Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature.

Schinzel-Giedion syndrome (SGS) is a severe multisystem disorder characterized by distinctive facial features, profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies. SGS is attributed to gain-of-function (GoF) variants in the SETBP1 gene, with reported variants causing canonical SGS located within a 12 bp hotspot region encoding SETBP1 residues aa868-871 (degron). Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron. The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS. This is the first report of a typical SGS caused by a, SETBP1 non-degron missense variant. This case expands the genetic spectrum of SGS and provides new insights into genotype-phenotype correlations.

Prenatal diagnosis of isolated bilateral clubfoot: Is amniocentesis indicated?

INTRODUCTION: The aim of this study is to evaluate the benefit of cytogenetic testing by amniocentesis after an ultrasound diagnosis of isolated bilateral talipes equinovarus. MATERIAL AND METHODS: This multicenter observational retrospective study includes all prenatally diagnosed cases of isolated bilateral talipes equinovarus in five fetal medicine centers from 2012 through 2021. Ultrasound data, amniocentesis results, biochemical analyses of amniotic fluid and parental blood samples to test neuromuscular diseases, pregnancy outcomes, and postnatal outcomes were collected for each patient. RESULTS: In all, 214 fetuses with isolated bilateral talipes equinovarus were analyzed. A first-degree family history of talipes equinovarus existed in 9.8% (21/214) of our cohort. Amniocentesis was proposed to 86.0% (184/214) and performed in 70.1% (129/184) of cases. Of the 184 karyotypes performed, two (1.6%) were abnormal (one trisomy 21 and one triple X syndrome). Of the 103 microarrays performed, two (1.9%) revealed a pathogenic copy number variation (one with a de novo 18p deletion and one with a de novo 22q11.2 deletion) (DiGeorge syndrome). Neuromuscular diseases (spinal muscular amyotrophy, myasthenia gravis, and Steinert disease) were tested for in 56 fetuses (27.6%); all were negative. Overall, 97.6% (165/169) of fetuses were live-born, and the diagnosis of isolated bilateral talipes equinovarus was confirmed for 98.6% (139/141). Three medical terminations of pregnancy were performed (for the fetuses diagnosed with Down syndrome, DiGeorge syndrome, and the 18p deletion). Telephone calls (at a mean follow-up age of 4.5 years) were made to all parents to collect medium-term and long-term follow-up information, and 70 (33.0%) families were successfully contacted. Two reported a rare genetic disease diagnosed postnatally (one primary microcephaly and one infantile glycine encephalopathy). Parents did not report any noticeably abnormal psychomotor development among the other children during this data collection. CONCLUSIONS: Despite the low rate of pathogenic chromosomal abnormalities diagnosed prenatally after this ultrasound diagnosis, the risk of chromosomal aberration exceeds the risks of amniocentesis. These data may be helpful in prenatal counseling situations.

Identification of a novel LMX1B nonsense variant associated with congenital talipes equinovarus by prenatal exome sequencing: A case report.

BACKGROUND: Congenital talipes equinovarus (CTEV) is a rotational foot deformity that affects muscles, bones, connective tissue, and vascular or neurological tissues. The etiology of CTEV is complex and unclear, involving genetic and environmental factors. Nail-patella syndrome is an autosomal dominant disorder caused by variants of the LIM homeobox transcription factor 1 beta gene (LMX1B, OMIM:602575). LMX1B plays a key role in the development of dorsal limb structures, the kidneys, and the eyes, and variants in this gene may manifest as hypoplastic or absent patella, dystrophic nails, and elbow and iliac horn dysplasia; glomerulopathy; and adult-onset glaucoma, respectively. This study aimed to identify pathogenic variants in a fetus with isolated talipes equinovarus diagnosed by ultrasound in the second trimester, whose father exhibited dysplastic nails and congenital absence of bilateral patella. METHODS: Prenatal whole-exome sequencing (WES) of the fetus and parents was performed to identify the genetic variant responsible for the fetal ultrasound abnormality, followed by validation using Sanger sequencing. RESULTS: A novel heterozygous nonsense variant in exon 6 of LMX1B (c.844C>T, p.Gln282*) was identified in the fetus and the affected father but was not detected in any unaffected family members. This nonsense variant resulted in a premature termination codon at position 282, which may be responsible for the clinical phenotype through the loss of function of the gene product. CONCLUSIONS: Our study indicating that a fetus carrying a novel nonsense variant of LMX1B (c.844C>T, p.Gln282*) can exhibit isolated talipes equinovarus, which expands the LMX1B genotypic spectrum and is advantageous for genetic counseling.

COL1A1 regulates the apoptosis of embryonic stem cells by mediating the PITX1/TBX4 signaling.

PURPOSE: The purpose of this study is to explore the regulatory function of COL1A1 against the apoptosis of embryonic stem cells (ESCs) and the potential function in congenital talipes equinovarus (CTEV). METHODS: Muscle tissues were collected from 20 children with CTEV and 20 children without CTEV, followed by detecting the expression of COL1A1 using the RT-PCR method. COL1A1 was knocked down in H1 and H9 human ESCs using the RNA interference technology, followed by determining the level of COL1A1, PITX1, TBX4, HOXD10, Fas, FasL, and Bax using the Western blotting assay. RESULTS: COL1A1 was found markedly upregulated in muscle tissues of CTEV children. In H1 and H9 human ESCs, compared to the empty vector, COL1A1, PITX1, TBX4, HOXD10, Fas, FasL, and Bax were found notably downregulated after transfected with the siRNA targeting COL1A1. CONCLUSION: COL1A1 induced the apoptosis of ESCs by mediating the PITX1/TBX4 signaling and might be a potential target for treating CTEV.

Fetal congenital talipes equinovarus: genomic abnormalities and obstetric follow-up results.

OBJECTIVE: The etiology of congenital talipes equinovarus (CTEV) is unknown, and the relationship between chromosome microdeletion/microduplication and fetal CTEV is rarely reported. In this study, we retrospectively analyzed fetal CTEV to explore the relationship among the CTEV phenotype, chromosome microdeletion/microduplication, and obstetric outcomes. METHODS: Chromosome karyotype analysis and single nucleotide polymorphism (SNP) array were performed for the 68 fetuses with CTEV. RESULTS: An SNP array was performed for 68 fetuses with CTEV; pathogenic copy number variations (CNVs) were detected in eight cases (11.8%, 8/68). In addition to one case consistent with karyotype analysis, the SNP array revealed seven additional pathogenic CNVs, including three with 22q11.21 microdeletions, two with 17p12p11.2 microduplications, one with 15q11.2 microdeletions, and one with 7q11.23 microduplications. Of the seven cases carrying pathogenic CNVs, three were tested for family genetics; of these, one was de novo, and two were inherited from either the father or mother. In total, 68 fetuses with CTEV were initially identified, of which 66 cases successfully followed-up. Of these, 9 were terminated, 2 died in utero, and 55 were live births. In 9 cases, no clinical manifestations of CTEV were found at birth; the false-positive rate of prenatal ultrasound CTEVdiagnosis was thus 13.6% (9/66). CONCLUSION: CTEV was associated with chromosome microdeletion/microduplication, the most common of which was 22q11.21 microdeletion, followed by 17p12p11.2 microduplication. Thus, further genomic detection is recommended for fetuses with CTEV showing no abnormalities on conventional karyotype analysis.

Incidence and prevalence of congenital clubfoot in Apulia: a regional model for future prospective national studies.

BACKGROUND: Congenital clubfoot is a fairly common and severe congenital malformation, most often of idiopathic origin. A smaller percentage of cases is related to chromosomal abnormalities and genetic syndromes. It is estimated that 0.5/1000 newborns are affected worldwide, with a male to female ratio of 2:1 and greater distribution in developing countries (80%). The "European Surveillance of Congenital Anomalies (EUROCAT)" reported clubfoot prevalence in European newborns, but data regarding Italy are missing or poor. We aim to provide detailed data on clubfoot incidence according to the Apulian Regional Registry on Congenital Malformations and to report current knowledge on clubfoot genetic factors. METHODS: We extrapolated data from the Regional Registry of Congenital Malformations to evaluate incidence and prevalence of congenital clubfoot in Apulia, Italy over a period of four years (2015-2018). We also performed a narrative review focusing on genetic mutations leading to congenital clubfoot. RESULTS: Over the period from 2015 to 2018 in Apulia, Italy, 124,017 births were recorded and 209 cases of clubfoot were found, accounting for an incidence rate of 1.7/1,000 and a prevalence rate of 1.6/1,000. Six families of genes have been reported to have an etiopathogenetic role on congenital clubfoot. CONCLUSIONS: Incidence and prevalence of congenital clubfoot in Apulia, Italy, are comparable with those reported in the other Italian regions but higher than those reported in previous studies from Europe. Genetic studies to better classify congenital clubfoot in either syndromic or isolated forms are desirable.

Prenatal diagnosis and genetic etiology analysis of talipes equinovarus by chromosomal microarray analysis.

BACKGROUND: With the advancement of molecular technology, fetal talipes equinovarus (TE) is believed to be not only associated with chromosome aneuploidy, but also related to chromosomal microdeletion and microduplication. The study aimed to explore the molecular etiology of fetal TE and provide more information for the clinical screening and genetic counseling of TE by Chromosomal Microarray Analysis (CMA). METHODS: This retrospectively study included 131 fetuses with TE identified by ultrasonography. Conventional karyotyping and SNP array analysis were performed for all the subjects. They were divided into isolated TE group (n = 55) and complex group (n = 76) according to structural anomalies. RESULTS: Among the total of 131 fetuses, karyotype analysis found 12(9.2%) abnormal results, while SNP array found 27 (20.6%) cases. Trisomy 18 was detected most frequently among abnormal karyotypes. The detection rate of SNP array was significantly higher than that of traditional chromosome karyotype analysis (P < 0.05). SNP array detected 15 (11.5%) cases of submicroscopic abnormalities that karyotype analysis did not find. The most common CNV was the 22q11.2 microdeletion. For both analyses, the overall detection rates were significantly higher in the complex TE group than in the isolated TE group (karyotype: P < 0.05; SNP array: P < 0.05). The incremental yield of chromosomal abnormalities in fetuses with unilateral TE (22.0%) was higher than in fetuses with bilateral TE (19.8%), but this difference was not statistically significant (P > 0.05). Abnormal chromosomes were most frequently detected in fetuses with TE plus cardiovascular system abnormalities. CONCLUSION: Fetal TE is related to chromosomal microdeletion or microduplication. Prenatal diagnosis is recommended for fetuses with TE, and CMA testing is preferred. CMA can improve the detection rate of chromosomal abnormalities associated with fetal TE, especially in pregnancies with complex TE.

A novel PIEZO2 mutation in a fetus from a Chinese family with Gordon syndrome.

We describe a fetus from a Chinese family whose parents were both healthy but showed multiple malformations, including clubfoot, camptodactyly, micrognathia, and cleft palate. Genomic DNA was extracted from the peripheral blood of the proband's parents and skeletal muscle tissue from the aborted fetus to determine the diagnosis and underlying cause. Whole-exome sequencing revealed that the fetus was heterozygous for a novel variant of uncertain significance in exon 56 (c.8576G>A; p.Trp2859*) of the Piezo-type mechanosensitive ion channel component 2 gene (PIEZO2) (NM_001378183.1). A diagnosis of Gordon syndrome (GS) was made from the presence of this variant and ultrasonic manifestation. Sanger sequencing of the proband's parents resulted in normal chromatograms, suggesting that this was either a de novo variant in the fetus or, less likely, the result of germline mosaicism in the proband's mother or father. This is the first description of GS caused by a PIEZO2 variant in which the fetus was the proband. A prenatal diagnosis of GS can be established by fetal ultrasound examination combined with genetic testing.

Vitelline vascular remnant causing intestinal obstruction in a patient with TARP syndrome.

BACKGROUND: TARP syndrome, characterized by talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava, is an X-linked recessive condition caused by deleterious variants in RBM10. Vitelline vascular remnants (VVR) are a rare vitelline duct anomaly with approximately 26 cases previously reported. There are no previously reported cases of VVRs in patients with TARP syndrome. CASE: We present a male neonate diagnosed with TARP syndrome via trio whole exome sequencing who had classic features of this syndrome, although his course was additionally complicated by feeding intolerance with multiple episodes of abdominal distension. Serial imaging and contrast studies of the upper GI tract and small bowel demonstrated small bowel obstruction of unclear etiology. Given the poor prognosis associated with this condition, life-sustaining measures were withdrawn, and he passed away at 38 days of age. On autopsy, a VVR was unexpectedly identified with proximal bowel dilation, explaining his feeding intolerance. CONCLUSIONS: We highlight the importance of full post-mortem examination in understanding the complete spectrum of manifestations of genetic syndromes and provide a review of the literature.

Prenatal isolated clubfoot increases the risk for clinically significant exome sequencing results.

OBJECTIVE: To examine the diagnostic yield of exome sequencing (ES) in singleton pregnancies with isolated fetal clubfoot. METHODS: Clinical data from singleton pregnancies with a sonographic diagnosis of isolated clubfoot and ES results between 2018 and 2021 were retrospectively obtained from a single referral medical center. The recorded data include maternal age, gestational age at sonographic diagnosis, the indication for genetic testing, ES results, and pregnancy outcomes. RESULTS: During the study period, 38 fetuses were prenatally diagnosed with isolated clubfoot by ultrasound and underwent ES after the copy number variant analysis was non-diagnostic. Through the trio-ES analysis, pathogenic or likely pathogenic variants were detected in 4 of 38 (10.5%) with the following genes: BRPF1, ANKRD17, FLNA, and KIF1A. All are de novo with three of autosomal dominant inheritance and one of X-linked recessive inheritance. CONCLUSION: Sonographic diagnosis of clubfoot, even isolated, increases the risk for monogenic syndromes. Exome sequencing should be an option for genetic investigation for such pregnancies.

What Is the Exact Contribution of PITX1 and TBX4 Genes in Clubfoot Development? An Italian Study.

Congenital clubfoot is a common pediatric malformation that affects approximately 0.1% of all births. 80% of the cases appear isolated, while 20% can be secondary or associated with complex syndromes. To date, two genes that appear to play an important role are PTIX1 and TBX4, but their actual impact is still unclear. Our study aimed to evaluate the prevalence of pathogenic variants in PITX1 and TBX4 in Italian patients with idiopathic clubfoot. PITX1 and TBX4 genes were analyzed by sequence and SNP array in 162 patients. We detected only four nucleotide variants in TBX4, predicted to be benign or likely benign. CNV analysis did not reveal duplications or deletions involving both genes and intragenic structural variants. Our data proved that the idiopathic form of congenital clubfoot was rarely associated with mutations and CNVs on PITX1 and TBX4. Although in some patients, the disease was caused by mutations in both genes; they were responsible for only a tiny minority of cases, at least in the Italian population. It was not excluded that other genes belonging to the same TBX4-PITX1 axis were involved, even if genetic complexity at the origin of clubfoot required the involvement of other factors.

Prenatal Diagnosis of Talipes Equinovarus by Ultrasound and Chromosomal Microarray Analysis: A Chinese Single-Center Retrospective Study.

Background: There are few studies on the detection rate by chromosomal microarray analysis (CMA) of the prenatal diagnosis of talipes equinovarus (TE) compared to conventional karyotyping. We aimed to explore the molecular etiology of fetal TE and examine the detection rate by CMA, which provides more information for the clinical screening and genetic counseling of TE. Methods: In this retrospective study, pregnancies diagnosed with fetal TE were enrolled and clinical data for all cases were retrieved from our medical record database, including demographic data for pregnancies, ultrasound findings, karyotype/CMA results, and pregnant and perinatal outcomes. Results: Among the 164 patients, 17 (10.4%) clinically significant variants were detected by CMA. In 148 singleton pregnancies, the diagnostic rate of clinically significant variants was significantly higher in the non-isolated TE group than in the isolated TE group (10/37, 27.0% vs. 6/111, 5.4%, P < 0.001). In twin pregnancies, 1 (6.3%) pathogenic copy number variant was present in the other 16 twin pregnancies. Conclusions: This study demonstrates that CMA is useful for the prenatal genetic diagnosis of fetal TE. Fetal TE with the associated structural malformation correlates with a higher probability of clinically significant variants. This data may aid prenatal diagnosis and genetic counseling for fetal TE.

Genetic studies in isolated bilateral clubfoot detected by prenatal ultrasound.

OBJECTIVE: To evaluate the contribution of genetic investigations in case of isolated bilateral clubfoot detected by routine prenatal ultrasound. Pathogenic Copy Number Variations is about 3.9% in fetuses with isolated clubfoot (uni- or bilateral). We hypothesize that this rate could be higher in a homogenous group of fetuses with bilateral clubfoot. METHODS: This retrospective single-center study included all women referred to our fetal-medicine center between 2013 and 2020 after ultrasound detection of isolated bilateral clubfoot. Genetic counseling was offered in which the woman was offered an amniocentesis for CMA and targeted investigation for Prader-Willi Syndrome (PWS), Steinert's disease and Spinal Muscular Atrophy (SMA). RESULTS: 34 women were referred, 18 of them consented to undergo genetic studies by amniocentesis (18/34; 52.9%). Pathogenic copy number variations (CNVs) were found in 2/18 (11.1%) of cases. One of these CNVs was directly linked to the clubfoot pathology (a deletion in 5q31.1 containing PITX1 gene). Four fetuses (4/18, 22.2%) had variants of unknown significance (VUS). No PWS, SMA or Steinert's disease was found. No case diagnosed with isolated clubfoot prenatally had additional anomalies postnatally. CONCLUSIONS: In the case of bilateral isolated clubfoot detected at the antenatal ultrasound, invasive prenatal testing should be offered, and if accepted, a CMA should be done, as pathogenic variations were observed in up to 11.1% of women who got amniocentesis. The findings of this study do not support the systematic recommendation of molecular studies for PWS, SMA, Steinert's disease.

The molecular genetics of human appendicular skeleton.

Disorders that result from de-arrangement of growth, development and/or differentiation of the appendages (limbs and digit) are collectively called as inherited abnormalities of human appendicular skeleton. The bones of appendicular skeleton have central role in locomotion and movement. The different types of appendicular skeletal abnormalities are well described in the report of "Nosology and Classification of Genetic skeletal disorders: 2019 Revision". In the current article, we intend to present the embryology, developmental pathways, disorders and the molecular genetics of the appendicular skeletal malformations. We mainly focused on the polydactyly, syndactyly, brachydactyly, split-hand-foot malformation and clubfoot disorders. To our knowledge, only nine genes of polydactyly, five genes of split-hand-foot malformation, nine genes for syndactyly, eight genes for brachydactyly and only single gene for clubfoot have been identified to be involved in disease pathophysiology. The current molecular genetic data will help life sciences researchers working on the rare skeletal disorders. Moreover, the aim of present systematic review is to gather the published knowledge on molecular genetics of appendicular skeleton, which would help in genetic counseling and molecular diagnosis.

Establishment of a control induced pluripotent stem cell line SMBCi018-A from a patient with congenital talipes equinovarus.

Congenital talipes equinovarus (CTEV) is a congenital malformation affecting approximately 1/700-1/1000 of live borns. To date extensive epidemiological and biological studies have been operated to solve this issue, the most meaningful findings in clubfoot genetics involve PITX1 variants, which were associated with clubfoot phenotype in mice and humans. According to recent studies, the PITX1-TBX4 transcriptional pathway regulatory for early limb development has identified a key developmental pathway in clubfoot etiology by the common disease-rare hypothesis. However, the precise mechanisms causing this disease remain elusive. The pluripotent stem cell line SMBCi018-A will enable proper in vitro disease modeling of CTEV.

The possible role of hypoxia in the affected tissue of relapsed clubfoot.

Our aim was to study the expression of hypoxia-related proteins as a possible regulatory pathway in the contracted side tissue of relapsed clubfoot. We compared the expression of hypoxia-related proteins in the tissue of the contracted (medial) side of relapsed clubfoot, and in the tissue of the non-contracted (lateral) side of relapsed clubfoot. Tissue samples from ten patients were analyzed by immunohistochemistry and image analysis, Real-time PCR and Mass Spectrometry to evaluate the differences in protein composition and gene expression. We found a significant increase in the levels of smooth muscle actin, transforming growth factor-beta, hypoxia-inducible factor 1 alpha, lysyl oxidase, lysyl oxidase-like 2, tenascin C, matrix metalloproteinase-2, matrix metalloproteinase-9, fibronectin, collagen types III and VI, hemoglobin subunit alpha and hemoglobin subunit beta, and an overexpression of ACTA2, FN1, TGFB1, HIF1A and MMP2 genes in the contracted medial side tissue of clubfoot. In the affected tissue, we have identified an increase in the level of hypoxia-related proteins, together with an overexpression of corresponding genes. Our results suggest that the hypoxia-associated pathway is potentially a factor contributing to the etiology of clubfoot relapses, as it stimulates both angioproliferation and fibroproliferation, which are considered to be key factors in the progression and development of relapses.

Whole Exome Sequencing in Individuals with Idiopathic Clubfoot Reveals a Recurrent Filamin B (FLNB) Deletion.

BACKGROUND: Clubfoot, a congenital deformity that presents as a rigid, inward turning of the foot, affects approximately 1 in 1000 infants and occurs as an isolated birth defect in 80% of patients. Despite its high level of heritability, few causative genes have been identified, and mutations in known genes are only responsible for a small portion of clubfoot heritability. QUESTIONS/PURPOSES: (1) Are any rare gene variants enriched (that is, shared) in unrelated patients with isolated clubfoot? (2) Are there other rare variants in the identified gene (Filamin B) in these patients with clubfoot? METHODS: Whole-exome sequence data were generated from a discovery cohort of 183 unrelated probands with clubfoot and 2492 controls. Variants were filtered with minor allele frequency < 0.02 to identify rare variants as well as small insertions and deletions (indels) resulting in missense variants, nonsense or premature truncation, or in-frame deletions. A candidate deletion was then genotyped in another cohort of 974 unrelated patients with clubfoot (a replication cohort). Other rare variants in the candidate gene were also investigated. A segregation analysis was performed in multigenerational families of individuals with clubfoot to see if the genotypes segregate with phenotypes. Single-variant association analysis was performed using the Fisher two-tailed exact test (exact p values are presented to give an indication of the magnitude of the association). RESULTS: There were no recurrent variants in the known genes causing clubfoot in this study. A three-base pair in-frame codon deletion of Filamin B (FLNB) (p.E1792del, rs1470699812) was identified in 1.6% (3 of 183) of probands with clubfoot in the discovery cohort compared with 0% of controls (0 of 2492) (odds ratio infinity (inf) [95% CI 5.64 to inf]; p = 3.18 x 10-5) and 0.0016% of gnomAD controls (2 of 125,709) (OR 1.01 x 103 [95% CI 117.42 to 1.64 x 104]; p = 3.13 x 10-8). By screening a replication cohort (n = 974 patients), we found two probands with the identical FLNB deletion. In total, the deletion was identified in 0.43% (5 of 1157) of probands with clubfoot compared with 0% of controls and 0.0016% of gnomAD controls (OR 268.5 [95% CI 43.68 to 2.88 x 103]; p = 1.43 x 10-9). The recurrent FLNB p.E1792del variant segregated with clubfoot, with incomplete penetrance in two families. Affected individuals were more likely to be male and have bilateral clubfoot. Although most patients had isolated clubfoot, features consistent with Larsen syndrome, including upper extremity abnormalities such as elbow and thumb hypermobility and wide, flat thumbs, were noted in affected members of one family. We identified 19 additional rare FLNB missense variants located throughout the gene in patients with clubfoot. One of these missense variants, FLNB p.G2397D, exhibited incomplete penetrance in one family. CONCLUSION: A recurrent FLNB E1792 deletion was identified in 0.43% of 1157 isolated patients with clubfoot. Given the absence of any recurrent variants in our discovery phase (n = 183) for any of the known genes causing clubfoot, our findings support that novel and rare missense variants in FLNB in patients with clubfoot, although rare, may be among the most commonly known genetic causes of clubfoot. Patients with FLNB variants often have isolated clubfoot, but they and their family members may be at an increased risk of having additional clinical features consistent with Larsen syndrome. CLINICAL RELEVANCE: Identification of FLNB variants may be useful for determining clubfoot recurrence risk and comorbidities.

Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report.

Objectives: Gordon syndrome (GS), also known as pseudohypoaldosteronism type II, is a rare tubular disease characterized by hypertension, hyperkalemia, and metabolic acidosis. Its causative genes are CUL3, KLHL3, WNK1, and WNK4, and they are associated with varying severity of the disease. Herein, we report the first case of GS caused by a CUL3 mutation in a patient with short stature in Korea.Case presentation: A 7-year-old boy had hypertension, metabolic acidosis, and persistent hyperkalemia, which were initially detected during the evaluation of short stature. He was born small for gestational age at late preterm gestation. Laboratory test findings showed hyperkalemia with low trans-tubular potassium gradient, hyperchloremic metabolic acidosis with a normal anion gap, and low plasma renin levels. Genetic analysis revealed a heterozygous de novo mutation in the CUL3 gene (c.1377+1G > C in intron 9). Thus, a diagnosis of GS was made. The results of the endocrine function test (including growth hormone stimulation tests) were normal. After thiazide treatment, the patient's electrolyte levels were normalized. However, he presented with persistent hypertension and short stature.Conclusions: GS should be considered in children with short stature, hypertension, and hyperkalemia, and early treatment may reduce complications.

Genotype-phenotype correlation in clubfoot (talipes equinovarus).

Clubfoot (talipes equinovarus) is a congenital malformation affecting muscles, bones, connective tissue and vascular or neurological structures in limbs. It has a complex aetiology, both genetic and environmental. To date, the most important findings in clubfoot genetics involve PITX1 variants, which were linked to clubfoot phenotype in mice and humans. Additionally, copy number variations encompassing TBX4 or single nucleotide variants in HOXC11, the molecular targets of the PITX1 transcription factor, were linked to the clubfoot phenotype. In general, genes of cytoskeleton and muscle contractile apparatus, as well as components of the extracellular matrix and connective tissue, are frequently linked with clubfoot aetiology. Last but not least, an equally important element, that brings us closer to a better understanding of the clubfoot genotype/phenotype correlation, are studies on the two known animal models of clubfoot-the pma or EphA4 mice. This review will summarise the current state of knowledge of the molecular basis of this congenital malformation.