Orofacial clefts (OC) are a congenital anomaly typically classified as syndromic or non-syndromic. Among the syndromic cases, Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) are primarily caused by pathogenic variants in IRF6, which encodes a transcriptional factor essential for orofacial development. Our aim is to identify and characterize IRF6 variants in two syndromic OC cases and assess their structural and functional consequences through computational modeling. Sequencing of IRF6 exons 3, 4, 7, and 9 was conducted in one proband with VWS and one proband with PPS, as well as their parents. Structural impacts were measured through comparative modeling based on the IRF4-DNA complex, followed by molecular dynamics simulations. Binding free energies and protein-DNA interactions were assessed using MM/GBSA calculations and hydrogen bond occupancy analysis. We identified two pathogenic variants: NP_006138.1:p.(Ala16Val) in a VWS proband and NP_006138.1:p.(Arg84Cys) in a PPS proband, both confirmed as de novo. Variants were classified as pathogenic by the American College of Medical Genetics and Genomics criteria, and by most pathogenicity predictors. Molecular dynamics simulations showed that NP_006138.1:p.(Ala16Val) induces long-range allosteric effects with increased structural fluctuations, while NP_006138.1:p.(Arg84Cys) directly disrupts critical DNA-binding interactions. MM/GBSA analysis demonstrated reduced DNA-binding affinity for both variants, with NP_006138.1:p.(Arg84Cys) showing the most severe electrostatic disruption. Our computational analyses suggest that pathogenic IRF6 variants may impact DNA binding through distinct molecular mechanisms: NP_006138.1:p.(Ala16Val) potentially through allosteric conformational changes and NP_006138.1:p.(Arg84Cys) likely through direct disruption of the protein-DNA interface.

Rare heterozygous variants in IRF6 (interferon regulatory factor-6) gene cause van der Woude syndrome 1 (VWS1) or Popliteal Pterygium syndrome, two forms of syndromic cleft lip/palate (CLP) that present with a variety of congenital malformations due to impairment ectodermal homeostasis. These malformations include, in addition to CLP, lip pits, pterygia, and intraoral and eyelid fibrous bands. Amniotic band sequence (ABS) is a rare condition of unknown genetic etiology that involves a range of congenital anomalies caused by the entanglement of fibrous bands, which disrupt fetal body parts. However, ABS co-occurs with CLP and other malformations that cannot be explained by this mechanism. Therefore, investigating the genetic relationship between ABS and CLP may provide clues regardind the genes involved in these conditions. Here, we report a case of a girl diagnosed with VWS1, autism, intellectual disability, and congenital right limb anomalies compatible with ABS. Molecular analysis revealed a novel, rare heterozygous missense variant in IRF6 (NM_006147.3:c.970T>C) located in exon 7, inherited from her father. This variant results in the replacement of serine by proline at position 324 of the IRF6 protein with potentially deleterious effects. This report expands the mutational landscape of IRF6 and provides further support for a possible link between the genetics of CLP and ABS.

Popliteal pterygium syndrome (PPS) is a rare congenital disorder characterized by orofacial, cutaneous, musculoskeletal, and genital anomalies. Surgical interventions are necessary to address the severe knee flexion contracture and equinovarus deformity, but there are no established treatment guidelines. We present the case of a one-year-old patient with PPS and discuss the challenges in managing the knee deformity. The surgical option chosen for the unilateral knee contracture of 80° consisted of skin management by a large Z-plasty, lengthening of popliteal vessels by grafts, lengthening of the tibial and peroneal nerves by autografts and allografts, capsular releases, and tendon releases to improve mobility and preserve foot sensibility. With a three-year follow-up, the surgical interventions resulted in proper ability to walk freely. Wearing of a foot orthesis was necessary to balance the leg length differences and support the midfoot deformity. Furthermore, sensation of the foot could be restored in terms of touch sensibility and perfusion was always stable during growth. The treatment of PPS requires a multidisciplinary approach, considering the rarity and complexity of the syndrome. Surgical interventions aim to release contractures, correct deformities, and preserve foot sensibility. Each treatment option has its advantages and disadvantages, highlighting the need for individualized care.

Popliteal pterygium syndrome is a rare congenital disorder characterized by facial, genitourinary, and musculoskeletal anomalies, with popliteal webbing being notably challenging. A 4-year-old boy presented with progressive limping, cleft palate, and genital malformations. He had no follow-up care after an intraoral band excision at 15 days old. The boy underwent surgery for left-sided popliteal webbing, followed by genital and cleft palate repair. A modified jumping man Z-plasty flap was used for the popliteal webbing, followed by splinting. Subsequent follow-ups showed no complications. Enhancing care in resource-constrained settings requires addressing challenges such as delayed interventions due to late follow-up, limited awareness between communities and healthcare professionals, social stigma, and inadequate healthcare understanding. These obstacles hinder timely diagnosis and intervention, underscoring the need for increased awareness and effective early intervention strategies. Early detection and parental counseling are critical in managing popliteal pterygium syndrome. Timely surgical planning, including addressing orofacial and genital deformities and using Z-plasty for webbing release, is essential. Postoperative splinting significantly improves outcomes.

Popliteal pterygium syndrome (PPS) is a rare inherited disorder involving the face, limbs, and genitalia. The most prominent and handicapping deformity associated with this syndrome is Popliteal pterygium. Popliteal pterygium is a contracture band that extends from ischial tuberosity to calcaneum. It is a dense fibrous band difficult to correct surgically. We report a case of PPS with her two other family members diagnosed with Van der Woude syndrome. Single-stage surgical release is ineffective due to shortened neurovascular and surrounding soft tissues. Multimodality treatment with surgical release and motivated parents may help these children to rehabilitate.