RESUMEN
BACKGROUND: Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. METHODS: We performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations. RESULTS: We identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin A (FLNA) (c.4952 C > T (p.A1448V), c.6727C > T (p.C2160R), c.5966 G > A (p.G2236E)) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19-21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor ß-integrin 1 (ITGß1). CONCLUSIONS: FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.
Asunto(s)
Filaminas/genética , Genes Ligados a X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Síndrome del Abdomen en Ciruela Pasa/genética , Adulto , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Predisposición Genética a la Enfermedad , Genotipo , Hemicigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Linaje , Fenotipo , Síndrome del Abdomen en Ciruela Pasa/fisiopatología , Secuenciación del ExomaRESUMEN
OBJECTIVE: To design a novel system of scoring prune belly syndrome (PBS) phenotypic severity at any presenting age and apply it to a large pilot cohort. PATIENTS AND METHODS: From 2000 to 2017, patients with PBS were recruited to our prospective PBS study and medical records were cross-sectionally analysed, generating individualised RUBACE scores. We designed the pragmatic RUBACE-scoring system based on six sub-scores (R: renal, U: ureter, B: bladder/outlet, A: abdominal wall, C: cryptorchidism, E: extra-genitourinary, generating the acronym RUBACE), yielding a potential summed score of 0-31. The 'E' score was used to segregate syndromic PBS and PBS-plus variants. The cohort was scored per classic Woodard criteria and RUBACE scores compared to Woodard category. RESULTS: In all, 48 males and two females had a mean (range) RUBACE score of 13.8 (8-25) at a mean age of 7.3 years. Segregated by phenotypic categories, there were 39 isolated PBS (76%), six syndromic PBS (12%) and five PBS-plus (10%) cases. The mean RUBACE scores for Woodard categories 1, 2, and 3 were 20.5 (eight patients), 13.8 (25), and 10.6 (17), respectively (P < 0.001). CONCLUSIONS: RUBACE is a practical, organ/system level, phenotyping tool designed to grade PBS severity and categorise patients into isolated PBS, syndromic PBS, and PBS-plus groups. This standardised system will facilitate genotype-phenotype correlations and future prospective multicentre studies assessing medical and surgical treatment outcomes.
Asunto(s)
Fenotipo , Síndrome del Abdomen en Ciruela Pasa/clasificación , Índice de Severidad de la Enfermedad , Pared Abdominal/patología , Niño , Preescolar , Criptorquidismo/clasificación , Femenino , Humanos , Masculino , Proyectos Piloto , Estudios Prospectivos , Uréter/diagnóstico por imagen , Obstrucción del Cuello de la Vejiga Urinaria/terapia , Reflujo Vesicoureteral/diagnóstico por imagenRESUMEN
PURPOSE: A rapid test for testicular torsion in children may obviate the delay for testicular ultrasound. In this study we assessed testicular tissue percent oxygen saturation (%StO2) measured by transscrotal near infrared spectroscopy as a diagnostic test for pediatric testicular torsion. MATERIALS AND METHODS: This was a prospective comparison to a gold standard diagnostic test study that evaluated near infrared spectroscopy %StO2 readings to diagnose testicular torsion. The gold standard for torsion diagnosis was standard clinical care. From 2013 to 2015 males with acute scrotum for more than 1 month and who were less than 18 years old were recruited. Near infrared spectroscopy %StO2 readings were obtained for affected and unaffected testes. Near infrared spectroscopy Δ%StO2 was calculated as unaffected minus affected reading. The utility of near infrared spectroscopy Δ%StO2 to diagnose testis torsion was described with ROC curves. RESULTS: Of 154 eligible patients 121 had near infrared spectroscopy readings. Median near infrared spectroscopy Δ%StO2 in the 36 patients with torsion was 2.0 (IQR -4.2 to 9.8) vs -1.7 (IQR -8.7 to 2.0) in the 85 without torsion (p=0.004). AUC for near infrared spectroscopy as a diagnostic test was 0.66 (95% CI 0.55-0.78). Near infrared spectroscopy Δ%StO2 of 20 or greater had a positive predictive value of 100% and a sensitivity of 22.2%. Tanner stage 3-5 cases without scrotal edema or with pain for 12 hours or less had an AUC of 0.91 (95% CI 0.86-1.0) and 0.80 (95% CI 0.62-0.99), respectively. CONCLUSIONS: In all children near infrared spectroscopy readings had limited utility in diagnosing torsion. However, in Tanner 3-5 cases without scrotal edema or with pain 12 hours or less, near infrared spectroscopy discriminated well between torsion and nontorsion.