Smith-Magenis syndrome resulting from a de novo direct insertion of proximal 17q into 17p11.2

Purpose: Smith-Magenis syndrome (SMS), a probable contiguous gene syndrome due to an interstitial deletion of chromosome 17 band p11.2, is associated with a distinct and complex phenotype, including physical, developmental, and neurobehavioral features. The majority of SMS patients are deleted for a common~4 Mb interval that includes the gene SREBF1, a transmembrane transcription factor that regulates the low density lipoprotein (LDL) receptor and plays a crucial role in cholesterol homeostasis. A systematic study of fasting lipid profiles of patients with SMS was conducted to determine the frequency of cholesterol abnormalities. Methods: Fasting lipid profiles were examined in 49 children (27F/22M) between the ages of 0.6 years to 17.6 years (mean, 6.9 years) with a cytogenetically confirmed diagnosis of SMS. Observed values for serum total cholesterol (TC), triglycerides (TG), LDL cholesterol, and high density lipoprotein cholesterol were compared with published norms. The body mass index (BMI) was used as a measure of nutritional status. Results: Mean TC was significantly higher than published NHANES III pediatric norms (P Ͻ 0.0008). Overall 28 of 49 (57%) SMS subjects had lipid values greater than the 95th percentile for age and gender for at least one or more of the following: TC, TG, and/or LDL. Only 16 SMS subjects (32%) were within normal limits for all three of these variables. BMI values showed minimal positive correlation to SMS lipid values; however, no consistent effect was found. Thus BMI values alone do not explain the marked trend in increased TC, TG, and/or LDL observed in the SMS group. Based on the American Academy of Pediatrics recommended lipid levels for children and adolescents, only one third of SMS subjects fall within normal range for TC and LDL; an additional one third each measure "borderline" or "high" for these values.

Section: Study Populationsupporting

confidence: 54%

Section: Molecular Analysismentioning

confidence: 99%

Hypercholesterolemia in children with Smith-Magenis syndrome: del (17)(p11.2p11.2)

Smith

Gropman

Bailey-Wilson

et al. 2002

“…Several publications have also presented many "expanded phenotypes" for genetic and metabolic conditions in association with ASDs' phenotypes. [10][11][12][13][14][15] These factors have led to an increase in the number of referrals to the clinical geneticist and an increase in the diagnostic yield.…”

mentioning

confidence: 99%

Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions

Schaefer

Mendelsohn

2013

439

393

Autism spectrum disorders (ASDs), also known as pervasive developmental disorders, are a behaviorally defined group of neurodevelopmental disorders that are usually diagnosed in early childhood. They are characterized by varying degrees of limitations in communication and social interaction and by atypical, repetitive behaviors with an onset before 3 years of age. The phenotype of ASDs is extremely heterogeneous, with differences from person to person in a wide range of symptoms and severity as well as differences between the various subtypes of ASDs (e.g., autistic disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified).Multiple lines of epidemiologic evidence support the strong role of genetics in the etiology of ASDs. 1-3 Results of population studies of unselected cases of autism are most consistent with multifactorial inheritance. Until quite recently, the accepted recurrence risk for full siblings of a child with autism has been in the range of 3-10%. [4][5][6] Overall, only 2-3% of families have more than one affected child (possibly because of voluntary avoidance of pregnancy after a child is diagnosed). Most studies have reported a sex bias in the recurrence risk in keeping with the presumption of a "multifactorial" mode of inheritance (higher risk if the affected person is of the less commonly affected sex). As such, the reported risk is 7% of another affected child if the first affected child is female and 4% if the first affected child is male. 7 If multiple children (two or more) have autism, the recurrence risk is on the order of 33-50% for any future pregnancy. 7 Two recent studies 8,9 have reported even higher recurrence risks of 11 and 19% with single-sibling involvement. The first 8 was a retrospective self-enrolled/self-identified study using an interactive website. The diagnosis was confirmed, but the identification of second siblings may be a source of ascertainment bias. The second 9 was an international multisite prospective study in 664 families with a calculated 19% recurrence risk. Interestingly, the typically reported sex bias was not noted in one of these studies. 8 Both were single studies that bear replication.The autism spectrum disorders are a collective of conditions that have in common impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased dramatically over the past two decades. In addition, increased attention has been paid to these conditions by both lay and professional groups. These trends have resulted in an increase in the number of referrals to clinical geneticist for the evaluation of persons with autism spectrum disorders. The primary roles of the geneticist in this process are to define etiology when possible, to provide genetic counseling, and to contribute to case management. In deciding on the appropriate evaluation for a particular patient, the geneticist will consider a host of factors: (i) ensuring an accurate diagnosis of autism befor...

“…10 One patient (1221) has a complex chromosomal rearrangement leading to deletion of 17p11.2. 17 The deletion was of paternal origin in 17/30 (56.6%) cases and maternal in 13/30 (43.3%).…”

Section: Resultsmentioning

confidence: 99%

Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)]

Potocki

Shaw²,

Stankiewicz³

et al. 2003

107

114

Purpose: This report delineates the phenotypic features in a cohort of 58 individuals with Smith-Magenis syndrome (SMS) and compares features of patients with the common microdeletion to those of patients with variable sized deletions, and the three previously reported patients who harbor a mutation in RAI1 (retinoic acid induced 1).Methods: From December 1990 thru September 1999, 58 persons with SMS were enrolled in a 5-day multidisciplinary clinical protocol at the General Clinical Research Center (GCRC), Texas Children's Hospital. Each patient had a cytogenetically evident deletion in 17p11.2. Results: Of the 51 patients in whom the molecular extent of the chromosomal deletion could be delineated by pulsed-field gel electrophoresis (PFGE) and/or fluorescent in situ hybridization (FISH), 39 (Ϸ76%) had the common SMS deletion. Smaller or larger deletions were seen in Ϸ12% and Ϸ10% of patients, respectively, and 1 patient had a complex chromosomal rearrangement including a deletion in 17p11.2. Parent of origin was determined by polymorphic marker analysis in a subset of patients: maternal Ϸ43%, paternal Ϸ57%. All patients had impaired cognitive and adaptive functioning and had at least one objective measure of sleep disturbance. Other common features (seen in Ͼ 50% of patients) include short stature, ophthalmological, and otolaryngological anomalies, hearing impairment, abnormal EEG, and scoliosis. Cardiac and renal anomalies were seen in Ϸ45% and Ϸ19% of patients, respectively. There are no statistically significant differences in the incidence of these abnormalities in patients with the common deletion compared to those