Imprinting disorders Notes

Chapter 2 Acyanotic Defects NOTES IMPRINTING DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Genetic, epigenetic mutations/defects within imprinting controlling regions of genes ▪ Disruption of methylation of cytosine bases in CpG dinucleotides of DNA RISK FACTORS ▪ Increased incidence in individuals conceived using assisted reproductive technology SIGNS & SYMPTOMS ▪ Angelman syndrome ▫ Seizures, severe intellectual disability, jerky/tremulous limbs, characteristic facial appearance (e.g. large mouth, protruding tongue, prominent nose), excitability, impaired speech ▪ Beckwith–Wiedemann syndrome ▫ Premature birth, abdominal wall defects, embryonal tumors ▪ Prader–Willi syndrome ▫ Infancy: poor feeding, low muscle tone, weak cry, diminished reflexes ▫ Early childhood obesity, developmental delay, behavioral problems ▫ Dysmorphic facial features DIAGNOSIS OTHER DIAGNOSTICS ▪ History, clinical examination ▪ Fluorescence in situ hybridization (FISH), genotyping, methylation DNA testing ▪ Methylation-sensitive multiplex ligation probe analysis (MS-MLPA) TREATMENT MEDICATIONS ▪ Angelman syndrome: antiepileptic therapy ▪ Prader–Willi syndrome: thyroid, sex hormone replacement therapy OTHER INTERVENTIONS ▪ Angelman syndrome: speech therapy ▪ Beckwith–Wiedemann syndrome: tumor surveillance, abdominal wall repair ▪ Prader–Willi syndrome: food restriction, vitamin D/calcium supplements OSMOSIS.ORG 169

ANGELMAN SYNDROME osms.it/angelman-syndrome PATHOLOGY & CAUSES ▪ Genetic neurological disorder; severe developmental delay, intellectual disability, absence of speech, ataxia, dysmorphic features, unprovoked episodes of laughter CAUSES ▪ Maternal 15q11-q13 deletion ▪ Loss of function of UBE3A ▪ Paternal uniparental disomy 15 (both copies of chromosome 15 from father) SIGNS & SYMPTOMS ▪ Seizures, severe intellectual disability ▪ Ataxia, toe-walking, jerky/tremulous limbs ▪ Hypopigmentation, microcephaly, maxillary hypoplasia, large mouth, protruding tongue, prominent nose, wide-spaced teeth ▪ Inappropriate laughter (“happy puppet”), excitability, impaired speech 170 OSMOSIS.ORG DIAGNOSIS OTHER DIAGNOSTICS ▪ FISH, genotyping, methylation DNA testing TREATMENT MEDICATIONS ▪ Antiepileptic therapy for seizures OTHER INTERVENTIONS ▪ Speech therapy; emphasis on nonverbal methods of communication

Chapter 26 Imprinting Disorders BECKWITH–WIEDEMANN SYNDROME osms.it/beckwith-wiedemann_syndrome PATHOLOGY & CAUSES ▪ Pediatric overgrowth syndrome; visceromegaly, predisposition to tumors CAUSES ▪ Error in imprinted gene expression in chromosome 11p15.5 region ▪ Usually sporadic, may be inherited in autosomal dominant fashion SIGNS & SYMPTOMS Fetal macrosomia, premature birth Macroglossia Renal medullary hyperplasia Abdominal wall defects ▫ Omphalocele, umbilical hernia, diastasis recti ▪ Hypoglycemia due to islet cell hyperplasia ▪ Puberty, episeal fusion (early symptoms) ▪ Embryonal tumors (e.g. Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) ▪ ▪ ▪ ▪ DIAGNOSIS OTHER DIAGNOSTICS ▪ Clinical diagnosis ▪ MS-MLPA ▫ Detect majority of epigenetic, genetic etiologies TREATMENT OTHER INTERVENTIONS ▪ Tumor surveillance with abdominal MRI/CT scan ▪ Abdominal wall repair for omphalocele ▪ Assess, treat airway insufficiency; feeding evaluation in presence of macroglossia ▪ Assess, treat hypoglycemia for neonates OSMOSIS.ORG 171

PRADER–WILLI SYNDROME osms.it/prader-willi_syndrome PATHOLOGY & CAUSES ▪ Genetic multisystem disorder; weak muscle tone; delayed growth, development; behavioral abnormalities (e.g. insatiable hunger) CAUSES ▪ Paternal 15q11-q13 deletion (maternal gene unchanged) ▪ Maternal uniparental disomy 15 (both copies of chromosome 15 from mother) ▪ Defects in imprinting center controlling chromosome 15 activity of genes ▪ Associated with dysregulation of hypothalamic-pituitary axis COMPLICATIONS ▪ Sleep apnea (central/obstructive), scoliosis, osteoporosis, hypothyroidism, Type II diabetes SIGNS & SYMPTOMS ▪ Infancy ▫ Poor feeding, low muscle tone, weak cry, diminished reflexes ▪ Overeating (hyperphagia), early childhood obesity ▪ Developmental delay ▫ Intellectual disability; delayed motor, language development ▪ Behavioral problems ▫ Inflexibility, obsessive-compulsive characteristics ▪ Low sex hormones in childhood, hypogenitalism/hypogonadism; cryptorchidism in individuals who are biologically male 172 OSMOSIS.ORG ▪ Dysmorphic facial features in childhood ▫ Almond-shaped eyes, narrow forehead, thin upper lip ▪ Small hands/feet, short stature DIAGNOSIS OTHER DIAGNOSTICS ▪ History, clinical examination ▪ Fluorescence in situ hybridization (FISH), genotyping, methylation DNA testing TREATMENT MEDICATIONS ▪ Human recombinant growth hormone therapy ▫ Decrease body weight/fat, increase muscle mass ▪ Address complications ▫ Thyroid, sex hormone replacement therapy OTHER INTERVENTIONS ▪ Food restriction ▪ Address complications ▫ Vitamin D, calcium supplements