Rare Chromosome 14 Imprinting Disorder Comes Into Focus in Largest Chinese Pediatric Series Yet

Temple syndrome, a rare imprinting disorder rooted in a small stretch of chromosome 14, has long been one of the most elusive diagnoses in pediatric endocrinology. Children born small, growing slowly, and sometimes entering puberty far too early can drift through years of specialist appointments before anyone thinks to examine the methylation marks on their DNA. A new study from Chinese hospitals, published in Frontiers in Endocrinology, now offers the largest look yet at how the condition presents in Chinese children, combining six carefully worked-up cases with a sweeping review of 167 patients reported worldwide.

The biology behind Temple syndrome, abbreviated TS14, is a textbook example of genomic imprinting. Most genes come in two active copies, one from each parent, but a small set of imprinted genes carries chemical tags that silence one parental copy. At chromosome 14q32, a cluster of imprinted genes including DLK1 and MEG3 depends on methylation marks that are normally laid down on the paternal allele. When that pattern is disrupted, whether through maternal uniparental disomy, in which a child inherits both copies of chromosome 14 from the mother, through an epimutation that strips methylation from the paternal allele, or through a deletion of the paternally inherited region, the dosage of growth-regulating genes goes awry. The result is a syndrome first described by Ian Temple and colleagues in 1991, marked by intrauterine growth retardation, poor feeding, low muscle tone in infancy, delayed motor milestones, small hands and feet, and, strikingly, a tendency toward early puberty.

What makes TS14 so easy to miss is that its features overlap heavily with two better-known imprinting disorders, Prader-Willi syndrome and Silver-Russell syndrome. All three can begin with a small-for-gestational-age baby who struggles to feed and grow. But central precocious puberty, driven by premature activation of the hypothalamic-pituitary-gonadal axis, is a hallmark that rarely appears in those other conditions, and it has emerged as one of the most valuable diagnostic clues. Before this study, only four pediatric cases had ever been reported from China, a gap the researchers attribute to limited regional awareness rather than true rarity.

The six children in the new series, all boys, were seen at the Children’s Hospital of Nanjing Medical University and the Children’s Hospital Affiliated to Shandong University between April 2019 and September 2025. Every one of them was born small for gestational age and every one showed persistent postnatal growth retardation. Their reasons for referral varied widely: one nine-and-a-half-year-old came in with testicular enlargement and pubic hair; a three-month-old arrived with poor feeding and floppy muscle tone; an eleven-year-old sought help for short stature and rapidly progressing puberty; another three-year-old presented with speech delay and features suggestive of autism; a three-month-old was referred for craniosynostosis, the premature fusion of skull sutures; and a final three-year-old simply was not growing.

The diagnostic workup followed a two-tier strategy that the authors argue should become standard practice. Whole exome sequencing served as the first screen, casting a wide net across the protein-coding genome. When sequencing revealed regions of homozygosity on chromosome 14, stretches of DNA inherited identically from both parents that signal uniparental disomy, or when clinical suspicion remained high despite negative results, the team turned to methylation-specific multiplex ligation-dependent probe amplification, or MS-MLPA. This assay uses the methylation-sensitive enzyme HhaI to compare digested and undigested DNA, quantifying methylation at fifteen probes within the 14q32 imprinting control region while simultaneously detecting copy number changes. Loss of methylation at the MEG3 probes, combined with either normal copy number or a deletion, confirmed the diagnosis in every child.

The molecular findings proved unexpectedly rich. Three patients had straightforward maternal uniparental disomy of chromosome 14, confirmed by tracing homozygous variants back to the mother’s chromosomes. One patient, whose exome sequencing was entirely negative, turned out to have a paternal epimutation, a pure chemical defect invisible to standard sequencing, which the authors cite as proof that a negative exome never rules out TS14. But the remaining two children carried far more: one harbored a de novo two-megabase deletion on 14q32 that removed not only the imprinted genes but also DYNC1H1, a gene linked to neurodevelopmental delay and autism-like features, while another carried a deletion encompassing YY1, associated with a distinct syndrome involving craniosynostosis. A sixth child, through maternal uniparental disomy, had unmasked a homozygous variant in GALC, the gene behind late-onset Krabbe disease. These co-occurring defects, the authors suggest, may create blended phenotypes in which features from two genetic diagnoses intertwine, complicating any attempt to attribute symptoms to TS14 alone.

Treatment outcomes added a cautiously optimistic note. The boy with central precocious puberty received a gonadotropin-releasing hormone analog to suppress his early puberty, followed by recombinant human growth hormone at a dose standard for children born small for gestational age. Over eighteen months of combined therapy, his height climbed from 1.75 standard deviations below the mean to just 0.75 below, a gain of a full standard deviation score. The eleven-year-old, treated with a long-acting weekly growth hormone formulation, gained 1.74 standard deviation scores over two and a half years. Neither child experienced serious side effects, though the first developed mild, recurrent low thyroxine levels that responded to a small dose of levothyroxine, a known consequence of growth hormone therapy on the thyroid axis.

The literature review painted a broader and more sobering picture. Across 167 molecularly confirmed cases, the core features held remarkably steady across ethnicities: small size at birth, growth failure, low tone, early puberty, and characteristic facial features such as a broad forehead and a fleshy nasal tip. Yet Asian patients showed notably lower rates of facial dysmorphism and obesity, and higher rates of micropenis and cryptorchidism, differences the authors attribute partly to variation in diagnostic practice and reporting. Adult height data, available for only a small subset excluding Japanese cohorts, revealed a median final height of 3.15 standard deviations below the mean, with untreated patients faring worst at a median of minus 3.3, and some individuals reaching adult heights as low as minus 3.3 standard deviations. Treated patients, by contrast, reached a median of minus 1.88, though the authors are careful to stress that this unadjusted comparison may simply reflect that the shortest children were the ones selected for therapy.

That caution threads through the entire paper. Growth hormone and puberty-blocking therapy appear to improve growth velocity in the short term, and longer-term follow-up from Dutch and Japanese cohorts suggests meaningful gains, with one study reporting a mean improvement of 1.76 standard deviation scores after five years of treatment. But no prospective controlled trials exist, the optimal timing of therapy remains unknown, and whether treatment ultimately normalizes adult height is still an open question. The authors also note that apparent inconsistencies in the literature, such as untreated patients achieving near-final heights comparable to treated ones, may stem from selection bias, since children with milder short stature are less likely to be treated at all.

What the study delivers most clearly is a diagnostic roadmap. For any child presenting with small size at birth, persistent growth failure, low muscle tone, feeding difficulties, or unexplained early puberty, TS14 deserves a place on the differential list, and methylation-specific testing of the 14q32 region should be pursued even when exome sequencing comes back clean. The six Chinese cases, including three with additional molecular findings that would have been invisible a decade ago, demonstrate how comprehensive genomic testing can untangle overlapping diagnoses and refine the clinical picture. As awareness grows, the researchers hope, fewer children will wait years for answers, and the questions about how best to treat them can finally be studied properly.

Subject of Research: Temple syndrome, a rare chromosome 14q32 imprinting disorder, characterized in Chinese children through a case series and literature review

Article Title: Temple syndrome in Chinese children: a case series and literature review

Article References: Yuan, Y., Chen, Y., Zhu, Z., Liu, C., Zheng, B., Zhou, W., Wang, C., Gu, W., & Wu, S. (2026). Temple syndrome in Chinese children: a case series and literature review. Frontiers in Endocrinology, 17, Article 1871637. https://doi.org/10.3389/fendo.2026.1871637

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1871637

Keywords: Temple syndrome, TS14, imprinting disorder, chromosome 14q32, uniparental disomy, methylation, growth hormone, precocious puberty, whole exome sequencing, MS-MLPA, pediatric endocrinology, small for gestational age