Townes-Brocks syndrome (TBS) is a rare autosomal dominant disorder typically characterized by the triad of anorectal malformations, external ear anomalies and hand malformations such as preaxial polydactyly, caused by mutations in the SALL1 gene. Kidney involvement, although less common, can progress to end-stage kidney failure. Early recognition of the characteristic features, particularly those related to SALL1, is crucial for accurate diagnosis, management, and genetic counseling. Here, we present a Turkish family with TBS in which the diagnosis was delayed due to the absence of the classic triad. The proband exhibited significant developmental delay, kidney failure and a congenital foot abnormality, while other family members showed milder manifestations. A multigene panel revealed a heterozygous variant in SALL1 (NM_002968.3:c.2287dup p.R763Kfs*42), which was also identified in the affected family members presenting with milder phenotypes. This case highlights the broad clinical spectrum of TBS, even within the same family. Because major features may not always be present, it can sometimes be overlooked or misdiagnosed; as in our case, which presents with nearly isolated kidney abnormalities. Our report emphasizes the importance of a comprehensive approach, detailed family history and genetic testing in patients with chronic kidney disease of unknown origin.

Genetic causes of chronic kidney disease present a diverse group. Some of them are associated with extrarenal malformations, especially ear anomalies. Genetic diagnosis is essential to confirm the diagnosis, search for additional potential manifestations, and predict the prognosis. We report a case of a 10-year-old girl with elevated creatinine in whom the presence of auricular appendices led to clinical suspicion of a genetic cause of chronic kidney disease. After investigation, Townes-Brocks syndrome was confirmed with the absence of anorectal and limb abnormalities. Therefore, it can be less apparent and needs to be suspected of. Rare causes of renal diseases can be suspected already after examination. Malformations of the ears are particularly associated with chronic kidney disease, which should be screened for in such cases. Genetic confirmation allows for the establishment of diagnosis and comprehensive management. Townes-Brocks syndrome highlights the importance of chronic kidney disease suspicion in a child when malformations of the ears are present in a child. SALL1-related Townes-Brocks syndrome (SALL1-TBS) is characterized by the triad of imperforate anus or anal stenosis, dysplastic ears (overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment), and thumb malformations (duplication of the thumb [preaxial polydactyly], triphalangeal thumbs, and, rarely, hypoplasia of the thumbs) without hypoplasia of the radius. Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux). Foot malformations (flat feet, overlapping toes) and genitourinary malformations are common. Congenital heart disease occurs in 15% of affected individuals. Developmental delay and/or learning difficulties occur in approximately 15% of affected individuals. Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation. The diagnosis of SALL1-TBS is established in a proband with characteristic clinical findings and a heterozygous pathogenic variant in SALL1 identified by molecular genetic testing. Treatment of manifestations: Immediate surgical intervention for imperforate anus; stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation; standard treatment of gastroesophageal reflux; early treatment of hearing loss; surgery for severe malformations of the hands; hemodialysis and possibly kidney transplantation for ESKD; management of genitourinary anomalies per urologist or gynecologist; surgery or medical treatment by cardiologist for congenital heart defects; developmental and educational support as needed; neuropsychiatric management as needed for behavioral issues; growth hormone therapy for those with growth hormone deficiency; management of ocular issues per ophthalmologist. Surveillance: Assess for constipation and assess growth and thyroid function at each visit; annual audiology evaluation; monitor kidney function annually in individuals with and without kidney anomalies, even if kidney function is normal on initial examination; monitor developmental progress, educational needs, and behavioral assessment annually; ophthalmology examination per ophthalmologist. Agents/circumstances to avoid: Medications that cause renal or otic toxicity. Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with SALL1-TBS in order to identify as early as possible those who would benefit from clinical evaluation and prompt initiation of treatment for kidney disease and other features of SALL1-TBS. Pregnancy management: Consider prenatal cardiac and nephrology evaluations in pregnant women with SALL1-TBS. SALL1-TBS is inherited in an autosomal dominant manner. About 50% of individuals diagnosed with SALL1-TBS have the disorder as the result of a de novo pathogenic variant. Each child of an individual with SALL1-TBS has a 50% chance of inheriting the pathogenic variant. Once the SALL1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

The VACTERL association is a non-random cluster of congenital malformations involving six distinct conditions: vertebral defects (V), anal atresia (A), cardiac defects (C), tracheoesophageal malformation (TE), renal defects (R), and limb anomalies (L), and is diagnosed when a fetus exhibits three or more of these. Its prevalence is approximately 0.47-0.58 per 10,000 live births. This paper examines the effect of disruptions in the Sonic Hedgehog and cilia-associated signaling pathways, genetically related developmental variations, and maternal environmental factors on the development of VACTERL. In the SHH signaling pathway, we focus on the effects of Sonic Hedgehog ligands, GLI transcription factors, and factors influencing GLI activity (RAC1 and ZIC3), as well as downstream targets (FOXF1 and HOXD13) and other genes and proteins involved in the regulation of SHH signaling (FGF8 and LPP), in the pathogenesis of VACTERL. In this context, ZIC3, which was shown to play a major role in VACTERL pathogenesis in large-scale resequencing, and TRAP1, which was associated with VACTERL pathogenesis in whole-exome resequencing, were highlighted. We also examine the cilia-associated signaling pathways, particularly the role of IFT172 and candidate ciliopathy genes. In addition, we describe the influence of TRAP1, COL11A2, SALL4, WBP11, Copy Number Variants, and maternal environmental factors on VACTERL. We also discuss current diagnostic, therapeutic, and prognostic approaches including prenatal and postnatal treatment options. Furthermore, we highlight the advantages of thoracoscopic surgery over traditional open-surgical treatment while discussing the differential diagnosis of VACTERL from other neonatal malformations with similar symptoms, such as Townes-Brocks syndrome, Baller-Gerold syndrome, and CHARGE syndrome.

Chromosomal abnormalities, such as Trisomy 8 (T8), and genetic mutations may contribute to the unique clinical phenotype of Behçet's Disease (BD). This study aims to characterize the clinical and genetic features of patients presenting with BD-like symptoms associated with T8 (T8-BD). We analyzed a cohort of 8 patients with T8-BD and associated genetic variants, including 1 newly identified case from our center and 7 previously reported in the literature. Genetic sequencing and karyotyping analyses were conducted, with Sanger sequencing used to confirm variants. We assessed clinical phenotypes, genetic backgrounds, treatments, and clinical outcomes. This study comprised predominantly female (87.5%) and East Asian (87.5%) patients, spanning pediatric to elderly populations, with a high comorbidity prevalence (87.5%), including autoimmune lymphoproliferative syndrome (ALPS), myelodysplastic syndrome (MDS), atypical familial Mediterranean fever (FMF), primary myelofibrosis (PM), polycythemia vera (PV), and Townes-Brocks syndrome (TBS). Uniform presentations included oral aphthosis (100%), intestinal lesions (100%), with most cases exhibiting fever (85.7%), anemia (85.7%), and elevated C-reactive protein (CRP) levels (85.7%). Genetic variants were identified in NRAS, JAK2, MEFV, PTPN11, and SALL1, comprising 5 missense variants and 1 nonsense mutation, including a de novo NRAS mutation newly reported in a pediatric patient. Treatment involved glucocorticoids (GC) combined with immunosuppressants (33.3%), a combination of GC, immunosuppressants, and biologics (50%), and anti-oral aphthosis medications (16.7%), with most patients achieving remission, except for one fatal outcome. Patients with T8-BD and genetic mutations exhibit distinct clinical features. Greater clinical awareness of autoinflammatory syndromes, combined with genetic and chromosomal analysis, is recommended in patients with BD-like symptoms who do not fully meet BD diagnostic criteria, especially those presenting with oral ulcers and systemic inflammation. This approach may enhance diagnostic precision and inform tailored treatment strategies.

Townes-Brocks syndrome (TBS, MIM#107480) is an autosomal dominant disorder linked to SALL1 alterations and characterized by a clinical triad (anorectal, thumb, and external-ear malformations), along with variable features. Renal failure and deafness can occur at any age, making follow-up essential. Some genotype-phenotype correlations have been suggested but data are limited. We collected clinical and molecular data from 49 patients with a SALL1 (likely) pathogenic variant identified in our laboratory or through collaborations, and reviewed the 207 SALL1 related-TBS patients previously reported in the literature. We performed statistical analysis to study genotype-phenotype correlations based notably on the variant position in relation to the glutamine-rich region. In our series, 25% of individuals presented with the clinical triad compared to 49.7% in the literature. The deafness frequency was similar (65%). Renal failure was diagnosed in 39.6% of our patients compared to 29.3% in the literature. Developmental delay or intellectual disability affected 9% of patients. Of the 22 SALL1 variants in our series, 35% were located upstream of the glutamine-rich region, compared to 6.5% in the literature. Statistical analysis was performed on all patients, of which 26 and 200 carried a variant upstream and downstream of the glutamine-rich region, respectively. A significant increase in deafness, dysplastic ear, and thumb malformations and a significant decrease in renal failure were observed in the individuals carrying a variant located downstream of the region, but the patients were significantly younger. Future studies should aim to elucidate the complex pathophysiological mechanisms and prognosis of TBS, functionally and prospectively.