RESUMO
OBJECTIVE: To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics. STUDY DESIGN: We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum, PIK3CA-related overgrowth spectrum (PROS), vascular overgrowth, or isolated LO, based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield. RESULTS: This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions, and 11% reclassified. Beckwith-Wiedemann spectrum was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PIK3CA-related overgrowth spectrum had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. Vascular overgrowth demonstrated significant clinical overlap with other syndromes. A molecular diagnosis of isolated LO proved challenging, with only 21% of cases classifiable into a specific condition. CONCLUSIONS: LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which is crucial for addressing potential cancer predisposition, enabling precision medicine treatments, and guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of a tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield.
Assuntos
Síndrome de Beckwith-Wiedemann , Classe I de Fosfatidilinositol 3-Quinases , Humanos , Estudos Retrospectivos , Feminino , Masculino , Classe I de Fosfatidilinositol 3-Quinases/genética , Criança , Pré-Escolar , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Lactente , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , AdolescenteRESUMO
OBJECTIVE: To provide information on evolution over time of leg length discrepancy in patients with syndromic and isolated lateralized overgrowth. STUDY DESIGN: This retrospective study investigates leg length discrepancy longitudinally in 105 patients with lateralized overgrowth either isolated (n = 37) or associated with Beckwith-Wiedemann spectrum (n = 56) or PIK3CA-related overgrowth spectrum (n = 12). Discrepancy was measured by standard methods and categorized as minor, mild, severe, and critical, based on the thresholds of 1, 2 and 5, respectively. RESULTS: The period of observation from diagnosis was 1.7 ± 2.6 to 9.0 ± 6.0 years. Leg length discrepancy was 11.0 ± 7.2 mm at diagnosis and 17.1 ± 14.4 mm at last visit. Both final leg length discrepancy and change over time were correlated with discrepancy at diagnosis (r2 = 0.45, P < .001 and r2 = 0.05, P = .019, respectively). Among minor leg length discrepancy at diagnosis, 47.5% remained minor, 40.0% become mild, and 12.5% severe. Among patients with discrepancy classified as severe at diagnosis, 84.6% remained severe and 15.4% evolved to critical. The isolated lateralized overgrowth group showed a milder evolution over time compared with Beckwith-Wiedemann spectrum and PIK3CA-related overgrowth spectrum groups. Among patients with Beckwith-Wiedemann, those with paternal chromosome 11 uniparental disomy had more severe leg length discrepancy at diagnosis and evolution over time. CONCLUSIONS: Leg length discrepancy associated with isolated or syndromic lateralized overgrowth tends to worsen with growth and correlates with discrepancy at first observation. Among the genotypic groups, isolated lateralized overgrowth tends to have a milder evolution, whereas Beckwith-Wiedemann spectrum predisposes to a more severe outcome, especially if associated with paternal chromosome 11 uniparental disomy genotype.
Assuntos
Síndrome de Beckwith-Wiedemann , Perna (Membro) , Genótipo , Humanos , Estudos Retrospectivos , Dissomia UniparentalRESUMO
OBJECTIVE: To review the clinical characteristics in a series of 25 patients with VACTERL (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, cardiac defects, renal and limb anomalies) association who were ascertained for upper limb involvement. STUDY DESIGN: The study involved a review of clinical and radiologic data from patients with VACTERL association collected by a hand surgery clinic between 2004 and 2013. RESULTS: Radial axis involvement was found in all 25 patients (100%), with severe thumb function impairment in 79% and complete absence of the radius in roughly 33%. Costovertebral anomalies were the most frequent feature, found in 23 patients (92%). All 3 core features (anal atresia, tracheoesophageal fistula with esophageal atresia, and costovertebral anomalies) were present in only 12% of the patients. Twelve patients (48%) had abnormalities not part of the VACTERL spectrum, showing a specific pattern of non-VACTERL-type malformations, including genitourinary abnormalities (12%), single umbilical artery (8%), and tethered cord (8%). Previously unreported clinical findings were concurrent hypoplasia of both the odontoid process and the coccyx in 2 patients and an isolated sacral dimple in 2 patients. CONCLUSION: Upper limb involvement in VACTERL association is a specific feature of the radial axis that occurs in monolateral form in approximately 75% of cases and, when bilateral, always occurs in a nonsymmetrical fashion. Odontoid and coccygeal hypoplasia and sacral dimple are newly reported malformations of the VACTERL phenotype.