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.

Suggestive Findings

TS14 should be considered in probands with the following clinical findings and family history.

Clinical findings

• Birth weight and/or length two standard deviations below the mean with preserved head size
• Hypotonia
• Feeding difficulties in infancy, including poor suck and/or reluctance to feed
• Postnatal growth deficiency with head sparing transitioning to increased weight gain, truncal obesity, and high fat mass typically around age four to six years
• Developmental delay with or without intellectual disability
• Intellectual disability, typically in the mild-to-moderate range
• Precocious puberty
• Small hands and feet
• Irregular or crowded teeth
• Scoliosis
• Typical facial features, which are distinct from those in Silver-Russell syndrome and become less recognizable with age (see Figure 1):
  • High forehead
  • Prominent supraorbital ridges
  • Low nasal bridge
  • Short and upturned nose
  • Bulbous nasal tip
  • Short philtrum
  • Downturned corners of the mouth
  • High-arched palate
  • Micrognathia
  • Low-set ears

Figure 1.

Facial features of individuals with Temple syndrome from infancy to adolescence Modified with permission from Kagami et al [2017], Gillessen-Kaesbach et al [2018], and Lande et al [2018]

Note: Atypical clinical features may be present when TS14 is associated with multilocus imprinting disturbance (MLID) (TS14-MLID); see Genotype-Phenotype Correlations.

Family history. Most probands with TS14 represent a simplex case (i.e., a single occurrence in a family). However, there may be a family history consistent with either autosomal dominant inheritance (e.g., affected males and females in multiple generations) or with the features of MLID (infertility, multiple miscarriages, molar pregnancies, offspring with features of one or more imprinting disorders, and multiple different offspring with an imprinting disorder; see Maternal Effect Gene-Related Multilocus Imprinting Disturbances). This latter family history finding relates only to those individuals with TS14 due to epimutation of MEG3/DLK1:intergenic (IG)-differentially methylated region (DMR) leading to loss of methylation. Absence of these family history findings does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of TS14 is established in a proband with suggestive findings who has hypomethylation of the MEG3:transcriptional start site (TSS)-DMR identified by molecular genetic testing due to one of the following:

• Uniparental disomy (UPD) of the maternal chromosome 14q32 region (upd(14)mat) (~50%-60%)
  Some affected individuals have upd(14)mat from a Robertsonian 13;14 translocation [Ogawa et al 2025].
• Isolated constitutional or mosaic hypomethylation of the normally methylated paternal MEG3/DLK1:IG-DMR and paternal MEG3:TSS-DMR leading to silencing of the paternally expressed genes (~30%-40% of affected individuals)
• A heterozygous deletion of the paternally inherited 14q32 region including DLK1 (~10% of affected individuals). See Table 1 and Figure 2; Figure 3 is a schematic of the imprinted chromosome 14q32 locus [Eggermann et al 2023, Baena et al 2024, Ogawa et al 2025].

Figure 2.

Algorithm for genetic diagnosis of Temple syndrome 1. At the time of writing, many laboratories perform DNA methylation and copy number analysis in parallel using commercial methylation-specific multiplex ligation-mediated probe amplification (MS-MLPA). (more...)

Figure 3.

Schematic of the chromosome 14q32.2 imprinted region, showing parent-of-origin-specific DNA methylation and gene expression The top panel represents the normal situation, and the lower panels represent genetic changes leading to Temple syndrome. Black (more...)

Molecular genetic testing for TS14 includes first-tier testing (DNA methylation of the 14q32 imprinted region, often in parallel with copy number analysis by methylation-specific ligation-dependent probe amplification [MS-MLPA]). If there is evidence of MEG3:TSS-DMR hypomethylation, second-tier testing can be pursued next to identify the specific molecular cause and clarify recurrence risks (see Figure 2, Genetic Counseling, and Molecular Genetics).

Clinical Description

Temple syndrome (TS14) is characterized by pre- and postnatal growth failure with head sparing. After birth, hypotonia with poor feeding may be seen. If untreated, affected children may transition to having precocious puberty and early-onset obesity with high fat mass and low lean mass. Short stature can be exacerbated by untreated precocious puberty. Most affected individuals have developmental delay, but only about one third have intellectual disability. Craniofacial features are also common (see Figure 2).

Table 2 summarizes the clinical features reported in 196 individuals who were reported at different ages. The reports focused on different clinical manifestations; therefore, the frequency of some clinical features may differ from that suggested by the summary data [Ioannides et al 2014, Zada et al 2014, Rosenfeld et al 2015, Stalman et al 2015, Tamminga et al 2015, Briggs et al 2016, Goto et al 2016, Sachwitz et al 2016, Severi et al 2016, Shin et al 2016, Bertini et al 2017, Beygo et al 2017, Luk 2017, Geoffron et al 2018, Gillessen-Kaesbach et al 2018, Kimura et al 2018, Lande et al 2018, Tortora et al 2019, Juriaans et al 2022, Yordanova et al 2024, Iwanishi et al 2025, Ogawa et al 2025].

Prenatal findings. Growth restriction (small for dates) in an affected fetus is typically present in the second trimester; other prenatal findings can include oligohydramnios, hypoplastic placenta, and decreased fetal movements. Premature delivery occurs in ~20% of affected pregnancies.

Growth/feeding. Most affected individuals (82%) are born small for gestational age (birth weight and/or length two or more standard deviations below population means), with about half having relative macrocephaly (head circumference 1.5 SD above the birth weight and/or length SD for that particular individual). About three quarters of affected individuals have short stature during childhood and as adults.

• Neonatal hypotonia is common (81%) and often leads to feeding difficulties due to a poor suck (67%), which may contribute to poor weight gain.
• Some individuals have poor appetite in infancy and others have gastroesophageal reflux disease.
• Despite these issues, many affected individuals develop an elevated body mass index (BMI) in early childhood. This is hypothesized to be due to atypical body composition, with significantly reduced lean body mass and elevated fat mass, rather than purely from hyperphagia or food-seeking behaviors, which are observed in a minority of affected individuals [Juriaans et al 2022, Ogawa et al 2025].

Endocrinology. Findings may include the following:

• Precocious puberty in approximately 86% of affected individuals, which on average starts at age seven years in both boys and girls, but in some cases is seen as early as age four years
  Note: Failure to identify and treat precocious puberty can compromise final adult height (see Management).
• Early-onset obesity in 20%, which can exacerbate the cardiometabolic syndrome
• Hypothyroidism in 5% of affected individuals
• Recurrent hypoglycemia in about 4% of affected individuals
• Growth hormone deficiency, although this is not a common feature in affected individuals

Affected individuals can experience a cardiometabolic syndrome, including hypertension, at an early age as a primary feature of this condition.

• Hypercholesterolemia has been observed as early as age six years.
• Type 2 diabetes mellitus has been observed as early as age nine years (13%).

Dental. Irregular or crowded teeth are observed in 52% of individuals with TS14.

Musculoskeletal features. About 75% of individuals with TS14 have small hands and feet and approximately 34% of individuals have clinodactyly. A little under half of affected individuals have hyperextensible joints and about one quarter develop scoliosis. Body asymmetry has been reported in about 16%.

Developmental delay (DD) and intellectual disability (ID). Most affected individuals experience developmental delay, but only a minority have true intellectual disability, ranging from mild to moderate.

• Motor delay is common and may be exacerbated by hypotonia. In one study, the average age of sitting was 10 months and the average age of walking was 19 months [Ogawa et al 2025].
• About 60% of affected individuals have speech delay.
• ID was noted in 21.6% of affected individuals in one study [Ogawa et al 2025], although other studies estimate that 24%-36% of affected individuals have ID.
• Affected individuals who have normal cognitive development can have learning disabilities.
  • Juriaans et al [2022] noted a disharmonic intelligence profile, with a higher verbal IQ than performance IQ, causing a negative impact on schooling.
  • Due to this finding and other neurobehavioral manifestations, a large number of affected individuals have special education needs [Geoffron et al 2018, Juriaans et al 2022, Ogawa et al 2025].
• Most affected adults are able to live independently and have a job.
  • Many attend college after high school.
  • In adults with TS14, it is estimated that social participation (which includes those with intelligence in the normal range and those who have mild ID but are able to have a job) is 98.2%.

Neurobehavioral/psychiatric manifestations. Neurodevelopmental disorders such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and pervasive developmental disorders are seen in about 20% of affected individuals [Juriaans et al 2022].

• In adolescence or adulthood, some affected individuals develop hikikomori (extreme avoidance of social contact) [Ogawa et al 2025].
• A high pain threshold had been noted by affected individuals or by their caregivers [Bertini et al 2017; G Kerkhof, G Gazdagh, JH Davies, & A Juriaans, unpublished data].

Hearing impairment. About 30% of affected individuals have recurrent ear infections, which can lead to conductive hearing loss (see Management).

Respiratory abnormalities. Obstructive sleep apnea is often seen in those who develop obesity. Primary sleep-disordered breathing unrelated to obesity may also occur.

Genitourinary abnormalities. About 30% of males with TS14 will have cryptorchidism and/or micropenis [Ioannides et al 2014, Ogawa et al 2025].

Facial features. Characteristic facial features are present in approximately 80% of affected individuals (see Suggestive Findings and Figure 1).

Rare findings. Two individuals with TS14 due to a paternally derived 14q32 deletion were reported to have thyroid dysfunction and were subsequently diagnosed with papillary thyroid carcinoma [Severi et al 2016]. At this time, there is not enough data to suggest that malignancy of this type is associated with TS14. It is unclear if this is a rare component of TS14 or a rare co-occurrence of two unrelated conditions.

Prognosis. The life expectancy in TS14 is expected to be similar to the general population, but data is limited on long-term outcomes. Since many adults with health problems and disabilities have not undergone advanced genetic testing, it is likely that some undiagnosed adults with TS14 are living in the community and having families [Kagami et al 2008, Ogawa et al 2025, Yang et al 2024].

Genotype-Phenotype Correlations

The phenotype and clinical history of TS14 is similar in affected individuals with different molecular etiologies [Ogawa et al 2025], with the exception of those who have features of TS14 due to maternal effect gene-related multilocus imprinting disturbances. Individuals with TS14 due to this molecular mechanism may have clinical features seen in other imprinting disorders such as Beckwith-Wiedemann syndrome or Silver-Russell syndrome depending on the loci involved.

Prevalence

TS14 appears to be rare, although the prevalence is unknown. Currently, about 190 affected individuals are described in the literature.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Temple syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for TS14. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Because individuals 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.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

A proband with Temple syndrome (TS14) typically represents a simplex case (i.e., a single affected family member) and has the disorder as the result of an epigenetic or de novo event resulting in hypomethylation of the MEG3:transcriptional start site (TSS)-differentially methylated region (DMR).

Genetic mechanisms underlying hypomethylation of MEG3:TSS-DMR include the following:

• Uniparental disomy of the maternal chromosome 14q32 region (upd(14)mat). Note: Some affected individuals have upd(14)mat from a Robertsonian 13;14 translocation.
• Hypomethylation of the normally methylated paternal MEG3/DLK1:intergenic (IG)-DMR and paternal MEG3:TSS-DMR leading to silencing of the paternally expressed genes
• Heterozygous deletion of the paternally inherited 14q32 region leading to absence of paternally expressed genes (including DLK1)

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 (MLID).

If the diagnosis of TS14 in the proband has been established by methylation analysis of the MEG3:TSS-DMR, deletion analysis (if not already performed in conjunction with methylation analysis) and parent-of-origin analysis are required to distinguish upd(14)mat, epimutation, and deletions involving the DMRs. Parent-of-origin analysis for chromosome 14 using polymorphic DNA markers (which requires a DNA sample from the proband and both parents) can distinguish upd(14)mat and biparental chromosome 14 (suggesting an epimutation) (see Establishing the Diagnosis and Figure 2).

TS14-MLID. A proband with TS14 caused by epimutation (loss of methylation) of MEG3/DLK1:IG-DMR may have TS14-MLID. TS14-MLID may be associated with biallelic inactivation of ZNF445 [Kagami et al 2021] or may involve pathogenic variants in maternal effect genes (MEGs) that are present in the mother. Findings in a family history suggestive of MEG-related MLID include infertility, multiple miscarriages, molar pregnancies, offspring with features of one or more imprinting disorders, and multiple different offspring with an imprinting disorder (see Maternal Effect Gene-Related Multilocus Imprinting Disturbances). TS14-MLID is not discussed further in this section.

Risk to Family Members

Parents of a proband

• A parent of a proband with TS14 may have a predisposing genetic alteration associated with the disorder such the following:
  • Maternal or paternal Robertsonian 13;14 translocation. A parent who is a carrier of a balanced Robertsonian 13;14 translocation would be expected to be unaffected; however, the presence of a maternal or paternal Robertsonian 13;14 translocation predisposes to the development of upd(14)mat via trisomy rescue or monosomy rescue, respectively.
  • Paternal deletion of 14q32. The father of the proband may have a 14q32 deletion. If the father has somatic and gonadal mosaicism for the deletion, he may have clinical manifestations related to the deletion, the nature of which would depend on the parental origin of the involved chromosome and the distribution of the deletion in somatic tissues. If the father has a constitutional deletion of paternal origin, he would be expected to have clinical features of TS14.
• Evaluation of the parents to clarify recurrence risk is recommended; specific testing recommendations depend on the genetic mechanism underlying hypomethylation of MEG3:TSS-DMR in the proband (see Sibs of a proband).

Sibs of a proband. The risk to sibs depends on the underlying genetic mechanism in the proband and the genetic status of the parents. If first-tier testing of the proband (DNA methylation of the 14q32 imprinted region and deletion analysis) indicates that the proband has:

• Hypomethylation of MEG3:TSS-DMR and no 14q32 deletion, then second-tier testing of the proband (parent-of-origin testing for chromosome 14) should be performed to distinguish upd(14)mat from an epimutation.
  • If upd(14)mat is identified, karyotype analysis of the proband is recommended to identify those probands who have a Robertsonian translocation or isochromosome 14q. If a Robertsonian translocation or isochromosome 14q is identified in the proband (or if the chromosomal status of the proband is unknown), parental karyotyping is recommended to determine if either parent of the proband is a carrier of a predisposing chromosomal translocation.
    • If both parents have normal karyotypes, it is presumed that upd(14)mat occurred in the proband as a de novo event and the recurrence risk to sibs is <1%.
    • If either of the parents has a Robertsonian translocation, the recurrence risk to sibs is increased. Note: While upd(14)mat mediated by parental Robertsonian translocation has been identified in multiple individuals with TS14, sib recurrence of upd(14)mat mediated by this mechanism has not been reported. Sibs of the proband are at increased risk of having an unbalanced form of the translocation.
  • If an epimutation is diagnosed (by exclusion of upd(14)mat), the recurrence risk to sibs depends on the presence or absence of MLID (see Maternal Effect Gene-Related Multilocus Imprinting Disturbances).
• Hypomethylation of MEG3:TSS-DMR and a deletion of the paternally inherited 14q32 region, targeted deletion analysis is recommended for the father of the proband.
  • If the deletion is identified in the father, the recurrence risk to sibs is 50% if the father has a constitutional deletion and up to 50% if the father has a mosaic deletion.
  • If the deletion identified in the proband is not identified in paternal leukocyte DNA, it is presumed that the deletion occurred as a de novo event and the recurrence risk to sibs is <1%. Note: Testing of paternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only. (Gonadal mosaicism for a deletion involving the 14q32.2 imprinted region has not been reported to date.)

Offspring of a proband. The risk to offspring of an individual with TS14 depends on the genetic status and sex of the proband:

• If the proband has a chromosome alteration predicted to result in uniparental disomy in offspring (e.g., a Robertsonian translocation or isochromosome 14q), offspring of the proband are at risk for upd(14)mat-mediated TS14 or upd(14)pat-mediated Kagami-Ogata syndrome, depending on the sex of the proband and the underlying mechanism for the development of uniparental disomy (i.e., trisomy rescue or monosomy rescue). Carriers of a balanced Robertsonian translocation are also at risk of having a child with an unbalanced form of the rearrangement.
• If the proband has a deletion involving the 14q32 imprinted region, offspring of the proband are at risk for TS14 or Kagami-Ogata syndrome depending on the sex of the proband. If the proband is male, offspring are predicted to have a 50% risk for TS14. If the proband is female, offspring are predicted to have a 50% risk for Kagami-Ogata syndrome [Yang et al 2024].

Other family members. The risk to other family members depends on the genetic status of the proband's parents:

• If the father of the proband is heterozygous for a deletion involving the 14q32 imprinted region, the father's sibs are at risk of having the deletion.
• If a chromosome alteration involving 14q32.2 (e.g., a Robertsonian translocation) is identified in a parent of the proband, the parent's sibs are at risk of having the chromosome alteration.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Genomic variants. 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 changes. 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 [Eggermann et al 2016]. Genetic counseling regarding the potential limitations of prenatal testing for epigenetic alterations should be undertaken [Eggermann et al 2016].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Temple syndrome is caused by genetic and epigenetic alterations involving the imprinted region on chromosome 14q32.2.

Structure and character of the 14q32.2 imprinted region. In an approximately 700-kb interval on 14q32, gene expression is limited by parent of origin: the protein-coding genes DLK1 and RTL1 are expressed from the paternally inherited allele, whereas the noncoding genes MEG3 (also known as GTL2), RTL1as, MEG8, and large clusters of small nucleolar RNA and microRNA [Cavaillé et al 2002] are expressed from the maternally inherited allele (see Figure 3).

Two differentially methylated regions (DMRs) act as imprinting control regions (ICs or ICRs) for parent-of-origin restriction of imprinted genes on 14q32. The intergenic (IG) DMR between MEG3 and DLK1 (MEG3/DLK1:IG-DMR) retains the gonadal DNA methylation acquired in sperm, and thus is paternally methylated; this DMR governs the methylation of the secondary DMR upstream of MEG3 (MEG3:transcriptional start site [TSS]-DMR) [Kagami et al 2010, Beygo et al 2015]. In unaffected individuals, both the MEG3/DLK1:IG-DMR and MEG3:TSS-DMR are methylated on the paternally inherited allele, whereas individuals with TS14 have reduced DNA methylation at both DMRs [Kagami et al 2010, Kagami et al 2015].

The region contains two further secondary DMRs with somatically acquired maternal methylation: one in intron 2 of MEG8 (MEG8:Int2-DMR), whose methylation mirrors that of the IG-DMR [Beygo et al 2017], and one overlapping the second exon of DLK1 (DLK1:Int1-DMR), but their functions are currently unknown [Hernandez Mora et al 2018].

Mechanisms of disease causation include the following (see Figure 3):

• Maternal uniparental disomy (UPD) for chromosome 14
• Hypomethylation of the MEG3/DLK1:IG-DMR and MEG3:TSS-DMR on the paternal chromosome, leading to a maternal chromosome-like expression pattern
  • This is diagnosed by exclusion of UPD in individuals with hypomethylation of the 14q32 DMRs with no evidence of copy number change.
  • Hypomethylation may also be mosaic, i.e., not affecting all cells in the tissue tested.
• Deletions in the paternally inherited chromosome, leading to absence of paternally expressed genes
  • The minimum overlap of cases published to date is DLK1 itself (reviewed in Baena et al [2024]), although deletion of exon 1 only is associated with central precocious puberty (CPP) rather than TS14.
  • Some published deletions do not involve these paternally methylated DMRs (MEG3/DLK1:IG-DMR and MEG3:TSS-DMR); in such cases, no distinctive DNA methylation disturbance would be detected.
  • Deletion of the methylated DMR of paternal origin does not affect phenotype, whereas loss of the unmethylated DMR of maternal origin leads to Kagami-Ogata syndrome (see Genetically Related Disorders) [Baena et al 2024].

Laboratory technical considerations. Many laboratories use methylation-specific multiplex ligation-mediated probe amplification (MS-MLPA), which enables simultaneous methylation analysis of MEG3:TSS-DMR and deletion analysis of the multiple loci at the 14q32.2 imprinted region.

• First-line DNA methylation testing of 14q32 normally assesses the MEG3:TSS-DMR instead of the MEG3/DLK1:IG-DMR, whose DNA methylation is technically difficult to assay. The DNA methylation of MEG3 is determined by that of the germline IG-DMR and can normally be taken as a proxy for that of the IG-DMR.
• Some methylation-specific PCR tests have limited sensitivity to detect low-level mosaicism of hypomethylation or UPD.
• High-density SNP array analysis of the affected individual can detect smaller deletions and uniparental isodisomy of 14q32.2 but cannot detect uniparental heterodisomy of 14q32.2 or DNA methylation changes of the 14q32 DMRs.
• If a deletion does not affect copy number probes in a commercial MS-MLPA kit used for first-line diagnosis, then diagnosis of TS14 will be missed by this method.

Author Notes

Drs Kagami (pj.og.dhccn@sm-imagak), Ogata (pj.ca.dem-amah@atagomot), Ogawa (pj.og.dhccn@t-ihcugamay), Davies (ku.shn.shu@seivad.nitsuj), Kerkhof (ln.cmsumsare@fohkrek.g), Gazdagh (ku.shn.shu@hgadzag.alleirbag), and Juriaans (ku.ca.notos@snaairuj.f.a) are actively involved in clinical research regarding individuals with Temple syndrome. They would be happy to communicate with persons who have any questions regarding diagnosis of Temple syndrome or other considerations.

Acknowledgments

TO and MK are supported by the Japan Agency for Medical Research and Development (AMED) JP25ek0109805.

AFJ and DJGM are supported by the Medical Research Council MR/X021173/1.

Revision History

• 2 April 2026 (ma) Review posted live
• 22 April 2025 (gg) Original submission

Literature Cited

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