent relative obesity; variable developmental delay; and typical face, characterised by a square outline with frontal bossing, a "dished-out" mid-face, biparietal narrowing, and long philtrum. All recorded bone ages were less than the 75th centile, and two were below the 10th centile. The authors believe the original diagnosis was incorrect and that these cases likely represent a previously undescribed autosomal dominant macrocephaly syndrome.

Sotos syndrome: evolution of facial phenotype subjective and objective assessment.

Sotos syndrome is characterised by pre- and post-natal growth acceleration, advanced bone age, developmental delay and a typical facial Gestalt. We have evaluated 45 individuals with Sotos syndrome who were between age 1 and 25 years, in order to better define the change in facial appearance over time. In each individual, a thorough assessment was made, serial photographs were reviewed, and a series of anthropometric craniofacial measurements was obtained. These were compared with age- and sex-matched normal standards. Both clinical and anthropometric evaluations show that the facial appearance which most clinical geneticists would regard as "classical" is established early in life. The head is large and dolichocephalic, with a rounded and prominent forehead, accentuated by frontoparietal balding. There is narrowing at the temples, fullness of the cheeks, and tapering to a pointed chin. With time, the normal process of facial change occurs, superimposed on that typical Gestalt. As the face lengthens, the dominance of the forehead diminishes and the chin achieves greater prominence. The mandible is long and narrow inferiorly, square or pointed, but prognathism is rare. In a small proportion of patients, a rounder face early in life may challenge diagnosis, but follow-up of these large newborn and older infants should allow diagnosis by early childhood. Visualisation of pattern profiles at different ages, supplemented by statistical measures of variability and similarity, support the clinical impressions outlined above.

The neuroimaging findings in Sotos syndrome.

We reviewed the neuroimaging studies of 40 patients with classic Sotos syndrome. The studies consisted of CT scans only in 4 patients and one or more MRI scans in 36 patients. The diagnosis of Sotos syndrome was made using well-established clinical criteria. The neuroimaging studies of each patient were evaluated subjectively by visual inspection and the chief findings were tabulated and grouped into five categories: 1) ventricular abnormalities, 2) extracerebral fluid spaces, 3) midline abnormalities, 4) migrational abnormalities, and 5) others. The most common abnormality of the cerebral ventricles was prominence of the trigone (90%), followed by prominence of the occipital horns (75%) and ventriculomegaly (63%). The supratentorial extracerebral fluid spaces were increased for age in 70% of the patients and the fluid spaces in the posterior fossa were increased in 70% also. A variety of midline abnormalities were noted but anomalies of the corpus callosum were almost universal. Gray matter heterotopias occurred in only 3 (8%) of 36 patients. Periventricular leukomalacia, presumably the result of prenatal or perinatal difficulties and unrelated to the basic condition, was the most common of the miscellaneous other abnormalities noted. The neuroimaging findings of Sotos syndrome are distinct enough to allow differentiation of this syndrome from other mental retardation syndromes with macrocephaly.

Metacarpophalangeal pattern profile analysis in Sotos and Marfan syndrome.

Patients with Sotos and Marfan syndrome have unusually long metacarpals and phalanges which may make the differential diagnosis difficult in younger children. Using Q-scores, we compared metacarpophalangeal pattern profile (MCPP) analysis in these two syndromes and identified distinct and different pattern profiles. This illustrates that the MCPPs are specific in these syndromes, even at an early age, and not related solely to the unusually long metacarpals and phalanges. For this study we used data from 50 Sotos patients (34 from the United Kingdom and 16 from the Netherlands, with a total of 95 hand films) and 36 Marfan patients (from the Netherlands, with 98 hand films). Of all patients over age 3 years the bone length (including the epiphysis) was determined. The patients under 7 1/2 years (29 Sotos and 12 Marfan) were also measured without inclusion of the epiphysis. The patients measured without epiphysis had a relative short metacarpal 1 (MC1) and long distal phalanx 1 (DPh1) in Sotos syndrome, and a relative long MC1 and short DPh1 in Marfan syndrome. Between age 3 and 7 1/2 years more than 90% of the films could be classified correctly using these two variables. Of the roentgenograms measured with epiphyses, about 80% were classified correctly.

Language and behavior in children with Sotos syndrome.

OBJECTIVE: To examine language and behavior in children with Sotos syndrome, an overgrowth syndrome involving advanced bone age, characteristic facies, and developmental disability. METHOD: Twenty-seven children with Sotos syndrome were compared with 20 children with overgrowth, intellectual disability, and facies not characteristic of Sotos syndrome. Ages ranged from 5 to 16 years. Direct assessment was undertaken with standardized measures of intelligence and language abilities. Behavior was examined by parent and teacher report. RESULTS: Children with Sotos syndrome had levels of intelligence in the severely disabled to average range, with the majority falling in the borderline range. Mean level of intelligence was significantly higher than that observed for children in the comparison group. Language abilities were developed to a level consistent with overall level of intelligence. Rates of parent- and teacher-reported behavior problems were significantly higher than normal, but, with the exception of temper tantrums, did not differ from those observed in children in the comparison group. Attention-deficit hyperactivity disorder was observed in 38% of children with Sotos syndrome. They were more irritable and had more stereotypic behavior and inappropriate speech than is expected in children with intellectual disabilities, and they were more withdrawn and had more stereotypic behavior than children in the comparison group. CONCLUSIONS: Assessment of language abilities revealed no specific language impairment. High rates of behavior problems were observed, but these were not higher than those observed for other large, delayed, dysmorphic children.

Generational equity in America: a cultural historian's perspective.

This paper examines the issue of generational equity in America through the lenses of cultural history and social criticism. It argues that generational equity reflects broader problems of contemporary aging policy, whose troubles in turn reflect the decline of American military and economic power, the legitimation crisis of the liberal welfare state, and population aging. The question of justice between the young and the old is also linked to the 'spiritual situation of the age'--in particular to American culture's inability to provide convincing answers to existential concerns like the quality of life in old age, the unity of the life cycle, and the meaning of aging. Both communitarian and liberal approaches to generational equity presuppose a life course or lifespan perspective, whose unifying ideological power took shape historically in a bourgeois culture that provided widely shared images of the integrity of the life course. The social power of this perspective emerged over the last century, when the U.S., along with other Western democracies, institutionalized the life course by creating age-homogeneous schools for youthful preparation, employment for middle-aged productivity, and publicly funded retirement benefits for the aged. The ideal of a society legitimately ordered by the natural divisions of human lifetime is now under siege in large part because its view of old age is neither socially nor spiritually adequate and because the social meanings of life's stages are in great flux. In our century, vastly improved medical and economic conditions of old age have been accompanied by a loss of cultural meaning and vital social roles for older people.

"Song of ourselves": a quantitative history of American autobiographies.

This article highlights the major descriptive findings of an exploratory, quantitative study of American autobiographies published before 1945. Of particular importance for gerontology, age-cohort distributions of autobiographers are graphed, demonstrating that the genre itself has been created predominantly by men and women aged 55 and over. This study suggests that these writers offer scholars a virtually untapped resource for the historical phenomenology of aging.

An apparently new acrocraniofacial syndrome with cranial nerve and visceral anomalies.

We report details of a neonate with cranial bone dysplasia, broad nasal bridge, microphthalmia, optic and olfactory nerve anomalies, pulmonary segmentation defects, polydactyly, abnormally positioned and shaped thumbs, absent mesentery to the gut and streak gonads. Review of the literature and relevant databases does not identify a likely diagnosis.

The political and moral economy of aging: not such strange bedfellows.

The authors develop E.P. Thompson's concept of moral economy as a useful complement to contemporary political economic analysis in problem areas involving moral conflict. Defined as the shared assumptions underlying norms of reciprocity in which an economic system is grounded, moral economy is seen as holding particular relevance for the study of aging. The evolution of pension systems, the "senior revolt" against catastrophic coverage in the United States, and debates over the allocation of health resources between generations are used to illustrate the utility of a combined political and moral economy for enriching our understanding in these areas. Marx's concept of a "morality of emancipation" is described as holding particular promise for the development of a new moral economy of old age that would move beyond alienation by giving broad attention to quality of life issues at each stage of the life course.