Iwona Maruniak-Chudek

Mutations in the Human Laminin β2 (LAMB2) Gene and the Associated Phenotypic Spectrum

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease‐causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N‐terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist. Hum Mutat 31:992–1002, 2010.

Ophthalmological Aspects of Pierson Syndrome

PURPOSE To study the ocular phenotype of Pierson syndrome and to increase awareness among ophthalmologists of the diagnostic features of this condition. DESIGN Retrospective, observational case series. METHODS A multicenter study of 17 patients with molecularly confirmed Pierson syndrome. The eye findings were reviewed and compared to pertinent findings from the literature. RESULTS The most characteristic ocular anomaly was microcoria. A wide range of additional abnormalities were found, including posterior embryotoxon, megalocornea, iris hypoplasia, cataract, abnormal lens shape, posterior lenticonus, persistent fetal vasculature, retinal detachment, variable axial lengths, and glaucoma. There was high interocular and intrafamilial variability. CONCLUSIONS Loss-of-function mutations in laminin beta2 (LAMB2) cause a broad range of ocular pathology, emphasizing the importance of laminin beta2 in eye development. Patients with Pierson syndrome can initially present with ocular signs alone. In newborns with marked bilateral microcoria, Pierson syndrome should be considered and renal function investigated.

Serum and Urinary NGAL in Septic Newborns

Neutrophil gelatinase-associated lipocalin (NGAL) is postulated to be a potentially new and highly specific/sensitive marker of acute kidney injury (AKI). The aim of this study was to assess the impact of inflammation on serum and urine NGAL in newborns that were treated due to infection. We determined serum and urine NGAL concentrations in 73 infants (51 with sepsis; 22 with severe sepsis) admitted to the Intensive Care Unit in the first month of life, for three consecutive days during the course of treatment for infection. 29 neonates without infection served as the control group. Septic patients, in particular, severe sepsis patients, had increased serum and urinary NGAL levels in the three subsequent days of observation. Five septic patients who developed AKI had elevated serum and urinary NGAL values to a similar extent as septic neonates without AKI. A strong correlation was found between the concentration of serum and urinary NGAL and inflammatory markers, such as CRP and procalcitonin. Serum and urinary NGAL levels were also significantly associated with NTISS (neonatal therapeutic intervention scoring system) values. We conclude that increased serum and urinary NGAL values are not solely a marker of AKI, and more accurately reflect the severity of inflammatory status.

Comparison of prenatal and postnatal treatments of spina bifida in Poland – a non-randomized, single-center study

Abstract Objective: The aim of this study was a comparison of the outcomes of intrauterine myelomeningocele (MMC) repairs (IUMR) in type II Chiari malformation (II CM) fetuses with clinical data of newborns and infants operated on postnatally. Methods: The study group (SG) comprised 46 pregnant women whose type II CM children underwent IUMR, while 47 pregnant women whose type II CM children were operated on postnatally constituted the control group (CG). A total of 24 SG and 20 CG patients reached the endpoint of the study. Results: High incidence of prelabor rupture of membranes (24 (52.2%), CI: 3.74 (1.69–8.26) (p < 0.001) was noted in the group of prenatal surgeries as compared to controls. The need for ventriculoperitoneal shunt implantation was statistically significantly lower (p < 0.008) in the group of children after IUMR as compared to controls (5 (27.8%) and 16 (80%), respectively, CI: 0.35 (0.16–0.75). None of the postnatally treated CG children can walk without adaptive equipment. In contrast, two children from the SG (2 (11.1%) CI: 1.86 (1.00–3.48) p < 0.05) are able to walk independently. Conclusions: Prenatal MMC closure significantly lowers further adverse evolution of the II CM. Further studies are needed, especially on preventive measures for preterm labor and iatrogenic preterm prelabor rupture of membranes (iPPRM) in the postoperative course of IUMR.

Is serum cystatin C a better marker of kidney function than serum creatinine in septic newborns

INTRODUCTION Several studies have claimed that the estimation of serum cystatin C could be a better marker of kidney excretory function than serum creatinine. However, its role in the diagnosis of reduced kidney function was not unquestionably confirmed. The aim of this study was to analyze the concentrations of serum cystatin C in neonates with sepsis. MATERIAL/METHODS Thirty-two neonates (gestational age from 34 to 40 weeks) admitted to the NICU during the first 14 days of life were enrolled. Serum cystatin C concentrations were estimated by ELISA during three successive days in neonates treated for infection. The study group consisted of 9 newborns with sepsis, 14 with severe sepsis and 9 with septic shock. RESULTS/DISCUSSION At the beginning of the observational period the mean serum concentration of cystatin C in the study group was 1.35 mg/L (95% CI 1.20-1.49). Surprisingly, the lowest concentration of cystatin was observed in patients with septic shock (1.23 mg/L; 95%CI 0.92-1.54) within the observation period. Higher concentrations were found in neonates with sepsis (1.47 mg/L; 95%CI 1.04-1.90) and severe sepsis (1.50; 1.12-1.87). There was no correlation between serum cystatin C concentration and serum creatinine or gestational age. A significant correlation was discovered between chronological age and cystatin C (R=-0.439, p=0.01). There was a tendency for cystatin C to decline during the second observational day in patients with sepsis (to 1.53 mg/L; 95%CI: 1.19-1.86) and severe sepsis (to 1.32 mg/L; 95%CI: 1.07-1.57), while a slight insignificant increase in patient with septic shock (to 1.28 mg/L; 95%CI: 0.88-1.68) was revealed. The interrelation between age and cystatin C concentration disappeared in the following days of stay in the NICU. Even in patients who died in the course of septic shock the observed changes in cystatin C levels were small and did not exceed those of serum creatinine. CONCLUSIONS Cystatin C is not a useful marker of kidney function in neonates with sepsis.

Factors limiting usefulness of serum and urinary NGAL as a marker of acute kidney injury in preterm newborns

Abstract Background: Neutrophil gelatinase-associated lipocalin (NGAL) is postulated to be a highly sensitive and specific marker of acute kidney injury (AKI). The aim of this study was to assess the factors affecting serum and urine total NGAL in preterm newborns, limiting the role of this new potential marker of AKI. Methods: Serum and urinary total NGAL concentrations were determined in 57 preterm infants admitted to the Neonatal Intensive Care Unit in the following points of time: first week of life, between 8 and 14 days of life, and after the fourth week of life. Patients’ clinical conditions were evaluated based on NTISS (Neonatal Therapeutic Intervention Scoring System). Two gestational age subgroups were distinguished: ≤29 and 30 to 35 weeks of gestation. We sought correlation between total NGAL values and gestational age, birth weight, Apgar score and severity of clinical condition, with particular interest in inflammatory status. Results: Serum and urinary total NGAL concentration correlated with inflammatory markers, such as CRP and procalcitonin, as well as with NTISS values. Birth weight and gestational age influence urinary NGAL (uNGAL) values in the first two weeks of life. In AKI (N = 8) patients uNGAL values were significantly higher than in non-AKI newborns. Conclusions: We conclude that inflammatory status and prematurity limits the specificity of total NGAL measurement as a marker of AKI.

Zonulin: A Potential Marker of Intestine Injury in Newborns

Introduction Zonulin (ZO), a new diagnostic biomarker of intestinal permeability, was tested in newborns presenting symptoms of infection and/or inflammation of the gut or being at risk of intestinal pathology. Material and Methods Serum ZO was assessed in 81 newborns diagnosed with sepsis, necrotizing enterocolitis (NEC), rotavirus infection, and gastroschisis, also in extremely low gestational age babies, and in controls (healthy newborns). ZO concentration was compared to C-reactive protein (CRP) and procalcitonin (PCT) values, leucocyte and platelet count, basic demographic data, and the value of the Neonatal Therapeutic Intervention Scoring System (NTISS). Results Median values of ZO were markedly higher in groups with rotavirus infection and gastroschisis (36.0 (1-3Q: 26.0–43.2) and 20.3 (1-3Q: 17.7–28.2) ng/ml, resp.) versus controls (3.5 (1-3Q: 2.7–4.8) ng/ml). Its concentration in the NEC group was twice as high as in controls but did not reach statistical significance. ZO levels were not related to NTISS, CRP, and PCT. Conclusions Zonulin is a promising biomarker of intestinal condition, markedly elevated in rotavirus infections. Its role in defining the severity of necrotizing enterocolitis and the risk for perforation is not well described and needs further evaluation. An increase in zonulin may not be parallel to the release of inflammatory markers, and low CRP should not exclude an injury to neonatal intestine.

[Copeptin - stable C-terminal fragment of pre-provasopressin as a new stress marker in newborns].

Stress stimuli, including diseases, disturb homeostasis of the body and enhance secretion of various hypothalamus, pituitary and adrenal gland hormones. One of the main hypothalamic hormones secreted in stress conditions is arginine vasopressin (AVP). Vasopressin concentration in the blood reflects the severity of disease and disorders of blood volume. Measurement of vasopressin is difficult and subjected to considerable laboratory error because of the short half-life in serum and its instability in withdrawn blood samples. This hormone and copeptin are peptides produced during the cleavage of a larger precursor polypeptide: pre-provasopressin. Both peptides are formed in equimolar amounts. Copeptin is a more stable peptide, measurement of which can be performed with higher accuracy. This paper presents the importance of copeptin as a marker of stress, with particular emphasis on the neonatal period, analyzing the impact of gestational age and the route of delivery. Its potential application for assessing the degree of hydration in the adaptation period is also discussed.

Pheochromocytoma in pregnancy

Pheochromocytoma occurs with a frequency estimated at 2-7 per 100,000 pregnant women. Unrecognized, and thus untreated pheochromocytoma is associated with very high (40-50%) maternal and fetal mortality. Pheochromocytoma occurs sporadically or as a family trait. Its presence should be suspected in women with paroxysmal or established hypertension, especially before the 20th week of pregnancy, accompanied by headaches and palpitations, and excessive sweating, muscle tremors, vomiting, anxiety, vasomotor disturbances and blurred vision. The variety of clinical presentations and rarity are the cause of not including the disease in differential diagnosis of hypertension in pregnancy. Biochemical tests are essential in the diagnosis of pheochromocytoma, and involving the assessment of methoxycatecholamine urinary excretion. The second step in the diagnostics is magnetic resonance imaging of adrenal glands. Adrenalectomy is the treatment of choice for pheochromocytoma with adrenal location, which depends on the timing of the tumor diagnosis. Conservative treatment for 10-14 days with pharmacological blockade of alpha-adrenergic receptors should precede the surgery. Early diagnosis and properly planned treatment of pheochromocytoma significantly reduces the risk to the mother and fetus.

Baseline Diameters of Inferior Vena Cava and Abdominal Aorta Measured by Ultrasonography in Healthy Term Neonates During Early Neonatal Adaptation Period

To evaluate normative sonographic measurements of the inferior vena cava (IVC), aorta (Ao), and IVC/Ao ratio in the first 2 days of life in term neonates.