Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search.

Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.

Atypical presentation of ACCES syndrome resembling dominant Spondyloepiphyseal dysplasia tarda.

Aplasia Cutis Congenita with Ectrodactyly Skeletal Syndrome (ACCES, OMIM #619959) is an extremely rare multiple congenital anomalies syndrome caused by haploinsufficiency of the UBA2 gene. This syndrome presents with growth retardation, dysmorphic facial features, neurodevelopmental delay, skeletal problems including ectrodactyly, developmental dysplasia of the hip (DDH) and scoliosis, skin findings such as aplasia cutis, and some internal organ abnormalities. Our 13-year-old female patient and her 38-year-old father had a skeletal dysplasia phenotype with disproportionate short stature, bilateral DDH, mild epiphyseal involvement, scoliosis, and increased lumbar lordosis. Both were neurodevelopmentally normal and had mild dysmorphic facial features and mild ectodermal findings. The dominant inheritance pattern in the pedigree suggested a pre-diagnosis of spondyloepiphyseal dysplasia tarda. The exome sequencing analysis of the patient has identified a novel heterozygous variant, NM_005499.2:c.460-2A >G, in the UBA2 gene, and the father was found heterozygous either. The isolated spondyloepiphyseal involvement of our patients was an unusual presentation compared to patients with ACCES syndrome previously reported in the literature. Considering the highly variable expressiveness of ACCES syndrome and the co-occurrence of familial hip dysplasia and vertebral problems, we suggest that this syndrome can also be classified under "Spondyloepi(meta)physial dysplasia (SE(M)D)" in the nosology of genetic skeletal disorders.

Rare manifestations of sarcoidosis in a young boy.

Sarcoidosis is a chronic multisystem granulomatous disease of unknown etiology. It is rare in young children. A 9-year-old boy presented with failure to thrive, skin rashes, persistent fever, and respiratory symptoms since 5 years of age. Blood investigations done showed elevated serum calcium and angiotensin converting enzyme levels and biopsy of the rashes on the left shin revealed non-caseating granulomatous lesion. Computed tomography of chest revealed interstitial lung disease and examination of eyes showed bilateral uveitis. He also had sensorineural hearing impairment, nephrocalcinosis, and short stature. The patient was treated with oral steroids and mycophenolate mofetil. At follow up, there was improvement in his systemic features including rashes and arthritis. Early detection, diagnosis, and appropriate treatment of sarcoidosis are vital for disease control and to avoid morbidity.

A Japanese Boy with Dysmorphic Syndrome with Multiple Pituitary Hormone Deficiency and Gingival Fibromatosis Due to a Pathogenic KCNQ1 Variant.

A six-year-old boy presented with short stature and gingival fibromatosis (GF). Dysmorphic features included slant optic fissures, a high-arched palate, thick earlobes, and an edematous face. Laboratory tests showed low levels of serum insulin-like growth factor-1 and serum free thyroxine but normal serum thyrotropin levels. Provocative tests suggested growth hormone deficiency, central hypocortisolemia, and hypothalamic hypothyroidism. At 12 years old, hypogonadotropic hypogonadism was observed. Next-generation sequencing revealed a heterozygous missense variant, KCNQ1 p. (P369L), in the proband and mother. The coexistence of multiple pituitary hormone deficiencies and GF helps diagnose KCNQ1-variant dysmorphic syndrome through genetic testing.

Gut microbiota and metabolic changes in children with idiopathic short stature.

BACKGROUND: Idiopathic short stature (ISS) is characterized by short stature with unknown causes. Recent studies showed different gut microbiota flora and reduced fecal short-chain fatty acids in ISS children. However, the roles of the microbiome and metabolites in the pathogenesis of ISS remains largely unknown. METHODS: We recruited 51 Chinese subjects, comprising 26 ISS children and 25 normal-height control individuals. Untargeted metabolomics was performed to explore the fecal metabolic profiles between groups. A shotgun metagenomic sequencing approach was used to investigate the microbiome at the strains level. Mediation analyses were done to reveal correlations between the height standard deviation (SD) value, the gut microbiome and metabolites. RESULTS: We detected marked differences in the composition of fecal metabolites in the ISS group, particularly a significant increase in erucic acid and a decrease in spermidine, adenosine and L-5-Hydroxytryptophan, when compared to those of controls. We further identified specific groups of bacterial strains to be associated with the different metabolic profile. Through mediation analysis, 50 linkages were established. KEGG pathway analysis of microbiota and metabolites indicated nutritional disturbances. 13 selected features were able to accurately distinguish the ISS children from the controls (AUC = 0.933 [95%CI, 79.9-100%]) by receiver operating characteristic (ROC) analysis. CONCLUSION: Our study suggests that the microbiome and the microbial-derived metabolites play certain roles in children's growth. These findings provide a new research direction for better understanding the mechanism(s) underlying ISS.

Spondyloenchondrodysplasia With Immune Dysregulation, but Without Skeletal Dysplasia, in a Six-Year-Old Boy: A Case Report.

Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is a rare autosomal recessive genetic disorder caused by a homozygous mutation of the ACP5 gene. Spondyloenchondrodysplasia is a type of immune-osseous dysplasia manifesting with skeletal dysplasia, immunologic dysfunction, and neurological manifestations. We report the case of a six-year-old boy with SPENCDI who presented with post-viral illness Coombs-positive hemolytic anemia, thrombocytopenia, and fever, based on which he was diagnosed with Evans syndrome. He was previously diagnosed with spastic diplegia, short stature, and celiac disease. The diagnosis was confirmed with genetic testing which displayed a homozygous frameshift mutation of the ACP5 gene c.549del p.(Gln184Serfs*28). This case report discusses the clinical presentation of SPENCDI and highlights the importance of considering this rare genetic disorder in patients presenting with short stature, immunologic dysregulation, and neurological involvement.

Effect of clinical whole exome sequencing in aetiological investigation and reproductive risk prediction for a couple with monogenic inherited diseases.

Objective: To determine the genetic causes of monogenic inherited diseases in a couple using clinical whole exome sequencing (WES) and advise on their reproductive choices. Methods: WES was applied to a couple seeking reproductive advice, the female with short stature and the male with congenital cataracts. Results: (1) The woman exhibited a 13.8 Kb heterozygous deletion at chrX: 591590-605428 (hg19). This region corresponds to exons 2-6 of the short-stature homeobox-containing (SHOX) gene (NM000451). Associated diseases involving the SHOX gene range from severe Leri-Weill dyschondrosteosis to mild nonspecific short stature. Meanwhile, further validation using a quantitative reverse transcription polymerase chain reaction assay confirmed the heterozygous deletion of the SHOX gene in the proband, as well as other family members with similar clinical characteristics (the proband's mother, aunt, and cousin). Multiple pathogenic reports of this variant have been included in the HGMD database. Per the American College of Medical Genetics and Genomics (ACMG) classification criteria, this deletion is classified as pathogenic. (2) For the male patient, a heterozygous variant was detected in the CRYBB3 gene: NM004076: c.226G>A (p.Gly76R). Variants in the CRYBB3 gene can cause Cataract 22 (OMIM: 609741). At present, this variant locus is not included in databases such as the gnomAD, while both SIFT and PolyPhen2 deem this locus 'damaging'. Moreover, further validation by Sanger sequencing confirmed that the variant was inherited from the male patient's mother, who also had cataracts. According to ACMG standards and guidelines, the c.226G>A (p.Gly76Arg) variant in the CRYBB3 gene is classified as having 'uncertain significance'. Conclusion: WES identified pathogenic variants in both individuals, suggesting a 25% chance of a healthy child naturally. Third-generation assisted reproductive techniques are recommended to minimize the risk of affected offspring.

Utility of SHOX2 and RASSF1A gene methylation detection on the residual cytology material from endobronchial ultrasound-guided transbronchial needle aspiration.

Objective: This study aims to assess the effectiveness of Short Stature Homeobox 2 (SHOX2) and RAS Association Domain Family 1 Isoform A (RASSF1A) gene methylation detection in residual liquid-based cytology (LBC) materials from Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) and investigate the diagnostic accuracy of a comprehensive diagnostic approach. Material and Methods: Between June 2022 and May 2023, a total of 110 cases that underwent EBUS-TBNA were enrolled in the study. SHOX2 and RASSF1A genes methylation detection using the residual cytological material, LBC, and cell block (CB) were conducted for each EBUS-TBNA case. The sensitivity and specificity of cytology, CB histopathology, SHOX2, and RASSF1A methylation in diagnosing EBUS-TBNA samples were determined based on follow-up data. Results: Among the 72 cases confirmed as pulmonary carcinomas, the methylation test yielded positive results in 24 adenocarcinoma cases, 10 squamous cell carcinoma cases, and 14 small cell carcinoma cases. The sensitivity of the comprehensive diagnosis (combining LBC, CB, and methylation detection) in distinguishing metastatic pulmonary epithelial malignancies in mediastinal and hilar lymph nodes or masses from benign lesions was higher (97.22%, 70/72) than that of morphological diagnosis alone (LBC and CB) (88.89%, 64/72; P < 0.05). Conclusion: SHOX2 and RASSF1A methylation detection demonstrates a high sensitivity and negative predictive value in the identification of pulmonary epithelial malignancies and holds promise as a valuable ancillary approach to enhance morphological diagnosis of EBUS-TBNA.

Biometrics of the Hand's Middle Finger to Determine Stature in Chilean University Students / Biometría del Dedo Medio de la Mano para Determinar Estatura en Estudiantes Universitarios Chilenos

SUMMARY: Biometrics and forensic osteology play a significant role in human identification, as the morphological uniqueness of every individual enables the differentiation and recognition of skeletal remains. Through meticulous analysis of human remains, it is possible to determine key demographic attributes such as stature, a significant parameter in the forensic identification process. This information is of practical relevance for the identification of individuals in contexts such as disasters, vehicular accidents, terrorist attacks, armed conflicts, and forensic investigations. The objective of this study was to determine the correlation between the hand's middle finger length and stature in a group of Chilean students. A total of 211 students of both sexes from La Araucanía region, Chile, participated in the study. After obtaining informed consent to participate voluntarily in the study, each individual underwent a general anthropometric examination, followed by a specific assessment of the length of the middle finger (MFL) of both hands. The results of the multiple linear regression analysis indicated a significant prediction of stature using the length of the right (R-MFL) and left (L-MFL) middle fingers, F (2, 207) = 79.80, p < 0.001. The equations for estimating stature based on the length of the middle fingers are as follows: for R-MFL, Stature = 91.265 + (8.092 x R-MFL), and for L-MFL, Stature = 83.967 + (8.889 x L-MF). Based on these results, it was found that the length of the middle finger of both hands is predictive of stature.

La biometría y la osteología forense desempeñan un papel relevante en la identificación humana, dado que la singularidad morfológica de cada individuo permite la diferenciación y reconocimiento de restos óseos. Mediante el análisis meticuloso de los restos humanos, es posible determinar atributos demográficos clave como la estatura, un parámetro significativo en el proceso de identificación forense. Esta información posee relevancia práctica para la identificación de personas en contextos de desastres, accidentes vehiculares, ataques terroristas, conflictos armados e investigaciones forenses. El objetivo de este estudio fue determinar la correlación entre la longitud del dedo medio de la mano con la estatura, en un grupo de estudiantes chilenos. Se evaluaron 211 estudiantes de ambos sexos de la región de La Araucanía, Chile. Tras obtener el consentimiento informado para participar voluntariamente en el estudio, se sometió a cada individuo a un examen antropométrico general, seguido de una evaluación específica de la longitud del dedo medio (MFL) de ambas manos. Los resultados del análisis de las regresiones lineales múltiples indicaron una significativa predicción de estatura utilizando la longitud de los dedos medios derecho (R-MFL) e izquierdo (L-MFL), F (2, 207) = 79.80, p < 0.001. Las ecuaciones para estimar estatura basados en la longitud de los dedos medios son las siguientes: para R-MFL, Stature = 91.265 + (8.092 x R-MFL) y para L-MFL, Stature = 83.967 + (8.889 x L- MF). A partir de estos resultados, se encontró que la longitud del dedo medio de ambos manos es predictora de estatura.

Anthropometric investigation of cephalic parameters for stature estimation: Through regression analysis.

Background: Stature or body height is one of the most important and useful anthropometric parameters which determines the physical identity of an individual. Cranium encompasses hard tissue components with approximately immortal behavior, reason being cranial measurements were selected for the present study for estimation of stature. Objective: This investigation aimed to assess the stature of unknown using cephalometric parameters by creating equations through regression analysis. Materials and Methods: We selected 361 dental students for the present research; among them, 210 were females and 151 were males in the age range of 21-32 years. Stature and cephalic parameters, i.e., fronto-occipital circumference, head length, and head breadth were measured for each contributor following standard methods and techniques. Cephalic Index was calculated by using the formula: Cephalic Index (CI) = (Head width/Head length) ×100. Karl Pearson's correlation coefficient of stature with cephalic parameters was calculated, and regression analysis was done to generate the formulae for stature estimation. Results: Results indicated that all cephalic measurements have strong correlation with stature, and among them, circumference of head was found to be the most reliable predictor. Conclusion: Stature of unknown or deceased can be identified using cephalic parameters as an auxiliary practice.

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.

Growth hormone therapy does not impact the development of intracranial hypertension in children with Chiari malformation.

OBJECTIVES: Patients with Chiari malformation (CM) are prone to a variety of neurological sequelae, including benign intracranial hypertension (BIH). In these patients, BIH is attributed to impaired cerebrospinal fluid (CSF) flow due to anatomical abnormalities of the posterior fossa. Occasionally, patients with CM may require growth hormone therapy (GHT), which can increase the production of CSF. It is thought that patients with CM who undergo GHT are at high risk of BIH-associated symptoms (BIHAS). We describe the incidence of neurological symptoms in 34 patients with CM before and during GHT. METHODS: The database of a pediatric endocrinology center was queried for patients with CM who received GHT from 2010-22. Records were reviewed for adverse events. Demographic and radiological data were collected and analyzed. Patients with neoplastic disease, active inflammation, or acute trauma were excluded. CM diagnoses were independently assigned by a neuroradiology department. Patients were grouped based on the presence and nature of symptoms before and during GHT. Relationships between starting dose/BMI and occurrence of BIHAS/all GHT-associated symptoms were evaluated. RESULTS: GHT was not associated with new-onset or worsening of preexisting BIHAS in 33 out of 34 patients with CM. Five complex patients continued to have preexisting BIHAS, which did not worsen. Of the four patients who developed new-onset BIHAS during GHT, three patients' symptoms were attributed to other medical conditions. No patient permanently discontinued GHT due to BIHAS. CONCLUSIONS: Growth hormone therapy is likely a safe treatment in patients with Chiari malformation and is unlikely to cause BIHAS.

Adding Letrozole to Growth Hormone and Gonadotropin-Releasing Hormone Analog Increases Height in Girls With Short Stature: A Hospital Record-Based Retrospective Study.

OBJECTIVE: There have been rare data on letrozole for height improvement in girls. This study aimed to clarify the efficacy and safety of combination therapy with recombinant human growth hormone (rhGH), GnRHa, and letrozole in improving the height of girls with short stature and advanced bone age. METHODS: This was a hospital record-based retrospective study. Follow-up was conducted on girls with short stature who received treatment with rhGH, GnRHa, and letrozole in our hospital. The treatment group included a total of 29 participants. Before treatment, the mean age of the patients was 11.17 years, and the mean treatment duration was 17.31 months. The control group consisted of 29 short-statured girls who received rhGH/GnRHa treatment, with the mean age and treatment duration of 12.43 years and 16.59 months, respectively. RESULTS: The predicted adult heights (PAHs) before and after treatment were 155.38 and 161.32 cm (P < .001). The ΔPAH in the treatment group was 4 cm higher than that in the control group (5.85 vs 1.82 cm, P < .001). Significant differences were noted in the height standard deviation scores of bone age (P < .001) and chronological age (P = .003) before and after treatment. There was an increasing body mass index during therapy (P = .039). The height gain was 8.71 ± 4.46 cm, and the growth rate was 6.78 ± 3.84 cm per year. CONCLUSION: Combined treatment with GH, GnRHa, and letrozole can enhance the adult height and PAH in short-statured girls, and no significant side effects have been reported.

Promising horizons in achondroplasia along with the development of new drugs.

Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the fibroblast growth factor receptor 3 (FGFR3) group. The downstream signal transduction of FGFR3 consists of STAT1 and RAS/RAF/MEK/ERK pathways. The mutant FGFR3 found in ACH is continuously phosphorylated and activates downstream signals, resulting in abnormal proliferation and differentiation of chondrocytes in the growth plate and cranial base synchondrosis. A patient registry has been developed and has contributed to revealing the natural history of ACH patients. Concerning the short stature, the adult height of ACH patients ranges between 126.7-135.2 cm for men and 119.9-125.5 cm for women in many countries. Along with severe short stature, foramen magnum stenosis and spinal canal stenosis are major complications: the former leads to sleep apnea, breathing disorders, myelopathy, hydrocephalus, and sudden death, and the latter causes pain in the extremities, numbness, muscle weakness, movement disorders, intermittent claudication, and bladder-rectal disorders. Growth hormone treatment is available for ACH only in Japan. However, the effect of the treatment on adult height is not satisfactory. Recently, the neutral endopeptidase-resistant CNP analogue vosoritide has been approved as a new drug for ACH. Additionally in development are a tyrosine kinase inhibitor, a soluble FGFR3, an antibody against FGFR3, meclizine, and the FGF2-aptamer. New drugs will bring a brighter future for patients with ACH.

Diagnosis, Treatment, and Outcomes of Males with Central Precocious Puberty.

Central precocious puberty (CPP) among males is less frequent than among females but more likely to have an underlying pathologic cause. Diagnosis of CPP is often straightforward among males because increased testicular volume, the first sign of puberty, can be verified although careful central nervous system (CNS) assessment is generally necessary. Treatment with gonadotropin-releasing hormone agonist (GnRHa) is indicated, given in conjunction with any therapy needed for CNS lesions. Monitoring of treatment usually can consist of evaluating growth and physical puberty and with testosterone levels as the only lab data. Short-term and long-term outcome data indicate efficacy and safety, although data are limited. Such data need to be reported.

Estrogen Receptor 1 Gene Polymorphism and its Association with Idiopathic Short Stature in North Indian Population.

Background: In the hypothalamic-pituitary-gonadotrophin (HPG) axis, estrogen plays a key role in the bone maturation regulation and growth plates closure. This study was designed to explore the link between single nucleotide polymorphisms (SNPs) in estrogen receptor 1 (ESR1) gene with idiopathic short stature (ISS) susceptibility in the North Indian population. Methods: Four SNPs of the ESR1 gene (rs543650, rs6557177, rs2234693 and rs9340799) were genotyped by Sanger sequencing in 52 ISS patients and 68 controls. Linkage disequilibrium (LD) and haplotyping were done by SNPstat and SHESISplus softwares. Extent of LD was determined by calculating D' and r2 values in SNPs paired combinations. Results: A significant positive association was found between rs6557177 and rs543650 genotype and ISS susceptibility as compared to controls. The frequencies of the rs6557177 CC genotype (p=0.030; OR=0.13; 95% CI:0.01-1.10) and rs543650 genotype TT (p =0.043; OR=0.29; 95% CI: 0.09-0.92) were observed to be increased in ISS group as compared with the control group. However, no significant correlation was observed between clinical parameters of patients and these SNPs. rs543650 shown strong LD with rs2234693 and rs9340799, similarly rs2234693 and rs9340799. Conclusion: Our study showed that CC genotype at rs6557177 and TT genotype of rs543650 of ESR1 constitutes risk factor for developing ISS in North Indian children. In the future, these findings may lead to a better understanding of the SNPs associated with ISS susceptibility.

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".

Biological Identification of Skulls in Indonesian and Thai Populations: Ancestry Estimation, Sex Determination, Stature Estimation, and Age Estimation / Identificación Biológica de Cráneos en Poblaciones de Indonesia y Tailandia: Estimación de Ascendencia, Determinación del Sexo, Estimación de Estatura y Estimación de Edad

SUMMARY: This review article will present an overview of biological profiles in forensic utilities. The biological profile of the skull in the existing literature can help to identify humans, especially if the condition of the victim found is a result of mutilation or a bomb explosion. When it comes to the precision of identifying skeletal remains, the human skull is frequently cited as being first in the estimation of age and ancestry and second in terms of sex and stature. It can be an alternative to assessing the following biological parameters: sex, age, stature, and ancestry. The implementation of biological profiles in the identification process is very important considering that some cases require the assistance of forensic anthropology. This review article shows the importance of the value of skulls. The method that can be applied is craniometry which can be used to determine sex, age, stature, and estimated ancestry. Different results will occur depending on the completeness of the skull. Therefore, estimation formulas have different accurate results. Discriminant function analysis has been performed on various measurement sets and its discriminant power has been validated by many researchers. Geometric morphometric analysis has become the main tool for shape analysis and many attempts have been made to use it in analyzing skulls. Several methods supported by technology have also been developed. It is hoped that the review article will show significant differences in results between studies in Thailand and Indonesia, even though they are in the same racial group.

Este artículo presenta una descripción general de los perfiles biológicos en las utilidades forenses. El perfil biológico del cráneo en la literatura existente puede ayudar a identificar a los humanos, especialmente si la condición en la que se encuentra la víctima es el resultado de una mutilación o la explosión de una bomba. Cuando se trata de la precisión en la identificación de restos óseos, el cráneo humano se cita con frecuencia como el primero en la estimación de edad y ascendencia y el segundo en términos de sexo y estatura. Puede ser una alternativa para evaluar los siguientes parámetros biológicos: sexo, edad, estatura y ascendencia. La implementación de perfiles biológicos en el proceso de identificación es importante considerando que algunos casos requieren la asistencia de la antropología forense. Este artículo de revisión muestra la importancia del valor de las cnezas óseas. El método que se puede aplicar es la craneometría para determinar el sexo, la edad, la estatura y la ascendencia estimada. Se pueden obtener diferentes resultados dependiendo de la integridad del cráneo. Por lo tanto, las fórmulas de estimación tienen resultados precisos diferentes. Se ha realizado un análisis de función discriminante en varios conjuntos de medidas y muchos investigadores han validado su poder discriminante. El análisis a través de la morfometría geométrica se ha convertido en la principal herramienta para el análisis de formas y se ha utilizado frecuentemente en el análisis de cráneos. También se han desarrollado varios métodos apoyados en la tecnología. Se espera que este trabajo muestre diferencias significativas en los resultados entre los estudios realizados en Tailandia e Indonesia, aunque pertenezcan al mismo grupo racial.

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.