Townes-Brocks Syndrome With Consistent Renal Hypodysplasia and Variable Extrarenal Features Across Three Generations...

Townes-Brocks syndrome (TBS) is a rare autosomal dominant disorder caused by pathogenic variants in SALL1, classically defined by dysplastic ears, anorectal malformations, and thumb anomalies. Renal involvement is a major determinant of prognosis.

We report a Serbian family with multiple members with TBS and molecular confirmation of a SALL1 familial nonsense variant (c.1509C>A, p. Tyr503Ter). Detailed phenotypic data were obtained from paediatric and adult medical records. Seven affected patients across three generations exhibited a remarkably consistent renal phenotype characterized by bilateral renal Hypodysplasia and chronic kidney disease (CKD), contrasted by variable extrarenal features. The proband developed CKD progressing to end-stage renal disease (ESRD) in adolescence, requiring kidney transplantation. Her first male cousin (patient 2) presented with anal atresia, dysplastic ears, hypospadias, and congenital hypothyroidism, and currently has stable CKD stage II. Mother of patient 2 has CKD stage III with small hyperechogenic kidneys and proteinuria. The affected grandfather has ESRD and sensorineural hearing loss. Notably, none of the affected individuals fulfilled the complete classical triad of TBS.

This family demonstrates intrafamilial phenotypic variability of TBS but with strikingly consistent renal involvement linked to a familial SALL1 variant. TBS should be considered in patients with congenital anomalies of the kidney and Urinary tract (CAKUT) even in the absence of typical limb or anorectal anomalies. Early molecular diagnosis enables appropriate surveillance and timely management of progressive kidney disease.