TGF-ß and BMP Signaling Pathways in Skeletal Dysplasia with Short and Tall Stature.

The transforming growth factor ß (TGF-ß) and bone morphogenetic protein (BMP) signaling pathways play a pivotal role in bone development and skeletal health. More than 30 different types of skeletal dysplasia are now known to be caused by pathogenic variants in genes that belong to the TGF-ß superfamily and/or regulate TGF-ß/BMP bioavailability. This review describes the latest advances in skeletal dysplasia that is due to impaired TGF-ß/BMP signaling and results in short stature (acromelic dysplasia and cardiospondylocarpofacial syndrome) or tall stature (Marfan syndrome). We thoroughly describe the clinical features of the patients, the underlying genetic findings, and the pathomolecular mechanisms leading to disease, which have been investigated mainly using patient-derived skin fibroblasts and mouse models. Although no pharmacological treatment is yet available for skeletal dysplasia due to impaired TGF-ß/BMP signaling, in recent years advances in the use of drugs targeting TGF-ß have been made, and we also discuss these advances.

Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.

ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

An integrative skeletal and paleogenomic analysis of stature variation suggests relatively reduced health for early European farmers.

Human culture, biology, and health were shaped dramatically by the onset of agriculture ∼12,000 y B.P. This shift is hypothesized to have resulted in increased individual fitness and population growth as evidenced by archaeological and population genomic data alongside a decline in physiological health as inferred from skeletal remains. Here, we consider osteological and ancient DNA data from the same prehistoric individuals to study human stature variation as a proxy for health across a transition to agriculture. Specifically, we compared "predicted" genetic contributions to height from paleogenomic data and "achieved" adult osteological height estimated from long bone measurements for 167 individuals across Europe spanning the Upper Paleolithic to Iron Age (∼38,000 to 2,400 B.P.). We found that individuals from the Neolithic were shorter than expected (given their individual polygenic height scores) by an average of −3.82 cm relative to individuals from the Upper Paleolithic and Mesolithic (P = 0.040) and −2.21 cm shorter relative to post-Neolithic individuals (P = 0.068), with osteological vs. expected stature steadily increasing across the Copper (+1.95 cm relative to the Neolithic), Bronze (+2.70 cm), and Iron (+3.27 cm) Ages. These results were attenuated when we additionally accounted for genome-wide genetic ancestry variation: for example, with Neolithic individuals −2.82 cm shorter than expected on average relative to pre-Neolithic individuals (P = 0.120). We also incorporated observations of paleopathological indicators of nonspecific stress that can persist from childhood to adulthood in skeletal remains into our model. Overall, our work highlights the potential of integrating disparate datasets to explore proxies of health in prehistory.

Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome.

Latent transforming growth factor ß (TGFß)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGFß in the extracellular matrix (ECM) as well as for correct assembly of ECM components. Variants in LTBP2, LTBP3, and LTBP4 have been identified in several autosomal recessive Mendelian disorders with skeletal abnormalities with or without impaired development of elastin-rich tissues. Thus far, the human phenotype associated with LTBP1 deficiency has remained enigmatic. In this study, we report homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families. Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly). In vitro studies on proband-derived dermal fibroblasts indicate distinct molecular mechanisms depending on the position of the variant in LTBP1. C-terminal variants lead to an altered LTBP1 loosely anchored in the microfibrillar network and cause increased ECM deposition in cultured fibroblasts associated with excessive TGFß growth factor activation and signaling. In contrast, N-terminal truncation results in a loss of LTBP1 that does not alter TGFß levels or ECM assembly. In vivo validation with two independent zebrafish lines carrying mutations in ltbp1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. In addition, one of the mutant zebrafish lines shows voluminous and hypo-mineralized vertebrae. Overall, our findings in humans and zebrafish show that LTBP1 function is crucial for skin and bone ECM assembly and homeostasis.

Exome Sequencing Identifies Multiple Genetic Diagnoses in Children with Syndromic Growth Disorders.

OBJECTIVE: To evaluate the presence of multiple genetic diagnoses in syndromic growth disorders. STUDY DESIGN: We carried out a cross-sectional study to evaluate 115 patients with syndromic tall (n = 24) or short stature (n = 91) of unknown cause from a tertiary referral center for growth disorders. Exome sequencing was performed to assess germline single nucleotide, InDel, and copy number variants. All variants were classified according to ACMG/AMP guidelines. The main outcome measured was the frequency of multiple genetic diagnoses in a cohort of children with syndromic growth disorders. RESULTS: The total diagnostic yield of the cohort was 54.8% (63/115). Six patients had multiple genetic diagnoses (tall stature group = 2; short stature group = 4). The proportion of multiple diagnoses within total cases was 5.2% (6/115), and within solved cases was 9.5% (6/63). No characteristics were significantly more frequent when compared with patients with single or multiple genetic findings. Among patients with multiple diagnoses, 3 had syndromes with overlapping clinical features, and the others had syndromes with distinct phenotypes. CONCLUSION: Recognition of multiple genetic diagnoses as a possibility in complex cases of syndromic growth disorders opens a new perspective on treatment and genetic counseling for affected patients, defying the medical common sense of trying to fit all findings into one diagnosis.

Clinical and genetic investigation of 14 families with various forms of short stature syndromes.

Skeletal dysplasias are a heterogeneous group of disorders presenting mild to lethal defects. Several factors, such as genetic, prenatal, and postnatal environmental may contribute to reduced growth. Fourteen families of Pakistani origin, presenting the syndromic form of short stature either in the autosomal recessive or autosomal dominant manner were clinically and genetically investigated to uncover the underlying genetic etiology. Homozygosity mapping, whole exome sequencing, and Sanger sequencing were used to search for the disease-causing gene variants. In total, we have identified 13 sequence variants in 10 different genes. The variants in the HSPG2 and XRCC4 genes were not reported previously in the Pakistani population. This study will expand the mutation spectrum of the identified genes and will help in improved diagnosis of the syndromic form of short stature in the local population.

Is human height based on a Lucas sequence relationship between the foot height, tibial length, femur length and upper body length?

This is a retrospective chart and radiographic review of 145 patients who underwent full-body EOS imaging; 109 males and 36 females. The mean ages of the female and male subsets are 28.8 (SD = 11.6) years and 29.5 (SD = 11.8) years, respectively. The sum of the foot height (Ft) and the tibial length (T) for each subject was compared to their femur length (Fe). Subsequently, the sum of the tibial (T) and femoral lengths (Fe) were compared to their respective upper body lengths (UB), as measured from the tops of the femoral heads. A linear regression test was performed to determine whether a Lucas sequence-based relationship exists between Ft + T and Fe, and between T + Fe and UB. The regression for the relationship between Ft + T and Fe for the entire cohort (R = 0.82, R2 = 0.70), the female subset (R = 0.94, R2 = 0.88) and the male subset (R = 0.75, R2 = 0.57), all demonstrated a strong positive correlation between Ft + T and Fe and showed that Ft + T is a likely predictor of Fe. The regression test for the entire cohort demonstrated a moderately positive correlation between T + Fe and UB (R = 0.41, R2 = 0.17, F(1, 145) = 29.42, p = 2.4E-07). A stronger correlation was found for the relationship between T + Fe and UB (R = 0.57, R2 = 0.32, F(1, 35) = 16.64, p = 2.5E-05) for the female subset relative to the male subset (R = 0.20, R2 = 0.038, F(1, 35) = 4.37, p = 0.04). There appears to be a Lucas sequence relationship between the lengths of the foot height, tibial length, femoral length and upper body length, which together make up standing height. This mathematical proportion relationship is stronger in females than males.

Ciliopathies are responsible for short stature and insulin resistance: A systematic review of this clinical association regarding SOFT syndrome.

SOFT syndrome (Short stature-Onychodysplasia-Facial dysmorphism-hypoTrichosis) is a rare primordial dwarfism syndrome caused by biallelic variants in POC1A encoding a centriolar protein. To refine the phenotypic spectrum of SOFT syndrome, recently shown to include metabolic features, we conducted a systematic review of all published cases (19 studies, including 42 patients). The SOFT tetrad affected only 24 patients (57%), while all cases presented with short stature from birth (median height: -5.5SDS([-8.5]-[-2.8])/adult height: 132.5 cm(103.5-148)), which was most often disproportionate (90.5%), with relative macrocephaly. Bone involvement resulted in short hands and feet (100%), brachydactyly (92.5%), metaphyseal (92%) or epiphyseal (84%) anomalies, and/or sacrum/pelvis hypoplasia (58%). Serum IGF-I was increased (median IGF-I level: + 2 SDS ([-0.5]-[+ 3])). Recombinant human growth hormone (rhGH) therapy was stopped for absence/poor growth response (7/9 patients, 78%) and/or hyperglycemia (4/9 patients, 45%). Among 11 patients evaluated, 10 (91%) presented with central distribution of fat (73%), clinical (64%) and/or biological insulin resistance (IR) (100%, median HOMA-IR: 18), dyslipidemia (80%), and hepatic steatosis (100%). Glucose tolerance abnormalities affected 58% of patients aged over 10 years. Patients harbored biallelic missense (52.4%) or truncating (45.2%) POC1A variants. Biallelic null variants, affecting 36% of patients, were less frequently associated with the SOFT tetrad (33% vs 70% respectively, p = 0.027) as compared to other variants, without difference in the prevalence of metabolic abnormalities. POC1A should be sequenced in children with short stature, altered glucose/insulin homeostasis and/or centripetal fat distribution. In patients with SOFT syndrome, rhGH treatment is not indicated, and IR-related complications should be regularly screened and monitored.PROSPERO registration: CRD42023460876.

Inadequate linear catch-up growth in children born small for gestational age: Influencing factors and underlying mechanisms.

A minority of children born small for gestational age (SGA) may experience catch-up growth failure and remain short in adulthood. However, the underlying causes and mechanisms of this phenomenon are not yet fully comprehended. We reviewed the present state of research concerning the growth hormone-insulin-like growth factor axis and growth plate in SGA children who fail to achieve catch-up growth. Additionally, we explored the factors influencing catch-up growth in SGA children and potential molecular mechanisms involved. Furthermore, we considered the potential benefits of supplementary nutrition, specific dietary patterns, probiotics and drug therapy in facilitating catch-up growth.

Sugar-Sweetened Beverage Consumption and Height Loss in Adults: A Longitudinal Analysis in the EPIC-Norfolk Study.

BACKGROUND: Height loss in aging has been recognized to reflect a decline in musculoskeletal health but not investigated in relation to dietary factors, such as sugar-sweetened beverages (SSBs), the consumption of which may deteriorate musculoskeletal health. OBJECTIVES: This study aimed to evaluate the longitudinal association of habitual consumption of total SSBs and its subtypes with height loss and examine effect-modification by age, sex, and anthropometry. METHODS: We evaluated 16,230 adults aged 40-79 y in the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort. At baseline (1993-1997), SSB consumption (soft drinks, squashes, sweetened milk beverages, sweetened coffee/tea, and sweetened alcoholic beverages) was assessed using 7-d food diaries. Height was objectively measured at the baseline, second (1997-2000), and third (2004-2011) health checks. Multivariable linear regression was used to examine baseline SSB consumption and the rate of height change over the follow-up. RESULTS: The median (IQR) height change was -1.07 (-2.09 to -0.28) cm/10 y. Adjusted for potential confounders including behavioral factors, medications, and baseline body mass index (BMI), total SSB consumption was associated with height loss (ß: -0.024; 95% CI: -0.046, -0.001 cm/10 y per 250 g/d of SSB), and similar results were seen for the individual beverages, except for sweetened milk beverages (ß: +0.07; 95% CI: -0.16, 0.30), with wide CIs. No effect-modification by prespecified factors was evident, except for baseline BMI (P-interaction = 0.037). Total SSB consumption was associated with height loss (-0.038; 95% CI: -0.073, -0.004) in participants with BMI ≤ 25 kg/m2 but not apparently in those with BMI > 25 kg/m2. CONCLUSIONS: SSB consumption was modestly associated with height loss, particularly in adults with normal weight status.

Spondyloocular Syndrome: First Case of Rare Osseous and Ocular Syndrome from India with Novel Mutation and Expanded Phenotypic Spectrum.

Spondyloocular syndrome (SOS) is a rare autosomal recessive skeletal and ocular disorder with variable phenotypes. It is caused by pathogenic mutation in the XYLT2 gene, which encodes the enzyme xylo-transferase, necessary for the synthesis of proteoglycan. It is characterized by generalized osteoporosis, short stature, hearing impairment, eye abnormalities, and cardiac defects. Till date only 24 cases have been reported worldwide with no cases documented from India. We subjected the patient to relevant biochemical investigations and Dual Energy X-ray Absorptiometry (DEXA) scan along with Next Generation Clinical Exome Sequencing (NGCES). We report a case of 23-year-old male who presented with recurrent long bone fractures, congenital heart defects, eye abnormalities (bilateral corneal opacities and atrophic bulbi), and short stature. In addition, our patient also had genu valgum and right-sided hydrocele which have never been reported in SOS till date. On genetic analysis, NGCES revealed a novel pathogenic frameshift variant c.191_192 delCA, p.(Thr64fs*22) in the XYLT2 gene. The patient is doing well on six monthly zoledronic acid infusions.

LZTFL1, a rare cause of Bardet-Biedl syndrome: A new patient with severe short stature and moderate intellectual disability, more than casual associations?

Bardet-Biedl syndrome (BBS) is an inherited ciliopathy affecting multiple organs and systems with wide clinical and genetic heterogeneity. To date, biallelic variants of the LZTFL1 gene have been reported only in six patients with BBS. We identified a homozygous LZTFL1 nonsense variant in a boy presenting with classical BBS features. In addition, he showed a more pronounced cognitive impairment than previously reported subjects and severe short stature, matching the phenotype displayed by some other patients with LZTFL1 variants and lztfl1 knock-out mice. This case report contributes to a better understanding of the clinical spectrum associated with LZTFL1 pathogenic variants, and highlights possible genotype-phenotype correlations.

RMRP-related short stature: A report of six additional Japanese individuals with cartilage hair hypoplasia and literature review.

Biallelic pathogenic variants in RMRP, the gene encoding the RNA component of RNase mitochondrial RNA processing enzyme complex, have been reported in individuals with cartilage hair hypoplasia (CHH). CHH is prevalent in Finnish and Amish populations due to a founder pathogenic variant, n.71A > G. Based on the manifestations in the Finnish and Amish individuals, the hallmarks of CHH are prenatal-onset growth failure, metaphyseal dysplasia, hair hypoplasia, immunodeficiency, and other extraskeletal manifestations. Herein, we report six Japanese individuals with CHH from four families. All probands presented with moderate short stature with mild metaphyseal dysplasia or brachydactyly. One of them had hair hypoplasia and the other immunodeficiency. By contrast, the affected siblings of two families showed only mild short stature. We also reviewed all previously reported 13 Japanese individuals. No n.71A > G allele was detected. The proportions of Japanese versus Finnish individuals were 0% versus 70% for birth length < -2.0 SD, 84% versus 100% for metaphyseal dysplasia and 26% versus 88% for hair hypoplasia. Milder manifestations in the Japanese individuals may be related to the difference of genotypes. The mildest form of CHH phenotypes is mild short stature without overt skeletal alteration or extraskeletal manifestation and can be termed "RMRP-related short stature".

Indian patients with CHST3-related chondrodysplasia with congenital joint dislocations.

CHST3-related chondrodysplasia with congenital joint dislocations (CDCJD, #MIM 143095), is a rare genetic skeletal disorder caused by biallelic loss of function variants in CHST3. CHST3 is critical for the sulfation of chondroitin sulfate. This study delineates the clinical presentation of nine individuals featuring the key symptoms of CDCJD; congenital joint (knee and elbow) dislocations, short trunk short stature progressive vertebral anomalies, and metacarpal shortening. Additional manifestations include irregular distal femoral epiphysis, supernumerary carpal ossification centers, bifid humerus, club foot, and cardiac abnormalities. Sanger sequencing was carried out to investigate molecular etiology in eight patients and exome sequencing in one. Genetic testing revealed five homozygous variants in CHST3 (four were novel and one was previously reported). All these variants are located on sulfotransferase domain of CHST3 protein and were classified as pathogenic/ likely pathogenic. We thus report on nine individuals with CHST3-related chondrodysplasia with congenital joint dislocations from India and suggest monitoring the health of cardiac valves in this condition.

Gut microbiota in regulation of childhood bone growth.

Childhood stunting and wasting, or decreased linear and ponderal growth associated with undernutrition, continue to be a major global public health challenge. Although many of the current therapeutic and dietary interventions have significantly reduced childhood mortality caused by undernutrition, there remain great inefficacies in improving childhood stunting. Longitudinal bone growth in children is governed by different genetic, nutritional and other environmental factors acting systemically on the endocrine system and locally at the growth plate. Recent studies have shown that this intricate interplay between nutritional and hormonal regulation of the growth plate could involve the gut microbiota, highlighting the importance of a holistic approach in tackling childhood undernutrition. In this review, I focus on the mechanistic insights provided by these recent advances in gut microbiota research and discuss ongoing development of microbiota-based therapeutics in humans, which could be the missing link in solving undernutrition and childhood stunting.

Comparison of international height and BMI-for-age growth references and their correlation with adiposity in Brazilian schoolchildren.

This study verified the diagnostic accuracy of the nutritional status classified by the international height and BMI references of the World Health Organization (WHO) (WHO/2007), International Obesity Task Force (IOTF/2012) and MULT (2023). The data pool was composed by 22 737 subjects aged five to 16 years from the Santos and Porto Alegre surveys. A correlation matrix between the z-scores of the BMI references and the skinfold measurements was calculated through the Pearson correlation coefficient (r), and the subject's nutritional status was classified according to the international growth references. The accuracy for diagnosing obesity was performed separately by sex and using the 95th percentile of the triceps and subscapular skinfold sum, while Lin's concordance coefficient, Bland-Altman method and the Cohen's Kappa coefficient (Kappa) were used to verify the concordance and reliability among the BMI references. The correlation matrix showed a high positive correlation among the BMI z-scores (r ≥ 0·99) and among the skinfold measurements (r ≥ 0·86). The prevalence of stunting was higher when applying the MULT reference (3·4 %) compared with the WHO reference (2·3 %). The Bland-Altman plots showed the lowest critical difference (CD) between the height references of WHO and MULT (CD = 0·22). Among the BMI references, the WHO obesity percentile presented lower performance than MULT for boys, presenting a lower +LR value (WHO = 6·99/MULT 18 years = 10·99; 19 years = 8·99; 20 years = 8·09) for the same -LR values (0·04). Therefore, MULT reference holds promise as a valuable tool for diagnosing childhood obesity, particularly when considering sex differences. This enhances its suitability for assessing the nutritional status of Brazilian schoolchildren.

Comparison of predictive accuracy of knee height equations in children.

Knee height can be a proxy for height when standing height cannot be reliably measured. We compared two commonly used equations (Chumlea and Rumapea) that estimate standing height from knee height. We prospectively enrolled 210 children without scoliosis or kyphosis aged 7-12 years (mean age: 10.2 years, 47.6% males) and measured their knee heights and standing heights. A two-tailed T-test was used to compare predicted heights from each of the equations to actual standing height. Chumlea equation was found to be unreliable (p = 0.0376) while Rumapea equation was found to be reliable in estimating standing height (p = 0.878). Additionally, Rumapea equation was also found to be more accurate than Chumlea equation when results were segregated based on gender and race. In conclusion, the Rumapea equation yields more accurate estimates of standing heights than the Chumlea equation in US children aged 7-12 years.

Impact of delay in the diagnosis on the severity of celiac disease.

BACKGROUND AND AIM: Celiac disease (CeD) has now become a global disease with a worldwide prevalence of 0.67%. Despite being a common disease, CeD is often not diagnosed and there is a significant delay in its diagnosis. We reviewed the impact of the delay in the diagnosis on the severity of manifestations of CeD. METHODS: We reviewed clinical records of 726 consecutive patients with CeD from the Celiac Clinic database and the National Celiac Disease Consortium database. We extracted specific data including the demographics, symptoms at presentation, time of onset of symptoms, time to diagnosis from the onset of the symptoms, and relevant clinical data including fold-rise in anti-tissue transglutaminase antibody (IgA anti-tTG Ab) and severity of villous and crypt abnormalities as assessed using modified Marsh classification. RESULTS: The median duration between the onset of symptoms and the diagnosis of CeD was 27 months (interquartile range 12-60 months). A longer delay in the diagnosis of CeD from the onset of symptoms was associated with lower height for age, lower hemoglobin, higher fold rise in IgA Anti tTG titers, and higher severity of villous and crypt abnormalities. About 18% of patients presented with predominantly non-gastrointestinal complaints and had a longer delay in the diagnosis of CeD. CONCLUSIONS: There is a significant delay in the diagnosis of CeD since the onset of its symptoms. The severity of celiac disease increases with increasing delay in its diagnosis. There is a need to keep a low threshold for the diagnosis of CeD in appropriate clinical settings.

Impact of childhood nephrotic syndrome on obesity and growth: a prospective cohort study.

BACKGROUND: Children with nephrotic syndrome are at risk of obesity and growth impairment from repeated steroid treatment. However, incidence and risk factors for obesity and short stature remain uncertain, which is a barrier to preventative care. Our aim was to determine risk, timing, and predictors of obesity and short stature among children with nephrotic syndrome. METHODS: We evaluated obesity and longitudinal growth among children (1-18 years) enrolled in Insight into Nephrotic Syndrome: Investigating Genes, Health, and Therapeutics. We included children with nephrotic syndrome diagnosed between 1996-2019 from the Greater Toronto Area, Canada, excluding congenital or secondary nephrotic syndrome. Primary outcomes were obesity (body mass index Z-score ≥ + 2) and short stature (height Z-score ≤ -2). We evaluated prevalence of obesity and short stature at enrolment (< 1-year from diagnosis) and incidence during follow-up. Cox proportional hazards models determined the association between nephrotic syndrome classification and new-onset obesity and short stature. RESULTS: We included 531 children with nephrotic syndrome (30% frequently relapsing by 1-year). At enrolment, obesity prevalence was 23.5%, 51.8% were overweight, and 4.9% had short stature. Cumulative incidence of new-onset obesity and short stature over median 4.1-year follow-up was 17.7% and 3.3% respectively. Children with frequently relapsing or steroid dependent nephrotic syndrome within 1-year of diagnosis were at increased risk of new-onset short stature (unadjusted hazard ratio 3.99, 95%CI 1.26-12.62) but not obesity (adjusted hazard ratio 1.56, 95%CI 0.95-2.56). Children with ≥ 7 and ≥ 15 total relapses were more likely to develop obesity and short stature, respectively. CONCLUSIONS: Obesity is common among children with nephrotic syndrome early after diagnosis. Although short stature was uncommon overall, children with frequently relapsing or steroid dependent disease are at increased risk of developing short stature. Effective relapse prevention may reduce steroid toxicity and the risk of developing obesity or short stature.

A study on genotypes and phenotypes of short stature caused by epigenetic modification gene variants.

Mendelian disorders of the epigenetic machinery (MDEMs) are caused by genetic mutations, a considerable fraction of which are associated with epigenetic modification. These MDEMs exhibit phenotypic overlap broadly characterized by multiorgan abnormalities. The variant detected in genes associated with epigenetic modification can lead to short stature accompanied with multiple system abnormalities. This study is aimed at presenting and summarizing the diagnostic rate, clinical, and genetic profile of MDEMs-associated short stature. Two hundred and fourteen short-stature patients with multiorgan abnormalities were enrolled. Clinical information and whole exome sequence (WES) were analyzed for these patients. WES identified 33 pathogenic/likely pathogenic variants in 19 epigenetic modulation genes (KMT2A, KMT2D, KDM6A, SETD5, KDM5C, HUWE1, UBE2A, NIPBL, SMC1A, RAD21, CREBBP, CUL4B, BPTF, ANKRD11, CHD7, SRCAP, CTCF, MECP2, UBE3A) in 33 patients (15.4%). Of note, 19 variants had never been reported previously. Furthermore, these 33 variants were associated with 16 different disorders with overlapping clinical features characterized by development delay/intelligence disability (31/33; 93.9%), small hands (14/33; 42.4%), clinodactyly of the 5th finger (14/33; 42.4%), long eyelashes (13/33; 39.4%), and hearing impairment (9/33; 27.3%). Additionally, several associated phenotypes are reported for the first time: clubbing with KMT2A variant, webbed neck with SETD5 variant, retinal detachment with CREBBP variant, sparse lateral eyebrow with HUWE1 variant, and long palpebral fissure with eversion of the lateral third of the low eyelid with SRCAP variant.Conclusions: Our study provided a new conceptual framework for further understanding short stature. Specific clinical findings may indicate that a short-stature patient may have an epigenetic modified gene variant.