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Conditions

Temple syndrome

Temple syndrome is a rare genetic condition characterised by pre- and postnatal growth restriction, hypotonia, early onset of puberty, variable developmental delay and mild dysmorphism of the face, hands and feet.

Overview

Temple syndrome is an imprinting condition, caused by aberrant expression of imprinted genes at chromosome region 14q32. It is characterised by growth restriction, developmental delay, hypotonia, early onset of puberty and facial features including micrognathia and frontal bossing.

Clinical features

Clinical features of Temple syndrome include:

  • Growth restriction:
    • prenatal growth failure and low birth weight;
    • postnatal growth failure and feeding difficulties; and
    • short stature.
  • Musculoskeletal anomalies:
    • hypotonia with normal muscle power;
    • scoliosis; and
    • small hands and feet
  • Developmental symptoms:
    • motor delay; and
    • variable developmental delay, from normal to severe.
  • Dysmorphic symptoms (mild to moderate; often not evident in infancy):
    • frontal bossing;
    • micrognathia;
    • depressed nasal bridge; and
    • high arched palate.
  • Endocrine symptoms:
    • central obesity developing from four to six years, sometimes associated with compulsive hyperphagia; and
    • early pubertal development (as early as the age of three).

Differential diagnoses include Silver-Russell and Prader-Willi syndromes.

Genetics

Temple syndrome is a genomic imprinting condition, caused by aberrant expression of the genes at the imprinted locus at 14q32.

Temple syndrome results from over-expression of the maternally expressed genes or lack of expression of the paternally expressed genes at this locus. This may be caused by:

  • most commonly, maternal uniparental disomy of chromosome 14 (UPD14);
  • deletion of the paternally inherited copy of 14q32; or
  • an altered epigenetic state at the imprinting control region, IG-DMR.
    • The IG-DMR region is normally methylated on the paternally inherited allele and unmethylated on the maternally inherited allele. Loss of DNA methylation on the paternally inherited IG-DMR can cause Temple syndrome.

All types of Temple syndrome can be identified by testing for methylation status at the IG-DMR, which will appear to be hypomethylated. A microarray is likely to identify cases of Temple syndrome caused by deletions and extensive uniparental disomy, but will not identify cases caused by altered epigenetic status at the imprinting control region.

For information about testing, see Presentation: Clinical suspicion of Silver-Russell syndrome

Inheritance and genomic counselling

Genomic counselling for Temple syndrome is complex because chance of recurrence depends on the underlying genetic mechanism, which should be established before advice is given. Genomic testing of the affected individual and their parents is recommended.

  • Cases caused by maternal UPD14 are likely to have arisen sporadically because of nondisjunction and trisomy/monosomy rescue. In these circumstances, the chance of recurrence is therefore low (below 1%).
  • If a parent is a carrier of a Robertsonian translocation involving chromosome 14, the overall chance of UPD is estimated to be less than 0.5%.
  • If an affected child is found to carry a deletion of the paternally inherited copy of 14q32, this is most likely to have arisen de novo. If the paternal chromosomes are found to be normal, the chance of recurrence is again low (less than 1%).
  • Rarely, an altered epigenetic state at the imprinting control region can arise de novo as an isolated methylation anomaly, or can be caused by a point mutation, and in this latter case the chance of recurrence may be higher (up to 50%).
  • Some cases of altered methylation at 14q32 are associated with multi-locus imprinting disturbance, which can be either sporadic or a result of maternal-affect genes. In the latter case, recurrence can be high because all pregnancies will carry the chance of being affected by multi-locus imprinting disturbance to varying degrees, causing phenotypes ranging from early miscarriage to normal development, depending on the locus involved and the extent of the methylation alteration.

A male patient with Temple syndrome caused by a paternally inherited deletion of 14q32 will have up to a 50% chance of passing the condition to his own children. A female patient with Temple syndrome caused by the same deletion of 14q32, however, will have a 50% chance of her children developing Kagami-Ogata syndrome (resulting from paternal UPD14).

Management

Management of children with Temple syndrome is complex and should be delivered via a multidisciplinary team. This is likely to involve a community paediatrician, a paediatric endocrinologist (growth hormone therapy, treatment for premature puberty), a nutritionist and, where necessary, an orthopaedic surgeon (scoliosis). In the case of developmental delay, special education may be needed.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 25/04/2023
  • Next review due: 25/04/2025
  • Authors: Dr Elizabeth Radford
  • Reviewers: Dr Renuka Dias, Dr Amy Frost, Dr Ellie Hay, Dr Emile Hendriks, Professor Karen Temple