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. ESCO2 spectrum disorder is characterized by mild-to-severe prenatal growth restriction, limb malformations (which can include bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening of the upper and/or lower limbs), hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia), flexion contractures (involving elbows, wrists, knees, ankles, and feet [talipes equinovarus]), craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations), and ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal opacities). Intellectual disability (ranging from mild to severe) is common. Early mortality is common among severely affected infants; mildly affected individuals may survive to adulthood. The diagnosis of ESCO2 spectrum disorder is established in a proband with suggestive clinical findings and either biallelic pathogenic variants in ESCO2 identified by molecular genetic testing or premature centromere separation identified by cytogenetic testing. Treatment of manifestations: Individualized treatment to improve quality of life; feeding and nutrition support; management of limb malformations through a multidisciplinary neuromuscular clinic including orthopedics, physical medicine, and physical and occupational therapy with adaptative devices, prostheses, therapy, stretching, night splints, and casts as needed; hand surgery as needed to facilitate early development of prehensile grasp and improve motor function; specialized bottle and surgery for cleft lip and/or palate; surgical treatment for craniosynostosis and micrognathia; treatment of ocular issues per ophthalmologist; developmental and educational support including speech therapy; standard treatment for ophthalmologic, cardiac, urogenital, and kidney abnormalities; prompt treatment of infection with management per infectious disease specialist; treatment of stroke per neurologist; treatment of malignancy per oncologist; family and social support. Surveillance: Assess growth, limb mobility and function, development and educational needs, blood pressure, frequency of infections, and home adaptation needs at each visit; assessment of feeding, speech development, and hearing (in those with cleft lip and palate) per craniofacial team; kidney function tests annually; follow up for ophthalmologic and cardiac anomalies per treating physicians; physical examination including full skin and neurologic examination for evidence of malignancy annually; referral to neurologist including brain imaging for vascular anomalies and aneurysms in those with intellectual disability, corneal opacities, and/or heart defects; assess for clinical manifestations of aneurysms and vascular malformations annually starting in adolescence; serum immunoglobulin levels in infancy. ESCO2 spectrum disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ESCO2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the ESCO2 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible. Prenatal testing for pregnancies at increased risk is also possible by cytogenetic testing of fetal cells obtained by amniocentesis or chorionic villus sampling in conjunction with ultrasound examination.

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.

Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous type of interferonopathy resulting from defects in the processing or sensing of nucleic acids. The AGS phenotype encompasses a broad range of neurological and non-neurological findings. It presents with a congenital or subacute onset, manifesting as microcephaly, spasticity, dystonia, seizures, cortical blindness, and psychomotor retardation in the first year of life. The radiological and laboratory findings of AGS are generally accompanied by intracranial calcification, white matter abnormalities, cerebral atrophy, and cerebrospinal fluid lymphocytic pleocytosis. A case diagnosed as AGS type 4 among patients presenting to the Balikesir University Medical Faculty pediatric neurology clinic, Türkiye, between August 1, 2024, and February 1, 2025, and undergoing genetic testing was included in the study. The patient exhibited a coarse facial appearance, a low ear line, scoliosis, contractures in the upper and lower extremities, hyperactive deep tendon reflexes, an equivocal Babinski response, and upper and lower extremity muscle strength of 3/5. The patient was started on levetiracetam at 20 mg/kg in two doses for epilepsy. Whole exome sequencing revealed a homozygous pathogenic variant in RNASEH2A. Parental genetic analyses for the targeted variant were heterozygous. In conclusion, the diagnosis of AGS relies on clinical characteristics and genetic testing. Basic neurological characteristics include developmental delay, dystonia, microcephaly, brain calcification, and leukodystrophy. Although data concerning genotype-phenotype in AGS type 4 have been reported in the literature, these are still limited.

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.

Townes-Brocks syndrome (TBS) is an autosomal dominant disorder characterised by the triad of anorectal, thumb, and ear malformations. It may also be accompanied by defects in kidney, heart, eyes, hearing, and feet. TBS has been demonstrated to result from heterozygous variants in the SALL1 gene, which encodes zinc finger protein believed to function as a transcriptional repressor. The clinical characteristics of an atypical TBS phenotype patient from a Chinese family are described, with predominant manifestations including external ear dysplasia, unilateral renal hypoplasia with mild renal dysfunction, and hearing impairment. A novel heterozygous variant c.3060T>A (p.Tyr1020*) in exon 2 of the SALL1 gene was identified in this proband. Pyrosequencing of the complementary DNA of the proband revealed that the variant transcript accounted for 48% of the total transcripts in peripheral leukocytes, indicating that this variant transcript has not undergone nonsense-mediated mRNA decay. This variant c.3060T > A is located at the terminal end of exon 2, proximal to the 3' end of the SALL1 gene, and exerts a relatively minor impact on protein function. We suggest that the atypical TBS phenotype observed in the proband may be attributed to the truncated protein retaining partial SALL1 function.