Short Stature Research Articles

Anthropometrics and cancer prognosis: a multi-center cohort study.

Anthropometric indicators have been shown to be associated with the prognosis of patients with cancer. However, any single anthropometric index has limitation in predicting the prognosis. This study aimed to observe the predictive role of seven anthropometric indicators based on body size on the prognosis of patients with cancer. A principal component analysis (PCA) on seven anthropometric measurements: height, weight, body mass index (BMI), hand grip strength (HGS), triceps skinfold thickness (TSF), mid-upper arm circumference (MAC), and calf circumference (CAC) was conducted. Principal components (PCs) were derived from this analysis. Cox regression analysis was used to investigate the association between the prognosis of patients with cancer and the PCs. Subgroups and sensitivity analyses were also conducted. Through PCA, four distinct PCs were identified, collectively explaining 88.3% of the variance. PC1, primarily characterized by general obesity, exhibited a significant inverse association with the risk of cancer death (adjusted HR=0.86, 95% CI (0.83, 0.88)). PC2 (short stature with high TSF) was not significantly associated with cancer prognosis. PC3 (high BMI coupled with low HGS) demonstrated a significant increase with the risk of cancer-related death (adjusted HR=1.08, 95% CI (1.05, 1.11)). PC4 (tall stature with high TSF) exhibited a significant association with increased cancer risk (adjusted HR=1.05, 95% CI (1.02, 1.07)). These associations varied across different cancer stages. The stability of the results was confirmed through sensitivity analyses. Different body sizes are associated with distinct prognostic outcomes in patients with cancer. The impact of BMI on prognosis is influenced by both HGS and subcutaneous fat. This finding may influence the clinical care of cancer and improve the survival of cancer patients.

Additive association of blood pressure and short stature with stroke incidence in 450,000 Japanese adults: the Shizuoka study.

Short stature was suggested to be a risk factor for cardiovascular events. Because short stature increases central blood pressure, this study aimed to investigate a longitudinal association between short stature, blood pressure, and incidence of cardiovascular disease by the analysis of insurance-based real-world dataset. We analyzed data from 463,844 adults aged 40 or older with a mean age of 66.7 enrolled in National Health Insurance, excluding individuals who experienced a stroke or myocardial infarction, or required long-term care. Data from annual health checkups were used to obtain baseline clinical information. Comorbidities and incidences of stroke and myocardial infarction were obtained from the insurance data. During a 5.5-year follow-up period, we observed 11,027 cases of stroke. Adults of a short stature exhibited a higher incidence rate in both men (≤155 cm: 99.7, >175 cm: 24.4) and women (≤140 cm: 85.9, >160 cm: 13.7). Although those in the short stature group had higher blood pressure, and often took antihypertensive drugs, the inverse association between height and stroke incidence was independent of these factors (hazard ratio for 5 cm shorter in height; men: 1.06 [1.03-1.09], women: 1.11 [1.06-1.13]). Short stature and blood pressure showed additive association with stoke incidence (log-rank p < 0.001). No significant association was observed with myocardial infarction (men: 1.01 [0.95-1.06], women: 1.06 [0.98-1.14]). In a longitudinal analysis of a large general Japanese population, short stature was linked to an increased risk of stroke in both genders in any blood pressure range.

Understanding the burden of teenage pregnancy: A five-year analysis at a tertiary care center of northern Karnataka in India

: The present study was planned to comprehensively investigate the epidemiological aspects and clinical feto-maternal outcomes associated with teenage pregnancy, to provide a holistic understanding of teenage pregnancy and the possible solutions. : This is retrospective record-based research conducted over a five-year period, spanning from January 2018 to December 2022, in the department of Obstetrics and Gynaecology of a tertiary care centre in northern part of Karnataka, India. The teenage pregnancy was considered as all pregnancies that occurred in women aged between 13 to 19 years who visited the institute for delivery during the study period. A comprehensive analysis was conducted, encompassing various facets of their antenatal experiences, delivery methods, postpartum complications, as well as the well-being of the new-borns. : A total of deliveries 52,715 deliveries had been recorded in our institute during the study period. Among these deliveries, 1,754 were among teenagers, resulting in a prevalence rate of 3.33%. Nearly one-fifth (19.16%) of teenage mothers were short stature whereas only 7.02% of adult mothers were short stature. The relatively higher proportion of teenage mothers were underweight. Maternal and fetal complication were comparatively higher among teenage mothers whereas caesarean sections were relatively more among adult mothers. : The present study emphasizes the importance of targeted healthcare interventions, including improved prenatal care, nutritional support, and education for teenage mothers, to mitigate these risks and improve the overall health and well-being of both mothers and their infants.

A case of a syndrome characterized by short stature, and developmental delay caused by heterozygous variation in the FOXP4 gene

A case of a syndrome characterized by short stature, and developmental delay caused by heterozygous variation in the FOXP4 gene

Growth patterns by birth size of preterm children born at 24-29 gestational weeks for the first 3 years.

Concerns are prevalent about preterm infant long-term growth regarding plotting low on growth charts at discharge, stunting, underweight, high body fat and subsequent cardiometabolic morbidities. To examine (a) longitudinal growth patterns of extremely and very preterm infants to 3 years corrected age (CA) (outcome), categorised by their birthweight for gestational age: small, appropriate and large for gestational age (SGA, AGA and LGA, respectively) (exposure); and (b) the ability of growth faltering (<-2 z-scores) to predict suboptimal cognitive scores at 3 years CA. Post-discharge head, length, weight and weight-4-length growth patterns of the PreM Growth cohort study infants born <30 weeks and < 1500 g, who had dietitian and multi-disciplinary support before and after discharge, were plotted against the World Health Organization growth standard. Infants with brain injuries, necrotising enterocolitis and bronchopulmonary dysplasia were excluded. Of the included 405 infants, the proportions of infants with anthropometric measures > - 2 z-scores improved with age. The highest proportions <-2 z-scores for length (24.2%) and weight (24.0%) were at 36 gestational weeks. The proportion with small heads waslow by 0 months CA (1.8%). By 3 years CA, only a few children plotted lower than -2 z-scores for length, weight-4-length and weight (<6%). After zero months CA, high weight-4-length and body mass index > + 2 z-scores were rare (2.1% at 3 years CA). Those born SGA had higher proportions with shorter heights (16.7% vs. 5.2%) and lower weights (27.8% vs. 3.5%) at 3 years CA compared to those born AGA. The ability of growth faltering to predict cognitive scores was limited (AUROC 0.42, 95% CI 0.39, 0.45 to 0.52, 95% CI 0.41, 0.63). Although children born <30 weeks gestation without major neonatal morbidities plot low on growth charts at 36 weeks CA most catch up to growth chart curves by 3 years CA.

Heightism, growth hormone treatment, and social functioning: a holistic approach to a persistent clinical challenge.

Use of recombinant human growth hormone (rhGH) treatment to increase height in children with non-growth hormone deficient short stature is becoming more common. Yet, the evidence to support the notion that augmenting height directly leads to increased well being, specifically psychosocial well being, is inconsistent, with high-quality evidence lacking. Review of recent studies demonstrates that the association between height augmentation and psychosocial well being is complex. The direct contribution of height to well being may be less than the current model of clinical care of short stature assumes. Rather, the new studies provide evidence to support a role for psychosocial factors, including height-related beliefs, social support, and coping skills, in promoting psychosocial well being, specifically quality of life and self-esteem. Clinical care of short stature would benefit from incorporating a holistic model of care that considers psychosocial interventions in addition to, or instead of, rhGH treatment.

FBXO11 variants are associated with intellectual disability and variable clinical manifestation in Chinese affected individuals.

F-box protein 11 (FBXO11) is a member of F-Box protein family, which has recently been proved to be associated with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA, OMIM: 618089). In this study, 12 intellectual disability individuals from 5 Chinese ID families were collected, and whole exome sequencing (WES), sanger sequencing, and RNA sequencing (RNA-seq) were conducted. Almost all the affected individuals presented with mild to severe intellectual disability (12/12), global developmental delay (10/12), speech and language development delay (8/12) associated with a range of alternate features including increased body weight (7/12), short stature (6/12), seizures (3/12), reduced visual acuity (4/12), hypotonia (1/12), and auditory hallucinations and hallucinations (1/12). Distinguishingly, malformation was not observed in all the affected individuals. WES analysis showed 5 novel FBXO11 variants, which include an inframe deletion variant, a missense variant, two frameshift variants, and a partial deletion of FBXO11 (exon 22-23). RNA-seq indicated that exon 22-23 deletion of FBXO11 results in a new mRNA structure. Conservation and protein structure prediction demonstrated deleterious effect of these variants. The DEGs analysis revealed 148 differentially expressed genes shared among 6 affected individuals, which were mainly associated with genes of muscle and immune system. Our research is the first report of FBXO11-associated IDDFBA in Chinese individuals, which expands the genetic and clinical spectrum of this newly identified NDD/ID syndrome.

Detection of genetic mutations underlying early-onset systemic lupus erythematosus.

We aimed to investigate the presence of monogenic causes of systemic lupus erythematosus (SLE) in our early-onset SLE patients. Fifteen pediatric SLE cases who had early disease onset (≤6 years) were enrolled in this study. All patients fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) criteria. Genomic DNA was used for whole exome sequencing (WES). Pathogenic variants were confirmed by Sanger sequencing. The median age at diagnosis of 15 early-onset SLE patients included in the study was 4 (2-6) years (F/M = 12/3). Significant gene mutations were detected in five of these patients (33.3%). Patients 1 and 2 with homozygous DNASE1L3 mutations [c.320+4_320+7del and G188A (c.563G>C) variants] had skin involvement and oral ulcers. One of them (patient 1) had arthritis and nephritis, and another (patient 2) had nonscarring alopecia and thrombocytopenia. They are currently clinically inactive but have positive serological findings. Patient 3 with homozygous pathogenic ACP5 mutation [G109R (c.325G>A) variant] had arthritis, nephritis, short stature, and skeletal dysplasia. Patient 4 with a heterozygote novel IFIH1 mutation [L809F (c.2425C>T) variant] had skin findings and leukopenia. Patient 5 with novel C1S variant [homozygous C147W (c.441C>G) variant] had marked skin findings, oral ulcers, nonscarring alopecia, pancytopenia, and low total hemolytic complement CH50 level. All patients have responded to the treatments and have low Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, on therapy. Genetic causes should be investigated in early-onset SLE, for better management and genetic counseling. On the other hand, multicenter studies may help to further define genotype-phenotype associations.

Megalencephaly: Classification, Genetic Causes, and Related Syndromes

AbstractMegalencephaly is a developmental disorder due to an abnormal neuronal proliferation and migration during intrauterine or postnatal brain development that leads to cerebral overgrowth and neurological dysfunction. This cerebral overgrowth may affect the whole encephalon or only a region; when it involves one hemisphere it is referred to as hemimegalencephaly. Megalencephaly presents with a head circumference measurement of 2 standard deviations above the average measure for age. This group of disorders is clinically characterized by early onset and refractory to therapy epilepsy, neurodevelopmental disorders, behavioral problems, and autism spectrum disorder. Syndromic forms of megalencephaly should be considered when associated with other congenital abnormalities. Megalencephaly in fact could be associated with segmental overgrowth and cutaneous/vascular abnormalities (i.e., Proteus syndrome, CLOVES [congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis, and/ or skeletal abnormalities] syndrome, Klippel-Trenaunay syndrome, megalencephaly-capillary malformation-polymicrogyria syndrome , megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus syndrome, etc.) or generalized overgrowth (i.e., Weaver or Beckwith-Wiedemann syndrome) as well as with nanism in achondroplasia where megalencephaly is associated with disproportionate short stature, primary skeletal dysplasia, characteristic facies (prominent forehead, flat nasal bridge), narrow chest, and normal intelligence. It is possible to identify three main groups of disorders associated with megalencephaly: idiopathic or benign, metabolic, and anatomic. The idiopathic (benign) form indicates an abnormal increased head circumference in absence of neurological impairment, such as in benign familial megalencephaly. In metabolic megalencephaly (such as in organic acid disorders, metabolic leukoencephalopathies, or lysosomal diseases) there is an increase of different constituents that increase the size of the brain, whereas in the anatomical form there are underlying genetic causes. Neuroimaging is crucial for diagnosis, as it can reveal a generalized brain growth or a segmental one and possible specific frameworks associated. In all these conditions it is necessary to identify possible microdeletion-microduplication by chromosomal arrays.

Role of Ayurvedic Herbs in the Management of Celiac Disease

Celiac disease or gluten-sensitive enteropathy is an autoimmune hypersensitivity disorder affecting the small intestine. It occurs due to an inappropriate immune reaction to gluten, which results in inflammation and damage to the small intestine. One of the most prevalent illnesses, celiac disease, is brought on by both environmental (gluten) and genetic causes of human leukocyte antigen (HLA) and non-HLA genes. The prevalence of celiac disease has been estimated to approximate 0.5%-1% in different parts of the world. Due to improved physician awareness and expertise, as well as the widespread use of extremely sensitive and precise diagnostic tests for celiac disease, the prevalence of celiac disease has considerably grown in the past 30 years. While older children have either limited or unusual symptoms, only a small percentage of celiac patients have the classic signs of the condition like chronic or intermittent diarrhea, failure to thrive, weight loss, delayed puberty, short stature, nausea, vomiting, chronic abdominal pain, abdominal distension, chronic constipation. Early detection of celiac disease is crucial to preventing long-term consequences. According to Ayurveda, some symptoms of celiac disease found in Grahani Dosha. Grahani is described as an Agni Adhisthana by most of Acharya. Mandagini is the root cause of Ama Dosha, and it is a crucial factor for the manifestation of most diseases. The treatment approach of celiac disease in Ayurveda medicinal science involves the intake of various preparations of some specific medicinal plants like Kutaja (Holarrhena antidysenterica) Pippali, (Piper longum Linn.), Chitraka, (Plumbago zeylanica) Guduchi, (Tinospora cordifolia) Ashwagandha, (Withania somnifera), Haridra (Curcuma longa Linn.), etc which have Agni Deepana and Ama Pachana properties. These illness-specific medicinal herbs help normalize digestive fire and evict "Ama" toxins from the body channels, which pacify the vitiated Agni and maintain homeostasis among vitiated Doshas.

Analysis of a child with SPONASTRIME dysplasia due to compound heterozygous variants of TONSL gene

To explore the clinical features and genetic etiology of a child with SPONASTRIME dysplasia (SD). A 9-month-old female who had presented at the Linyi People's Hospital in August 2022 for short stature was selected as the study subject. Clinical data of the child were collected, and whole exome sequencing (WES) was carried out. Sanger sequencing was used for validating the candidate variants. The child has manifested short stature, mid-face hypoplasia, joint laxity, internal knee rotation, irregularities in the metaphysis of long bones, and flat and concave lumbar vertebrae. WES revealed that she has harbored compound heterozygous variants of the TONSL gene, namely c.3088G>T (p.Glu1030*) and c.3053G>A (p.Arg1018His), which were inherited from her phenotypically normal parents. Neither variant was reported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.3088G>T variant was classified as likely pathogenic (PVS1+PM2_Supporting), whilst the c.3053G>A was classified as a variant of uncertain significance (PM2_Supporting+PM3+PP3). The c.3088G>T and c.3053G>A compound heterozygous variants of the TONSL gene probably underlay the pathogenesis in this patient. Above finding has facilitated the clinical diagnosis and genetic counseling for her family.

Clinical and genetic analysis of a patient with short stature due to variant of RPL13 gene

To analyze the clinical phenotype and genetic characteristics of a patient with Isidor-Toutain spinal epiphyseal dysplasia (SEMD) due to variant of RPL13 gene. A pregnant woman at 18 weeks of gestation who had presented at Quzhou Maternal and Child Health Care Hospital on January 14, 2023 was selected as the study subject. Whole exome sequencing (WES) was carried out for the patient, and candidate variant was validated by Sanger sequencing and bioinformatic analysis. The woman was 37 years old with extremely short stature (135 cm) and "O" shaped legs. WES revealed that she has harbored a c.548G>C (p.Arg183Pro) missense variant of the RPL13 gene (NM_000977.4). The same variant was not found in her fetus. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS4+PM2_Supporting+PP3+PP4). Isidor-Toutain type SEMD due to variants of the RPL13 gene may have variable expressivity and diverse clinical phenotypes. Above finding has facilitated the differential diagnosis and genetic counseling for this family.

Insulin-like growth factor 1 and sex hormones for assessment of anthropometric and pubertal growth of Egyptian children and adolescents with type 1 diabetes mellitus (single center study)

BackgroundThis study aimed to assess the anthropometric measures and pubertal growth of children and adolescents with Type 1 diabetes mellitus (T1DM) and to detect risk determinants affecting these measures and their link to glycemic control.Patients and methodsTwo hundred children and adolescents were assessed using anthropometric measurements. Those with short stature were further evaluated using insulin-like growth factor 1 (IGF-1), bone age, and thyroid profile, while those with delayed puberty were evaluated using sex hormones and pituitary gonadotropins assay.ResultsWe found that 12.5% of our patients were short (height SDS < -2) and IGF-1 was less than -2 SD in 72% of them. Patients with short stature had earlier age of onset of diabetes, longer duration of diabetes, higher HbA1C and urinary albumin/creatinine ratio compared to those with normal stature (p < 0.05). Additionally, patients with delayed puberty had higher HbA1c and dyslipidemia compared to those with normal puberty (p < 0.05). The regression analysis revealed that factors associated with short stature were; age at diagnosis, HbA1C > 8.2, and albumin/creatinine ratio > 8 (p < 0.05).ConclusionChildren with uncontrolled T1DM are at risk of short stature and delayed puberty. Diabetes duration and control seem to be independent risk factors for short stature.

Case Report: Identification of a novel PRR12 variant in a Chinese boy with developmental delay and short stature

Proline Rich 12 (PRR12) protein is primarily expressed in the brain and localized in the nucleus. The variants in the PRR12 gene were reported to be related to neuroocular syndrome. Patients with PRR12 gene presented with intellectual disability (ID), neuropsychiatric disorders, some congenital anomalies, and with or without eye abnormalities. Here, we report an 11-year-old boy with a novel PRR12 variant c.1549_1568del, p.(Pro517Alafs*35). He was the first PRR12 deficiency patient in China and presented with ID, short stature, and mild scoliosis. He could not concentrate on his studies and was diagnosed with attention deficit hyperactivity disorder (ADHD). The insulin-like growth factor 1 (IGH-1) was low in our patient, which may be the cause of his short stature. Patients with neuroocular syndrome are rare, and further exploration is needed to understand the reason for neurodevelopmental abnormalities caused by PRR12 variants. Our study further expands on the PRR12 variants and presents a new case involving PPR12 variants.

Challenges in the Surgical Orthopedic Treatment of Long Bone Fracture in a Rare Case of Pycnodysostosis

Pycnodysostosis is a rare autosomal recessive disorder caused by an inactivating mutation in cathepsin K (CTSK) and characterized by dysmorphic facial features, a short stature, acro-osteolysis, osteosclerosis with increased bone fragility, and delayed closure of cranial sutures. Although the satisfying healing potential, many issues exist in managing fractures in pycnodysostosis patients. In this paper, we report the challenges faced in managing a fracture of the femoral shaft in a 14-year-old boy coming from a low-income family. The patient was administered to the Paediatric Surgical Emergency Department of the Children's Hospital in Rabat for the management of a closed fracture of the left femur. Despite being of small stature with dysmorphic facial features, a prominent forehead, and brachydactyly, he never had a medical consultation before. The patient then underwent a surgical reduction. We attempted titanium elastic nail fixation, but metaphyseal drilling was not feasible due to the high bone density, and the narrow medullary canal eliminated this option. Therefore we opted for the palate fixation. Sclerotic bone made drilling extremely difficult. The postoperative fracture was successfully healed.

Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a mouse model of Snyder-Robinson syndrome.

Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene, which encodes spermine synthase, and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle tone/hypotonia and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human gene variants and disease presentations. Here, we evaluated molecular and neurological presentations in the G56S mouse model, which carries a missense mutation in the Sms gene. The lack of SMS protein in the G56S mice resulted in increased spermidine/spermine ratio, failure to thrive, short stature and reduced bone density. They showed impaired learning capacity, increased anxiety, reduced mobility and heightened fear responses, accompanied by reduced total and regional brain volumes. Furthermore, impaired mitochondrial oxidative phosphorylation was evident in G56S cerebral cortex, G56S fibroblasts and Sms-null hippocampal cells, indicating that SMS may serve as a future therapeutic target. Collectively, our study establishes the suitability of the G56S mice as a preclinical model for SRS and provides a set of molecular and functional outcome measures that can be used to evaluate therapeutic interventions for SRS.

Preliminary investigation into the genetic etiology of short stature in children through whole exon sequencing of the core family.

A comprehensive survey was carried out to investigate the genetic etiology of short stature in children by whole exon sequencing of a core family cohort to find and study mutations in multiple genes to assess their potential correlations to low height in children. The study included 56 pediatric patients from the Department of Pediatrics at the Zhangzhou Affiliated Hospital of Fujian Medical University. The participants met strict inclusion criteria, including age, Han Chinese ethnicity, low height standard deviation score, and the absence of known causes for short stature. Core pedigrees were identified using exome sequencing. After sequencing, variations were categorized and interpreted according to a variety of factors, including inheritance, location, type, and disease-causing gene databases. Variants were verified by Sanger sequencing. Most of the 97 gene mutations were missense. ACAN, PHEX, and COL2A1 were the most common gene mutations. Copy number variations were identified, particularly associated with the PHEX gene. Protein functional studies revealed that the mutations had a considerable influence on disease-promoting damage. The chromosomal locations with the highest enrichment of these genes were chr12, chr5, and chr2. In conclusion, the study revealed numerous genetic changes that may substantially impact physiological processes and disease. These findings establish the basis for further investigations into their diagnostic and therapeutic capabilities.

A Rare Consanguineous Case of Alazami Syndrome in a Jordanian Family: Clinical Presentation, Genetic Analysis, and Therapeutic Approaches - A Case Report

Objective: Alazami syndrome (AS) is an infrequent genetic disorder inherited in an autosomal recessive pattern, characterized by the presence of multiple congenital abnormalities. This study explores a case of a 4-year-old girl with AS, examining symptoms, genetic factors, and treatment efficacy. Case report: A 4-year-old girl, born to consanguineous Jordanian parents, displayed dysmorphic features including low birth weight, microcephaly, hyperthyroidism, short stature, blue sclera, triangular-shaped face, deep-set eyes, narrow palpebral fissures, and a prominent forehead. Examination revealed height (92 cm) and weight (7.7 kg) below the 5th and 3rd percentiles respectively. Blood tests and renal ultrasound were normal. Whole exome sequencing (WES) identified a homozygous eight-base pair deletion within exon 5 of the LARP7 gene on chromosome 4q25, confirming the diagnosis of AS, an autosomal recessive disorder. This variant induces frameshift mutations leading to premature stop codons, suggesting a probable mechanism of illness via loss of function. Treatment involving growth monitoring and therapy led to significant improvements in height, weight, and communication skills within three months. Conclusion: We describe a rare autosomal recessive AS case due to consanguinity, with a frameshift mutation in the LARP7 gene found via WES. Our AS treatment program effectively alleviates symptoms and enhances developmental progress.

IntraCardiac echocardiography-guided leaflet modification for coronary protection prior to transcatheter valve-in-valve replacement.

A 79-year-old man with a failed 25-mm CE Magna Ease 3300 surgical prosthesis (Edwards Lifesciences) and of high re-operative surgical risk (STS 8%) presented with dyspnea, NYHA III. Cardiac computed tomography angiography revealed anatomy that was high risk for coronary occlusion with a short right coronary artery height of 6 mm and a valve-to-coronary distance of 2 mm.

Novel 14q32.2 paternal deletion encompassing the whole DLK1 gene associated with Temple syndrome

BackgroundTemple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal expressed genes and a silencing the paternally expressed genes in the 14q32 imprinted domain. Classical TS14 phenotypic features include pre- and postnatal short stature, small hands and feet, muscular hypotonia, motor delay, feeding difficulties, weight gain, premature puberty along and precocious puberty.MethodsAn exon array comparative genomic hybridization was performed on a patient affected by psychomotor and language delay, muscular hypotonia, relative macrocephaly, and small hand and feet at two years old. At 6 years of age, the proband presented with precocious thelarche. Genes dosage and methylation within the 14q32 region were analyzed by MS-MLPA. Bisulfite PCR and pyrosequencing were employed to quantification methylation at the four known imprinted differentially methylated regions (DMR) within the 14q32 domain: DLK1 DMR, IG-DMR, MEG3 DMR and MEG8 DMR.ResultsThe patient had inherited a 69 Kb deletion, encompassing the entire DLK1 gene, on the paternal allele. Relative hypermethylation of the two maternally methylated intervals, DLK1 and MEG8 DMRs, was observed along with normal methylation level at IG-DMR and MEG3 DMR, resulting in a phenotype consistent with TS14. Additional family members with the deletion showed modest methylation changes at both the DLK1 and MEG8 DMRs consistent with parental transmission.ConclusionWe describe a girl with clinical presentation suggestive of Temple syndrome resulting from a small paternal 14q32 deletion that led to DLK1 whole-gene deletion, as well as hypermethylation of the maternally methylated DLK1-DMR.