Temple Syndrome

Excerpt

Clinical characteristics: Temple syndrome (TS14) is characterized by pre- and postnatal growth failure with head sparing, hypotonia with poor feeding, precocious puberty, early-onset obesity with high fat mass and low lean mass, short stature (which can be exacerbated by untreated precocious puberty), and characteristic facial features. Affected individuals can experience cardiometabolic syndrome, including hypertension, hypercholesterolemia, and diabetes, at an early age as a primary feature of the condition. While developmental delay (particularly speech delay) is common, only about one third of affected individuals have true intellectual disability. Less common findings include neurodevelopmental disorders (autism spectrum disorder, attention-deficit/hyperactivity disorder), genitourinary anomalies, conductive hearing loss, hyperextensible joints, scoliosis, and body asymmetry.

Diagnosis/testing: The diagnosis of Temple syndrome is established in a proband with suggestive findings who has hypomethylation of the MEG3:transcriptional start site (TSS)-differentially methylated region (DMR) identified by molecular genetic testing due to uniparental disomy of the maternal chromosome 14q32 region (upd(14)mat), isolated constitutional or mosaic hypomethylation of the normally methylated paternal MEG3/DLK1:intergenic (IG)-DMR and paternal MEG3:TSS-DMR leading to silencing of the paternally expressed genes, OR a heterozygous deletion of the paternally inherited 14q32 region including DLK1.

Management: Treatment of manifestations: Feeding therapy for poor weight gain; a nasogastric tube may be required in the first few first months of life but is not typically required long term; growth hormone therapy for those who have true growth hormone deficiency; growth hormone therapy may be considered for those who have short stature or fulfill the small for gestational age indication (after performing a sleep study to evaluate for obstructive sleep apnea); standard treatment for developmental delay / intellectual disability, obesity, hypertension, hyperlipidemia, diabetes mellitus, gastroesophageal reflux disease, crowded or abnormal dentition, central precocious puberty, hypothyroidism, scoliosis, conductive hearing loss, obstructive sleep apnea, and undescended testes.

Surveillance: Measurement of height/length, weight, BMI (in those older than age 2 years), and nutritional intake every three months for the first two years of life and every six months thereafter; dental evaluation every six months (or as clinically indicated) after tooth eruption; evaluate for healthy lifestyle, nutritional status, and excessive calorie intake with consideration of calorie restriction at each visit in those who have rapid weight gain or obesity; assessment for signs/symptoms of precocious or accelerated puberty at each visit from age three to seven years; consider bone age assessment annually from age five years or if early signs of puberty are noted, whichever is sooner, until around age 14-15 years; monitor growth velocity at each visit for those on growth hormone therapy; repeat sleep study three months after initiation of growth hormone that is used to treat short stature and/or as clinically indicated; measure thyroid function annually or as clinically indicated; for affected individuals in infancy and childhood, inquire about frequency of hypoglycemia at each visit; in those who are school age and older, monitor for signs of both hypoglycemia and hyperglycemia at each visit; metabolic assessment (fasting glucose, high-density lipoprotein, low-density lipoprotein, triglyceride, cholesterol, C-peptide, HbA1c, liver profile, thyroid function test) annually starting at age six years; monitor blood pressure at least annually in those older than age six years; evaluate for scoliosis at each visit until skeletal maturity; assessment of mobility and self-help skills at each visit; monitor developmental progress and educational needs and evaluate for emergence of neurobehavioral problems at each visit; audiology evaluation annually or as clinically indicated; assessment for symptoms of sleep apnea at each visit.

Pregnancy management: Because people with TS14 are at elevated risk of developing obesity and metabolic syndrome in adulthood, women with TS14 should be closely monitored for the development of gestational diabetes during pregnancy.

Genetic counseling: A proband with TS14 typically represents a simplex case and has the disorder as the result of an epigenetic or de novo event resulting in hypomethylation of MEG3:TSS-DMR. The recurrence risk of TS14 is dependent on the genetic mechanism underlying hypomethylation of MEG3:TSS-DMR; reliable recurrence risk assessment requires identification of the genetic mechanism in the proband. While the majority of families are presumed to have a low recurrence risk, TS14 can occur as a result of a predisposing genetic alteration (e.g., a Robertsonian translocation involving chromosome 14 or a deletion involving chromosome 14q32) that can be associated with up to a 50% recurrence risk depending on the nature of the genetic alteration, the sex of the transmitting individual, and presence or absence of multilocus imprinting disturbance (due to a maternal effect pathogenic variant in the mother or biallelic ZNF445 pathogenic variants in the proband). If a genomic alteration (i.e., a deletion involving the 14q32 region or a Robertsonian 13;14 translocation) is identified in a family member with TS14, prenatal and preimplantation genetic testing for the genomic alteration is possible. Methylation testing of fetal DNA to examine abnormal methylation patterns of the DMRs (MEG3/DLK1:IG-DMR and MEG3:TSS-DMR) is not recommended. While DNA extracted from amniotic fluid is currently believed to provide the most reliable tissue source for evaluating fetal methylation status, false negative findings have been reported.