ML in Rare Facial Disorders: Hemifacial Microsomia, Parry-Romberg Syndrome, Moebius Syndrome, Treacher Collins Syndrome, Apert Syndrome, and Crouzon Syndrome-From Etiological Mapping and Pathology to AI-Driven Bio-Computational Gene Therapy

Diagnosis of rare diseases based on facial phenotype: a quantitative assessment using 2D and 3D photography in Stickler syndrome

Stickler syndrome (SS) is a rare genetic disorder caused by mutations in collagen-encoding genes. Patients with SS are at an increased risk of retinal detachment, with ophthalmologic complications often presenting as the first symptom due to significant diagnostic delays. These delays contribute to severe visual impairment, even in early childhood, making diagnostic uncertainty a major clinical challenge. This study assessed the feasibility of early SS detection using facial features. Supervised machine learning models, including XGBoost and support vector machines (SVM), were applied to 2D and 3D facial photographs to differentiate individuals with SS from healthy controls. The models achieved 92% accuracy in identifying SS patients using full-face 2D and 3D photographs. When focusing specifically on the orbitonasal region in 3D images, classification accuracy increased to 96%. Facial morphology in rare diseases such as Stickler syndrome can serve as a highly accurate, non-invasive screening tool. AI-based analysis has the potential to reduce diagnostic delays and prevent associated complications, improving patient outcomes.

Clinical and genetic features of syndromic craniosynostosis in 18 Chinese probands: novel candidate genes and phenotypes of known pathogenic genes

Introduction Craniosynostosis is a common congenital disorder characterized by premature fusion of one or more cranial sutures, categorized into non-syndromic (NSCS) and syndromic craniosynostosis (SCS). SCS accounts for ∼30% of cases, often accompanied by severe clinical complications, with 20%–25% of patients lacking a clear molecular etiology. Methods We enrolled 18 Chinese SCS patients and analyzed their clinical and genetic data via whole-exome sequencing (WES), copy number variation (CNV) analysis, and Sanger sequencing validation. Results We identified 15 single nucleotide variants, 2 insertions/deletions, and one microdeletion at 11q23.3q25. Thirteen probands harbored pathogenic/likely pathogenic variants in known craniosynostosis-related genes: FGFR2 (n = 4), FGFR3 (n = 2), TWIST1 (n = 2), and one each in ERF, EFNB1, SON, HUWE1, and KRAS. Three probands carried variants in PTEN, SRCAP, PQBP1, none of which have previously been associated with craniosynostosis. Notably, a de novo nonsense variant (c.562G>T, p. Glu188Ter) was identified in NOG, a promising candidate gene for craniosynostosis. Discussion Our findings broaden the genotypic spectrum of craniosynostosis and further highlight the genetic heterogeneity underlying this disorder. The discovery of variants in PTEN, SRCAP, PQBP1, and NOG identifies novel candidate genes and uncovers potential disease mechanisms.

King-Denborough syndrome: a clinicogenetic case report

King–Denborough syndrome is a rare RYR1-related congenital myopathy characterized by dysmorphic features, muscle weakness, and susceptibility to malignant hyperthermia, often posing a diagnostic challenge in early infancy. We report a one-year-old female child presenting with developmental delay and generalized hypotonia. Clinical evaluation revealed craniofacial dysmorphism, bilateral ptosis, and esotropia, raising suspicion of an underlying congenital myopathy. Initial laboratory and imaging workup were inconclusive except for transient elevation of creatine kinase. Whole exome sequencing identified a heterozygous missense variant in the RYR1 gene (c.14126C>T; p.Thr4709Met), along with a likely pathogenic FOXP1 variant. In view of the characteristic clinical phenotype, a diagnosis of King–Denborough syndrome was considered. The child was managed with supportive therapy and developmental interventions, and caregivers were counselled regarding the risk of malignant hyperthermia. This case underscores the importance of clinicogenetic correlation in diagnosing rare myopathies and highlights the need for early recognition to enable appropriate counselling and prevention of anaesthetic complications.

Scalp-Ear-Nipple Syndrome (SEN) in Pediatric Patients With Multiple Co-morbidities: A Case Report

Scalp-Ear-Nipple syndrome (SEN), or Finlay-Marks syndrome, is an exceedingly rare congenital disorder characterized by scalp aplasia, auricular malformations, and nipple hypoplasia or absence. Fewer than 100 cases have been described, and phenotypic variability complicates diagnosis and management. Two male neonates presented with large aplasia cutis congenita (ACC) defects and variable phenotypic features. The first patient, born at 37 weeks, exhibited the classic triad of occipital ACC, bilateral cupped ears, and athelia, along with PDA and left upper eyelid coloboma. Genetic testing identified a pathogenic KCTD1 mutation and a 47, XXY karyotype consistent with Klinefelter syndrome. The second patient, born at term, had an isolated midline scalp defect with distal limb anomalies including hallux hypoplasia and nail dysplasia. Genetic testing for Adams-Oliver syndrome and SEN-associated genes was negative. Both patients underwent staged reconstructive strategies using biologic allografts and Integra Dermal Regeneration Template to promote epithelialization and soft tissue coverage. Reconstruction was coordinated through a multidisciplinary craniofacial team. Patients showed progressive epithelialization and calvarial regeneration with normal neurodevelopment, and stable wound healing with age-appropriate neurologic development throughout follow-up. This case series highlights phenotypic variability in SEN syndrome, including a novel co-occurrence with Klinefelter syndrome. Early recognition, genetic evaluation, and staged reconstruction are essential to optimize outcomes in patients with syndromic ACC.

Recognizing Stuve–Wiedemann syndrome in childhood: clinical insights from 11 patients with founder and novel LIFR variants

Background. Stuve–Wiedemann syndrome is a rare autosomal recessive bent-bone dysplasia characterized by dysautonomia and distinctive skeletal abnormalities, most commonly caused by biallelic LIFR variants. Methods. Eleven patients from ten unrelated families with molecularly confirmed Stuve–Wiedemann syndrome were evaluated. Detailed demographic, perinatal, clinical, radiographic, and molecular data were collected. All patients underwent Sanger sequencing of LIFR. Results. Respiratory problems and episodic hyperthermia were present in all patients, while feeding difficulties, hypotonia, growth failure, developmental delay, craniofacial dysmorphism, oral abnormalities, and ocular involvement were also common. All patients demonstrated long-bone bowing, cortical thickening, and flared metaphyses. A biallelic LIFR variant was identified in all patients, occurring in the homozygous state in nine patients and in the compound heterozygous state in two patients. The recurrent c.2074C>T; p.(Arg692Ter) variant was homozygous in seven patients and compound heterozygous in one patient. Three novel LIFR variants were also identified. Conclusion. Stuve–Wiedemann syndrome is characterized by a high mortality rate during the first two years of life due to severe dysautonomia, and orthopedic complications worsen progressively with age; therefore, early diagnosis and lifelong multidisciplinary follow-up are essential. Furthermore, the high rate of consanguinity in Türkiye, together with the recurrent p.(Arg692Ter) variant in LIFR identified in multiple unrelated families, supports the possibility of a founder effect and suggests that the frequency of Stuve–Wiedemann syndrome in our population may be higher than expected. Our findings further characterize the previously reported clinical manifestations of Stuve–Wiedemann syndrome while expanding the molecular spectrum through the identification of three novel LIFR variants.

Yunis Varon Syndrome: Characteristic Limb Abnormalities and Refining of the Phenotype.