Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort.

BACKGROUND: Townes-Brocks syndrome (TBS) is a rare genetic disorder characterised by multiple malformations. Due to its phenotypic heterogeneity and rarity, diagnosis and recognition of TBS can be challenging and there has been a lack of investigation of patients with atypical TBS in large cohorts and delineation of their phenotypic characteristics. METHODS: We screened SALL1 and DACT1 variants using next-generation sequencing in the China Deafness Genetics Consortium (CDGC) cohort enrolling 20 666 unrelated hearing loss (HL) cases. Comprehensive clinical evaluations were conducted on seven members from a three-generation TBS family. Combining data from previously reported cases, we also provided a landscape of phenotypes and genotypes of patients with TBS. RESULTS: We identified five novel and two reported pathogenic/likely pathogenic (P/LP) SALL1 variants from seven families. Audiological features in patients differed in severity and binaural asymmetry. Moreover, previously undocumented malformations in the middle and inner ear were detected in one patient. By comprehensive clinical evaluations, we further provide evidence for the causal relationship between SALL1 variation and certain endocrine abnormalities. Penetrance analysis within familial contexts revealed incomplete penetrance among first-generation patients with TBS and a higher disease burden among their affected offspring. CONCLUSION: This study presents the first insight of genetic screening for patients with TBS in a large HL cohort. We broadened the phenotypic-genotypic spectrum of TBS and our results supported an underestimated prevalence of TBS. Due to the rarity and phenotypic heterogeneity of rare diseases, broader spectrum molecular tests, especially whole genome sequencing, can improve the situation of underdiagnosis and provide effective recommendations for clinical management.

Osteoblastoma of the thumb with a novel PRSS44::ALK fusion and literature review of osteoblastoma of hands and feet bones.

Osteoblastomas (OBs) are benign neoplasms constituting approximately 1% of primary bone tumors with a predilection for the spine and sacrum. We describe an OB of the proximal phalanx of the left thumb in a 38-year-old female. MRI of left hand demonstrated a 29-mm mildly expansile enhancing lesion involving the entire proximal phalanx of the first digit. Histology displayed a bone-forming tumor consisting of trabeculae of remodeled woven bone framed by plump osteoblasts in a vascularized background. Next-generation sequencing analysis identified a PRSS44::ALK fusion gene.

Nail-patella syndrome with nephropathy in a de novo LMX1B mutation: triangular lunula of the thumb and lack of finger creases as clues.

Nail-patella syndrome (NPS) is an autosomal dominant disease caused mostly by mutations in the LMX1B gene and is characterized by hypoplastic nails, hypoplastic patella, elbow deformities, glaucoma, and nephropathy, sometimes leading to kidney failure. The combination and the severity of symptoms vary greatly from patient to patient. Because a kidney biopsy may show nonspecific findings, patients with nephropathy alone may not be diagnosed without undergoing genetic testing. We examined the case of a 6-year-old girl with persistent high proteinuria who was not diagnosed by kidney biopsy but had a diagnosis of a de novo mutation in the LMX1B gene following genetic testing. Retrospectively, only the thumbs showed triangular lunulae, while the third and fourth fingers lacked skin creases over the distal interphalangeal joints, which is subtle but characteristic of NPS. Notifying pediatric nephrologists of these findings can help avoid unnecessary kidney biopsies and lead to early detection of the disease.

Surgical Reconstruction of Type IV Hypoplasia of the Thumb (Floating Thumb) in Infants: A Retrospective Analysis of Functional Outcomes and Radiographic Alignment.

BACKGROUND Congenital hypoplasia of the thumb type IV, also known as floating thumb, is a condition in which 2 small phalanges are attached to the hand with a thin skin bridge. Surgical management options for this condition vary from amputation to flap reconstruction. MATERIAL AND METHODS This retrospective study analyzed 11 infants with congenital hypoplasia of the thumb type IV who underwent surgical reconstruction using a modified vascularized polydactylous hallux flap. The study included 6 male and 5 female infants, aged 6 to 24 months. Functional evaluations and radiographic studies were conducted postoperatively. RESULTS All 11 patients underwent the complete surgical protocol. Successful vascular and nerve anastomoses were performed during the initial procedure, ensuring sufficient blood supply and neural connectivity to the transferred toes. The second operation showed promising outcomes, including improvements in thumb opposition, grasp strength, and overall function. Postoperative assessments demonstrated satisfactory radiographic alignment and no major complications during the follow-up period. CONCLUSIONS The modified vascularized polydactylous hallux flap reconstruction is a viable surgical option for managing congenital hypoplasia of the thumb type IV in infants. This technique effectively restores thumb opposition, grasp strength, and overall hand function, with satisfactory radiographic alignment and minimal complications. The study findings support the efficacy and safety of this surgical approach in addressing this rare congenital anomaly.

A novel heterozygous variant of the SALL1 gene with atypical Townes-Brocks syndrome phenotypes in Chinese family.

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.

HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly.

Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. SHH/GLI3 signaling regulates cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 signaling also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a downstream modifier of the SHH/GLI signaling axis capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression of Cdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator, Pax9. These findings establish HES1 as a critical downstream effector of SHH/GLI3 signaling in the development of PPD.

The First Patient with Tibial Hemimelia-Polysyndactyly-Triphalangeal Thumb Syndrome Caused by De Novo c.423+4916 T>C ZRS Variant: A Case Report.

Genetic variants in the zone of polarizing activity regulatory sequence (ZRS) that induce ectopic expression of the SHH gene have been associated with different ZRS-related phenotypes. We report the first patient with a de novo variant, c.423+4916 T>C, in ZRS (previously classified as a variant of uncertain significance) that causes tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS). A two-month-old male patient presented with bilateral preaxial polydactyly, triphalangeal thumb, and tibial agenesis and was heterozygous for the variant c.423+4916T>C (neither of his parents was a carrier). The findings obtained from the family study were sufficient to reclassify the variant from "uncertain significance" to "likely pathogenic" according to three criteria from the American College of Medical Genetics and Genomics guidelines, as follows: (1) absence of gnomAD, (2) confirmation of paternity and maternity, and (3) strong phenotype-genotype association. In ZRS-associated syndromes, a wide clinical spectrum has been observed, ranging from polydactyly to THPTTS; our patient has the most severe and rare phenotype. We did not perform functional assays. However, the c.423+4916T>C variant is flanked by three variants, which have been proven not only to cause the phenotype but also to increase the expression of SHH. Through all this data gathering, we consider the c.423+4916T>C variant to be causative of THPTTS.

Update of surgical treatment of polydactyly.

PURPOSE OF REVIEW: Polydactyly presents with variable extent of duplication and may involve preaxial/radial (hand)/medial (foot), postaxial/ulnar (hand)/lateral (foot) or central duplication. This review will summarize recent advancements in the surgical management of this common entity. RECENT FINDINGS: Modifications to classification systems aim to help guide surgical management of polydactyly. Attempts have been made at quantifying preoperative angulation of the duplicated digits to minimize the chance of residual or recurrent deformity after surgical reconstruction. As a result, consideration should be given to the need for soft tissue correction vs. osteotomy to optimize the clinical outcome. On-top plasty is an option that may be beneficial in 'unequal' preaxial polydactyly, where neither duplicate is preferred on its own. SUMMARY: Polydactyly is one of the most common congenital anomalies in the hands and feet. Determination of surgical intervention often begins with classification systems that exist, which primarily separate these into preaxial, postaxial, and central. Referral for surgical consideration is indicated, given the management is often surgical.

Patients with KCNH1-related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome.

De novo missense variants in KCNH1 encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap between these two syndromes suggests that they belong to a spectrum of KCNH1-related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (present in 20/23 reported cases).We report a series of seven patients with ID and de novo pathogenic KCNH1 variants identified by whole-exome sequencing or an epilepsy gene panel in whom the diagnosis of TBS/ZLS had not been first considered. Four of these variants, p.(Thr294Met), p.(Ala492Asp), p.(Thr493Asn) and p.(Gly496Arg), were located in the transmembrane domains S3 and S6 of Kv10.1 and one, p.(Arg693Gln), in its C-terminal cyclic nucleotide-binding homology domain (CNBHD). Clinical reappraisal by the referring clinical geneticists confirmed the absence of the distinctive gingival and nail features of TBS/ZLS.Our study expands the phenotypical spectrum of KCNH1-related encephalopathies to individuals with an attenuated extraneurological phenotype preventing a clinical diagnosis of TBS or ZLS. This subtype may be related to recurrent substitutions of the Gly496, suggesting a genotype-phenotype correlation and, possibly, to variants in the CNBHD domain.

Surgical Results of Ulnar Component Excision and Radial Component Reconstruction in Patients With Preaxial Polydactyly of the Hand.

PURPOSE: Resection of the underdeveloped digit and reconstruction of the robust digit is the standard treatment option for preaxial polydactyly of the hand. As an underdeveloped digit, the radial component is usually excised, whereas the ulnar component excision is rarely needed. This study aimed to evaluate the surgical results of ulnar component excision and radial component reconstruction in patients with preaxial polydactyly of the hand. METHODS: We retrospectively reviewed the medical records and radiographs of 809 patients (861 thumbs) who underwent surgery for preaxial polydactyly of the hand from November 2006 to June 2018. Among these, 22 (2.6%) thumbs in which the ulnar component was more hypoplastic or had more severe deformities than the radial component were treated with ulnar component excision and radial component reconstruction. The mean follow-up duration was 49 months (range, 12-142 months). We evaluated the Japanese Society for Surgery of the Hand scores and whether the patients were satisfied with the thumb function and appearance at the final follow-up. We also recorded any complications, such as reoperation. RESULTS: The mean Japanese Society for Surgery of the Hand score was 12.8 (range, 5-17). Six patients had poor results, 7 had fair results, and 2 had good results; however, none of the patients had an excellent result. Satisfaction with thumb function and appearance was reported in 11 (50%) and 6 (27%) cases, respectively. Thirteen of 22 (59.1%) cases involved reoperations, and the most common reason for reoperation was interphalangeal joint deviation of the remaining thumb. CONCLUSIONS: Ulnar component excision and radial component reconstruction are rare operative choices in preaxial polydactyly of the hand. Surgeons and patients should be aware that a considerable number of patients treated with this method required reoperations and had low clinical outcome scores. TYPE OF STUDY/ LEVEL OF EVIDENCE: Prognostic IV.

Nonvascularized Iliac Crest Bone Graft for Reconstruction of the First Metacarpal in Type IIIB Thumb Hypoplasia: A Radiographic Follow-Up Study.

PURPOSE: To present a radiographic follow-up study of the use of a nonvascularized iliac crest bone graft as a treatment for modified Blauth type IIIB thumb hypoplasia. METHODS: From January 2015 to December 2019, nonvascularized iliac crest bone grafts were used to reconstruct the first metacarpal in 23 cases with type IIIB thumbs. The average follow-up duration was 1.9 years (range 1.0-3.9 years). We evaluated the patients' serial x-rays and measured the width and length changes of the reconstructed first metacarpals. RESULTS: Survival of the graft, judged radiographically, was achieved in 20 cases (20/23, 87%), with an average reduction of 33% in the width of the graft. Shortening of the graft (average 2.3 mm, range 0.1-5.6 mm) was noted in 11 of the 20 cases, and an increase in the length of the graft (average 4.2 mm, range 0.7-8.6 mm) was observed in the other 9. Bone graft failure (3/23, 13%) occurred in 3 cases because of significant bone resorption. CONCLUSIONS: For type IIIB thumb hypoplasia, a nonvascularized iliac crest bone graft was a feasible method to reconstruct the first metacarpal, with a 13% risk of graft failure, 33% average reduction in graft width, and 55% reduction in graft length. However, in cultures that value the preservation of a 5-digit hand, this technique may provide an alternative to excision with index pollicization. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Temple syndrome and Kagami-Ogata syndrome: clinical presentations, genotypes, models and mechanisms.

Temple syndrome (TS) and Kagami-Ogata syndrome (KOS) are imprinting disorders caused by absence or overexpression of genes within a single imprinted cluster on human chromosome 14q32. TS most frequently arises from maternal UPD14 or epimutations/deletions on the paternal chromosome, whereas KOS most frequently arises from paternal UPD14 or epimutations/deletions on the maternal chromosome. In this review, we describe the clinical symptoms and genetic/epigenetic features of this imprinted region. The locus encompasses paternally expressed protein-coding genes (DLK1, RTL1 and DIO3) and maternally expressed lncRNAs (MEG3/GTL2, RTL1as and MEG8), as well as numerous miRNAs and snoRNAs. Control of expression is complex, with three differentially methylated regions regulating germline, placental and tissue-specific transcription. The strong conserved synteny between mouse chromosome 12aF1 and human chromosome 14q32 has enabled the use of mouse models to elucidate imprinting mechanisms and decipher the contribution of genes to the symptoms of TS and KOS. In this review, we describe relevant mouse models and highlight their value to better inform treatment options for long-term management of TS and KOS patients.

Improving Metacarpophalangeal Joint Instability by Joint Implantation in Parallel From a Supernumerary Thumb in Severely Hypoplastic Duplicated Thumbs.

ABSTRACT: Here, we present 2 cases of a severely hypoplastic duplicated thumb classified as Wassel types 5 and 6 and discuss whole-joint implantation from a supernumerary thumb as an alternative to stabilize the hypoplastic metacarpophalangeal (MCP) joint. The aim of the surgical treatment of thumb polydactyly is to reconstruct a functional and aesthetically pleasing thumb. Hypoplasia of joint components and abnormal tendon alignment lead to unpleasing results with angular deformity of the reconstructed thumb. In 2 cases, the MCP joint of the dominant digit was hypoplastic and unstable in all directions. The main problem was underdevelopment of the affected MCP joint, and it was reasonable to attempt to stabilize the unstable joint by adding another redundant joint in parallel. Whole-joint implantation with a flap on a vascular pedicle is useful to repair both joint instability and soft tissue hypoplasia, as in case 1. The vascularized joint can maintain balanced growth potential. However, nonvascularized interphalangeal (IP) joint implantation is a simple solution for repairing MCP joint instability, as in case 2. These joints have no tendon insertions, so we believe they are acting as a splint supporting the hypoplastic joint for a long period. The transfer of composite tissues from the foot has been reported for reconstruction of finger and thumb hypoplasia. Duplicated thumb operation is usually recommended at 1 year old. Similarly, nonvascularized joint implantation in parallel may be a promising choice to overcome MCP joint instability and to maintain range of motion in hypoplastic cases with a duplicated thumb.In conclusion, joint implantation in parallel from a supernumerary thumb could prevent angular deformity and is an alternative to overcome MCP joint instability in cases of a severely hypoplastic duplicated thumb without any donor morbidity.

Outcome After Pollicization for Congenital Thumb Deficiency: A Cohort Study of Cases in a Single Unit, 1987 to 2016.

PURPOSE: To investigate the functional and aesthetic outcomes in a cohort with pollicizations performed due to congenital anomalies in our hospital. METHODS: From 1987 to 2016, we performed pollicizations in 32 hands of children aged 1 to 8 years (median, 2 years). We followed-up on 31 of the hands from 1 to 31 years (median, 10 years) after the procedure. The participants and their caregivers self-assessed their function and appearance with visual analogue scales and patient-reported outcome measures (Patient-Reported Outcomes Measurement Information System Pediatric Upper Extremity; the short version of the Disability of Arm, Shoulder and Hand Outcome Measure; and EQ-5D-3L). We examined the hands with regard to motion, strength, sensitivity, and function. RESULTS: There were 2 complications and 6 reoperations. Participants with mild anomalies (radial longitudinal deficiency Bayne type N/0 to 2) had better subjective and objective hand function than participants with severe anomalies (radial longitudinal deficiency Bayne type 3-4, ulnar dimelia, 5-finger hand). Hands with preoperatively near-normal index fingers had, in most cases, good thumb opposition and pinch, and hands in both groups benefited from the creation of a cylinder grip. Grip and pinch strength were lower than reported in cohort studies where an additional opponensplasty had been performed. CONCLUSIONS: Hands with severe congenital anomalies also benefited from the procedure. We recommend a simplified follow-up program to identify cases where additional surgeries to enhance strength should be considered during growth of the child. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Mid-term to Long-term Follow-up Results of Reconstruction for Thumb Radial Polydactyly.

BACKGROUND: Preaxial or radial polydactyly is one of the most common hand congenital anomalies in newborns. Contemporary reconstruction methods include ligament reconstruction, excision of the polydactylous thumb, osteotomy, and other surgical techniques according to the type of polydactyly. The purpose of this study was to report mid-term to long-term reconstruction results for thumb (radial) polydactyly. METHODS: We retrospectively reviewed the medical records of patients who underwent reconstruction surgery for preaxial polydactyly. Clinical outcomes, including the range of motion (ROM), pain, and complications, were evaluated. We assessed the final radiographs of the reconstructed thumb to identify the potential development of arthritis or other remaining deformities. After excluding cases without a simple radiograph and cases with a short follow-up period of fewer than 5 years, 26 thumbs were included. The surgical technique followed including excision of polydactylout thumb was tailored to the type of polydactyly. If the nail size of the thumbs was similar, the Bilhaut-Cloquet method was preferred. RESULTS: The mean age of the patients at the surgery and final follow-up was 14.9 months (range: 8 to 30 mo) and 11.9 years (range: 5.8 to 19.3 y), respectively. The mean follow-up was 128.8 months years (range: 60 to 219 mo), and the mean ROM of the thumb was 32.7 and 57.5 degrees in the distal interphalangeal joint (DIP) and metacarpophalangeal (MP) joint, respectively. Ulnar or radial side instability was prominent in 7 patients in the involved joints (26.9%). One patient underwent interphalangeal (IP) fusion for extension lag with pain. The radiologic evaluation revealed that 2 patients developed radiographic evidence of IP joint arthritis (7.7%). Radial deviation of the MP or IP joint existed in 13 cases (range: 5 to 40 degrees) (50.0%), and ulnar deviation of the MP or IP joint existed in 2 cases (range: 19 to 20 degrees) (7.7%). CONCLUSIONS: In mid-term to long-term experience, sequelae such as joint instability, joint stiffness, and remaining deformity cannot be neglected. An unstable MP joint may result if the DIP joint remains stiff or has a lower ROM. LEVEL OF EVIDENCE: Level IV-therapeutic studies.

Modified Bilhaut-Cloquet Procedure for the Reconstruction of Wassel Type III Radial Polydactyly.

BACKGROUND: The purpose of this research is to study the modified surgical effect of Wassel type III radial polydactyly thumbs of equal or nearly equal size treated. METHODS: The study sample consisted of 12 reconstructed cases of Wassel type III radial polydactyly. The proximal phalanx was unequally combined by the curvature osteotomy and aligned the articular surface, and the distal phalanx was symmetrically combined. A fragment bone was filled in the depression of the distal phalanx to correct nail curvature and prevent seagull deformities. Twelve cases were available for assessment using an evaluation form on the Japanese Society for Surgery of the Hand. RESULTS: An average functional point was 13.75 points (maximum 14 points). The interphalangeal joint motion was reduced, but this joint was stable in all cases. The cosmetic score was averaged 3.6 (maximum 4 points), and most parents were satisfied with the postoperative appearance and functional results. CONCLUSION: Our modification of Bihaut-Cloquet procedure is an effective way to provide a well-functioning thumb for Wassel type III radial polydactyly thumbs. LEVEL OF EVIDENCE: Level IV.

[Analysis of SALL1 gene variant in a boy with Townes-Brocks syndrome without anal atresia].

OBJECTIVE: To explore the genetic basis for a child presented with renal failure and multi-cystic dysplastic kidney without anal atresia. METHODS: Peripheral blood sample of the child and his parents were collected and subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing. RESULTS: The 40-day-old infant had presented with vomiting brown matter in a 7 days neonate and was transferred for kidney failure. Clinical examination has discovered renal failure, polycystic renal dysplasia, congenital hypothyroidism, bilateral thumb polydactyly, sensorineural hearing loss and preauricular dermatophyte. Genetic testing revealed that he has harbored a previously unreported c.824delT, p.L275Yfs*10 frameshift variant of SALL1 gene, which was confirmed by Sanger sequencing as de novo. CONCLUSION: The patient was diagnosed with Townes-Brocks syndrome due to the novel de novo variant of SALL1 gene. Townes-Brocks syndrome without anal atresia is rare. Above finding has also enriched the mutational spectrum of the SALL1 gene.

Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome.

Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.

Adult diagnosis of Townes-Brocks syndrome with renal failure: Two related cases and review of literature.

Townes-Brocks syndrome (TBS) is a rare autosomal dominant syndrome, resulting from heterozygous variant in SALL1 gene and initially characterized by the triad of anorectal, thumb, and ear malformations. Essentially described in children, adult case reports are uncommon. Renal involvement has already been reported in adults and children but poorly described. Structural abnormalities such as hypodysplasia, unilateral renal agenesis or multicystic kidneys have been described, as well as functional impairment (with or without structural abnormalities) that may progress to end-stage renal disease (ESRD). We report two adult cases (mother and daughter) which exhibited kidney hypoplasia (focal and segmental glomerulosclerosis for the mother) and ESRD. The mother had unilateral polydactyly. TBS was suggested after physical examination. TBS diagnosis was confirmed by identification of a SALL1 variant. We conducted a literature review to evaluate the renal anomalies in TBS cases diagnosed in adulthood. Among 44 adult cases of TBS with genetic confirmation (including our two cases), 10 had kidney disease. The circumstances of renal failure diagnosis were incidental findings (2/5), gout (2/5), or repeated episodes of pyelonephritis (1/5). The median age of kidney disease diagnosis was 30 years old and of renal transplant 49 years old. The most frequent renal malformation was bilateral kidney hypoplasia. TBS is probably underestimated in adulthood and this report highlights that less obvious elements of morphology such as dysplasic ears can facilitate the diagnosis of TBS. As long-term prognosis of renal involvement in TBS patients remains largely unknown, a regular evaluation is required throughout life for patients.

Vertical transmission of a large calvarial ossification defect due to heterozygous variants of ALX4 and TWIST1.

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss-of-function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4-related EPF phenotype. This report demonstrates comorbid disorders of Saethre-Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification.