Temple and Kagami-Ogata Syndromes (Chromosome 14q32 Imprinting Disorders)

Temple syndrome (TS14) and Kagami-Ogata syndrome (KOS14): mirror-image disorders of the DLK1–DIO3 domain at 14q32.2

Literature and regulatory information updated: 17 October 2026.

0. Initial Reference Table

1. Introduction

1.1 Founding descriptions

The history of the chromosome 14 imprinting disorders begins in 1991 with two almost simultaneous observations in carriers of Robertsonian translocations. Temple, Cockwell, Hassold, Pettay and Jacobs described in the Journal of Medical Genetics a boy who had inherited a balanced Robertsonian 13;14 translocation from his mother and in whom neither chromosome 14 was of paternal origin; the authors presented him as the first human case of maternal uniparental disomy (UPD, uniparental disomy) of chromosome 14 [25]. The boy had hydrocephalus, bifid uvula, precocious puberty, short stature and small testes; early motor milestones were delayed, but language was advanced and, at 17 years, his intellectual development made university entrance foreseeable [2, 25]. At the same time, Wang, Passage, Yen, Shapiro and Mohandas described a 9-year-old girl with intellectual disability and multiple congenital anomalies, carrying a balanced Robertsonian translocation rob(13q14q) also present in her father; her mother had a balanced t(1;14)(q32;q32) translocation, and study with the probes D14S13 and D14S22 showed that both chromosomes 14 were of paternal origin, in heterodisomy, with chromosomes 1 and 13 biparental [26]. Wang and colleagues proposed that UPD could explain abnormal phenotypes in carriers of apparently balanced familial translocations, an idea that became the basis of counselling for these carriers [6, 26].

In the following decade reports of upd(14)pat with a distinctive malformation complex accumulated. Kurosawa and colleagues attributed a recognisable pattern to it in 2002, and Kagami and colleagues described in 2005 three Japanese patients with complete or segmental paternal isodisomy (the latter distal to D14S981, at 14q23.3), hairy forehead, protruding philtrum, micrognathia, small thorax with coat-hanger ribs and abdominal wall defects; the thoracic deformity tended to lessen in older children, and the authors suggested that, once the respiratory failure of infancy was overcome, the condition improved with age [5]. In 2007, Temple and colleagues described the first isolated imprinting mutation of the DLK1/GTL2 locus with a clinical picture of upd(14)mat, which showed that the phenotype depended on the epigenetic state of the locus and not only on the origin of the chromosomes [2].

1.2 Molecular milestones

The decisive molecular milestone was the study by Kagami and colleagues published in Nature Genetics in 2008: in eight individuals with a upd(14)pat-like phenotype and three with a upd(14)mat-like phenotype, without UPD, they found deletions and epimutations of the 14q32.2 region, demonstrated that the IG-DMR (intergenic differentially methylated region) acts in cis on the maternal chromosome and associated excess RTL1 with the paternal phenotype and decreased DLK1 and RTL1 with the maternal phenotype [27]. This work established that the clinical pictures derive from the expression of the imprinted genes at 14q32.2 and not from the disomy itself, and paved the way for diagnosis by methylation analysis [4, 27]. There followed the definition of the hierarchy between the IG-DMR and the MEG3:TSS-DMR (Kagami 2010; Beygo 2015), the description of additional secondary DMRs (MEG8:Int2-DMR and DLK1:Int1-DMR) and, in 2021, the association between a homozygous truncating ZNF445 variant and TS14 with multilocus imprinting disturbance [1, 28].

1.3 Nomenclature and reclassifications

Buiting and colleagues suggested in 2008 the designation "Temple syndrome" because Temple had been the first to describe a patient with upd(14)mat and a patient with a DLK1/GTL2 epimutation [2]. Ioannides, Lokulo-Sodipe, Mackay, Davies and Temple analysed in 2014 51 published cases (40 with upd(14)mat, 5 with paternal deletions and 6 with loss of methylation of the IG-DMR) and consolidated the name and the clinical picture [2, 29]. Temple syndrome should not be confused with Temple-Baraitser syndrome, an autosomal dominant disorder due to de novo KCNH1 variants, with epilepsy, intellectual disability and aplasia or hypoplasia of the thumb and hallux nails, unrelated to 14q32 imprinting. For the paternal entity, the designation "upd(14)pat syndrome" became misleading when it was shown that epimutations and deletions produce the same picture; Kagami and colleagues proposed in 2015 the name "Kagami-Ogata syndrome", or "Wang-Kagami-Ogata" in honour of Wang's first description, and reserved "Temple syndrome" for the maternal mirror image [4, 7]. The European network of imprinting disorders adopted the designation "Kagami-Ogata syndrome" [5]. The 2017 Oxford Desk Reference still uses the forms "UPD14(pat). Wang Kagami syndrome" and "UPD14(mat). Temple syndrome" [3, 6]. The abbreviations TS14 and KOS14 are those of the two GeneReviews chapters [1, 4]. In Orphanet, the old entry ORPHA:263049 ("Uniparental disomy of chromosome 14") is obsolete, and each syndrome has three subtypes by mechanism [11, 13]. The OMIM number for Kagami-Ogata syndrome is #608149; table 2 of the 2024 interim statement on MLID gives "#608,140", a number that in OMIM corresponds to the NUP35 gene (2q32.1) and results from a typographical error [5, 14, 15].

The period 2024–2026 brought the first formal syntheses: the KOS14 GeneReviews (October 2024), the TS14 GeneReviews (April 2026), the British and Dutch cohort of 71 patients with a proposed clinical score (August 2026) and the 2nd international consensus on Silver-Russell syndrome (September 2026), which includes the MEG3:TSS-DMR in first-line testing and recommends following the Silver-Russell management pathway in TS14 until specific guidelines exist [1, 4, 16, 18].

1.4 Definition of the entities and scope

Temple syndrome is defined by absent expression of the paternally expressed genes at 14q32.2, mainly DLK1, as a consequence of upd(14)mat, loss of methylation of the paternal DMRs (epimutation) or a paternal deletion including DLK1; diagnosis rests on hypomethylation of the MEG3:TSS-DMR or on demonstration of a relevant paternal deletion [1]. Kagami-Ogata syndrome is defined by absent expression of the maternal RTL1as allele, with overexpression of RTL1, as a consequence of upd(14)pat, hypermethylation of the maternal DMRs, maternal deletions including the IG-DMR, the TSS-DMR or RTL1as, or rearrangements separating the maternal MEG3 promoter from RTL1as [4]. The two entities are treated together because they are mirror-image disorders of the same domain, because they share tests, mechanisms and counselling rules, and because the same deletion can cause one or the other in a family depending on the sex of the transmitting parent [1, 4, 7]. Central precocious puberty due to an isolated DLK1 defect (truncating variants or paternal deletions sparing the DMRs) is classified as a distinct entity and not as TS14, and mosaic trisomy 14 is a differential diagnosis and a potential confounder of testing; both are covered only in the differential diagnosis [1, 17, 30]. Silver-Russell syndrome, Beckwith-Wiedemann syndrome, Prader-Willi syndrome, Angelman syndrome and UPD(16)mat enter the differential.

2. Molecular Genetics and Pathophysiology

2.1 Genomic imprinting and uniparental disomy

Genomic imprinting is a germline epigenetic mark that makes the expression of certain genes depend on the parental origin of the allele; the best-studied mark is cytosine methylation in differentially methylated regions (DMRs), which function as imprinting control centres [3]. The Oxford Desk Reference counts about 30 recognised imprinting centres in the human genome [3]. An imprinting disorder arises when the functional dosage of imprinted genes is altered by four types of defect affecting the DMRs: uniparental disomy, epimutation (altered methylation without sequence change), copy number variant (CNV) or sequence variant in an imprinted gene [31]. Primary epimutations are generally reset in the next generation, whereas copy number and sequence alterations can be transmitted with an effect dependent on the sex of the transmitting parent [3].

UPD is the inheritance of both homologues of a chromosome pair from a single parent. Isodisomy refers to the two homologues being identical copies of a single parental chromosome and heterodisomy to their being the two distinct homologues of that parent [3]. The mechanisms of formation leave distinct signatures: trisomy rescue (TR, mitotic loss of the extra homologue of a trisomic zygote) and gamete complementation (GC, fusion of a disomic gamete with a nullisomic one) produce at least one heterodisomic segment; monosomy rescue (MR, duplication of the single homologue of a monosomic zygote) produces complete isodisomy; and post-fertilisation mitotic error (PE) produces complete or segmental isodisomy [12]. After trisomy rescue, in about a third of cases the two remaining chromosomes have the same parental origin [32]. Isodisomy may also unmask autosomal recessive disorders through homozygosity for a parental variant, which should be considered in each patient's phenotype [1, 2].

2.2 The DLK1–DIO3 imprinted domain at 14q32.2

The 14q32 domain spans about 700 kb. The coding genes DLK1 and RTL1 are expressed from the paternal allele; MEG3 (formerly GTL2), RTL1as, MEG8 and the large snoRNA and microRNA clusters are expressed from the maternal allele [1]. All the maternal non-coding genes form part of a large transcript initiated at the MEG3 promoter [4]. DIO3, in the same cluster, encodes type 3 iodothyronine deiodinase, which inactivates thyroxine (T4) and triiodothyronine (T3) and is highly expressed in the placenta and fetal tissues [33]; in the Japanese cohort of 60 patients there was no hyperthyroidism and there were no thyroid tumours, and the authors concluded that DIO3 is not imprinted, or only partially imprinted, in most tissues [17].

Two DMRs function as imprinting centres. The MEG3/DLK1:IG-DMR, intergenic, is a germline DMR that maintains the methylation acquired in the sperm, remaining methylated on the paternal allele, and governs methylation of the secondary DMR located upstream of MEG3, the MEG3:TSS-DMR, established after fertilisation [1]. In the body, both are methylated after paternal transmission and unmethylated after maternal transmission; in the placenta, the IG-DMR remains differentially methylated, whereas the MEG3:TSS-DMR is globally hypomethylated regardless of parental origin [4, 7]. The unmethylated maternal MEG3:TSS-DMR functions as the imprinting centre in the body and the unmethylated maternal IG-DMR functions as the imprinting centre in the placenta; in the body the regulation is hierarchical, because the MEG3:TSS-DMR remains unmethylated only if the IG-DMR is, but this hierarchy does not exist in the placenta [4, 7]. There are two additional secondary DMRs with maternal somatic methylation, the MEG8:Int2-DMR (whose methylation reflects that of the IG-DMR) and the DLK1:Int1-DMR (overlapping the second exon of DLK1), of unknown function [1].

The two published definitions of the IG-DMR differ because they delimit the region differently (the 2022 one refers to the segment interrogated, the 2024 one to the complete DMR); the coordinates are transcribed as published, without conversion [15, 36]. Methylation of the MEG3:TSS-DMR, subordinate to that of the IG-DMR, serves in routine practice as a reliable surrogate for detecting 14q32 alterations [1, 36].

2.3 Pathophysiology of Temple syndrome

In TS14, the three mechanisms converge on a maternal-type expression pattern: loss of DLK1 and RTL1 expression and biallelic expression of the maternal non-coding genes [1]. The KOS14 GeneReviews attributes TS14 primarily to absent DLK1 expression, to which absent RTL1 may add [4]. Two observations support the central role of DLK1: the minimal region of overlap of the paternal deletions published in patients with TS14 is DLK1 itself, and paternal deletions not involving the DMRs cause TS14 without detectable methylation disturbance [1]. Deletion of the methylated DMR of paternal origin does not alter the phenotype, whereas loss of the unmethylated DMR of maternal origin causes KOS14 [1].

The biology of DLK1 helps to explain the body composition of TS14. The DLK1 protein, also called preadipocyte factor 1, inhibits adipocyte differentiation [8]; its loss is associated with very low lean mass and high fat mass from early childhood, rapid weight gain from 4–6 years of age, and dyslipidaemia and diabetes that may arise without obesity or hyperphagia [1, 17]. The authors of the Japanese cohort propose loss of expression of DLK1, a negative regulator of adipogenesis, as the explanation for this dissociation between metabolic complications and body mass index [17]. Women with isolated DLK1 defects and central precocious puberty have more overweight, glucose intolerance, early-onset type 2 diabetes and hyperlipidaemia than women with idiopathic central precocious puberty, which strengthens the link between DLK1, reproduction and metabolism [34]. In the mouse, Dlk1 deficiency does not advance puberty (the animals reach it with low weight, leptin and kisspeptin) and deletion restricted to the central nervous system has no effect, which points to peripheral sources of DLK1 [37]; the discrepancy with humans is unresolved. Common DLK1 variants were associated with birth weight in Spanish boys (n = 949) with a polar overdominance pattern, and methylation of the IG-DMR and MEG3-DMR in cord blood was associated with small for gestational age (SGA) newborns in a Chinese case-control study of 330 newborns, with insulin mediating 11.7% of the association [38, 39]. These association studies do not establish clinical causality.

2.4 Pathophysiology of Kagami-Ogata syndrome

The primary pathogenic factor in KOS14 is increased expression of RTL1, of about 2.5 or 5 times control values, due to absence of the functional maternal RTL1as allele, whose microRNAs repress RTL1 in trans [4, 7]. The TS14 GeneReviews states, in its section on allelic disorders, that KOS14 results from "absent expression of RTL1"; this wording contradicts the pathogenesis section of the KOS14 GeneReviews, written by the authors who characterised the locus, and the 2015 study of 34 patients, which demonstrate RTL1 overexpression; the overexpression interpretation prevails [1, 4, 7]. In the placenta of patients with upd(14)pat, RTL1 expression is increased about 5-fold (two functional copies of RTL1 and none of RTL1as), which implies an increase of about 2.5-fold attributable solely to the absence of the RTL1as microRNAs [7].

[4, 7]

Kagami and colleagues concluded that the roughly 2.5-fold increase in RTL1 is sufficient for the body and placental phenotypes and that the differences in DLK1 dosage (1× or 2×) and RTL1 dosage (2.5× or 5×) have no recognisable clinical effect on follow-up [7]. Maternal deletion of the MEG3:TSS-DMR alone produces the typical body phenotype with an apparently normal placenta, whereas maternal deletion of the IG-DMR alone or of both DMRs produces the typical body and placental phenotypes, in keeping with the tissue hierarchy of the DMRs [7]. Two deletions of similar size, intragenic to MEG3 (hg19 chr14:101 291 322–101 297 145 and chr14:101 291 225–101 295 527), gave rise in one case to polyhydramnios and in the other to neither placentomegaly nor polyhydramnios, which excludes a positive role of MEG3 deficiency in the placental phenotype; the polyhydramnios of the first case was attributed to fetal factors, such as swallowing difficulty and hypotonia [12]. The smallest causal deletion described measures 203 bp, involves the MEG3 transcript and the MEG3:TSS-DMR and was identified by the US Undiagnosed Diseases Network after a diagnostic odyssey with several negative conventional tests; long-read sequencing detected the deletion, the phasing and biallelic hypermethylation of the MEG3:TSS-DMR in a single assay [40].

Overexpression of Rtl1 in adult mouse liver induces liver tumours and MEG3 behaves as a tumour suppressor in the mouse, which underpins the mechanistic hypothesis for hepatoblastoma risk [7]. In the murine model, paternal uniparental disomy of distal chromosome 12, homologous to human 14q, reproduces the axial skeletal phenotype (thin ribs and delayed ossification of the sternum, skull and feet) with little effect on the long bones [5]. A 2026 murine study showed that deletion of an intergenic regulatory element (IG-TRE) activates Dlk1 on both alleles and rescues the lethality of deletion of the intergenic CpG island, concluding that loss of expression of the domain is more deleterious than gain [41]; these are preclinical data without therapeutic translation.

2.5 Mechanisms of Temple syndrome and their frequencies

[1, 16, 17, 36]

In the Japanese cohort, 21 of the 31 UPDs resulted from trisomy rescue or gamete complementation (including three carriers of rob(13;14)(q10;q10)) and 10 from monosomy rescue or post-fertilisation mitotic error (including two segmental isodisomies and three 46,XX/46,XX,upd(14)mat mosaics) [17]. Median maternal age was higher in UPDs due to trisomy rescue or gamete complementation (36 years) than in the other causes (30 years; p = 0.0039), consistent with the greater frequency of disomic oocytes with reproductive age [1, 17]. Of the five deletions, one encompassed only DLK1 among the genes analysed, three DLK1 and RTL1 and one DLK1, RTL1 and DIO3 [17]. In the early series, epimutations and deletions appeared much less frequent than upd(14)mat, an ascertainment bias explained by the fact that the first patients were identified because they carried Robertsonian translocations and by the methodological limitations of the time [36].

2.6 Mechanisms of Kagami-Ogata syndrome

[4, 7, 12, 36]

In the series of 34 patients (33 Japanese and 1 Irish), the 23 UPDs were distributed among 13 complete isodisomies (monosomy rescue or post-zygotic error), 1 segmental isodisomy and 9 heterodisomies (trisomy rescue or gamete complementation); two patients had Robertsonian translocations involving chromosome 14 [7]. In the review of 53 patients, upd(14)pat accounted for about two thirds of cases; among non-Japanese patients, 9 of the 14 UPDs had an abnormal karyotype (3 paternally inherited rob(13;14) and 5 de novo isochromosomes 14q, with parental karyotypes always normal), whereas among Japanese patients UPDs with a normal karyotype due to monosomy rescue or post-zygotic error predominated [12]. The authors attributed the difference to methods (in Japan, methylation analysis regardless of karyotype; outside Japan, genotyping directed at patients with chromosomal abnormalities), which would also explain why epimutations had been described only in Japanese patients up to 2016; the predominance of monosomy rescue is related to advanced maternal age, which increases nullisomic oocytes through non-disjunction in meiosis I [4, 12]. A paternal Robertsonian translocation rob(13;14) predisposes to heterodisomic upd(14)pat through trisomy rescue, and a de novo isochromosome 14q produces complete isodisomy [12]. The only balanced rearrangement described that separates the MEG3 promoter from RTL1as is a 46,XX,t(2;14)(q11.2;q32.2)mat translocation that disrupts MEG3 [4]. The maternal epimutations of KOS14 always affect both DMRs (hypermethylation of the IG-DMR entails that of the TSS-DMR), are of unknown cause and are not accompanied by MLID [4].

2.7 Robertsonian translocations, isochromosomes and UPD 14

Robertsonian translocations involve acrocentric chromosomes 13, 14, 15, 21 and 22 and are present in about 1 in 1000 people; rob(13q14q) is the most common (about 1 in 1300) [6]. For the offspring of balanced carriers, the main risks are trisomy 21 or 13 and UPD of chromosomes 14 or 15, because complete trisomies 14 and 15 invariably miscarry and trisomy rescue may leave a UPD with a balanced karyotype [6]. Chromosomes 13, 21 and 22 have no apparent imprinted elements, so that UPD of these has an effect only by unmasking recessive disorders [6]. In an isochromosome 14q the risk of UPD is 100%, and at least half of Robertsonian translocations between homologues show UPD; a homologous translocation formed by zygotic fusion of a maternal homologue with a paternal one does not pose this problem [6]. Quantitative data by translocation type are given in section 8.

2.8 Multilocus imprinting disturbance and trans factors

MLID is a methylation disturbance at several imprinted loci on different chromosomes; the 2024 European interim statement defines it as a molecular designation and clarifies that disturbance of several DMRs in the same cluster (for example, the several DMRs at 14q32) or secondary to UPD or CNV does not constitute MLID [15]. In TS14, MLID occurs only in the subgroup with epimutation: 6 of the 29 British patients with loss of methylation (21%), 2 of whom had identified maternal-effect variants, and none of the Dutch patients or of those conceived by assisted reproductive technology (ART); 2 of the 22 Japanese patients with epimutation, one of them with a homozygous pathogenic ZNF445 variant [16, 17]. The homozygous truncating ZNF445 variant has been described in a single patient with TS14 and MLID, and its contribution remains to be established; OMIM treats the association as pending confirmation [2, 15, 28]. MLID in TS14 may also be associated with pathogenic variants in maternal-effect genes in the mother [1]. MLID has not been described in KOS14 [4, 15]. The 2024 statement notes that a diagnosis of MLID may have prognostic value and gives as an example precocious puberty in a child with a 14q32 imprinting defect [15].

2.9 Nomenclature of variants and rearrangements

Both syndromes result mainly from epigenetic, chromosomal and copy number alterations, so molecular description uses DMR nomenclature (the 2018 consensus cited in the 2026 consensus) and the International System for Human Cytogenomic Nomenclature (ISCN) for karyotypes and rearrangements, for example rob(13;14)(q10;q10), 46,XX/46,XX,upd(14)mat and 46,XX,t(2;14)(q11.2;q32.2)mat [4, 17, 18]. Deletions should be described by genomic coordinates with the reference genome version: the two 2016 intragenic MEG3 deletions are published in hg19 and the DMRs in GRCh38 [12, 15]. The DLK1 sequence variants associated with central precocious puberty (p.Gly199Alafs*11, p.Val271Cysfs*14 and p.Pro160Leufs*50, in five women from three Brazilian families) were published only in protein notation; they were not in ClinVar in October 2026 (ClinVar uses NM_003836.7 as the DLK1 transcript) and, without the original c. notation, could not be normalised in VariantValidator, so they are cited as published [34]. The familial deletion of about 14 kb associated with a 269 bp duplication, which removes the 5' untranslated region and exon 1 of DLK1 in a family with five affected women, is also cited by its original description [8].

2.10 Genotype-phenotype correlations, penetrance and allelic disorders

In TS14 no significant phenotypic differences have been demonstrated between upd(14)mat, epimutation and deletion, nor between UPDs due to trisomy or monosomy rescue, in the Japanese and European cohorts; deletions are too few for formal comparison [16, 17]. The exception is TS14 with MLID, which may present features of Beckwith-Wiedemann or Silver-Russell syndrome depending on the loci affected [1]. The 2026 consensus data nevertheless suggest gradients by subtype, such as the greater frequency of body asymmetry in loss of methylation (27.9%) than in upd(14)mat (7.5%) and deletion (10.5%) [18], and in the European cohort asymmetry was concentrated in patients with mosaic loss of methylation [16].

In KOS14 there are no clear correlations between mechanism and phenotype, and it is unknown whether the 2.5-fold increase in RTL1 associated with deletions that include RTL1as translates into a milder picture, given the small number of cases [4, 7]. Penetrance is described as complete, with full cheeks, protruding philtrum and bell-shaped thorax with coat-hanger ribs in all patients, although with possible ascertainment bias; two patients with mosaic upd(14)pat had, respectively, a mild picture and a typical picture, and near-normal low-level mosaics may go unnoticed [4]. Durations of tube feeding were longer in deletions and hairy forehead was significantly less frequent in epimutations, possibly because of mosaicism [7].

The allelic disorders of the locus include central precocious puberty due to an isolated DLK1 defect (truncating variants or paternal deletions, including deletion of exon 1 alone), which may be accompanied by growth restriction and increased fat mass but is designated central precocious puberty and not TS14 [1, 8, 17]. The KOS14 GeneReviews also mentions paternal DLK1 sequence variants as a cause of TS14; the TS14 GeneReviews, more recent and dedicated, classifies them as central precocious puberty, and this classification, more recent and consistent with the Japanese data, prevails [1, 4, 17]. Hypomethylation of the MEG8:Int2-DMR has been described in 10 of 17 patients with Silver-Russell due to pathogenic PLAG1 variants, which links the 14q32 cluster to the PLAG1 pathway [42].

3. Clinical Spectrum and Manifestations by System

3.1 Temple syndrome: data sources and limitations

The natural history of TS14 rests on literature reviews and on retrospective cohorts from reference centres. The review by Ioannides and colleagues gathered 51 cases published up to 2014 [29]; the Japanese cohort of Kagami and colleagues (2017) studied 32 patients, later integrated into the Japanese cohort of 60 patients of Ogawa and colleagues (2025), identified among 1139 patients referred for (epi)genetic diagnosis of imprinting disorders [17, 43]; the cohort of Juriaans and colleagues (2026) brought together 45 patients from Southampton (British national imprinting disorders service, a centre with Silver-Russell experience) and 26 from Rotterdam (reference centre for Prader-Willi and similar conditions), a total of 71 [16]; and the 2026 GeneReviews synthesises 196 individuals of varied ages described in reports with different foci [1]. Presentation frequencies reflect the specialisation of each centre (Prader-Willi in the Netherlands, Silver-Russell in the United Kingdom), and in Japan insurance coverage of genetic diagnosis and growth hormone for Prader-Willi, but not for Silver-Russell or TS14, introduces a referral bias favouring Prader-Willi-like pictures [16, 17]. Most patients described are children; adult data are scarce and most patients received growth hormone or GnRH agonists, so the figures mix natural history and treated course. Anthropometric values are expressed in standard deviations (SD) of the population reference; body mass index (BMI), intelligence quotient (IQ), autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are used in the tables with the usual abbreviations.

[1, 16, 17, 29]

GeneReviews itself gives different values between the summary table and the text: truncal obesity in 45% in the table and early-onset obesity in 20% in the text, short stature in 87% in the table and in about three quarters in the text, language delay in 64% and in about 60% [1]. The difference results from aggregation of series with different definitions and ages; the 20% obesity figure coincides with the Japanese cohort, which uses a strict definition, and the 45–47% figure corresponds to "overweight or obesity" at any point in the history [16, 17].

3.2 Prenatal and neonatal period

Fetal growth restriction is typically detected in the 2nd trimester and is accompanied by oligohydramnios, a hypoplastic placenta and reduced fetal movements; about 20% are born preterm [1]. In the Japanese cohort, median gestational age was 38 weeks (34–43), 15.0% were born before 37 weeks and median placental weight was −1.4 SD (n = 19) [17]. In the European cohort, median gestational age was 38.43 weeks, 23% were born preterm (33% in the United Kingdom versus 4% in the Netherlands; p = 0.004), 18% had reduced fetal movements and 37% were born by caesarean section [16]. Median birth weight was −2.21 SD, length −1.53 SD (rarely measured) and head circumference −0.71 SD; 68% were born SGA, but in about 30% there was neither SGA nor postnatal growth failure [16]. In Japan, median values at birth were −2.9 SD for weight, −1.9 SD for length and −1.2 SD for head circumference [17].

Relative macrocephaly at birth (head circumference at least 1.5 SD above the SD of weight or length) is present in about half of patients according to GeneReviews, in 63.6% in the Japanese cohort and in 30% in the first weeks in the European cohort, where it decreased with age [1, 16, 17]. Neonatal hypotonia (81%) causes poor suck and feeding difficulties (67%); some infants have poor appetite and others gastro-oesophageal reflux disease (GORD) [1]. In the European cohort, 87% had neonatal feeding difficulties and 57% required a nasogastric tube, for a median of 4 weeks (2–8) [16]. Hypoglycaemia, frequently associated with intercurrent illness, occurred in 28% of the European cohort; GeneReviews reports recurrent hypoglycaemia in about 4% [1, 16].

3.3 Growth and body composition

The growth pattern of TS14 combines early short stature, partial catch-up in childhood and reduced adult height [16]. In the European cohort, short stature (< −2 SD) affected 73% at 1–3 years, 58% at 3–5 years, 34% at 5–8 years and 15% at 11–13 years; after 14 years, median height was −1.86 SD, with −1.54 SD in the Netherlands (none of the 9 below −2 SD) and −2.52 SD in the United Kingdom (8 of 11 below −2 SD), a difference attributed to more frequent use of growth hormone in the Netherlands [16]. In the Japanese cohort, 87.0% had short stature at 24 months (median −3.5 SD) and near-final height (n = 20) was −2.3 SD (−5.5 to −0.7) [17]. In the 12 Japanese adults, median height was −2.1 SD [17].

The weight trajectory has two phases. In the first years, the BMI of most lies between 0 and −2.5 SD, but the BMI that is high for the apparent thinness reflects an atypical body composition, with very low lean mass and high fat mass, and not hyperphagia [1, 16]. The transition to rapid weight gain, truncal obesity and high fat mass typically occurs at 4–6 years (at 3–4 years in the European cohort), and after 5 years most have a BMI between 0 and +2 SD [1, 16]. Excessive appetite was reported in 44%, food seeking in 22% and hyperphagia (eating at night, stealing food, distress when food is refused, constant preoccupation with food) in 20%, with 35% in the Netherlands versus 9% in the United Kingdom (p = 0.017) [16]. In Japan, patients were described as "thin obese" in childhood, with truncal obesity from late childhood; obesity affected 20% (median age 9.2 years) and hyperphagia only 4 patients [17]. Growth hormone deficiency (GHD) is not common according to GeneReviews, but was diagnosed in 27% of those tested in the European cohort (two stimulation tests with peak < 6.7 µg/L), a percentage whose interpretation is discussed in section 7 [1, 16]. Before any treatment, all European patients had insulin-like growth factor 1 (IGF-1) above −2 SD, and 18% (7/38) had IGF-1 above +2 SD [16].

3.4 Puberty and the gonadal axis

Gonadotrophin-dependent central precocious puberty is one of the most constant and highest-impact features: 86% in GeneReviews, with mean onset at 7 years in both sexes and sometimes at 4 years [1]. In the European cohort (thelarche before 8 years in girls and testicular volume of at least 4 mL before 9 years in boys), the frequency was 62%, twice as high in girls (81%) as in boys (39%); all girls with loss of methylation had precocious puberty; median age at onset was 8 years and the minimum ages were 5.0 years (girls, United Kingdom) and 6.5 years (boys, Netherlands) [16]. In the Japanese cohort, 37 of the 43 patients who entered puberty had central precocious puberty (86.0%), diagnosed at a median age of 7.3 years in girls and 8.8 years in boys, with bone age advanced by 1.9 and 1.1 years, respectively [17]. In five Japanese girls treated only after menarche, thelarche occurred at 7.5 years (Japanese reference 9.6–10.0) and menarche at 8.5 years (reference 12.3 ± 1.25), only one year after thelarche [17]. The 2014 review recorded mean menarche at 10 years and 2 months [29]. Bone age at presentation in the European cohort was delayed in 12.5%, normal in 59% and advanced in 28%, with differences between bone age and chronological age of −2.1 to +5.6 years [16]. Without treatment, precocious puberty compromises final height through advanced skeletal maturation [1, 18].

About 30% of boys have cryptorchidism and/or micropenis (31.0% in the Japanese cohort; cryptorchidism in 29% in the European cohort) [1, 16, 17]. In Japan, none of the 24 patients aged at least 13 years had hypothalamic hypogonadism, unlike what is typical of Prader-Willi syndrome [17]. Clinical and biochemical hyperandrogenism had been described in two patients up to 2024 [44].

3.5 Metabolism and cardiometabolic risk

GeneReviews considers early cardiometabolic syndrome a primary feature of TS14, with hypertension, hypercholesterolaemia from 6 years and type 2 diabetes from 9 years (13%) [1]. In the Japanese cohort, hypercholesterolaemia affected 26.5% of patients aged at least 6 years (13/49; median age 17.5 years, range 6–47) and diabetes 12.8% of patients aged at least 9 years (5/39; median age 23 years, range 9–30); of the 10 patients with hypercholesterolaemia and known BMI, only 2 were obese at diagnosis, and 3 of the 5 diabetic patients were obese [17]. In the 12 Japanese adults, hypercholesterolaemia reached 63.6% and diabetes 41.7%, with a median BMI of 22.8 kg/m² [17]. In the European cohort, dyslipidaemia affected 38% (15/39) between 5.4 and 25.7 years (hypertriglyceridaemia in 10, hypercholesterolaemia in 3, raised low-density lipoprotein (LDL) cholesterol in 4), with a median age at first abnormality of 8.69 years; triglycerides often normalised on subsequent measurements, probably after dietary intervention [16]. Dyslipidaemia was more frequent in loss of methylation (56%) than in upd(14)mat (24%), without stated statistical significance [16].

3.6 Thyroid

Hypothyroidism affects about 5% (3 of 59 Japanese patients, one identified on newborn screening and two during growth hormone treatment, all mild and treated with levothyroxine) [1, 17]. Two patients with TS14 due to a paternal 14q32 deletion developed thyroid dysfunction and papillary thyroid carcinoma; the data are insufficient to establish an association, and the co-occurrence may be coincidental [1, 45]. None of the 60 Japanese patients had a thyroid tumour [17].

3.7 Neurodevelopment, cognition and behaviour

Motor delay is common, with sitting at a mean of 10 months and walking at 19 months in the Japanese cohort (head control at 6 months) [1, 17]. Language delay affects about 60–70% [1, 16]. Intellectual disability, generally mild to moderate, was recorded in 21.6% of the Japanese cohort and in 24–36% in other series, and the 2026 consensus reports cognitive deficits in 25–40% [1, 17, 18]. There are learning difficulties even with normal cognition, and the intellectual profile is uneven, with verbal IQ higher than performance IQ [1]. Many patients need special education (42% in the European cohort; 42.9% in a special class up to secondary school in Japan) [16, 17].

Autism spectrum disorders, ADHD and pervasive developmental disorders affect about 20% according to GeneReviews; in the European cohort, 38% had ASD symptoms (42% in the Netherlands, 34% in the United Kingdom) and 14% anxiety [1, 16]. Among 18 Japanese patients assessed for both dimensions, 1 (5.6%) had intellectual disability and a neurodevelopmental disorder, 10 (55.6%) intellectual disability only and 7 (38.9%) a neurodevelopmental disorder only [17]. In adolescence and adulthood, social isolation, school refusal and hikikomori, extreme avoidance of social contact, have been described [1, 17]. A high pain threshold emerged as a new feature in the European cohort (43%; 60% in the United Kingdom versus 23% in the Netherlands) and has implications for the detection of injuries and acute illness [1, 16].

3.8 Face, teeth, skeleton and other systems

The facial features, present in about 80%, differ from those of Silver-Russell and become less recognisable with age: high forehead, prominent supraorbital ridges, low nasal bridge, short upturned nose with a bulbous tip, short philtrum, downturned corners of the mouth, high-arched palate, micrognathia and low-set ears [1]. Orphanet adds dolichospondyly, slender long bones and craniofacial disproportion to the definition [11]. The hands and feet are small but structurally normal, which distinguishes them from brachydactyly, as in Prader-Willi syndrome and Smith-Magenis syndrome [1, 46]. Clinodactyly affects about 34–45%, joint hyperextensibility a little under half, scoliosis about a quarter and asymmetry about 16% [1, 16]. Irregular or crowded teeth are frequent, and in the European cohort a high, narrow palate was recorded in 16%, micrognathia in 14%, cleft palate in 3% and a single palmar crease in 19% [1, 16].

Recurrent otitis media (about 30–39%) may cause conductive hearing loss; hearing impairment affected 18% of the European cohort [1, 16]. Obstructive sleep apnoea syndrome (OSAS) is frequent in obese patients and there is also a primary sleep-disordered breathing unrelated to obesity; in the European cohort, 10% had sleep apnoea, potentially aggravated by micrognathia [1, 16]. Gastro-oesophageal reflux affected 13% and constipation 16% [16]. A cardiac anomaly (ventricular septal defect) was described in one Japanese patient, red-green colour vision deficiency in one boy and congenital deafness in another, frequencies compatible with those of the Japanese population [17].

3.9 Frequency of signs by molecular subtype

The Netchine-Harbison clinical scoring system (NH-CSS, Netchine-Harbison clinical scoring system), created for Silver-Russell, scores six criteria: SGA, postnatal growth failure, relative macrocephaly at birth, prominent forehead, body asymmetry and feeding difficulties or low BMI [18].

[18]

For comparison, the NH-CSS reaches 4 or more in 95.7% of patients with 11p15 loss of methylation and in 92.8% of patients with upd(7)mat [18]. In the European cohort, the NH-CSS was 3 or more in 56.5% of patients with TS14 and 4 or more in 34.8%, with SGA in 80.6% of UPDs versus 53.6% of losses of methylation and asymmetry in 2.8% versus 17.9% [16]. In the Japanese cohort, 57.9% had an NH-CSS of 4 or more [17]. In childhood, 47.4% of the Japanese patients had both a Silver-Russell-like and a Prader-Willi-like phenotype, 10.5% only a Silver-Russell-like phenotype, 29.8% only a Prader-Willi-like phenotype and 12.3% only SGA with short stature [17].

3.10 Course by life stage and adulthood

The typical sequence of TS14 is fetal growth restriction, hypotonia and feeding difficulties in the first year (which improve in the first 12 months and are less severe than in Silver-Russell or Prader-Willi), motor and language delay in early childhood, rapid weight gain and increased appetite from 3–6 years, precocious puberty at about 7–8 years and, in adolescence and adulthood, short stature, metabolic risk and, in some patients, neurobehavioural difficulties and social isolation [1, 16, 17]. Most adults live independently and work, and many attend higher education [1]. In the Japanese cohort, 11 of 12 patients (91.7%) who had completed secondary school were employed or in higher education; the text of the article gives the value as 98.2%, a numerical discrepancy in the source itself that GeneReviews reproduces as an estimate of social participation [1, 17]. It is likely that there are undiagnosed adults with offspring, as shown by the families in which a woman with TS14 due to a deletion transmitted the deletion to children with KOS14 [1, 27, 47].

3.11 Kagami-Ogata syndrome: data sources

The clinical description of KOS14 rests mainly on the series of 34 molecularly diagnosed patients of Kagami and colleagues (2015; 33 Japanese and 1 Irish, 13 male and 21 female), collected by questionnaire with standardised radiographic measurement of the thorax, and on the 2016 review by the same authors, which adds 18 non-Japanese patients from the literature [7, 12]. The series and review by Sakaria and colleagues (2021) showed similar data [4]. The authors found that the findings were comparable to those of 17 non-Japanese patients and that the phenotype is similar whatever the cause and ethnicity [7, 12]. The median age at last examination or death was only 2.8 years (0.0–15.0), so data on adulthood are limited to isolated reports [7].

[7]

3.12 Pregnancy and the perinatal period

Polyhydramnios is almost constant (more than 95%) and appears in the 2nd trimester, at a median of 25.5 weeks (14–30); it is attributed to placentomegaly (placenta more than 120% of normal weight in about 85%) and to deficient fetal swallowing [4, 12]. Amnioreduction is needed in most pregnancies after 25 weeks (about 80%) and in almost all after 30 weeks, usually repeated [4, 7]. Thoracic and abdominal anomalies are visible on prenatal ultrasound in about 40% of fetuses from 25 weeks, and the typical face, the bell-shaped thorax with coat-hanger ribs and omphalocele can be recognised on fetal ultrasound and magnetic resonance imaging from the 2nd trimester [4, 7]. Preterm delivery occurs in about 80%: GeneReviews gives a median of 32.5 weeks (30–35) and the 2015 series a median of 34 weeks (24–38), with two thirds of deliveries by caesarean section for fetal distress or polyhydramnios [4, 7]. Maternal serum alpha-fetoprotein may be raised from the 2nd trimester when omphalocele is present [4].

3.13 Growth

Prenatal growth is preserved or increased: none of the 34 patients had fetal growth restriction, 20 had overgrowth and birth weight ranged from −0.1 to +8.8 SD, disproportionately greater than length (−1.7 to +3.0 SD) and without generalised oedema, which led to the proposal of fetal muscle hypertrophy [4, 7]. Orphanet includes fetal macrosomia in the definition [13]. Postnatal growth is frequently compromised by the poor nutrition associated with respiratory failure and feeding difficulty: about 35% have height or weight below −2 SD, and between 1 and 15 years weight ranged from −6.0 to +4.0 SD and height from −8.7 to +1.1 SD [4, 7].

3.14 Face

The typical face is recognisable from birth and throughout childhood: full cheeks (more than 90%), protruding and deep philtrum (more than 95%), depressed nasal bridge (more than 90%), anteverted nares (80%), micrognathia (about 100%), short, webbed neck (more than 90%), frontal bossing (about 75%), hairy forehead (about 70%), blepharophimosis (70–75%) and puckered, narrow, tented lips (more than 50%) [4]. Full cheeks and protruding philtrum are the most common and specific facial signs and remain recognisable from infancy to school age and probably into adulthood [7, 12]. Hairy forehead was significantly less frequent in epimutations (1 in 5) [7].

3.15 Thorax, respiratory system and skeleton

The small bell-shaped thorax with coat-hanger ribs is present in all patients and, with the face, forms the pathognomonic core of the syndrome [4, 7]. Coat-hanger ribs are quantified by the coat-hanger angle (CHA, coat-hanger angle), the mean of the right and left angles between the horizontal axis at the 6th costovertebral junction and the highest point of the 6th posterior rib, and the bell-shaped thorax by the ratio between the middle and maximum thoracic diameters (M/W ratio) [4]. The CHA is increased from 30 weeks of gestation until at least 5 years of age and remains above normal in patients followed for more than 10 years, whereas the M/W ratio is decreased in early infancy and normalises later [4, 7]. The radiographic CHA of children with KOS14 was 35.1 ± 5.2°, versus −3.3 ± 13.0° in children with other skeletal dysplasias [48]. Radiographs show caudal bowing of the anterior ribs, cranial bowing of the posterior ribs and flaring of the iliac wings, without shortening or dysplasia of the long bones, in a predominantly axial involvement [5, 49].

Neonatal respiratory failure is almost universal: more than 90% require mechanical ventilation with oxygen, for a median of 1 month (0.1–17 months), unrelated to the genetic cause or to gestational age; about a third undergo tracheostomy, sometimes for severe laryngomalacia (about 40%) [4, 7]. Respiratory infections are the main cause of death in infancy [7]. Joint contractures (60–65%), kyphoscoliosis (about 40%) and coxa valga (about a third) are of variable severity [4].

3.16 Feeding and the abdominal wall

Feeding difficulty with impaired swallowing affects more than 95% and all patients who survived more than one week required tube feeding, for a median of 7.5 months (0.1–89), longer in patients with a deletion (median 51 months) [4, 7]. Diastasis recti (65–70%) and omphalocele (about 30%) reflect weakness of the abdominal wall, which contributes to constipation [4]. Inguinal hernias affected about a quarter [7].

3.17 Development and cognition

All patients assessed had developmental delay and intellectual disability, with a median developmental quotient or IQ of 55 (29–70) in 26 patients assessed between 10 months and 15 years [4, 7]. Median motor milestones were head control at 7 months (3–36), sitting without support at 12 months (8–27) and independent walking at 25.5 months (20–90) [4, 7]. Only two patients had mild delay, one with an epimutation and the other with mosaic upd(14)pat [4]. Brain magnetic resonance imaging was normal in five patients studied, and a simple seizure was described in one patient [4]. Despite the delay, the authors of the Japanese series state that all patients who overcame the critical phase attend school [12]. OMIM describes, based on another review, a spectrum ranging from normal to mildly impaired intellectual development, which contrasts with the constant intellectual disability of the Japanese series and may reflect growing recognition of mild forms and mosaics [5, 36].

3.18 Heart, hepatoblastoma and other manifestations

Cardiovascular malformations affect about 25%; of the eight confirmed cases, two had an atrial septal defect, one a ventricular septal defect, four a patent ductus arteriosus and one pulmonary stenosis, all mild, without the need for intensive medication or surgery, and without cardiomyopathy or conduction defects [4]. Hepatoblastoma occurred in 3 of the 34 patients in the 2015 series (8.8%), all with upd(14)pat, at 46 days, 218 days and 13 months; histology showed in one case poorly differentiated embryonal hepatoblastoma with macrotrabecular foci and in another a well-differentiated tumour [7]. The GeneReviews figure of 5–10% derives from this series, whereas the total of three cases among about 100 patients described corresponds to the literature as a whole; both figures are subject to selection bias [4, 7]. Orphanet includes the increased risk of hepatoblastoma in the definition of the syndrome [13].

3.19 Mortality and adulthood

Mortality is high before 5 years of age (20–25% according to GeneReviews; 8 of 34 patients, all before 4 years, in the 2015 series; about 30% in the 2016 review) and does not increase after that age [4, 7, 12]. The causes were neonatal respiratory distress syndrome, respiratory infections (one during influenza), hepatoblastoma and haemophagocytic syndrome [7]. Kaplan-Meier estimated survival was 78% in upd(14)pat, 100% in epimutation and 50% in deletion, and 25% with delivery at or before 29 weeks, 83% between 30 and 36 weeks and 86% at 37 weeks or later; the mortality of deletions was attributed mainly to prematurity and the absence of deaths in epimutations possibly to mosaicism [7]. In 2024 nine adults aged 18 years or over had been identified (four unpublished), the oldest aged 35 years [4]. This man, described as the first adult with KOS14 due to upd(14)pat, and the review of the other adults show variability of the neurocognitive phenotype, connective tissue abnormalities and uncertainty about long-term cancer risk [50]. No person with KOS14 has had known offspring, although reproductive function is expected to be preserved [4].

4. Clinical Recognition and Warning Signs

4.1 Temple syndrome: when to suspect

There are no consensus clinical criteria for TS14, and its recognition is difficult because many signs are non-specific, the phenotype changes with age and overlaps with those of Silver-Russell, Prader-Willi and non-syndromic SGA children [1, 2, 16]. The European cohort describes TS14 as an under-recognised multisystem growth disorder and shows context-dependent presentations: 27% had feeding difficulties and hypotonia without an NH-CSS of 4 or more ("Prader-Willi-like" presentation; 42% in the Netherlands and 11% in the United Kingdom), 12% had an NH-CSS of 4 or more without hypotonia ("Silver-Russell-like" presentation) and 12% had only SGA and unexplained short stature [16].

The 2026 consensus recommends routine testing of 14q32 methylation in all patients with an NH-CSS of 4 or more, considering it in patients with Prader-Willi features and normal 15q11.2 methylation and, with an NH-CSS of 3, testing when suspicion is strong, especially when the score is incomplete (child under 2 years, adolescent or adult) or there are features suggestive of TS14 [18]. Neonatal hypotonia, small hands and feet, rapid weight gain in childhood and precocious puberty are the clues that, in a child with suspected Silver-Russell, point to TS14 [18]. In the face of negative tests for Silver-Russell, Smith's Recognizable Patterns advises considering 14q32 alterations, upd(20)mat, upd(16)mat, CDKN1C and IGF2 variants and MLID [51]. The authors of the European cohort advocate routine molecular investigation for TS14 in neonatal hypotonia and suspected Prader-Willi, and note that the NH-CSS, with a negative predictive value of 89% for the classic causes of Silver-Russell, identifies TS14 poorly [16]. The Japanese proposal is to study TS14 in SGA children with short stature (and placental hypoplasia) who have a Silver-Russell-like and/or Prader-Willi-like phenotype in childhood and central precocious puberty, and in families with KOS14 due to a deletion [17].

4.2 Proposed clinical score for Temple syndrome

[16]

Juriaans and colleagues propose that a score of 2 or more justifies molecular testing for TS14; 66 of the 71 patients (93%) reached this threshold, and the five below it were all from the United Kingdom (one UPD and four losses of methylation, two with MLID) [16]. The distribution of scores was 1 point in 1 patient, 1.5 in 4, 2 in 4, 2.5 in 5, 3 in 7, 3.5 in 13, 4 in 11, 4.5 in 8, 5 in 10 and 5.5 in 6 [16]. The score was constructed and evaluated in the same cohort of confirmed patients, without a control group, so its specificity is unknown and there is no published external validation; it serves as a guidance tool and not as a diagnostic criterion.

4.3 Kagami-Ogata syndrome: when to suspect

KOS14, by contrast, is clinically recognisable. The face (full cheeks and protruding philtrum) and increased CHA are considered mandatory for the clinical diagnosis and a decreased M/W ratio is a diagnostic indicator in infancy; the combination of several characteristic features with the pathognomonic ones confirms the suspicion [4, 12]. The characteristic but non-specific features (abdominal wall defects, placentomegaly and polyhydramnios) are shared with Beckwith-Wiedemann syndrome and with androgenetic mosaicism [12].

A supernumerary marker chromosome may be a clue: an infant with paternal uniparental isodisomy 14 had mosaicism for a chromosome 14-derived marker in 88% of cells [5]. Uniparental isodisomy 14 was found in 1 of 81 spontaneous miscarriages with a normal karyotype, which shows that some affected pregnancies end early [5].

4.4 Emergency signs

In KOS14, the emergency signs are respiratory failure at birth (which requires a neonatal resuscitation team at delivery), respiratory infections in infancy (the main cause of death), signs of aspiration (choking, recurrent respiratory infections, unexplained food refusal) and, in infancy, an abdominal mass or raised alpha-fetoprotein suggestive of hepatoblastoma [4, 7]. In TS14, the emergency signs are hypoglycaemia (especially with fasting or intercurrent illness), whose detection may be delayed by the high pain threshold, and symptoms of obstructive sleep apnoea, particularly before or after starting growth hormone [1, 16, 18].

4.5 Newborn screening

There is no newborn screening for either syndrome. Newborn screening for congenital hypothyroidism identified one of the three Japanese patients with TS14 and hypothyroidism [17].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

Neither syndrome has published consensus clinical criteria, and the diagnosis is molecular [1, 4]. TS14 is established by hypomethylation of the MEG3:TSS-DMR or, more rarely, by demonstration of a paternal 14q32 deletion that includes DLK1; the 2026 consensus establishes that loss of methylation of the MEG3:TSS-DMR confirms TS14 and requires the subtype (UPD, CNV or epimutation) to be defined in order to estimate recurrence, cascade-test relatives and stratify management (recommendation 4.5, grade A+++) [1, 18]. KOS14 is established by hypermethylation of any of the DMRs of maternal origin or by maternal deletion of RTL1as; all known patients have hypermethylation of the IG-DMR and/or the MEG3:TSS-DMR, except the rare cases with an RTL1as deletion sparing the DMRs or with a balanced rearrangement [4, 12]. In the 2026 consensus, the letter (A to E) indicates the level of agreement allowed by the data and the number of "+" signs the proportion of votes (+ 26–49%, ++ 50–69%, +++ 70% or more) [18].

5.2 First-line test

The first-line test for both is MS-MLPA of 14q32, which measures in parallel the methylation of the MEG3:TSS-DMR and the copy number of several loci in the region, including the IG-DMR, the TSS-DMR and RTL1as [1, 4]. The 2026 consensus included the MEG3:TSS-DMR in the first-line panel for suspected Silver-Russell, alongside the H19/IGF2:IG-DMR and KCNQ1OT1:TSS-DMR (11p15), GRB10:alt-TSS-DMR and MEST:alt-TSS-DMR (chromosome 7) (recommendation 4.3, A+++), and requires the test to be performed by a scientist with experience in imprinting disorders, with consistent nomenclature of the regions tested (recommendations 4.1 and 4.2, A+++) [18]. Two commercial kits cover the region: ME034, recommended as first line by the Japanese authors, contains a MEG3:TSS-DMR probe for methylation and deletion but not for the IG-DMR, and also covers the PEG3:TSS-DMR; ME032 (UPD7/UPD14) contains probes for both DMRs, but the IG-DMR probe serves only for dosage [17, 36]. MLPA first determines dosage and, after digestion with the methylation-sensitive enzyme HhaI, methylation [12].

5.3 Temple syndrome algorithm

[1, 17, 18]

Without a karyotype, counselling should address the possibility of a parental Robertsonian translocation, and the report of a upd(14)mat should mention the risk of a translocation involving chromosome 14 [1, 18]. When MLID is suspected (NH-CSS of 3 to 6 with atypical features), other loci should be analysed and the MLID statement followed, whose report includes the loci affected, the associated phenotypes and any search for trans variants, including maternal-effect variants, especially with affected siblings or an adverse reproductive history (recommendation 4.7) [15, 18]. The 2024 statement does not recommend MLID testing as first line, except in exceptional circumstances under specialist referral [15]. In the Japanese cohort, the sequence was quantitative pyrosequencing of multiple DMRs, microsatellites at 9 chromosome 14 loci and karyotype, and fluorescence in situ hybridisation (FISH) and dense array-CGH of 14q32.2 for deletions; in the European cohort, one upd(14)mat was detected by genome sequencing (loss of heterozygosity of the whole of chromosome 14) and confirmed by MS-MLPA [16, 17].

5.4 Kagami-Ogata syndrome algorithm

[4, 12]

The flowchart of Ogata and Kagami begins with methylation of the IG-DMR and MEG3-DMR by any validated method (combined bisulfite restriction analysis, COBRA; bisulfite sequencing, MS-MLPA ME032 or pyrosequencing) and considers that hypermethylation of any of the DMRs of maternal origin confirms KOS14 [12]. Methylation-only methods and SNP arrays are not recommended on their own [4].

5.5 Diagnostic yield

In a study of 11 laboratories in 7 countries that tested 16,364 people for eight imprinting disorders, 82 of the 284 referrals for TS14 received a diagnosis (28.9%; 9.7–100% depending on the laboratory) and 71 of the 98 referrals for KOS14 (72.4%) [36]. The low rate for TS14 reflects the rarity of targeted referral and the mixed phenotypes that prompt the request; in the laboratories that test 14q32 in Silver-Russell referrals, 70 children with 14q32 alterations were identified, about 8.3% of the molecular diagnoses in that group [36]. Of the 4721 tested for Silver-Russell, 731 had the classic alterations of chromosomes 7 and 11 and 115 had unexpected diagnoses, including 14q32 alterations [36]. In the São Paulo series of 39 children with a diagnosis or suspicion of Silver-Russell, 1 (2.6%) had upd(14)mat [53]. In the Japanese cohort, 60 patients with TS14 were identified among 1139 referred patients, most for features suggestive of TS14, Silver-Russell or Prader-Willi (796), for SGA with non-syndromic short stature (251) or for central precocious puberty (90) [17]. In a series of 90 patients with central precocious puberty studied for MKRN3, DLK1, MECP2, KISS1, KISS1R and methylation, an (epi)genetic cause was identified in 12.2%, always TS14 or MKRN3 [8].

5.6 Limitations of testing

[1, 4, 16, 17, 36]

Methylation of the IG-DMR is technically difficult to measure, and the MEG3:TSS-DMR serves as a surrogate [1, 36]. All centres in the multicentre study tested peripheral blood, so cases of mosaicism may have been missed [36]. One patient with TS14 due to UPD was not diagnosed by methylation testing because of low-level mosaicism for trisomy 14 [54]. The 2026 consensus recommends testing an alternative tissue as second or third line when the NH-CSS is 5 or more with marked asymmetry (recommendation 4.6) and that reports state that mosaicism is not excluded and that a negative result does not exclude the disorder (recommendation 4.9) [18]. Deletions that do not affect the copy number probes of the commercial kit go unnoticed on MS-MLPA, such as the 203 bp deletion that only targeted analysis of genome sequencing and long-read sequencing revealed [1, 40].

5.7 Report content

The report should list all DMRs analysed with positive and negative results, specify the loci and associated disorders in unusual patterns, state the limitations regarding mosaicism and give the recurrence risk as precisely as possible (recommendation 4.9, A+++) [18]. In a upd(14)mat, it should mention the risk of a translocation involving chromosome 14 (recommendation 4.5) [18]. For MLID, the 2024 statement recommends referral to an expert centre and discussion of the report with a professional experienced in imprinting, especially where reports are delivered directly to families [15]. For deletions, the report should give the coordinates, the reference genome version, the genes and DMRs included and the parental origin; for DLK1 sequence variants, the transcript and version, Human Genome Variation Society (HGVS) notation, zygosity, parental origin and pathogenicity class according to ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology).

5.8 Radiological and ultrasound assessment

In KOS14, the neonatal chest radiograph allows measurement of the CHA and the M/W ratio [4]. Kuriki and colleagues measured the CHA on three-dimensional ultrasound in 30 normal pregnancies at 30–31 weeks (obtained in 25, 83%; five failures due to fetal position): the median was 19° (9–26°), with an interobserver intraclass correlation coefficient of 0.63 (95% confidence interval, CI: 0.32–0.81) [48]. The fetus with KOS14 described in the same work had a CHA of 39°, and the authors proposed 30° as a possible boundary between KOS14 and normal fetuses, a value based on a single case and not validated [48]. Fetal magnetic resonance imaging allows measurement of the M/W ratio [48]. In TS14 there are no diagnostic imaging tests; bone age and body composition serve management [18].

5.9 New methods

Several methods published in 2025 integrate methylation, structural variants and UPD in a single assay. Long-read sequencing targeted at 78 DMRs and 22 imprinting disorder genes was validated in controls and cases [55]; nanopore sequencing detected and classified the subtype of a TS14 case in a single step [56]; the ImprintCap capture panel, with 48 DMRs, was validated in 13 patients and 30 controls and detects MLID, low-level mosaicism and CNVs from coverage [57]. In a Chinese multicentre study of 294 fetal samples, targeted amplicon sequencing had, compared with MS-MLPA, a sensitivity of 90.9% (30/33), specificity of 97.7% (255/261), positive predictive value of 83.3%, negative predictive value of 98.8% and agreement of 96.9% [58]. These are analytical validation or proof-of-concept studies, without guideline status.

5.10 Prenatal diagnosis

Prenatal testing is possible when the familial alteration is known (14q32 deletion, Robertsonian translocation or other rearrangement), on chorionic villi or amniocytes [1, 4]. Fetal methylation testing of the DMRs is not recommended: amniotic fluid is the most reliable source, but there have been false negatives [1, 59]. The 2026 consensus adds that prenatal methylation has technical limitations (sample type, culture, fetal age, mosaicism) and does not predict clinical outcome [18]. When a Robertsonian translocation involving chromosome 14 or 15 is identified prenatally, ultrasound does not reliably assess UPD, which requires specific testing on amniocyte DNA and parental blood; preimplantation genetic testing may not detect UPD [6]. In KOS14 without a known familial risk, prenatal testing may be considered in the presence of polyhydramnios, a characteristic face, a small thorax with coat-hanger ribs and omphalocele, and has already revealed mosaic upd(14)pat [4]. Reproductive options are detailed in section 8.

6. Differential Diagnosis

6.1 Differential diagnosis of Temple syndrome

[1, 8, 15–18, 30, 34, 51]

Prader-Willi syndrome is the most difficult differential in infancy, because it shares hypotonia, poor suck and subsequent weight gain [1, 16]. In the children with TS14 in the Japanese cohort, the Prader-Willi criteria were met for hypotonia with poor suck in 77.2% and global delay in 47.3%, but excessive intake with central obesity after 6 years was present in only 9.1%, behavioural problems after 13 years in 4.8% and hypothalamic hypogonadism in none [17]. In TS14 puberty is precocious, whereas in Prader-Willi hypogonadism is more marked, and hyperphagia and food seeking, when present in TS14, are less intense [1, 17]. Normal 15q11.2 methylation in a hypotonic infant should lead to 14q32 testing [18].

Silver-Russell syndrome shares the NH-CSS, and 57–62% of patients with TS14 due to UPD or loss of methylation reach 4 or more points [18]. Asymmetry, almost constant in Silver-Russell due to 11p15 loss of methylation, is rare in TS14 (except in mosaic loss of methylation), and the 2026 consensus points to neonatal hypotonia, small hands and feet, rapid weight gain and precocious puberty as clues to TS14 [16, 18]. 14q32 methylation resolves the differential and forms part of the first-line panel, shared with Silver-Russell and the conditions that follow the same management pathway.

Central precocious puberty due to an isolated DLK1 defect is an allelic disorder. In the family described by Dauber and colleagues, a deletion of about 14 kb with a 269 bp duplication removing the 5' untranslated region and exon 1 of DLK1 caused precocious puberty in five women, with undetectable serum DLK1 and manifestation only in carriers through the paternal line [8]. Gomes and colleagues found three frameshift variants (p.Gly199Alafs*11, p.Val271Cysfs*14 and p.Pro160Leufs*50; published protein designations, without c. notation or transcript in the article abstract and absent from ClinVar, so they were not normalised to NM_003836.7) in five women from three families among 60 with central precocious puberty or early menarche, with segregation compatible with paternal expression; overweight, glucose intolerance or early-onset type 2 diabetes and hyperlipidaemia were more prevalent than in 20 women with idiopathic precocious puberty, and two sisters with p.Gly199Alafs*11 had polycystic ovary syndrome and infertility [34]. These patients do not have the features of TS14 apart from increased fat mass, and methylation analysis of the 14q32 DMRs should precede acceptance of an isolated DLK1 cause [8, 17]. Orphanet estimates the prevalence of genetic central precocious puberty in females (ORPHA:650077, genes DLK1, KISS1R and MKRN3) at 3.0 per 100,000 in Europe, a value covering all genetic causes and not specific to DLK1 [8].

Mosaic trisomy 14 is mechanistically related to UPD (trisomy rescue may leave a UPD) and may confound methylation testing [54]. In a 10-year-old Chinese girl with severe short stature, the karyotype was 47,XX,+14[6]/46,XX[94], the SNP array suggested about 50% trisomic cells and 14q32.2 dosage was increased without epimutation; she received somatropin at a dose of 0.22 mg/kg/week [30]. A case of prenatal diagnosis of mosaic trisomy 14 with an early malformation syndrome ended in termination of pregnancy at 17 weeks [60].

6.2 Differential diagnosis of Kagami-Ogata syndrome

[4, 6, 7, 12, 49]

Beckwith-Wiedemann syndrome is the main prenatal differential: omphalocele with polyhydramnios should prompt consideration of both, and the CHA on three-dimensional ultrasound helps to separate them [48]. The authors of the 2015 series recommend considering KOS14 in patients with atypical Beckwith-Wiedemann or without an identified molecular cause, because they share features, including embryonal tumours [7]. The short-rib dysplasias are distinguished radiologically: KOS14 has a bell-shaped thorax, coat-hanger ribs, full cheeks and micrognathia without other skeletal anomalies, whereas the short-rib dysplasias have additional bone changes (metaphyses, pelvis, polydactyly) [49]. Simpson-Golabi-Behmel syndrome shares overgrowth, abdominal wall defects and hepatoblastoma risk, but not the thorax [4].

6.3 The family of imprinting disorders

TS14 and KOS14 belong to the group of imprinting disorders that includes Silver-Russell, Beckwith-Wiedemann, Prader-Willi and Angelman syndromes and UPDs of other chromosomes, such as upd(16)mat and upd(20)mat [31, 36]. The distribution of mechanisms differs between groups: in TS14 and KOS14 UPD predominates and epimutations and deletions have similar frequency; in Prader-Willi and Angelman deletions predominate, favoured by low copy repeats; in Silver-Russell and Beckwith-Wiedemann epimutations predominate [12].

7. Treatments and Risk Management Strategies

7.1 Principles and organisation of care

There is no curative treatment or drug specifically approved for TS14 or KOS14, and there are no registered interventional trials for either [1, 4, 61]. Management is symptomatic and multidisciplinary. For TS14, the 2nd international Silver-Russell consensus recommends following the Silver-Russell management strategy until specific guidelines exist (recommendation 18.1, A+++), with adaptations drawn from Silver-Russell and Prader-Willi, and lists evidence-based TS14 management guidelines among its research priorities [18]. The TS14 GeneReviews bases its recommendations on the authors' experience and announces that a specific management strategy was in preparation during the consensus update [1]. For KOS14, recommendations come from GeneReviews and the 2016 expert review, without a formal guideline [4, 12]. In both, early referral to a developmental paediatrician, coordination by a case manager and social service support for families form part of the plan [1, 4, 18].

7.2 Temple syndrome: nutrition and feeding

Feeding difficulties in TS14 generally improve in the first year and are less severe than in Silver-Russell and Prader-Willi; gastrostomy is rarely needed [16, 18]. Because the tendency to rapid weight gain appears early, the 2026 consensus recommends avoiding tube feeding whenever possible and GeneReviews advises that a nasogastric tube or gastrostomy be used with caution and for a short duration, with monitoring of weight for height [1, 18]. Carers should know that nutritional goals change with age: hyperphagia and lack of satiety may appear from early childhood and require lifestyle counselling and calorie restriction, with continuous dietetic support [16, 18]. The dietitian assesses diet, weight and BMI every 3 months in the first 2 years and every 6 months thereafter [18].

The Silver-Russell nutritional pathway, applicable by extension, provides for repletion in the first 3 months and, from then on, monitoring for excessive gain, with Waterlow weight targets between 75% and 85%, weight for length between −2 and −1 SD in the first year and BMI between −2 and −1 SD thereafter; tube feeding is avoided if the child eats and is replete, gastrostomy (with or without fundoplication) or transgastric jejunostomy are the last resort, and oromotor and sensory assessment and screening for digestive dysmotility are recommended (recommendation 6) [18]. The consensus recommends cyproheptadine as an appetite stimulant in Silver-Russell (recommendation 6.8, A++), but the section dedicated to TS14 does not discuss it [18]. Obesity is treated according to the usual principles with a nutritionist, GORD with gastroenterology and oromotor dysfunction with feeding therapy [1].

7.3 Prevention and treatment of hypoglycaemia

Hypoglycaemia affected 28% of the European cohort, often during intercurrent illness, and the authors recommend teaching carers to recognise and treat it [16]. The Silver-Russell pathway (recommendation 7) includes teaching the signs of hypoglycaemia, ketonuria testing and the "safe fasting time"; complex carbohydrates and, at the last meal, high-molecular-weight glucose polymer (infants under 10 months) or uncooked cornstarch (older infants); a written emergency plan with early admission in the presence of ketonuria or hypoglycaemia, intravenous 10% dextrose with electrolytes during fever or preoperative fasting and discharge only after at least 12 hours of feeding without ketonuria; vaccination; and not using glucagon, because glycogen stores are poor [18]. Severe fasting hypoglycaemia is one of the reasons for starting growth hormone early (recommendation 7.8) [18]. The high pain threshold should be explained to families, because it may delay the detection of injuries and acute illness [1, 16].

7.4 Growth hormone in Temple syndrome

Recombinant growth hormone (GH, growth hormone) is somatropin. Short stature is frequent and the increase in fat mass with reduced lean mass is even more marked than in Silver-Russell; growth hormone reduces fat mass, increases lean mass, improves tone and short-term growth and probably adult height, although the data are limited [18]. In the expert opinion expressed in the 2026 consensus, growth hormone should be used in children with TS14, in combination with GnRH agonists when necessary, even if they do not meet the treatment criteria of the SGA guidelines [18]. In the Netherlands, growth hormone is routinely offered to all children with TS14, regardless of SGA status or growth hormone deficiency [16]. GeneReviews provides for replacement in proven deficiency, considers it for short stature and to improve body composition, and recommends polysomnography before starting treatment and about 3 months afterwards [1].

The 2026 consensus transposes the Silver-Russell rules to TS14 (recommendation 9). Before starting, caloric deficits should be corrected (9.1, A++); growth hormone stimulation tests should be avoided in Silver-Russell, because deficiency is not a feature of the syndrome and there is a risk of severe hypoglycaemia (9.2, A+++); treatment should start as early as possible, an age of 2–4 years being appropriate, with exceptions in some centres before 2 years (severe fasting hypoglycaemia, severe malnutrition despite support that would lead to gastrostomy, severe muscle hypotonia) (9.4); it may be considered for body composition even with normal height (9.5); the starting dose is about 33 µg/kg/day, using the lowest dose that achieves a minimum height increase of +0.5 SD in the first year, with a possible increase up to 67 µg/kg/day (9.6); a poor response requires review of the diagnosis, dose, IGF-1 and adherence (9.7); treatment stops at epiphyseal closure (bone age over 14 years in girls and over 16 in boys) (9.8); IGF-1 is measured before, at 6 months and at least annually (9.9); and an IGF-1 above +2 SD may be accepted by shared decision if needed for growth, given IGF-1 insensitivity (9.10) [18]. Growth hormone has no specific indication for Silver-Russell and is prescribed under the SGA indication; the SGA consensus allows treatment from 2 years of age with height of −2.5 SD or less [18].

The weekly equivalents in the first row result from multiplying the consensus daily doses by seven. The divergence on stimulation tests is real: the consensus advises against them in Silver-Russell, the European cohort recommends considering investigation for growth hormone deficiency in TS14 with short stature (deficiency found in 27% of those tested) and the Japanese authors consider true deficiency unlikely, because provocation tests were repeated, have low accuracy and IGF-1 was low-normal [16–18]. As the consensus recommends treatment even outside the SGA criteria, the indication in TS14 does not depend on the test result. Before starting growth hormone, polysomnography should be performed and symptoms of obstructive apnoea asked about (10% in the European cohort, potentially aggravated by micrognathia) [1, 16]. Immunoreactive IGF-1 was above +2 SD before treatment in 18% of European patients, and in a study of 13 children with TS14 treated for 5 years IGF-1 and binding protein 3 (IGFBP-3) rose rapidly with a relatively low IGF-1/IGFBP-3 ratio, so a higher immunoreactive IGF-1 may have to be tolerated [16, 66].

The available results are observational. In the 2018 British study, a median dose of 0.040 mg/kg/day was associated with a gain of +1.31 SD in the first year and a growth velocity of 5.30 cm/year [44, 67]. In the Japanese cohort, 32 patients started treatment at a median age of 4.2 years and with height of −3.4 SD; median height rose to −2.4 SD, increasing in the first 4–6 years and decreasing thereafter because of early cessation of growth, with a similar pattern in upd(14)mat and epimutation; near-final height of those treated (−2.4 SD, n = 11) was similar to that of those untreated (−2.1 SD, n = 9), but those treated were shorter at 2 years (p = 0.012), which precludes direct comparison [17]. In the European cohort, 63% received growth hormone (92% in the Netherlands, 40% in the United Kingdom), with median start at 5.96 years; near-final and final height appeared greater in those treated, with no difference in BMI trajectory and with larger head circumference at older ages [16]. In a Chinese series of 7 patients, 6 started prepubertal treatment at a median age of 2.42 years, with a mean gain of +1.19 SD in the first year (+1.15 SD in the three treated before 2 years) and motor and language improvement reported by carers, without standardised assessment and without adverse events [68].

Adverse effects and precautions follow the labels. The US Genotropin® label contraindicates somatropin in acute critical illness, active neoplasia, active proliferative or severe non-proliferative diabetic retinopathy, hypersensitivity and closed epiphyses, and in children with Prader-Willi with severe obesity or severe respiratory impairment (sudden deaths); it warns of glucose intolerance, intracranial hypertension (exclude papilloedema), fluid retention, hypoadrenalism, hypothyroidism (monitor thyroid function), slipped capital femoral epiphysis, progression of pre-existing scoliosis and pancreatitis; in the SGA trials (273 children), mild transient hyperglycaemia, one case of benign intracranial hypertension, two of central precocious puberty, two of jaw prominence, worsening of scoliosis, local reactions and progression of naevi were observed [62]. The Norditropin® label recommends fundoscopy before and periodically [63]. The Omnitrope® summary of product characteristics recommends measuring fasting insulin and glucose before and annually in SGA, performing an oral glucose tolerance test if there is a risk of diabetes, not administering in overt diabetes, measuring IGF-1 before and twice a year and not starting near the onset of puberty, and notes that experience in Silver-Russell is limited [64]. In the Japanese cohort, two of the three cases of hypothyroidism were identified during growth hormone treatment [17].

7.5 Central precocious puberty

Gonadotrophin-dependent central precocious puberty is frequent in TS14 and responds to GnRH agonists; without treatment, it worsens the height prognosis through advanced bone age [1, 18]. The Silver-Russell pathway (recommendation 10) includes monitoring for premature adrenarche and early or accelerated central puberty (10.1), assessing bone age from 5 years (10.2), measuring it together with luteinising hormone (LH), follicle-stimulating hormone (FSH) and oestradiol or testosterone (10.3), treating central puberty with a GnRH agonist in a personalised way for at least 2 years to preserve height (10.4), not starting the agonist after 12 years in girls or 13 in boys (10.5), considering an aromatase inhibitor in a personalised way when the height prognosis is severely compromised (10.6, A++, off-label use) and avoiding rapid weight gain, which favours insulin resistance, early adrenarche and polyendocrine metabolic ovarian syndrome, formerly called polycystic ovary syndrome (10.7) [18]. In Silver-Russell, the combination of growth hormone with a GnRH agonist is used when predicted adult height at the onset of puberty is below −2.5 SD [18]. In TS14, the Japanese authors recommend starting the agonist soon after pubertal onset: the five girls treated before menarche had menarche at a median age of 13.4 years, whereas the five treated only afterwards had it at 8.5 years [17]. In the European cohort, 15 patients were treated with an agonist [16]. The 2009 international consensus on GnRH analogues considered the benefit on adult height indisputable only in very early-onset precocious puberty (girls under 6 years), and the 2019 update is a narrative review, without graded recommendations [69, 70].

Monitoring includes a GnRH test, basal LH or sex steroids 1–2 months after starting and height and bone age every 6–12 months (Lupron Depot-PED®), or LH 1–2 months after starting and height every 3–6 months (Triptodur®) [71, 73]. The leuprorelin label contraindicates it in hypersensitivity and pregnancy and warns of the initial rise in gonadotrophins (with possible vaginal bleeding), psychiatric events (emotional lability, aggression), seizures, severe skin reactions and pseudotumour cerebri [71]. In the European Union, the paediatric formulations of leuprorelin and triptorelin have national rather than centralised authorisation, and their summaries of product characteristics were not consulted. The aromatase inhibitor anastrozole is used off-label; in a randomised trial in 25 children with Silver-Russell or Prader-Willi, adrenarche and advanced bone age, 18 months of anastrozole were well tolerated and slowed bone maturation; the consensus does not state a dose [18].

7.6 Metabolism and cardiovascular risk

Early cardiometabolic syndrome (hypertension, hyperlipidaemia, diabetes) is treated according to the usual standards [1]. The Silver-Russell pathway recommends annual screening for insulin resistance in childhood, including during growth hormone treatment, a 2-hour oral glucose tolerance test with insulin levels if there are clinical signs or a raised waist-to-height ratio, assessment of body composition every 3 years and at transition, metformin or other drugs if necessary and, after transition to adult endocrinology, lifelong annual cardiometabolic surveillance (blood pressure, lipids, insulin resistance, diabetes) (recommendations 11, 14 and 16) [18]. In TS14, metabolic complications may arise without obesity, so screening should not depend on BMI [17]. In the Japanese cohort, 4 of the 8 patients with LDL hypercholesterolaemia received drugs, statins (HMG-CoA reductase inhibitors) were effective in 2 and the other drugs apparently ineffective, and 4 followed diet and exercise only; of the 5 diabetic patients, 2 received insulin, 2 were controlled with oral antidiabetic agents (sodium-glucose cotransporter 2, SGLT2, inhibitors) and glucagon-like peptide 1 (GLP-1) receptor agonists, and 1 followed diet only [17]. Doses of these drugs follow the labels and general guidelines, without TS14-specific data. In the European cohort, raised triglycerides often normalised after dietary intervention [16].

7.7 Other interventions in Temple syndrome

7.8 Surgery and anaesthesia

The Silver-Russell pathway recommends postponing elective surgery until nutrition is adequate, admitting the day before, placing the child first on the operating list, monitoring blood glucose and giving intravenous 5% dextrose during and after the procedure, providing thermal protection for the child given their size and anticipating difficult intubation due to micrognathia and dental anomalies (recommendation 8) [18]. In TS14, micrognathia (14% in the European cohort) and obstructive sleep apnoea reinforce airway assessment [16]. In KOS14, laryngomalacia, previous tracheostomy, the small thorax and almost constant micrognathia make the airway and ventilation the critical points of any anaesthetic [4, 7].

7.9 Kagami-Ogata syndrome: perinatal period and respiratory care

Management of KOS14 begins in pregnancy: polyhydramnios frequently requires repeated amnioreductions after 25–30 weeks, and the high rate of preterm delivery and neonatal respiratory failure justifies delivery in a centre with neonatal intensive care [4, 7, 48]. Mechanical ventilation with oxygen is almost always needed immediately after birth; it was discontinued in infancy in 22 of the 34 patients in the 2015 series, after a median of 1 month, and about a third required tracheostomy, sometimes for severe laryngomalacia [4, 7, 12]. Upper and lower respiratory infections should be monitored and treated early, and exposure to respiratory infections should be avoided, especially in infancy [4]. The Japanese authors recommend careful management of respiratory infections, given that three of the eight deaths occurred during respiratory infections, one of them during influenza [7].

7.10 Kagami-Ogata syndrome: feeding, abdominal wall and rehabilitation

Tube feeding is almost always needed, with gastrostomy when prolonged, and feeding training or rehabilitation forms part of the plan; the threshold for clinical swallowing assessment and videofluoroscopy should be low in the presence of choking, poor weight gain, frequent respiratory infections or unexplained food refusal [4]. Thickening or cooling food may help, and oromotor assessment is repeated at each visit [4]. Omphalocele requires surgical repair [12], and abdominal wall weakness may cause constipation [4]. Physiotherapy aims to improve mobility and reduce late orthopaedic complications (contractures, scoliosis, hip dislocation), occupational therapy supports fine motor skills and activities of daily living, kyphoscoliosis is treated by orthopaedics (orthosis or surgery) and contractures by rehabilitation medicine; if there are expressive difficulties, augmentative and alternative communication is considered [4]. Heart disease, generally mild, is followed in cardiology; it may justify medication and there are no reports of cardiac surgery [4].

7.11 Hepatoblastoma in Kagami-Ogata syndrome

Hepatoblastoma is treated with standard surgery and chemotherapy [4]. In the 2015 series, two of the three patients underwent resection without chemotherapy because of poor general condition and the third received neither surgery nor chemotherapy; one died of hepatoblastoma [7]. The authors recommend periodic screening with serum alpha-fetoprotein and abdominal ultrasound, without a defined interval [7, 12]. GeneReviews proposes abdominal ultrasound and alpha-fetoprotein every 3 months until 3–4 years of age, based on the schedule recommended for hepatoblastoma in Beckwith-Wiedemann syndrome; infant alpha-fetoprotein should be interpreted by an experienced clinician [4]. The 2017 and 2024 recommendations of the American Association for Cancer Research (AACR) do not include KOS14 among the predisposition syndromes; the 2024 update recommends, for hepatoblastoma in Beckwith-Wiedemann syndrome, trisomy 18 and Simpson-Golabi-Behmel syndrome, alpha-fetoprotein and complete abdominal ultrasound every 3 months until the 3rd birthday (previously until 4 years), with a surveillance threshold of 1% risk, whereas in Europe the usual threshold is 5% [74, 75]. The interval applied to KOS14 is therefore an extrapolation by analogy and not a recommendation based on its own data.

7.12 Palliative care and family support

In KOS14, assessment of the need for palliative care and home nursing forms part of the initial evaluation [4]. The authors of the 2016 review stress that patients who survive the critical phase become free of ventilation, tracheostomy and tube feeding, that there were no deaths after 4 years and that all attend school; explaining this prognosis to parents during the intensive phase reduces anxiety and favours bonding [12].

7.13 Regulatory status

[8, 17, 18, 62–65, 71–73, 76]

The sources consulted do not give the date of the US extension of somatropin to the SGA indication or the access to and reimbursement of these drugs in TS14 in Portugal or Brazil. In Japan, genetic diagnosis and growth hormone are covered by insurance for Prader-Willi, but not for Silver-Russell or TS14 [17].

7.14 Evidence from intervention studies

[16–18, 44, 62, 64, 66–68]

No randomised trial has evaluated interventions in TS14 or KOS14. The somatropin trials in SGA did not identifiably include patients with TS14, and those of weekly growth hormone excluded patients with Silver-Russell [18]. The TS14 studies are observational, with treated and untreated groups that differ at baseline, heterogeneous doses and starting ages and country-dependent choice of treatment (use in the Netherlands was more than double that in Britain), so they do not allow estimation of a causal effect or indirect comparison of gains between studies [16, 17]. The sources consulted contain no negative, suspended or withdrawn trials for these disorders. A ClinicalTrials.gov search on 17 October 2026 identified only the French observational cohort RaDiCo-IDMet (NCT05945576, Institut National de la Santé et de la Recherche Médicale, INSERM), which includes patients with TS14 and KOS14, has been recruiting since 10 March 2017, plans 2000 participants and has an estimated primary completion in March 2028, with clinical, genetic, biological and morphometric outcomes [61]; the search did not cover the European and Japanese registries, and a negative result does not prove the absence of studies.

7.15 Developments in the last 12 months

No mechanism-directed therapy, preclinical or human, for TS14 or KOS14 was identified in the sources consulted [31].

7.16 Agents and circumstances to avoid

In KOS14, exposure to respiratory infections should be avoided, especially in infancy [4]. In TS14, unnecessary and prolonged tube feeding (because of rapid weight gain), prolonged fasting without a hypoglycaemia prevention plan and glucagon as treatment of hypoglycaemia should be avoided, according to the Silver-Russell pathway [1, 18]. Growth hormone should not be started without prior assessment of sleep apnoea [1, 16]. The GnRH agonist should not be started after 12 years in girls or 13 in boys [18].

7.17 Pregnancy, lactation, transition and adulthood

Women with TS14 who become pregnant need close surveillance for gestational diabetes, given the risk of obesity and metabolic syndrome in adulthood; in the Japanese cohort, one diabetic patient treated with oral antidiabetic agents needed insulin during pregnancy [1, 17]. A woman with TS14 may carry a deletion with a 50% risk of KOS14 in her offspring, which justifies preconception counselling (section 8) [1, 47]. GnRH agonists are contraindicated in pregnancy [71]. The sources consulted provide no data on lactation. At transition, the adult with TS14 should be followed by an adult endocrinologist, with lifelong annual cardiometabolic surveillance, psychological support and a case manager [18]. In KOS14, no adult has had known offspring, and data on adulthood are limited to reports showing neurocognitive variability, connective tissue abnormalities and uncertainty about long-term cancer risk [4, 50].

7.18 Guidelines and divergences between sources

[1, 16–18]

Given these divergences, the 2026 consensus takes priority as the only document with a formal voting methodology and endorsement by scientific societies; the surveillance table of the European cohort and GeneReviews complete the items that the consensus does not specify, and the differences are flagged in the surveillance table in section 11 [1, 16, 18].

8. Reproductive Options and Family Counselling

8.1 Principles

The recurrence risk depends on the mechanism, which makes definition of the molecular subtype mandatory (recommendation 4.5 of the 2026 consensus) together with counselling by a professional with experience in imprinting disorders (recommendation 17.1) [18]. Most probands with TS14 or KOS14 are isolated cases due to an epigenetic or de novo event, with a low risk for siblings; the risk may reach 50% when there is a predisposing alteration in a parent (14q32 deletion or Robertsonian translocation involving chromosome 14), depending on the type of alteration, the sex of the transmitting parent and the presence of MLID [1, 4]. Pure epimutations and UPDs do not generally raise the risk above the population level, whereas copy number alterations can be transmitted with an effect dependent on the sex of the transmitting parent [3]. The risk of CNVs depends on size, location and parental origin, and MLID may carry a higher risk when there is a maternal-effect trans variant [18].

8.2 Temple syndrome: risk to siblings by mechanism

[1]

A maternal Robertsonian 13;14 translocation predisposes to upd(14)mat through trisomy rescue, and a paternal one through monosomy rescue [1]. A father with a 14q32 deletion would himself have TS14 if he had inherited it from his father; if the deletion is a somatic and gonadal mosaic, the manifestations depend on parental origin and distribution [1]. When a parent carries the deletion or a chromosomal alteration, that parent's siblings are also at risk [1].

8.3 Kagami-Ogata syndrome: risk to siblings by mechanism

[4, 12]

Recurrence in siblings due to a maternal deletion has been described in several families [4]. A mother carrying the deletion will theoretically have KOS14 if she inherited it from her mother and TS14 if she inherited it from her father and the deletion includes DLK1; transmission from a mother with TS14 to children with KOS14 has been described in several families, whereas transmission from a mother with KOS14 to a child with KOS14 has not [4, 27]. A 2024 Chinese case describes the prenatal diagnosis of recurrent KOS14 inherited from a mother with TS14 [47]. When the mother is heterozygous for a deletion or translocation, her siblings are also at risk [4].

8.4 Risk to the proband's offspring

A man with TS14 due to a deletion has a 50% risk of transmitting the deletion and having children with TS14; a woman with TS14 due to a deletion has a 50% risk of having children with KOS14 [1, 47]. Likewise, a woman with KOS14 due to a deletion would have a 50% risk of children with KOS14 and a man with a deletion including DLK1 a 50% risk of children with TS14 [4]. A proband carrying a Robertsonian translocation or isochromosome 14q is at risk of offspring with TS14 (upd(14)mat) or KOS14 (upd(14)pat), depending on sex and the rescue mechanism, and of offspring with an unbalanced form [1, 4]. UPDs with a normal karyotype and pure epimutations do not generally raise the risk above the population level [3]. It is likely that there are undiagnosed adults with TS14 who have offspring, which reinforces counselling of women with TS14 before pregnancy [1].

8.5 Carriers of Robertsonian translocations

[6]

The UPD values below 0.5% derive from the 0.65% incidence of UPD in fetuses with a balanced Robertsonian translocation in Silverstein's study (2 in 315 prenatal diagnoses), corrected for the fact that some fetuses have a normal karyotype [6]. In a study of 174 acrocentric rearrangements at prenatal diagnosis, UPD was found in 1 of 168 non-homologous Robertsonian translocations (0.6%) and in 4 of 6 homologous rearrangements (66%); among 50 phenotypically abnormal carriers, 2 of the 48 with a non-homologous translocation and the 2 with a homologous translocation had UPD [6]. In 222 pregnancies of rob(13q14q) carriers, there were no live births with translocation trisomy 13; the miscarriage rate was 28% in female carriers and 20% in the partners of male carriers, and male infertility affected 11% [6]. An isochromosome has a 100% risk of UPD [6]. A de novo non-homologous Robertsonian translocation detected prenatally has a very low risk of abnormal phenotype and a risk of about 0.65% of UPD 14 or 15, with recurrence below 2% if parental karyotypes are normal; in homologous translocations, polymorphic markers clarify the origin of the homologues [6]. The Oxford Desk Reference recommends considering UPD testing in any rearrangement involving chromosome 14 or 15, in children with a balanced karyotype and compatible malformations or delay (with ethylenediaminetetraacetic acid, EDTA, samples from the child and parents), and offering karyotyping to at-risk adults in the family [6]. A Robertsonian translocation (14;22) identified prenatally led to the suspicion and diagnosis of KOS14 in a 2025 Japanese report [52].

8.6 Prenatal diagnosis and preimplantation genetic testing

When the familial alteration is known (14q32 deletion, Robertsonian translocation involving chromosome 14, other rearrangement), prenatal testing on chorionic villi or amniocytes and preimplantation genetic testing (PGT) are possible [1, 4]. PGT for a 14q32 microdeletion has been described in a family with KOS14 and TS14 [4, 78]. PGT may not detect UPD, and fetal methylation testing is not recommended because of false negatives [1, 6, 59]. In upd(14)pat or upd(14)mat with normal parental karyotypes and in epimutations, the risk is below 1% and prenatal testing is probably unjustified; even without ultrasound findings, a residual risk persists because of the variability and limitations of ultrasound [4]. In pregnancies without a known familial risk, polyhydramnios, omphalocele, a small thorax with coat-hanger ribs and the characteristic face may prompt prenatal testing for KOS14, which has already revealed alterations including mosaic upd(14)pat; targeted amplicon sequencing and MS-MLPA detected UPD in 13.4% and 11.0% of fetuses with regions of homozygosity of at least 5 Mb on chromosomes 6, 7, 11, 14, 15 or 20 on SNP array [4, 58].

8.7 Assisted reproduction and maternal age

ART was more frequent in the TS14 cohorts than in the population: 14% (8/58; 2 upd(14)mat and 6 losses of methylation) in the European cohort, versus a population prevalence of ART of 3.0–3.3% in the Netherlands and 1.29–3.15% in the United Kingdom, and 9.8% (5/51) in the Japanese cohort, versus about 4% in the Japanese population 11 years earlier [16, 17]. The Japanese authors consider ART a possible risk factor; none of the European patients conceived by ART had MLID [16, 17]. In KOS14, 1 of 21 patients was conceived by ART [7]. Advanced maternal age is associated with upd(14)mat due to trisomy rescue or gamete complementation (median 36 years) and with upd(14)pat due to monosomy rescue [4, 12, 17]. These data do not allow quantification of an individual risk for couples using ART.

8.8 Cascade testing and counselling of minors

Cascade testing is directed at the parents and their siblings when the proband has a deletion, translocation or other rearrangement; it is the molecular subtype that makes it possible to offer it [1, 4, 18]. Carrier testing for a deletion or translocation in asymptomatic minor siblings without immediate clinical implications may be deferred until the age at which the individual can decide, whereas diagnostic testing of siblings with compatible signs should be done without delay. In women with TS14 due to a deletion, discussion of the risk of KOS14 in their offspring should precede reproductive age [1, 47].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

None of the sources consulted provides a validated population prevalence of TS14 or KOS14. Orphanet classifies both in the prevalence class below 1 per 1,000,000 and records 53 cases or families for TS14 and 84 for KOS14, counts that measure published cases and not population frequency [11, 13]. The 2024 MLID statement records the prevalence of both as unknown [15]. GeneReviews estimates that about 190 patients with TS14 and about 100 with KOS14 have been described, and the authors of the KOS14 GeneReviews identified 76 patients in Japan, some of them unpublished [1, 4]. Both syndromes are considered underdiagnosed: TS14 because of a non-specific phenotype that changes with age, with tests that are not performed routinely in children with a Prader-Willi-like picture in many health systems, and KOS14 because of growing recognition of mild forms and mosaics [4, 16, 36]. The proportions of diagnoses among referred patients (60 cases of TS14 among 1139 referred in Japan; 28.9% diagnoses among targeted referrals for TS14 in 11 laboratories) measure test yield in selected populations and not frequency in the population [17, 36].

9.2 Cohorts and distribution by region

The Japanese predominance in the KOS14 and TS14 literature reflects the research of the Kagami and Ogata group and the Japanese policy of methylation analysis regardless of karyotype, and not a demonstrated difference in frequency [4, 12]. Outside Japan, UPDs with an abnormal karyotype were overrepresented in KOS14 because genotyping was directed at patients with chromosomal abnormalities [12]. The differences in presentation between the United Kingdom and the Netherlands (more hypotonia, hyperphagia and growth hormone use in the Netherlands; more prematurity, high pain threshold and MLID in the United Kingdom) mainly reflect the specialisation of the centres and treatment policies [16]. No founder populations or founder variants for these disorders were identified in the sources consulted, which is consistent with mostly sporadic mechanisms. Data from Portugal are limited to a 2025 case report whose content was not accessible, and those from Brazil to two series from São Paulo; the lack of other data in the sources consulted does not demonstrate their absence.

9.3 Demographic factors and special populations

Advanced maternal age is associated with upd(14)mat due to trisomy rescue or gamete complementation (median 36 versus 30 years in the other causes) and, in KOS14, with upd(14)pat due to monosomy rescue; in the 2015 series, 8 of the 34 mothers were aged 35 years or more [7, 12, 17]. Conception by ART was more frequent than in the population (section 8.7) [16, 17]. Carriers of Robertsonian translocations (about 1 in 1000 people) constitute the population with a known risk of UPD 14 [6]. Special populations include pregnant women with TS14 (surveillance for gestational diabetes), undiagnosed adults with TS14 (who may transmit deletions), preterm newborns with KOS14 (25% survival with delivery at or before 29 weeks) and patients with isodisomy, in whom autosomal recessive disorders may coexist [1, 7, 18]. None of the patients with KOS14 due to paternal isodisomy in the 2015 series had a recessive disorder [7].

9.4 Reference networks and patient associations

The European Reference Network ERN-ITHACA (rare congenital malformations and rare intellectual disability) participated in and co-funded the 2nd Silver-Russell consensus, which also covers TS14 [18, 19]. Endo-ERN (rare endocrine conditions) includes the imprinting disorders in thematic group 5 ("Growth & Genetic Obesity Syndromes"), although it does not expressly name TS14 or KOS14 [20]. The European network of imprinting disorders (European Network for Human Congenital Imprinting Disorders, EUCID.net; www.imprinting-disorders.eu) was the one that adopted the designation "Kagami-Ogata syndrome" [3, 5]. Among patient associations, the MAGIC Foundation (USA) is listed by the TS14 GeneReviews and co-funded the consensus, the Child Growth Foundation (United Kingdom) co-funded the consensus, Unique (Rare Chromosome Disorder Support Group) supports families with chromosomal alterations, including Robertsonian translocations, and The Ava Grace Foundation (USA) is aimed specifically at families with UPD 14, in particular KOS14 [1, 6, 21–24]. The KOS14 GeneReviews identified no specific resources [4]. Orphanet lists specialised centres, diagnostic tests and patient associations for both syndromes [11, 13].

10. Illustrative Clinical Case

10.1 Temple syndrome diagnosed at 18 years (Bulgaria)

Yordanova and colleagues described in 2024 a Bulgarian girl, the first child of non-consanguineous parents, with a paternal grandmother of short stature [44]. The pregnancy was singleton and uneventful; she was born by vaginal delivery at 38 weeks, with meconium-stained fluid and initial resuscitation, with a weight of 2350 g (2nd centile), length of 48 cm (25th centile) and head circumference of 34 cm (10th centile) on the Centers for Disease Control and Prevention (CDC) charts. In the neonatal period she had truncal hypotonia, poor growth and no weight gain, and needed a nasogastric tube until 3 months because of feeding difficulties [44].

At 7 months Silver-Russell was suspected, but upd(7)mat and H19 methylation were negative. Height remained below the 3rd centile until 6 years and, after 4 years, weight rose from the 25th to the 75th centile without linear improvement [44]. At 6 years and 10 months, because of decreasing growth velocity, somatropin was prescribed under the SGA without catch-up indication; during the supply process, within 3 months, thelarche, pubic hair and growth acceleration appeared at 7 years and 2 months, with a bone age of 9.5 years (Greulich-Pyle). She started triptorelin 3.75 mg intramuscularly every 28 days at 7 years and 5 months, continued until 11 years, and somatropin was never actually administered [44]. At 10 years, the neonatal overlap, the dysmorphic features and uncontrollable weight gain led to suspicion of Prader-Willi, but methylation was negative. She had facial acne at 9 years and, after stopping the agonist, rapid pubertal progression, with menarche at 12 years and 4 months [44].

At 16 years and 10 months she presented with hyperandrogenism (acne, oily hair, mild hirsutism with a Ferriman-Gallwey score of 13/36), with 17-hydroxyprogesterone of 9.78 ng/mL (reference 0.2–1.3), androstenedione of 13.4 nmol/L (1–11.5) and testosterone of 2.13 nmol/L (0–1.38); the picture was interpreted as compatible with non-classic congenital adrenal hyperplasia, without an adrenocorticotrophic hormone (ACTH) stimulation test or genetic testing, and treated with prednisone 5 mg at night for 6 months; reduction to 2.5 mg/day worsened the values and the dose returned to 5 mg [44]. The authors present her as the second patient with TS14 and clinical and biochemical hyperandrogenism and the first treated with prednisone [44].

The molecular diagnosis was made only at 18 years, at the Wessex Regional Genetic Laboratory (United Kingdom): complete hypomethylation of the DLK1/GTL2 imprinting centre at 14q32, that is, an epimutation; the authors do not mention MLID testing [44]. She was the first patient with confirmed TS14 in Bulgaria. With dietary and physical activity counselling, she lost weight; adult height was 141 cm (−4.76 SD), 5 cm below the lower limit of the familial target, with a BMI of 23.6 kg/m² (+0.48 SD), normal blood glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR) and lipids, and improvement of acne and hyperandrogenism with regularised cycles [44]. She remains in six-monthly follow-up, with transition to adult endocrinology at the same rare endocrine disease centre. Figure 1 of the article shows the growth curve on the CDC charts and Figure 2 a photograph taken by the patient herself at 10 years (https://pmc.ncbi.nlm.nih.gov/articles/PMC11629717/figure/figure-1/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC11629717/figure/figure-2/); the legends were consulted, but the values of the curve appear only in the image [44].

The case illustrates the typical sequence of TS14 (SGA with preserved head circumference, hypotonia and neonatal tube feeding, growth failure followed by weight gain after 4 years, precocious puberty at 7 years) and the path of successive exclusions of Silver-Russell and Prader-Willi before the diagnosis [44]. The authors consider the non-administration of growth hormone a missed opportunity, citing the gain of +1.31 SD in the first year in treated children with TS14 [44, 67]. Two practices in the report are not presented as routine: corticosteroid therapy for suspected non-classic congenital adrenal hyperplasia without diagnostic confirmation and the absence of MLID testing in an epimutation; the 2026 consensus now recommends 14q32 testing as first line in suspected Silver-Russell and growth hormone in TS14 even outside the SGA criteria [18].

10.2 Prenatal diagnosis of Kagami-Ogata syndrome by measurement of the coat-hanger angle (Japan)

Kuriki and colleagues described in 2022 a 24-year-old primigravida with a spontaneous pregnancy, referred at 25 weeks and 4 days for fetal omphalocele (3 cm defect with small bowel and liver in the sac); estimated fetal weight was 879 g (+0.34 SD) and there was severe polyhydramnios (maximum vertical pocket of 14 cm, amniotic fluid index of 36 cm) [48]. Three amnioreductions were performed (1850, 1800 and 2150 mL at 26, 28 and 30 weeks). Fetal magnetic resonance imaging at 30 weeks and 4 days showed omphalocele with a 6 cm defect and a narrow bell-shaped thorax, with an M/W ratio of 68%; three-dimensional ultrasound at 31 weeks and 6 days measured a CHA of 39°, between the sixth thoracic vertebra and the left rib [48].

Caesarean section was performed at 32 weeks because of contractions, cervical dilatation and breech presentation. The newborn girl weighed 1998 g, had Apgar scores of 4 and 3 at 1 and 5 minutes and had a prominent forehead, micrognathia and anteverted nares; the chest radiograph showed an M/W ratio of 64% (M 58 mm; W 90 mm) and a CHA of 42° (mean of 41° on the right and 43° on the left), and she was intubated and ventilated [48]. After genetic counselling, pyrosequencing showed hypermethylation of the MEG3/DLK1:IG-DMR and the MEG3:TSS-DMR with normal methylation of the other DMRs, and microsatellite analysis with parental DNA demonstrated segmental paternal uniparental isodisomy of chromosome 14 [48]. The subsequent course was not described.

Figure 1 of the article shows two-dimensional ultrasound at 28 weeks (large omphalocele and narrow thorax with polyhydramnios), three-dimensional ultrasound with the CHA of 39° and, for comparison, a normal fetus at 30 weeks and 1 day with a CHA of 19°; Figure 2 shows the sagittal and coronal sections of fetal magnetic resonance imaging (M/W ratio of 68%) and the neonatal radiograph with the measurements, according to the legends consulted (https://pmc.ncbi.nlm.nih.gov/articles/PMC10087373/figure/jog15425-fig-0001/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC10087373/figure/jog15425-fig-0002/) [48]. The case shows the combination of omphalocele and severe polyhydramnios that should prompt consideration of KOS14 and Beckwith-Wiedemann and the contribution of the bell-shaped thorax and the CHA to distinguishing them. The sonographic threshold of 30° proposed by the authors rests on this single case and 25 normal fetuses, and is not validated; the diagnosis still requires molecular confirmation [48].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis of Temple syndrome

A life expectancy similar to that of the general population is expected for TS14, but long-term data are limited and most patients described are children [1]. Adult height is reduced: −2.04 SD in the 2014 review, −2.3 SD near-final height in the Japanese cohort, −2.1 SD in the 12 Japanese adults and −1.86 SD after 14 years in the European cohort, with −1.54 SD in the Netherlands and −2.52 SD in the United Kingdom [16, 17, 29]. Cardiometabolic risk increases with age and may arise without obesity: in the Japanese adults, hypercholesterolaemia reached 63.6% and diabetes 41.7%, with a median BMI of 22.8 kg/m² [17]. Most adults live independently, work or attend higher education, although some have intellectual disability (16.7% of the Japanese adults) or neurodevelopmental disorders (25.0%), and some develop social isolation [1, 17]. The effect of growth hormone and GnRH agonists on adult height is probably favourable, but rests on observational data (section 7.4) [16, 18].

11.2 Prognosis of Kagami-Ogata syndrome

Mortality is concentrated in the first years: 20–25% before 5 years according to GeneReviews and 8 of 34 patients (23.5%), all before 4 years, in the 2015 series, mainly due to respiratory failure and respiratory infections; after 5 years there is no increase in mortality [4, 7]. Survival depends on gestational age at delivery (25% at or before 29 weeks, 83% between 30 and 36 weeks and 86% at 37 weeks or later) and was lower in deletions, mainly because of prematurity [7]. Survivors come off ventilation, tracheostomy and tube feeding, the shape of the thorax normalises after infancy (although the CHA remains increased) and all attend school, with intellectual disability of variable degree (median IQ of 55) [4, 7, 12]. Kyphoscoliosis and contractures may progress [4]. In 2024 nine adults were known, the oldest aged 35 years, with neurocognitive variability, connective tissue abnormalities and unknown long-term cancer risk [4, 50].

11.3 Initial evaluation after diagnosis

In TS14, the initial evaluation includes growth (weight, length or height, head circumference and BMI from 2 years), gastroenterological and nutritional assessment (reflux, need for tube feeding), dentition, fasting blood glucose with education about hypoglycaemia, signs of precocious puberty in boys from 3 to 9 years and girls from 3 to 8 years (with referral to endocrinology), thyroid-stimulating hormone (TSH) and investigation for growth hormone deficiency if growth is poor, after 6 years the lipid profile, fasting glucose, C-peptide, glycated haemoglobin (HbA1c), thyroid function, liver profile and blood pressure, a search for asymmetry, scoliosis and hypermobility, motor and developmental assessment, neuropsychiatric assessment after 12 months (sleep, ADHD, anxiety, ASD), education about the high pain threshold, audiology, polysomnography, a search for cryptorchidism, genetic counselling and family support [1]. In KOS14, the initial evaluation includes respiratory assessment immediately after birth, neurological and developmental assessment, orthopaedics, physical and rehabilitation medicine, physiotherapy and occupational therapy, gastroenterological and nutritional assessment (risk of aspiration, gastrostomy), echocardiogram, abdominal ultrasound and serum alpha-fetoprotein interpreted by an experienced clinician, genetic counselling and family support with home nursing [4].

11.4 Surveillance plan for Temple syndrome

11.5 Surveillance plan for Kagami-Ogata syndrome

In TS14, pubertal screening is the point on which the sources diverge most: the 2026 consensus proposes six-monthly observation from about 4 years, whereas GeneReviews and the European cohort propose assessment at every visit from 3 years, with different end ages; all agree on annual bone age from 5 years [1, 16, 18]. Thyroid surveillance also diverges: the European cohort recommends annual thyroid function from birth, GeneReviews annually or as clinically indicated and the consensus reserves ultrasound surveillance for the paternal deletion subtype; in the Japanese cohort, which included 5 patients with a deletion, there were no thyroid tumours in 60 patients [1, 16–18]. In KOS14, the hepatoblastoma surveillance interval results from an extrapolation, and the end age (3 or 4 years) varies depending on whether the 2024 AACR update or the 2017 schedule is followed [4, 74, 75]. The three hepatoblastomas in the 2015 series appeared at 46 days, 218 days and 13 months, all within this period [7].

12. Summary and Final Considerations

Temple and Kagami-Ogata syndromes are the two faces of the DLK1–DIO3 imprinted domain at 14q32.2. In TS14, loss of expression of the paternal genes, mainly DLK1, due to upd(14)mat, epimutation or paternal deletion, produces pre- and postnatal growth restriction with relative macrocephaly, hypotonia and feeding difficulties in the first year, small hands and feet, rapid weight gain with high fat mass from 3–6 years, central precocious puberty at about 7–8 years, cardiometabolic risk that may arise without obesity and short adult stature, with mild intellectual disability in a minority and neurodevelopmental disorders in about a fifth to a third. In KOS14, excess RTL1 due to absence of maternal RTL1as, through upd(14)pat, epimutation or maternal deletion, produces polyhydramnios with placentomegaly, fetal overgrowth, a face with full cheeks and protruding philtrum, a bell-shaped thorax with coat-hanger ribs, almost universal neonatal respiratory failure, abdominal wall defects, intellectual disability and risk of hepatoblastoma, with mortality of about a quarter before 5 years and a stable vital prognosis thereafter.

Diagnosis of both rests on MS-MLPA of 14q32, followed by study of parental origin and karyotype, because the molecular subtype determines the recurrence risk, which ranges from less than 1% in de novo UPDs and epimutations to 50% in transmitted deletions, with the particularity that the same deletion causes TS14 when transmitted by the father and KOS14 when transmitted by the mother. TS14 is underdiagnosed because of its overlap with Silver-Russell and Prader-Willi; the 2026 2nd international Silver-Russell consensus included the MEG3:TSS-DMR in first-line testing, recommends testing it also in children with a Prader-Willi picture and normal 15q11.2 methylation and establishes that management of TS14 follows the Silver-Russell pathway, with growth hormone even outside the SGA criteria, GnRH agonists for precocious puberty, prevention of hypoglycaemia, nutritional management aimed at avoiding excessive weight gain and lifelong metabolic surveillance. KOS14 requires neonatal intensive care, prolonged ventilatory and nutritional support, rehabilitation and surveillance for hepatoblastoma, whose schedule derives by analogy from Beckwith-Wiedemann syndrome.

The main gaps are the absence of population prevalence, clinical trials and specific guidelines for each syndrome, the scarcity of adult data (especially in KOS14), the lack of external validation of the proposed clinical scores and the divergence between sources on surveillance intervals and the role of growth hormone testing. The French RaDiCo-IDMet cohort, long-read sequencing methods and multilocus panels should help to answer some of these questions.

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