Temple Syndrome: Genetic Mechanisms, Diagnosis, and More

Temple syndrome is a rare genetic disorder affecting growth, metabolism, and development. Its symptoms overlap with other conditions, making early diagnosis difficult. Understanding the disorder is essential for timely intervention and management.

Genetic Mechanisms

Temple syndrome results from disruptions in genomic imprinting on chromosome 14q32, a region critical for growth and metabolism. Three main genetic alterations cause this disorder: maternal uniparental disomy of chromosome 14 (UPD(14)mat), paternal microdeletions, and epimutations affecting methylation patterns. These changes interfere with the normal expression of imprinted genes, which are regulated based on parental origin.

Maternal UPD(14)mat, the most common cause, occurs when both copies of chromosome 14 come from the mother, eliminating paternal gene expression. This absence disrupts genes such as DLK1, RTL1, and MEG3, with DLK1 playing a key role in cell differentiation and metabolism. Reduced DLK1 expression is linked to short stature and early-onset obesity, hallmark traits of the syndrome.

Paternal deletions in the 14q32 region remove essential regulatory elements, leading to a loss of paternally expressed genes. Unlike UPD(14)mat, deletions vary in size, influencing the severity of symptoms. Some partial deletions cause milder effects, while larger deletions result in significant growth and developmental impairments.

Epimutations involve abnormal DNA methylation that disrupts gene regulation without altering DNA sequence. In Temple syndrome, hypermethylation of the intergenic differentially methylated region (IG-DMR) and MEG3-DMR on the paternal chromosome disturbs normal gene expression. This mechanism has been observed in patients without detectable chromosomal abnormalities, underscoring the complexity of imprinting disorders.

Physical Characteristics

Temple syndrome is marked by growth restriction, often beginning with intrauterine growth retardation and continuing postnatally. Many affected individuals fall below the third percentile for height due to impaired DLK1 function, which influences skeletal development and metabolism. Without intervention, short stature persists into adulthood, often accompanied by increased fat mass relative to lean muscle.

Distinct craniofacial features aid in diagnosis. Affected individuals typically have a triangular face, broad forehead narrowing to a small chin, and a small mouth. These traits resemble those seen in Silver-Russell syndrome, requiring careful differentiation. Additional features include deep-set eyes, a prominent nasal bridge, and mildly dysplastic ears, which become more pronounced with age. Some cases report micrognathia, contributing to early feeding difficulties.

Hypotonia, or reduced muscle tone, is common in infancy, leading to delayed milestones such as sitting, crawling, and walking. This weakness is linked to disrupted neuromuscular signaling, likely due to impaired DLK1 function. While muscle tone may improve with age, residual weakness can affect coordination and endurance. Some individuals also have joint hypermobility, complicating motor development and requiring physical therapy.

Skeletal abnormalities, including scoliosis and brachydactyly (shortened fingers), are sometimes present. Scoliosis may develop in late childhood or adolescence, while brachydactyly, particularly affecting the fifth fingers, can include clinodactyly (curvature). These skeletal traits, though variable, may necessitate orthopedic evaluation.

Diagnostic Approaches

Diagnosing Temple syndrome requires a combination of clinical assessment and genetic testing. Due to its overlap with other imprinting disorders, such as Silver-Russell syndrome, physical traits and growth patterns alone are insufficient for diagnosis. Physicians assess prenatal and postnatal growth restriction, craniofacial features, and early feeding difficulties. Developmental delays and hypotonia further support suspicion, prompting molecular testing.

Genetic testing confirms the diagnosis, with methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and methylation-sensitive polymerase chain reaction (MS-PCR) detecting imprinting abnormalities at chromosome 14q32. These tests identify methylation defects linked to UPD(14)mat, paternal deletions, and epimutations. Additional tests, such as chromosomal microarray analysis or next-generation sequencing, help characterize structural variations.

Early diagnosis is essential for timely intervention. In pediatric cases, persistent short stature without an alternative cause should prompt testing. Endocrinologists and geneticists collaborate to determine appropriate testing strategies. Trio-based genetic testing, analyzing the genetic profiles of both parents and the child, can clarify ambiguous results and distinguish Temple syndrome from similar disorders.

Hormonal Considerations

Endocrine dysfunction significantly impacts growth and metabolism in Temple syndrome. A key issue is low insulin-like growth factor 1 (IGF-1) levels, despite normal or slightly reduced growth hormone (GH) secretion. This suggests GH resistance, contributing to persistent short stature and altered body composition. GH therapy has been explored but shows variable effectiveness due to imprinting-related disruptions.

Leptin and ghrelin imbalances also affect appetite and metabolism. Elevated leptin levels suggest resistance, potentially driving excessive weight gain. Ghrelin levels may also be altered, further complicating appetite control. These hormonal disturbances increase the risk of early-onset obesity, requiring careful metabolic management.

Possible Complications

Temple syndrome can lead to complications beyond growth and metabolic issues. Early-onset obesity increases the risk of insulin resistance and type 2 diabetes. Many individuals develop central adiposity, which elevates the risk of hypertension and dyslipidemia. Long-term metabolic monitoring is essential.

Hypotonia and joint hypermobility contribute to postural abnormalities and scoliosis, which may require orthopedic intervention. Muscle weakness can persist into adulthood, affecting endurance and increasing susceptibility to joint pain. Early physical and occupational therapy can improve functional outcomes.

Speech and feeding difficulties in early childhood, caused by oromotor dysfunction, may lead to persistent articulation issues or challenges with chewing and swallowing. Addressing these concerns early with therapy helps improve long-term outcomes.

Nutritional Factors

Nutritional management is crucial to prevent excessive weight gain and metabolic dysfunction. Infants may struggle with feeding due to weak suck reflexes and poor weight gain, requiring high-calorie formulas or feeding therapy. As children transition to solid foods, appetite regulation remains challenging due to hormonal imbalances.

Structured meal plans emphasizing nutrient-dense foods help manage weight and metabolic health. A lower glycemic index diet can stabilize blood sugar levels and prevent excessive fat accumulation. Adequate protein intake supports muscle maintenance, addressing hypotonia and reduced lean muscle mass. Regular monitoring by a dietitian can help tailor dietary recommendations to each individual’s needs.