Altered oral microbiome, but normal human papilloma virus prevalence in cartilage-hair hypoplasia patients.

BACKGROUND: Cartilage-hair hypoplasia (CHH) is a rare syndromic immunodeficiency with metaphyseal chondrodysplasia and increased risk of malignancy. In this cross-sectional observational study, we examined HPV status and oral microbiome in individuals with CHH. Oral brush samples were collected from 20 individuals with CHH (aged 5-59 years) and 41 controls (1-69 years). Alpha HPVs (43 types) were tested by nested PCR followed by bead-based probe hybridization. Separately, beta-, gamma-, mu- and nu- HPV types were investigated, and a genome-based bacterial microbiome sequencing was performed. RESULTS: We found a similar alpha HPV prevalence in individuals with CHH (45%) and controls (36%). The HPV types of individuals with CHH were HPV-16 (25%), 27, 28, and 78, and of controls HPV-3, 16 (21%), 27, and 61. Beta HPV positivity and combined beta/gamma/mu/nu prevalence was detected in 11% and 11% of individuals with CHH and in 5% and 3% of the controls, respectively. Individuals with CHH differed from the controls in bacterial microbiota diversity, richness, and in microbial composition. Individuals with CHH had lower abundance of species Mitsuokella sp000469545, Parascardovia denticolens, Propionibacterium acidifaciens, UMGS1907 sp004151455, Salinicola halophilus, Haemophilus_A paraphrohaemolyticus, Fusobacterium massiliense, and Veillonella parvula, and higher abundance of Slackia exigua. CONCLUSIONS: Individuals with CHH exhibit similar prevalence of HPV DNA but different bacterial microbiota on their oral mucosa compared to healthy controls. This may partly explain the previously observed high prevalence of oral diseases in CHH, and regular oral examination is warranted.

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

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a patient with Isidor-Toutain spinal epiphyseal dysplasia (SEMD) due to variant of RPL13 gene. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Molecular mechanism of thiram-induced abnormal chondrocyte proliferation via lncRNA MSTRG.74.1-BNIP3 axis.

Thiram, a widely used organic pesticide in agriculture, exhibits both bactericidal and insecticidal effects. However, prolonged exposure to thiram has been linked to bone deformities and cartilage damage, contributing to the development of tibial dyschondroplasia (TD) in broilers and posing a significant threat to global agricultural production. TD, a prevalent nutritional metabolic disease, manifests as clinical symptoms like unstable standing, claudication, and sluggish movement in affected broilers. In recent years, there has been growing recognition of the regulatory role of long non-coding RNA (lncRNA) in tibial cartilage formation among broilers through diverse signaling pathways. This study employs in vitro experimental models, growth performance analysis, and clinical observation to assess broilers' susceptibility to thiram pollution. Transcriptome sequencing analysis revealed a significant elevation in the expression of lncRNA MSTRG.74.1 in both the con group and the thiram-induced in vitro group. The results showed that lncRNA MSTRG.74.1 plays a pivotal role in influencing the proliferation and abnormal differentiation of chondrocytes. This regulation occurs through the negative modulation of apoptotic genes, including Bax, Cytc, Bcl2, Apaf1, and Caspase3, along with genes Atg5, Beclin1, LC3b, and protein p62. Moreover, the overexpression of lncRNA MSTRG.74.1 was found to regulate broiler chondrocyte development by upregulating BNIP3. In summary, this research sheds light on thiram-induced abnormal chondrocyte proliferation in TD broilers, emphasizing the significant regulatory role of the lncRNA MSTRG.74.1-BNIP3 axis, which will contribute to our understanding of the molecular mechanisms underlying TD development in broilers exposed to thiram.

Leucine improves thiram-induced tibial dyschondroplasia and gut microbiota dysbiosis in broilers.

Thiram, a commonly used agricultural insecticide and fungicide, has been found to cause tibial dyschondroplasia (TD) in broilers, leading to substantial economic losses in the poultry industry. In this study, we aimed to investigate the mechanism of action of leucine in mitigating thiram-induced TD and leucine effects on gut microbial diversity. Broiler chickens were randomly divided into five equal groups: control group (standard diet), thiram-induced group (thiram 80 mg/kg from day 3 to day 7), and different concentrations of leucine groups (0.3%, 0.6%, 0.9% leucine from day 8 to day 18). Performance indicator analysis and tibial parameter analysis showed that leucine positively affected thiram-induced TD broilers. Additionally, mRNA expressions and protein levels of HIF-1α/VEGFA and Ihh/PTHrP genes were determined via quantitative real-time polymerase chain reaction and western blot. The results showed that leucine recovered lameness disorder by downregulating the expression of HIF-1α, VEGFA, and PTHrP while upregulating the expression of Ihh. Moreover, the 16 S rRNA sequencing revealed that the leucine group demonstrated a decrease in the abundance of harmful bacteria compared to the TD group, with an enrichment of beneficial bacteria responsible for producing short-chain fatty acids, including Alistipes, Paludicola, CHKCI002, Lactobacillus, and Erysipelatoclostridium. In summary, the current study suggests that leucine could improve the symptoms of thiram-induced TD and maintain gut microbiota homeostasis.

Identification of kinesin family member (KIF22) homozygous variants in spondyloepimetaphyseal dysplasia with joint laxity, lepdodactylic type and demonstration of proteoglycan biosynthesis impairment.

Heterozygous variants in KIF22, encoding a kinesin-like protein, are responsible for spondyloepimetaphyseal dysplasia with joint laxity, leptodactilic type (lepto-SEMDJL), characterized by short stature, flat face, generalized joint laxity with multiple dislocations, and progressive scoliosis and limb deformity. By targeted gene sequencing analysis, we identified a homozygous KIF22 variant (NM_007317.3: c.146G>A, p.Arg49Gln) in 3 patients from 3 unrelated families. The clinical features appeared similar to those of patients carrying heterozygous KIF22 variant (c.443C>T or c.446G>A), although the spinal involvement appeared later and was less severe in patients with a recessive variant. Relatives harboring the c.146G>A variant at the heterozygous state were asymptomatic. The homozygous KIF22 variant c.146G>A affected a conserved residue located in the active site and potentially destabilized ATP binding. RT-PCR and western blot analyses demonstrated that both dominant and recessive KIF22 variants do not affect KIF22 mRNA and protein expression in patient fibroblasts compared to controls. As lepto-SEMDJL presents phenotypic overlap with chondrodysplasias with multiple dislocations (CMD), related to defective proteoglycan biosynthesis, we analyzed proteoglycan synthesis in patient skin fibroblasts. Compared to controls, DMMB assay showed a significant decrease of total sulfated proteoglycan content in culture medium but not in the cell layer, and immunofluorescence demonstrated a strong reduction of staining for chondroitin sulfates but not for heparan sulfates, similarly in patients with recessive or dominant KIF22 variants. These data identify a new recessive KIF22 pathogenic variant and link for the first time KIF22 pathogenic variants to altered proteoglycan biosynthesis and place the lepto-SEMDJL in the CMD spectrum.

Heterozygous variants in KIF22, encoding a kinesin-like protein, are responsible for spondyloepimetaphyseal dysplasia with joint laxity, leptodactilic type (lepto-SEMDJL), characterized by short stature, flat face, generalized joint laxity with multiple dislocations, and progressive scoliosis and limb deformity. We identified a homozygous KIF22 variant (NM_007317.3: c.146G>A, p.Arg49Gln) in 3 patients from 3 unrelated families. The clinical features appeared similar to those of patients carrying heterozygous KIF22. The homozygous KIF22 variant c.146G>A affected a conserved residue located in the active site and potentially destabilized ATP binding. As lepto-SEMDJL presents phenotypic overlap with chondrodysplasias with multiple dislocations, related to defective proteoglycan biosynthesis, we analyzed proteoglycan synthesis in patient skin fibroblasts and showed a significant decrease of total sulfated proteoglycan content in culture medium, similarly in patients with recessive or dominant KIF22 variants. These data identify a new recessive KIF22 pathogenic variant and link for the first time KIF22 pathogenic variants to altered proteoglycan biosynthesis.

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".

Relevance of Extending FGFR3 Gene Analysis in Osteochondrodysplasia to Non-Coding Sequences: A Case Report.

Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children's growth. Up to 552 genes, including fibroblast growth factor receptor 3 (FGFR3), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the FGFR3 gene: c.1138G>A and c.1138G>C in achondroplasia and c.1620C>A and c.1620C>G in hypochondroplasia. However, in some cases, the diagnostic investigations undertaken thus far have failed to identify the causal anomaly, which strengthens the relevance of the diagnostic strategies being further refined. We observed a Caucasian adult with clinical and radiographic features of achondroplasia, with no common pathogenic variant. Exome sequencing detected an FGFR3(NM_000142.4):c.1075+95C>G heterozygous intronic variation. In vitro studies showed that this variant results in the aberrant exonization of a 90-nucleotide 5' segment of intron 8, resulting in the substitution of the alanine (Ala359) for a glycine (Gly) and the in-frame insertion of 30 amino acids. This change may alter FGFR3's function. Our report provides the first clinical description of an adult carrying this variant, which completes the phenotype description previously provided in children and confirms the recurrence, the autosomal-dominant pathogenicity, and the diagnostic relevance of this FGFR3 intronic variant. We support its inclusion in routinely used diagnostic tests for osteochondrodysplasia. This may increase the detection rate of causal variants and therefore could have a positive impact on patient management. Finally, FGFR3 alteration via non-coding sequence exonization should be considered a recurrent disease mechanism to be taken into account for new drug design and clinical trial strategies.

miR-206a-3p suppresses the proliferation and differentiation of chicken chondrocytes in tibial dyschondroplasia by targeting BMP6.

The poultry skeletal system serves multiple functions, not only providing structural integrity but also maintaining the balance of essential minerals such as calcium and phosphorus. However, in recent years, the consideration of skeletal traits has been overlooked in the selective breeding of broilers, resulting in an inadequate adaptation of the skeletal system to cope with the rapid increase in body weight. Consequently, this leads to lameness and bone diseases such as tibial dyschondroplasia (TD), which significantly impact the production performance of broilers. Accumulating evidence has shown that microRNAs (miRNA) play a crucial role in the differentiation, formation, and disease of cartilage. However, the miRNA-mediated molecular mechanism underlying chicken TD formation is still poorly understood. The objective of this study was to investigate the biological function and regulatory mechanism of miRNA in chicken TD formation. Based on transcriptome sequencing of tibial cartilage in the healthy group and TD group, miR-206a-3p was found to be highly expressed in TD cartilage. The function of miR-206a-3p was explored through the transfection test of miR-206a-3p mimics and miR-206a-3p inhibitor. In this study, we utilized qRT-PCR, CCK-8, EdU, western blot, and flow cytometry to detect the proliferation, differentiation, and apoptosis of chondrocytes. The results revealed that miR-206a-3p suppressed the proliferation and differentiation of TD chondrocytes while promoting their programmed cell death. Furthermore, through biosynthesis and dual luciferase assays, it was determined that BMP6 was the direct target gene of miR-206a-3p. This finding was further supported by rescue experiments which confirmed the involvement of BMP6 in the regulatory pathway governed by miR-206a-3p. Our results suggest that miR-206a-3p can inhibits the proliferation and differentiation promote apoptosis through the target gene BMP-6 and suppressing the Smad2/3 signaling pathway in chicken TD chondrocytes.

[Clinical phenotype and genetic analysis of a child featuring short stature and multiple skeletal dysplasia].

OBJECTIVE: To analyze the clinical phenotype and genetic basis for a child featuring familial short stature. METHODS: A child who was admitted to Huzhou Maternal and Child Health Care Hospital on October 7, 2021 for growth retardation and pectus carinatum was selected as the study subject. Physical exam and medical imaging was performed. The child was subjected to whole exome sequencing, and candidate variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 1-year-old male, had manifested with slightly short stature (Z = -2.03), midfacial dysplasia, and multiple skeletal dysplasia such as pectus carinatum, irregular vertebral morphology, and defect of lumbar anterior bones. His mother, maternal grandmother and great-maternal grandfather also had short stature. WES revealed that the child has harbored a heterozygous c.2858dupA (p.Asp953GlufsTer476) frameshifting variant of the ACAN gene, which was inherited from his mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2858dup (p.Sp953Glufster476) variant was classified as likely pathogenic (PVS1+PM2_Supporting). The patient has shown marked improved height after receiving 11 months of treatment with human recombinant growth hormone (supplemental dose) starting from 20 months of age. CONCLUSION: The ACAN: c.2858dup (p.Asp953GlufsTer476) variant probably underlay the pathogenesis of short stature in this child.

Natural history of Wolcott-Rallison syndrome: A systematic review and follow-up study.

BACKGROUND AND AIMS: To systematically review the literature for reports on Wolcott-Rallison syndrome, focusing on the spectrum and natural history, genotype-phenotype correlations, patient and native liver survival, and long-term outcomes. METHODS: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow-up were extracted. Survival and correlation analyses were performed. RESULTS: Sixty-two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver-pancreas in one and combined liver-pancreas-kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p = .0057). One-, five- and ten-year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p = .013). CONCLUSION: Wolcott-Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver- or multi-organ transplantation is a feasible treatment option to improve survival.

Immune skeletal dysplasia with neurodevelopmental abnormalities caused by a novel variant of EXTL3 gene in a Chinese family.

BACKGROUND: Immune skeletal dysplasia with neurodevelopmental abnormalities (ISDNA) is an extremely rare, autosomal recessive genetic disorder characterized by various skeletal abnormalities, neurodevelopmental deficits, and abnormal immune system function. ISDNA is caused by variation in the exostosin-like 3 (EXTL3) gene, located on chromosome 8p21.2, whose primary function is the biosynthesis of heparan sulfate (HS) skeleton structure. Only a few variations in the EXTL3 gene have been discovered so far. In these years of development, many pathogenic variants in genetic diseases with genetic and phenotypic heterogeneity have been investigated using whole-exome sequencing (WES) technology. METHODS: In this research, a novel EXTL3 variant was first detected in a patient using WES, which was validated from Sanger sequencing in this family. Family history and clinical information were then collected through comprehensive medical examinations and genetic counseling. In silico prediction was then utilized to confirm the pathogenicity of the variant. RESULTS: A novel homozygous variant, NM_001440: c.2015G>A (p.Arg672Gln) in the EXTL3 gene, was identified using WES, which has never been reported before. Sanger sequencing was performed to confirm that the variant segregated with the disease within the family. CONCLUSION: This research identified a novel pathogenic variant in the EXTL3 gene responsible for ISDNA in a Chinese family. It showed the potential diagnostic role of WES in ISDNA, expanded the EXTL3 gene variation spectrum, and demonstrated that the diagnosis of ISDNA using WES is feasible and effective. More comprehensive genetic counseling and precise prenatal diagnosis for the next pregnancy can also be provided to families with genetic disorders.

Growing up with Marshall syndrome: A case report from infancy to age 12.5 years.

Marshall syndrome is an extremely rare genetic disorder usually diagnosed in infancy with a prevalence of <1 in 1 million. Based on the literature reviewed, this is the first case report to provide a longitudinal history of a child with Marshall syndrome (from birth to age 12.5 years). This longitudinal case report arose in part from desires of this child's parents to share the story of their early fears at her initial diagnosis and compare those to how well she has turned out.

Combined achondroplasia and short stature homeobox-containing (SHOX) gene deletion in a Danish infant.

Short stature or shortening of the limbs can be the result of a variety of genetic variants. Achondroplasia is the most common cause of disproportionate short stature and is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene (FGFR3). Short stature homeobox (SHOX) deficiency is caused by loss or defects of the SHOX gene or its enhancer region. It is associated with a spectrum of phenotypes ranging from normal stature to Léri-Weill dyschondrosteosis characterized by mesomelia and short stature or the more severe Langer mesomelic dysplasia in case of biallelic SHOX deficiency. Little is known about the interactions and phenotypic consequences of achondroplasia in combination with SHOX deficiency, as the literature on this subject is scarce, and no genetically confirmed clinical reports exist. We present the clinical findings in an infant girl with concurrent achondroplasia and SHOX deficiency. We conclude that the clinical findings in infancy are phenotypically compatible with achondroplasia, with no features of the SHOX deficiency evident. This may change over time, as some features of SHOX deficiency only become evident later in life.

Unexpected findings in cervical spine in spondylometaphyseal dysplasia Sutcliff type FN1-related.

The autosomal dominant spondylometaphyseal dysplasia Sutcliff type or corner fracture type FN1-related is characterized by a combination of metaphyseal irregularities simulating fractures ("corner fractures"), developmental coxa vara, and vertebral changes. It is linked to heterozygous mutations in FN1 and COL2A1. Vertebral changes as delayed vertebral ossification, ovoid vertebral bodies, anterior vertebral wedging, and platyspondyly have been observed in this condition, while odontoid abnormalities have not been reported. We report an odontoid anomaly in a girl with SMD-CF FN1-related showing the heterozygous variant c.505T>A; p.(Cys169Ser), presenting at 11.9 years of age with acute quadriparesis. Images showed spinal cord compression and injury associated with os odontoideum and C1-C2 instability. She required decompression and instrumented occipitocervical stabilization, suffering from residual paraparesis. This paper describes the first case of SMD-CF FN1-related accompanied by odontoid anomalies.

Role of trafficking protein particle complex 2 in medaka development.

The skeletal dysplasia spondyloepiphyseal dysplasia tarda (SEDT) is caused by mutations in the TRAPPC2 gene, which encodes Sedlin, a component of the trafficking protein particle (TRAPP) complex that we have shown previously to be required for the export of type II collagen (Col2) from the endoplasmic reticulum. No vertebrate model for SEDT has been generated thus far. To address this gap, we generated a Sedlin knockout animal by mutating the orthologous TRAPPC2 gene (olSedl) of Oryzias latipes (medaka) fish. OlSedl deficiency leads to embryonic defects, short size, diminished skeletal ossification and altered Col2 production and secretion, resembling human defects observed in SEDT patients. Moreover, SEDT knock-out animals display photoreceptor degeneration and gut morphogenesis defects, suggesting a key role for Sedlin in the development of these organs. Thus, by studying Sedlin function in vivo, we provide evidence for a mechanistic link between TRAPPC2-mediated membrane trafficking, Col2 export, and developmental disorders.

A mesomelic skeletal dysplasia, Kantaputra-like, not related to HOXD cluster region, and with phenotypic gender differences.

Mesomelic skeletal dysplasia is a heterogeneous group of skeletal disorders that has grown since the molecular basis of these conditions is in the process of research and discovery. Here, we report a Brazilian family with eight affected members over three generations with a phenotype similar to mesomelic Kantaputra dysplasia. This family presents marked shortening of the upper limbs with hypotrophy of the lower limbs and clubfeet without synostosis. Array-based CNV analysis and exome sequencing of four family members failed to show any region or gene candidate. Interestingly, males were more severely affected than females in this family, suggesting that gender differences could play a role in the phenotypic expressivity of this condition.

Identification of a novel heterozygous PTH1R variant in a Chinese family with incomplete penetrance.

BACKGROUND: Mutations in PTH1R are associated with Jansen-type metaphyseal chondrodysplasia (JMC), Blomstrand osteochondrodysplasia (BOCD), Eiken syndrome, enchondroma, and primary failure of tooth eruption (PFE). Inheritance of the PTH1R gene can be either autosomal dominant or autosomal recessive, indicating the complexity of the gene. Our objective was to identify the phenotypic differences in members of a family with a novel PTH1R mutation. METHODS: The proband was a 13-year, 6-month-old girl presenting with short stature, abnormal tooth eruption, skeletal dysplasia, and midface hypoplasia. The brother and father of the proband presented with short stature and abnormal tooth eruption. High-throughput sequencing was performed on the proband, and the variant was confirmed in the proband and other family members by Sanger sequencing. Amino acid sequence alignment was performed using ClustalX software. Three-dimensional structures were analyzed and displayed using the I-TASSER website and PyMOL software. RESULTS: High-throughput genome sequencing and Sanger sequencing validation showed that the proband, her father, and her brother all carried the PTH1R (NM_000316) c.1393G>A (p.E465K) mutation. The c.1393G>A (p.E465K) mutation was novel, as it has not been reported in the literature database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the p.E465K variant was considered to have uncertain significance. Biological information analysis demonstrated that this identified variant was highly conserved and highly likely pathogenic. CONCLUSIONS: We identified a novel heterozygous mutation in the PTH1R gene leading to clinical manifestations with incomplete penetrance that expands the spectrum of known PTH1R mutations.

SHOX Variations in Idiopathic Short Stature in North India and a Review of Cases from Asian Countries

Objective: Short stature homeobox (SHOX) haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis. The worldwide prevalence of SHOX variations in ISS varies from 2.5% to 15.0%. The aim of this study was to assess the implication of SHOX variation in ISS in North Indians and compare this with other cases of SHOX variations from Asian population. Methods: SHOX gene analysis was carried out by multiplex ligation-dependent probe amplification followed by Sanger sequencing in 54 patients with variable phenotypes. Comparison with other reports in a meta-analysis comprising the current study and 11 previous studies (n=979) was performed. Results: SHOX analysis resulted in 12.9% positivity (7.4% deletions and 5.5% duplications). SHOX association was seen significantly related to gender, with predominance in females (p=0.047). Short arms and forearms were the only significantly associated trait seen in 51.9% of children. The overall prevalence of SHOX variation was 15.2% in Asians with ISS. No significant difference was found in geographical region-specific analysis. Conclusion: This study summarises findings from the last decade and provides an updated picture of the prevalence of SHOX variations in Asians, emphasizing their potential as therapeutic targets in ISS patients. Further high quality, large investigations including functional validation is warranted to validate this association.

SOFT syndrome with kohlschutter-Tonz syndrome.

We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling. Rhizo-mesomelic dwarfism was detected antenatally. Within 24 hours of birth, he developed multiple seizures. Examination revealed severe short stature, dolichocephaly, broad forehead, deep set eyes, low set ears, bulbous nose, small, irregular teeth, pointed chin, and triangular facies. He had rhizomelic shortening, stubby fingers, pes planus, and scanty hair. Neurological evaluation revealed ataxia, hypotonia, and global developmental delay. Skeletal survey radiograph revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals and short cone-shaped phalanges with cupping of phalangeal bases. Clinical exome analysis revealed homozygous mutations involving the POC1A gene and the SLC13A5 gene responsible for SOFT syndrome and Kohlschutter-Tonz syndrome respectively, which were inherited from the parents. Both these syndromes are extremely rare, and their co-occurrence is being reported for the first time.