Carpenter syndrome type 2 (CRPT2) is a rare autosomal recessive disease mainly characterized by craniosynostosis and polysyndactyly. CRPT2 is the rarer subtype of Carpenter syndrome (CRPTS) and is caused by biallelic variants in the multiple epidermal growth factor-like domains 8 gene (MEGF8). Due to its rarity and phenotypic overlap with other craniosynostosis syndromes, definitive molecular diagnosis of CRPT2 can be challenging. Here, we describe a proband with CRPT2 carrying compound heterozygous variants in MEGF8: one de novo variant disrupting splicing and a maternally inherited missense variant. To resolve these variants, we leveraged long-read genome sequencing to phase the missense variant alleles and RNA sequencing to determine splicing impact. This case highlights the diagnostic value of using sequencing methods beyond the more conventional short-read exome sequencing. Our findings expand the spectrum of MEGF8 variants causing CRPT2 and underscore the utility of emerging sequencing technologies in elucidating complex or previously unresolved genotypes. Expanding access to such technologies is anticipated to accelerate rare disease diagnosis and deepen our understanding of the genetic mechanisms underlying these conditions.

The primary cilium is a signal transduction organelle whose dysfunction clinically causes ciliopathies in humans. RAB23 is a small GTPase known to regulate the Hedgehog signalling pathway and ciliary trafficking. Mutations of RAB23 in humans lead to Carpenter syndrome (CS), an autosomal recessive disorder clinically characterized by craniosynostosis, polysyndactyly, skeletal defects, obesity, and intellectual disability. Although the clinical features of CS bear some resemblance to those of ciliopathies, the exact relationship between the pathological manifestations of CS and the ciliary function of RAB23 remains ambiguous. Besides, the in vivo ciliary functions of RAB23 remain poorly characterised. Here, we demonstrate in vivo and in vitro Rab23 loss-of-function mutants modelling CS, including Rab23 conditional knockout (CKO) mouse mutants, CS patient-derived induced pluripotent stem cells (iPSCs), and zebrafish morphants. The Rab23-CKO mutants exhibit multiple developmental and phenotypical traits recapitulating the clinical features of human ciliopathies and CS, indicating a causal link between the loss of Rab23 and ciliopathy. In line with the ciliopathy-like phenotypes, all three different vertebrate mutant models consistently show a perturbation of primary cilia formation, intriguingly, in a context-dependent manner. Rab23-CKO mutants reveal cell-type specific ciliary abnormalities in chondrocytes, mouse embryonic fibroblasts, neural progenitor cells and neocortical neurons, but not in epithelial cells, cerebellar granule cells and hippocampus neurons. A profound reduction in ciliation frequency was observed specifically in neurons differentiated from CS patient iPSCs, whereas the patients' fibroblasts, iPSCs and neural progenitor cells maintained normal ciliation percentages but shortened cilia length. Furthermore, Rab23-KO neural progenitor cells show perturbed ciliation and desensitized to primary cilium-dependent activation of the Hedgehog signaling pathway. Collectively, these findings indicate that the absence of RAB23 causes dysfunctional primary cilia in a cell-type distinctive manner, which underlies the pathological manifestations of CS. Our findings present the first in vivo evidence validating the unique context-specific function of RAB23 in the primary cilium. Through the use of patient-derived iPSCs differentiated cells, we present direct evidence of primary cilia anomalies in CS, thereby confirming CS as a ciliopathy disorder.

Surgical correction of polysyndactyly of the toes requires not only functional separation of the digits but also creation of an aesthetically acceptable interdigital web, as postoperative appearance strongly affects psychosocial outcomes. Although traditional techniques, including Z-plasty and dorsal rectangular flaps as well as web-preserving flaps with or without skin grafting, have been described, complications such as web creep, wound dehiscence, and valgus deformity of the residual toes remain problematic. Here, we report a case of polysyndactyly involving the fourth, fifth, and sixth toes of the left foot in a five-year-old girl. A trapezoidal dorsal rectangular flap was created in the fourth interdigital space and combined with a triangular plantar flap to achieve a web that was narrow in the mid-portion and broader at the base. The dorsal flap base and plantar inset were advanced 2 mm proximally to enhance web depth. Residual skin defects were covered using a full-thickness skin graft harvested from the medial malleolar region. Six months postoperatively, the reconstructed web showed appropriate depth, tapering, and alignment consistent with the adjacent interdigital spaces. No valgus deviation was observed in the residual toes. The skin graft demonstrated excellent take with only minor pigmentation differences and no significant scar contracture or web creep. The patient's postoperative function and ambulation were uneventful. The combination of a trapezoidal dorsal rectangular flap and plantar triangular flap with proximal advancement of the inset facilitates the creation of a deep and natural-appearing interdigital web. Adjunctive full-thickness skin grafting allows tension-free closure of larger skin deficits, reducing the risk of secondary complications. Although this report describes a single case, the technique may be useful in the aesthetic reconstruction of polysyndactyly of the toes.

Presurgical nasoalveolar molding (PNAM) is a technique used in cleft lip and palate (CLP) patients to reshape the alveolus, lips, and nostrils before surgical intervention, thereby reducing cleft severity. This case report presents a 2-month-old male diagnosed with bilateral CLP and provisional Patau syndrome, characterized by additional anomalies such as right hind limb hypomobility and polysyndactyly. Due to the patient's cardiac condition, conventional nasoalveolar molding (NAM) was contraindicated. Instead, a modified nasal hook named Bhatia's hook was designed and fabricated using stainless steel wire and cold-cure acrylic, designed to mold the nasal structures without alveolar manipulation. The treatment objectives included improving nasal projection, reducing alar width and cleft gap, retracting the premaxilla, and centering the premaxilla. Over a 4-month period, biweekly adjustments led to significant improvements in nasal tip elevation, reduced septal deviation, decreased premaxillary protrusion, and minimized cleft size. Cheiloplasty performed at 6 months resulted in more effective surgical outcomes, including enhanced columella length and external nasal morphology. The successful management of this case underscores the potential of customized nasal hooks in improving surgical results for CLP patients with complicating factors. This modified nasal hook approach offers a viable alternative for nasal molding in patients with complex medical conditions, providing ease of fabrication and consistent force application. Bhatia V, Afeefa P, Ratre RK, et al. Presurgical Nasal Molding in a Bilateral Cleft Lip and Palate Patient with Patau Syndrome Using a Novel Bhatia's Hook: A Case Report. Int J Clin Pediatr Dent 2025;18(5):587-590. The FLNB-related disorders can be divided into two groups of conditions caused by loss of function or gain of function of filamin-B. Biallelic loss-of-function pathogenic variants in FLNB cause spondylocarpotarsal synostosis syndrome (FLNB-SCT). Monoallelic gain-of-function pathogenic variants in FLNB cause a spectrum of phenotypic severity ranging from apparently isolated clubfoot to Larsen syndrome (FLNB-LS), atelosteogenesis type 3 (FLNB-AO3), and atelosteogenesis type 1 (FLNB-AO1), which is perinatal lethal. For the purposes of this GeneReview, the previously described entities Piepkorn dysplasia and boomerang dysplasia are subsumed under the FLNB-AO1 spectrum. FLNB-SCT is characterized by postnatal disproportionate short stature; scoliosis and lordosis due to vertebral fusions; carpal and tarsal synostosis; and, variably, clubfeet, hearing loss, and dental enamel hypoplasia. FLNB-LS is characterized by combinations of congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis (which can be associated with a cervical myelopathy); short, broad, spatulate distal phalanges; distinctive craniofacial features (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal ossification centers. Individuals with FLNB-LS may also present with midline cleft palate and hearing loss. FLNB-AO1 and FLNB-AO3 are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. FLNB-AO1 is lethal in the perinatal period. At its most severe, the spectrum of phenotypes assigned FLNB-AO1 can present with perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges); macrobrachycephaly; prominent forehead; hypertelorism; and proptosis. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. In individuals with FLNB-AO3, survival beyond the neonatal period is possible with intensive and invasive respiratory support. The diagnosis of FLNB-SCT is established in a proband by identification of biallelic loss-of-function pathogenic variants in FLNB by molecular genetic testing. The diagnosis of other FLNB-related disorders (LS, AO1, AO3) is established in a proband by identification of a heterozygous gain-of-function pathogenic variant in FLNB by molecular genetic testing. Treatment of manifestations: Cervical spine instability in asymptomatic infants can be successfully managed with posterior arthrodesis. Function can be stabilized (if not improved) in infants with myelopathic signs by a combination of anterior decompression and circumferential arthrodesis. Hip dislocation in individuals with FLNB-LS usually requires operative reduction. Scoliosis and clubfeet are managed in a routine manner. Anesthetic agents that allow more rapid induction and recovery are preferred in those with laryngotracheomalacia. When possible, cleft palate and hearing loss are best managed by multidisciplinary teams. Surveillance: Annual orthopedic evaluation for progressive scoliosis; feeding and growth assessment for those with cleft palate by a multidisciplinary team; annual audiologic and dental evaluations. Pregnancy management: Delivery of an affected infant has the potential to be complicated by extended breech presentation due to dislocation of the hips and knees. FLNB-SCT is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FLNB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial FLNB pathogenic variants. Heterozygous sibs of a proband with FLNB-SCT can exhibit mild reductions in stature but no other medically significant phenotypic manifestations. Once the FLNB pathogenic variant(s) have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible. FLNB-LS, FLNB-AO1, FLNB-AO3, and FLNB-related apparently isolated clubfoot are inherited in an autosomal dominant manner. Comparatively mild (e.g., FLNB-LS) and severe (e.g., FLNB-AO3) forms of the autosomal dominant FLNB-related disorders can occur in the same family. Some individuals diagnosed with an autosomal dominant FLNB-related disorder have the disorder as the result of a pathogenic variant inherited from a heterozygous or mosaic parent. Some individuals have the disorder as the result of a de novo pathogenic variant (the vast majority of lethal FLNB conditions are the result of de novo pathogenic variants). Each child of a proband who is heterozygous for an FLNB pathogenic variant has a 50% chance of inheriting the pathogenic variant. Each child of a proband with somatic mosaicism for an FLNB pathogenic variant has up to a 50% chance of inheriting the pathogenic variant. Offspring who inherit an FLNB pathogenic variant from a proband with somatic mosaicism may be more severely affected than the proband. Once the FLNB pathogenic variant has been identified in an affected family member, prenatal/preimplantation genetic testing are possible.

To address the current lack of a prenatal classification system for fetal lower limb anomalies, we developed and evaluated the PRELLIM (PREnatal Lower LIMb impairment) classification. A systematic literature review was conducted to identify existing classifications. Based on sonographic features, we developed the PRELLIM classification and applied it to a retrospective cohort of fetuses with isolated lower limb anomalies assessed between 2007 and 2024 at Amsterdam UMC's fetal medicine unit. No standardized prenatal classification system for lower limb anomalies was found. PRELLIM distinguishes isolated and non-isolated anomalies and categorizes them into clinically relevant subgroups (absent/short, duplication, fusion, contracture, bowing and other). It was applied to 643 fetuses with isolated lower limb anomalies. Contractures were most common (n = 599; 93.2%), followed by poly(syn)dactyly (n = 26; 4.0%), reduction defects (n = 9; 1.5%), bowing (n = 5; 0.8%), and a case of sirenomelia (0.1%). Three additional cases (0.4%) were classified as "other": two lymphangiomas and one amniotic band with lower leg constriction. PRELLIM is the first prenatal classification tailored to sonographically detectable lower limb anomalies. It aims to enhance diagnostic consistency, improve interdisciplinary communication, and support prenatal counseling and decision-making.