Stefano Parrini

Absence of the inferior labial and lingual frenula in Ehlers-Danlos syndrome

The diagnosis of Ehlers-Danlos syndrome is based on distinctive phenotypical characteristics such as hyperelastic skin and hypermobile joints. To date, no congenital physical markers exist for identifying patients with Ehlers-Danlos syndrome. Absence of the inferior labial (100% sensitivity; 99.4% specificity) and lingual frenulum (71.4% sensitivity; 100% specificity) was found to be associated with classical and hypermobility types of Ehlers-Danlos syndrome.

Histologic chorioamnionitis and severity of illness in very low birth weight newborns.

Objective: Estimating the risk of in-hospital mortality in the neonatal intensive care unit provides important information for health care providers, and several neonatal illness severity scores have been developed. Histologic chorioamnionitis (HCA) is a known cause of neonatal morbidity and mortality. To date, the relationship between HCA and neonatal illness severity scores has not been rigorously tested. In this study, the relationships among HCA, initial illness severity, and neonatal outcomes were analyzed in very low birth weight (VLBW) newborns admitted to the neonatal intensive care unit. Design: Prospective. Setting: Neonatal intensive care unit. Patients: A total of 116 VLBW inborn infants (gestational age, 28.1 ± 2.82 wks; birth weight, 1009 ± 312 g) were categorized as HCA-positive (n = 67) and HCA-negative (n = 49). Interventions: Placental histology was performed to identify HCA. Illness severity evaluation included several different neonatal illness severity scores—Clinical Risk Index for Babies (CRIB), CRIB-II, Score for Neonatal Acute Physiology-II (SNAP-II), and Score for Neonatal Acute Physiology Perinatal Extension-II (SNAPPE-II)—as well as the recording of severe morbidity and in-hospital mortality. Measurements and Main Results: HCA-positive VLBW newborns showed significantly lower gestational age (p < .0001) and birth weight (p = .0010), together with higher CRIB, CRIB-II, SNAP-II, and SNAPPE-II scores at admission to the NICU (p ≤ .0001) and mortality rate (p = .0018) than HCA-negative infants. After adjustment for gender and gestational age in a multivariable logistic regression analysis, HCA was found to be an independent predictor of high illness severity: CRIB > 5 (odds ratio [OR], 21.37; 95% confidence interval [CI], 6.24–73.21); CRIB-II > 10 (OR, 56.17; 95% CI, 6.75–467.2); SNAP-II > 22 (OR, 43.05; 95% CI, 11.9–155.7), and SNAPPE-II > 42 (OR, 48.95; 95% CI, 10.18–235.4) (all p values <.0001). Conclusions: Our findings indicate that HCA is a major predictor of morbidity and mortality in VLBW newborns.

Early postnatal changes in the perfusion index in term newborns with subclinical chorioamnionitis.

Background: Chorioamnionitis (HCA) in term newborns is often subclinical and associated with neonatal morbidity and mortality. Objective: To assess the value of the pulse oximetry perfusion index (PI) in the early prediction of subclinical HCA in term newborns. Methods: PI cut-off values were first identified in 51 term newborns with HCA and 115 matched controls, retrospectively categorised on the basis of placental histology (study phase 1). The PI thresholds obtained were subsequently tested on an unselected case series of 329 prospectively recruited, term newborns (study phase 2). PI was evaluated during the first five minutes after delivery. Initial illness severity and short term clinical outcomes were determined. Results: In study phase 1, newborns with HCA had lower PI one and five minutes (p<0.0001) after delivery, lower one minute Apgar score (p  =  0.017), lower cord blood base excess (p  =  0.0001), together with higher rates of admission to neonatal intensive care unit (p  =  0.0001) and endotracheal intubation (p  =  0.017), and higher SNAP-PE (p<0.0001) and NTISS (p<0.0001) scores than those without HCA. In the prospective validation phase of the study, the PI cut-off values generated (one minute ⩽1.74, five minutes ⩽2.18) showed 100% sensitivity, 99.4% specificity, 93.7% positive predictive value, and 100% negative predictive value in identifying subclinical HCA. Early identification of HCA was associated with a decreased rate of admission to intensive care (p  =  0.012), as well as lower initial illness severity (p⩽0.0001) and therapeutic intensity (p  =  0.0006) than the newborns with HCA in phase 1. Conclusion: These findings suggest that early PI monitoring is helpful in identifying HCA in term newborns.

Abnormal vascular network complexity: a new phenotypic marker in hereditary non-polyposis colorectal cancer syndrome

Background: Hereditary non-polyposis colorectal cancer (HNPCC) (Lynch cancer family syndrome I (LCFS1) and II (LCFS2)) is one of the most common hereditary cancer disorders. HNPCC results from dominantly inherited germline mutations in mismatch repair (MMR) genes, leading to genomic instability and cancer. No predictive physical signs of HNPCC are available to date. Aims: Increased complexity in tumour associated vascular growth has been reported. Here, we tested the hypothesis that an increased vascular network complexity is a phenotypic marker for LCFS2. Methods: Fourteen subjects from an LCFS2 kindred (gene carriers, n = 5; non-carriers, n = 9) and 30 controls were examined. Fractal dimension (D) at two scales (D (1–46), and D (1–15), tortuosity (minimum path dimension, Dmin), and relative Lempel-Ziev complexity (L-Z) of the vascular networks from the lower gingival and vestibular oral mucosa were measured. Results: LCFS2 networks exhibited a significantly increased overall complexity at both larger (D (1–46): 1.82 (0.04) v 1.68 (0.08); p<0.0001) and smaller (D (1–15): 1.51 (0.11) v 1.20 (0.09); p<0.0001) scales, increased destructured randomness (L-Z: 0.77 (0.09) v 0.56 (0.03); p<0.0001), and decreased vessel tortuosity (Dmin: 1.02 (0.03) v 1.07 (0.04); p = 0.0005) compared with control patterns. The vascular networks of LCFS2 gene carriers showed higher complexity at the smaller scale (D (1–15): 1.59 (0.12) v 1.47 (0.07); p = 0.034), and higher destructured randomness (L-Z: 0.85 (0.11) v 0.73 (0.05); p = 0.013) than those of non-carriers. Conclusions: Increased oral vascular network complexity is a previously unrecognised phenotypic marker for LCFS2, and is related to gene mutation carrier status.

Early dynamic changes in pulse oximetry signals in preterm newborns with histologic chorioamnionitis.

Objective: No reliable clinical markers of histologic chorioamnionitis (HCA), a major and often subclinical cause of prematurity leading to high neonatal morbidity and mortality, are available to date. Increasing evidence indicates myocardial dysfunctions in affected fetuses and newborns. We sought to assess the value of nonlinear dynamics from pulse oximetry signals in identifying affected newborns. Design: Prospective case-control study. Setting: Tertiary level neonatal intensive care unit, Brindisi Hospital. Patients and Intervention: Pulse oximetry–derived signals (pulse rate, oxygen saturation, and perfusion index), recorded within the first 1.5 hrs of life, were analyzed for 110 very low-birth-weight infants, of whom 54 had histopathological evidence of HCA. Measurements and Main Results: Four different time series parameters were determined for nonlinear dynamical (NLD) analysis. Significantly decreased Lempel-Ziv, Lyapunov largest exponent, and correlation dimension, with significantly increased Hurst values for heart rate and perfusion index (p < .00001), were observed in newborns with HCA. Heart rate Lempel-Ziv ≤0.218 showed 100% sensitivity (95% confidence interval, 98.8–100) and 100% specificity (95% confidence interval, 98.6–100) in distinguishing cases from controls, with positive and negative predictive values of 100% and 95.7%, respectively. Conclusions: Our findings indicate that early autonomic tone balance abnormalities are present in newborns with HCA and suggest that early dynamic analysis of pulse oximetry signals could be useful in identifying affected infants.

Fordyce granules and hereditary non-polyposis colorectal cancer syndrome

Background: Germline mutations in mismatch repair (MMR) genes are found in only about half of clinically diagnosed families with hereditary non-polyposis colorectal cancer syndrome (HNPCC) (or Lynch syndrome). Early identification of gene carriers is essential to reduce cancer incidence and overall mortality. Aims: Recent evidence indicates an increase in size and number of sebaceous glands following activation of the hedgehog pathway, a crucial signalling pathway for animal development that is aberrantly activated in several types of cancer. Here we sought to assess a possible association between Fordyce granules (FGs—that is, ectopic sebaceous glands on the oral mucosa) and HNPCC. Methods: A total of 15 members of five different genetically unrelated HNPCC kindreds (MLH1 gene mutation n = 8; undetectable MLH1 protein at immunochemistry n = 4; clinical diagnosis n = 3) and 630 genetically unrelated age and sex matched healthy controls were examined. Following examination of the oral mucosa surface, subjects were categorised as either FGs positive or FGs negative. Results: Evidence of FGs was significantly associated with HNPCC (13/15 (86.7%) affected patients v 6/630 (0.95%) controls; p<0.0001), with a relative risk of 91.0 (95% confidence interval 40.05–206.76). The observed difference remained significant when carriers of germline mutations in MMR genes were considered (8/15 v 6/630; p<0.0001). The most common site for the FGs in HNPCC patients was the lower gingival and vestibular oral mucosa. Conclusions: Our findings suggest that a previously unrecognised activation of the sebaceous glands system occurs in HNPCC. The observation could be of value for attending physicians in identifying affected families and/or increase the accuracy of the currently available molecular genetics screenings.

Oral Mucosal Microvascular Abnormalities: An Early Marker of Bronchopulmonary Dysplasia

An abnormal pulmonary vasculature has been reported as an important component of bronchopulmonary dysplasia (BPD). We tested the hypothesis of an early abnormal vascular network pattern in infants with BPD. Fifteen infants with BPD (nine boys and six girls; gestational age 27.5 ± 2.0 wk; birth weight 850 ± 125 g) and 15 sex- and gestational age–matched infants (nine boys and six girls; gestational age 27.6 ± 2.6 wk; birth weight 865 ± 135 g) were examined on postnatal days 1 and 28. BPD infants showed a significantly higher prevalence of histologic chorioamnionitis (p = 0.009), as well as higher intubation duration (p = 0.0004), oxygen supplementation (p < 0.0001), and initial illness severity (p = 0.0002) than the BPD-negative population. The lower gingival and vestibular oral mucosa was chosen as the study area. The blood vessel area was determined, and the oral vascular networks were characterized by analyzing their complexity (D, at two scales: D 1–46, D 1–15), tortuosity (Dmin), and randomness (L-Z) of the vascular loops. Infants with BPD showed a significantly lower blood vessel area as well as a higher vascular network complexity (D 1–46, D 1–15, and L-Z) than control subjects (p < 0.0001). Our findings provide a new early clinical sign in BPD and stress the importance of an early disorder in the oral mucosal vascularization process in the disease pathogenesis.

Abnormal oral mucosal light reflectance: a new clinical marker of high risk for colorectal cancer

Background: A familial predisposition to colorectal cancer (CRC) has been clearly established, consisting of familial clustering in 15–20% and clear hereditary aetiology in 5–10% of overall CRC cases. Early identification of families and individuals at high risk is essential as intensive surveillance has been demonstrated to reduce cancer incidence and overall mortality. In the present study, the value of oral mucosal light reflectance in identifying hereditary non-polyposis colorectal cancer (HNPCC) carriers was investigated. Methods: Twenty members of six different genetically unrelated HNPCC kindred and 30 genetically unrelated age and sex matched healthy controls were examined. Lower gingival and vestibular oral mucosal reflectance was measured using an imaging spectrophotometer. Results: HNPCC carriers showed significantly lower values in the 590–700 nm wavelength range (p⩽0.0004). A reflectance cut off value ⩽47.9% at the 700 nm wavelength discriminated between HNPCC carriers and controls, with 100% sensitivity and 100% specificity. Conclusions: These findings may provide an additional phenotypic sign in HNPCC carriers, which could be used in first level CRC population screening programmes.

Congenital oral mucosal abnormalities in true umbilical cord knots.

Objective: The pathogenesis and clinical significance of true umbilical cord knots remain controversial. Here, we tested the hypothesis of the presence of congenital oral mucosal changes in newborns with true umbilical cord knots. Study design: Seven consecutive infants with true umbilical cord knots and 50 gestational age- and sex-matched controls were enrolled. The proportion of oral frenulum abnormalities and the two-dimensional vascular network geometry [fractal dimension, D, at two scales: D(1–46), and D(1–15), with the relative Lempel-Ziv complexity, (L-Z)], were analyzed. Results: Infants with true umbilical cord knots showed significantly higher proportions of mandibular frenulum agenesis compared to controls (p = 0.000006). The oral vascular networks of these infants exhibited a significantly higher D(1–46) and D(1–15) (p < 0.0001, respectively), and higher L-Z values (p < 0.0001) than control networks. Conclusion: These findings indicate the presence of significant congenital oral mucosal changes in newborn infants with true umbilical cord knots, thus suggesting a previously unrecognized association between true umbilical cord knots and a subclinical extracellular matrix disorder.

Abnormal oral mucosal light reflectance in Infantile hypertrophic pyloric stenosis

Objectives: Infantile hypertrophic pyloric stenosis (IHPS) is the most common condition requiring surgical intervention during the first weeks of life. The etiology of IHPS is unknown, although both neuronal nitric oxide synthase upregulation and an extracellular matrix abnormality are suspected. Familial predisposition is an important feature. Phenotypical markers of IHPS, such as hypoplasia or agenesis of the inferior labial frenulum, have been described. The authors tested the hypothesis that IHPS is associated with abnormal reflectance of the oral mucosa. Methods: Twenty-five children with surgically confirmed IHPS and 25 gender- and age-matched control subjects participated in the study. Reflectance of the lower gingival and vestibular oral mucosa in the optical spectrum was measured using an imaging spectrophotometer. Results: Patients with IHPS had significantly higher light reflectance values in the violet, blue, blue-green, green, yellow, and orange sections of the spectrum (all P values < 0.0001), with a maximum distance between group means at the 450-nm wavelength (t-value: 27.66, df = 48). A reflectance cutoff >5.26% at the 450-nm wavelength identified patients with IHPS with 100% sensitivity and 100% specificity. Conclusions: This study reports a previously unrecognized mucosal reflectance abnormality of the oral mucosa in IHPS, thus offering a new, accurate, and noninvasive phenotypic marker for the condition.