Background/Objectives: Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic disorder characterized by the bilateral absence of the radius and thrombocytopenia, often leading to functional limitations and gait asymmetries. Prosthetic devices are sometimes employed to improve mobility and posture, but their impact on gait mechanics in pediatric patients remains poorly understood. Methods: The methodology used is based on a study that evaluated the gait parameters of a 10-year-old child with TAR syndrome under static and dynamic conditions, both with and without the use of a custom-designed upper limb prosthesis. The analysis focused on assessing the prosthesis's impact on gait symmetry and biomechanics. A key aspect of the methodology involved studying the distribution of pressure forces on the ground during walking using the FreeMed EXTREME Maxi baropodometric platform. Results: Gait analysis demonstrated asymmetries between the left and right feet. In the absence of the prosthesis, the patient exhibited excessive forward loading and uneven pressure distributions. The use of a custom prosthesis, particularly with counterbalancing features, improved gait symmetry but led to increased reliance on the left foot. This foot experienced higher pressures (738-852 g/cm2) and longer ground contact times (690-865 ms) compared to the right foot (619-748 g/cm2 and 673-771 ms). The left foot displayed elevated forefoot pressures (61-65%), while the right foot bore weight laterally (66-74%). Conclusions: The custom prosthesis influenced gait mechanics by redistributing plantar pressures and modifying ground contact times, partially improving gait symmetry. However, compensatory strategies, such as increased loading on the left foot, could contribute to musculoskeletal strain over time. Individualized rehabilitation programs and prosthetic designs are essential for optimizing gait mechanics, improving mobility, and minimizing long-term complications in TAR syndrome patients.

Food protein-induced enterocolitis syndrome (FPIES) is a food allergy primarily affecting infants, often leading to vomiting and shock. Due to its poorly understood pathophysiology and lack of specific biomarkers, diagnosis is frequently delayed. Understanding FPIES genetics can shed light on disease susceptibility and pathophysiology-key to developing diagnostic, prognostic, preventive and therapeutic strategies. Using a well-characterised cohort of patients we explored the potential genome-wide susceptibility factors underlying FPIES. Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study. Notable genetic variants, including rs872786 (RBM8A), rs2241880 (ATG16L1) and rs2289477 (ATG16L1), were identified as significant findings in FPIES. A weighted SKAT model identified six other associated genes including DGKZ and SIRPA. DGKZ induces TGF-β signalling, crucial for epithelial barrier integrity and IgA production; RBM8A is associated with thrombocytopenia absent radius syndrome, frequently associated with cow's milk allergy; SIRPA is associated with increased neutrophils/monocytes in inflamed tissues as often observed in FPIES; ATG16L1 is associated with inflammatory bowel disease. Coexpression correlation analysis revealed a functional correlation between RBM8A and filaggrin gene (FLG) in stomach and intestine tissue, with filaggrin being a known key pathogenic and risk factor for IgE-mediated food allergy. A transcriptome-wide association study suggested genetic variability in patients impacted gene expression of RBM8A (stomach and pancreas) and ATG16L1 (transverse colon). This study represents the first case-control exome association study of FPIES patients and marks a crucial step towards unravelling genetic susceptibility factors underpinning the syndrome. Our findings highlight potential factors and pathways contributing to FPIES, including epithelial barrier dysfunction and immune dysregulation. While these results are novel, they are preliminary and need further validation in a second cohort of patients. Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur. The diagnosis of TAR syndrome is established in a proband with bilateral absent radii, present thumbs, and thrombocytopenia. Identification of a heterozygous null allele (most often a minimally deleted 200-kb region including RBM8A at chromosome band 1q21.1) in a compound heterozygous state with a heterozygous RBM8A hypomorphic allele on molecular genetic testing confirms the diagnosis. Treatment of manifestations: Orthopedic intervention as needed to maximize limb function. Platelet transfusion for thrombocytopenia as needed; to reduce the risks of alloimmunization and infection, avoid platelet transfusion in older individuals whose platelet counts exceed a particular threshold (10 platelets/nL). Standard treatments for cardiac and genitourinary anomalies. Avoidance of cow's milk to reduce the severity of gastroenteritis and to avoid exacerbations of thrombocytopenia. Central venous catheter as an alternative to repeated venipuncture. Surveillance: Platelet count when evidence of increased bleeding tendency (bruising, petechiae) occurs. Assess for gastrointestinal manifestations in children, which may indicate cow's milk allergy, at each visit. Serum electrolytes, blood urea nitrogen, and creatinine to assess kidney function per nephrologist. Agents/circumstances to avoid: Avoid cow's milk to reduce the severity of gastroenteritis and associated thrombocytopenia (in older children). Platelet function is somewhat impaired, suggesting that drugs such as nonsteroidal anti-inflammatory drugs or aspirin should be avoided or used with caution. TAR syndrome is caused by compound heterozygosity for a null allele and an RBM8A hypomorphic allele and is inherited in an autosomal recessive manner. However, because null alleles are rare (and often occur de novo in the proband) and RBM8A hypomorphic alleles are common, inheritance of TAR syndrome is associated with several features unusual in autosomal recessive disorders: a paucity of affected sibs, apparent parent-to-child transmission, and affected second- and third-degree relatives. The risk to sibs of a proband varies depending on the genetic status of the parents; for example: If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an RBM8A hypomorphic allele, each sib of an affected individual has at conception a 25% chance of being affected. If one parent is known to be heterozygous for a null allele and the other parent has biallelic RBM8A hypomorphic alleles, each sib of an affected individual has at conception a 50% chance of being affected. If one parent is known to be heterozygous for an RBM8A hypomorphic allele and the other parent has two normal RBM8A alleles, each sib of an affected individual has at conception a 50% chance of being an asymptomatic carrier of an RBM8A hypomorphic allele and a 50% chance of being unaffected and not a carrier. Individuals who are heterozygotes (carriers) for one TAR syndrome-related pathogenic variant (either an RBM8A hypomorphic allele or a null allele) are asymptomatic; individuals with biallelic RBM8A hypomorphic alleles are asymptomatic. Once the causative null allele and RBM8A hypomorphic allele have been identified in an affected family member, carrier testing for at-risk relatives as well as prenatal and preimplantation genetic testing are possible.

Whole-exome DNA sequencing is a rich source of clinically useful information for specialists, patients, and their families, as well as elucidating the genetic basis of monogenic and complex diseases in clinical diagnosis. However, interpreting and reporting variants encompassing exome and genome sequence analysis outcome data are one of the greatest challenges of the genomic era. In this study, we aimed to investigate the frequency and allele frequency spectrum of single nucleotide variants accepted as recessive disease carrier status in Turkish Cypriot exomes. The same sequencing platform and data processing line were used for the analysis of data from 100 Turkish Cypriot whole-exome sequence analysis. Identified variants were classified according to ACMG guidelines, and pathogenic variants were confirmed in other databases such as ClinVar, HGMD, Varsome, etc. Pathogenic variants were detected in 68 genes out of 100 whole-exome sequence data. The carriage rate was the highest in the CYP21A2 gene, causing 21-hydroxylase deficiency (14.70%), 11.76% in the HBB gene causing β-thalassemia, 10.29% in the BTD gene causing biotinidase deficiency, 8.82% in the CFTR gene causing cystic fibrosis, 8.82% in the RBM8A gene causing thrombocytopenia-absent radius syndrome, which is an ultra-rare disease, and 5.88% in the GAA gene causing glycogen storage disease II. The carriage of pathogenic variants in other genes causing the disease (GJB2, PAH, GALC, CYP11B2, COL4A3, HBA1, etc.) was determined as less than 5.00%. Also, the identified variations in the mentioned gene within the examined population were reported. The most prevalent mutation in North Cyprus was a missense variant (c.1360 C>T, p.Pro454Ser) detected in the CYP21A2 gene (rs6445), and the most frequently seen variant in the HBB gene was c.93-21G>A (rs35004220). We investigated reported pathogenic variants by estimating the lower and upper limits of carrier and population frequencies for autosomal recessive diseases, for which exome sequencing may reveal additional medically relevant information. Determining the lower and upper limits of these frequencies will shed light on preventive medicine practices and governmental actions.

This is a case of a female patient born with thrombocytopenia-absent radius syndrome, with bilateral upper extremity phocomelia, bilateral hip dislocations, and congenital fusion of the right knee with progressively worsening flexion contracture. At age 3 years and 5 months, the patient was treated with excision of the knee ankylosis and Van Nes rotationplasty. This proved durable at age 20 years (final follow-up) without any need for further surgery and without complication. This is the first known report of Van Nes rotationplasty as a durable treatment option in the management of congenital knee ankylosis, which may avoid reoperation and eliminate risk of recurrence.