Preterm infants with severe extrauterine growth retardation (EUGR) are at high risk of growth impairment during childhood.

UNLABELLED: Extrauterine growth retardation (EUGR) seriously affects premature newborns and is related to the impairment of growth during childhood. There are very limited data available concerning the growth outcome of EUGR children. Our aim was to assess the growth outcome in a cohort of children born before 34 weeks of gestation with severe EUGR. This was a retrospective multicenter study, performed in outpatient endocrinology clinic. A total of 103 premature children with weight and/or length below -2 standard deviation score (SDS) of "intrauterine" growth expectation at the time of discharge from hospital (within 42 weeks of postmenstrual age) were included in the study. The study participants underwent a thorough anthropometric assessment at a mean age of 3.9 years ± 1.7 SD. Of the EUGR children, 12.6 % showed a height below -2 SDS and 7.7 % even below -2.5 SDS. Growth impairment was more common in males than in females (17 vs. 8 %). The prevalence of subnormal weight (below -2 SDS) was 13.6 %, being higher in males than in females (17 vs. 10 %). BMI values below -2 SDS were found in 18.4 % of our study population (22.7 % in males and 12 % in females). The 19.6 % of EUGR children did not catch up in head circumference during early childhood. Length at term was the major predictor of height in childhood (P < 0.001). CONCLUSION: A significant proportion of children born prematurely with severe EUGR show growth retardation in childhood thus suggesting the need for a close clinical follow-up to determine their growth potential and implement effective intervention strategies.

Thyroid-stimulating hormone levels in the first days of life and perinatal factors associated with sub-optimal neuromotor outcome in pre-term infants.

AIM: To identify perinatal factors associated with sub-optimal neuromotor outcome in infants without evident central nervous system lesions (intraventricular hemorrhage/ periventricular leukomalacia), with gestational age ≤30 (group I) and of 31-32 weeks (group II). PATIENTS AND METHODS: A total of 102 premature infants admitted to the Neonatal Intensive Care Unit of Pisa, at 26-32 weeks of gestation, were studied. Data about perinatal factors and TSH values at 3-4 days of life were collected. The assessment of neuromotor development was performed at 18 months of corrected age, using the locomotor subscale of the Griffiths Scales of Mental Development. RESULTS: Risk factors supposed to be predictive of sub-optimal neuromotor outcome (odds ratio >1) were at ≤30 weeks: male sex, small for gestational age, patent duct arterious, respiratory distress syndrome, and at 31-32 weeks: Apgar at 5 min <7, respiratory distress syndrome, patent duct arterious and birth weight <1500 g. A strong correlation was also found between TSH screening values >4,3 mU/l and suboptimal neuromotor outcome in both groups. CONCLUSIONS: Several perinatal factors, acting on an immature and more vulnerable nervous system, such as the pre-term one, different for different gestational ages, are associated with a sub-optimal neuromotor outcome. Higher, but within the normal range, TSH values at screening seem to be a strong risk factor for neuromotor outcome in preterm infants without intraventricular hemorrhage or periventricular leukomalacia.

Neonatal outcome in newborns from mothers with endocrinopathies.

INTRODUCTION: Hypothyroidism and gestational diabetes are common endocrine disorders in pregnancy. Our aim is to evaluate the outcome of newborns from mothers with hypothyroidism and from mothers with gestational diabetes. PATIENTS AND METHODS: The study analysed 216 newborns: 112 from mothers with gestational diabetes and 104 from mothers with hypothyroidism. For each case, we included as a control a newborn of same sex and gestational age from a mother without diabetes or thyreopathy. RESULTS: In newborns from mothers with gestational diabetes there was an increased frequency of hypoglycaemia and hypocalcaemia, of lower head circumference and of small-for-gestational age (SGA) birth or macrosomy (LGA) than controls. The newborns from mothers with hypothyroidism are more frequently SGA or LGA and they have a slightly increased risk of hypoglycaemia. CONCLUSIONS: Newborns from mothers with diabetes mellitus or hypothyroidism have an increased risk of being SGA or LGA, and to develop a mild transient hypoglycaemia. Newborns from mothers with diabetes mellitus have also an increased risk to develop hypocalcaemia and to have a lower head circumference than controls. Thus, to prevent SGA or LGA births, it is very important an early diagnosis and treatment, and a strict metabolic control of these conditions.

Lethal autosomal recessive epidermolytic ichthyosis due to a novel donor splice-site mutation in KRT10.

Epidermolytic ichthyosis (EI; MIM 113800), previously named bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a rare and clinically variable defect of cornification characterized by generalized erythema, erosions, scaling and easily breaking blisters that become less frequent later in life while hyperkeratosis increases. EI is caused by dominant mutations in either KRT1 or KRT10, encoding keratin 1 (K1) and keratin 10 (K10), respectively. Usually, mutations are missense substitutions into the highly conserved α-helical rod domains of the proteins. However, three inbred pedigrees in which EI is transmitted as a recessive trait due to KRT10 null mutations have been described.

Low testosterone levels in pre-term newborns born small for gestational age.

Previous studies showed that small for gestational age (SGA) newborns have an increased prevalence of hypospadias and other congenital defects of external genitalia. We observed that in the first days of life, SGA male pre-term newborns have reduced testosterone levels compared with adequate for gestational age pre-term newborns, independently from the presence of abnormalities of the external genitalia.

Retinol-binding protein 4 in neonates born small for gestational age.

BACKGROUND: Retinol-binding protein 4 (RBP4) is an adipocyte-derived 'signal' that may contribute to the pathogenesis of insulin resistance and Type 2 diabetes. The relationship of RBP4 with insulin resistance and metabolic risk in human beings has been the subject of several studies. Subjects born small for gestational age (SGA) are at risk of insulin resistance and Type 2 diabetes. Though RBP4 could represent an early marker of insulin resistance, to date, none have determined RBP4 in SGA children. AIM: Our aim was to measure RBP4 concentrations in cord blood of SGA newborns compared with those in children born with a birth weight appropriate for gestational age (AGA) and to determine whether serum RBP4 levels at birth correlate with insulin sensitivity markers. SUBJECTS AND METHODS: Sixty-four newborns, 17 born SGA (mean gestational age: 36.4+/-2.1 weeks), and 47 born AGA (mean gestational age: 37.0+/-3.6 weeks) were studied. The main outcome measures included anthropometry, lipid profile, insulin, homeostasis model assessment, quantitative insulin-sensitivity check index, adiponectin, and RBP4. RESULTS: RBP4 concentrations were significantly reduced in SGA newborns (p<0.002). No relationship was found between RBP4 and insulin sensitivity parameters. Stepwise regression analysis revealed that birth weight was the major predictor of RBP4 serum concentrations (p<0.001). CONCLUSION: RBP4 is reduced in SGA newborns, birth weight representing the major determinant of RBP4 concentrations, and is not related to insulin sensitivity. No significant difference in adiponectin levels and insulin sensitivity markers was found between SGA and AGA neonates.

Movement analysis in early infancy: Towards a motion biomarker of age.

BACKGROUND: Early motor development is characterized by progressive changes in general movements paralleled by a gradual organization of the four limbs' repertoire towards the midline, as shown by computerised movement analysis. AIMS: Our aim was to test the performance of quantitative computerised kinematic indexes as predictors of post-term age in an independent cohort of typically developing subjects at fidgety age, tested cross-sectionally. SUBJECTS: We selected twelve low risk term infants, who were video recorded between 9 and 20 weeks (fidgety age) during one spontaneous movements session. STUDY DESIGN: We correlated post-term age with I)indexes of coordination including interlimb correlation of velocity and position, II)indexes of distance, including interlimb and limb-to- ground, both expressed as linear distance and as probability of midline limbs position III)indexes of global movement quality by calculating Hjorth's activity, mobility and complexity parameters. All indexes were calculated for both upper and lower limbs. RESULTS: Significant positive correlations were found between post-term age and indexes of distance, and probability of occurrence of upper-limb antigravity patterns, and with both indexes of global movement quality. By combining linear and non-linear parameters related to the upper limb kinematics, we determined individual post-term age with a mean error of <1 week (5.2 days). No correlations were found between age and indexes of coordination. CONCLUSIONS: Quantitative computerised analysis of upper-limb movements is a promising predictor of post-term age in typically developing subjects at fidgety age.

Delayed delivery of the second twin: Case report and literature review of diamniotic dichorionic twin pregnancy with very early preterm premature rupture of membranes.

In multiple pregnancies with threatened premature delivery or preterm premature rupture of membranes (pPROM) of a single sac, prolonging pregnancy after the delivery of the first baby may improve the chances of survival of the second baby. We report the delayed delivery of a second baby in a twin pregnancy with pPROM and very premature delivery of the first baby. This condition is exceptional and there are no validated medical protocols for its management; the scientific evidence is still controversial. In our case, after the birth of the first baby, pregnancy was continued for 29 days, with monitoring of maternal and fetal parameters, which enabled the delivery of the second baby with improved neonatal outcomes. This case supports the prolongation of the pregnancy of the second twin.

Adrenal hemorrhage in newborn: how, when and why- from case report to literature review.

BACKGROUND: Neonatal adrenal hemorrhage is a relatively uncommon condition (0.2-0.55%). Various risk factors have been reported in addition to birth asphyxia, such as sepsis, coagulation disorders, traumatic delivery, and perinatal injuries. Adrenal hemorrhage usually affects the right adrenal gland (about 70% of cases) while it involves the bilateral adrenal gland only in 10% of cases. In most cases, the event is asymptomatic but, in others, it may be so devastating to determine death by bleeding or adrenal insufficiency. CASE PRESENTATION: A case of bilateral neonatal adrenal hemorrhage, with adrenal insufficiency, but with no important risk factors and favorable evolution in a male infant. CONCLUSIONS: This case emphasizes the importance of keeping a non-interventional attitude, avoiding early surgery but carrying out a serial sonographic follow-up. Serial ultrasound monitoring is the most reliable approach during conservative management.

Molecular characterization of 6 unrelated Italian patients with 5alpha-reductase type 2 deficiency.

Steroid 5alpha-reductase (5alphaR) deficiency (OMIM number #264600) is a rare 46,XY disorder of sex differentiation caused by mutations in the 5alphaR type 2 gene (SRD5A2) resulting in dihydrotestosterone deficiency during fetal development. We report on the analysis of the SRD5A2 gene in 6 unrelated 46,XY Italian patients with external genitalia morphology ranging from predominantly female to nearly completely male. Three subjects were seen and assessed at birth, 1 patient was referred to us before puberty, and 2 at postpubertal age. Six different causative mutations (5 missense and 1 nonsense) and a rare polymorphism were identified. Four patients presented homozygous single-base substitutions. These SRD5A2 mutations were located in exon 2 (variant Cys133Gly), exon 4 (Gly196Ser and Ala207Asp) and exon 5 (Tyr235Phe). A fifth subject was a compound heterozygote who carried a nonsense mutation in exon 1 (Trp53X) and a second SRD5A2 alteration in exon 5 (Tyr235Phe). The final patient presented a mutation in only 1 allele (Gly34Trp) together with the Ala49Thr variant. The molecular characterization of these patients made it possible to identify novel mutations and to confirm, before gender assignment or any surgical approach, the suspected 5alphaR deficiency in 2 newborns, 1 of whom had inconclusive hormonal data. 5alphaR deficiency in subjects without parental consanguinity and the presence of compound heterozygotic patients suggest that SRD5A2 mutations carrier frequency may be higher than previously thought.

Serum iodothyronines in the human fetus and the newborn: evidence for an important role of placenta in fetal thyroid hormone homeostasis.

UNLABELLED: The pattern of circulating iodothyronines in the fetus differs from that in the adult, being characterized by low levels of serum T3. In this study, concentrations of various iodothyronines were measured in sera from neonates of various postconceptional age (PA). Results obtained in cord sera at birth (PA, 24-40 weeks), reflecting the fetal pattern, were compared with those found during extrauterine life in newborns of 5 days or more of postnatal life (PA, 27-46 weeks). The main findings are: Starting at 30 weeks of PA, serum levels increase linearly during extrauterine life; and at 40 weeks, they are more than 200% of those measured in cord sera from newborns of equivalent PA. Serum reverse T3 (rT3) levels during fetal life are higher than those measured during extrauterine life; but they significantly decrease, starting at 30 weeks of PA. Serum T3 sulfate (T3S) does not significantly differ between the two groups, showing the highest values at 28-30 weeks of PA, and significantly decreasing at 30-40 weeks. T3S levels are directly correlated with rT3, both in fetal and extrauterine life, whereas a significant negative correlation between T3S and T3 is found only during extrauterine life. IN CONCLUSION: 1) changes in serum concentrations of iodothyronines in umbilical cord and during postnatal life indicate that maturation of extrathyroidal type I-iodothyronine monodeiodinase (MD) accelerates, starting at 30 weeks of PA; 2) high levels of type III-MD activity in fetal tissues prevent the rise of serum T3, whereas they maintain high levels of rT3 during intrauterine life; 3) an important mechanism leading to the transition from the fetal to the postnatal thyroid hormone balance is a sudden decrease in type III-MD activity; iv) because placenta contains a high amount of type III-MD, it is conceivable that placenta contributes to maintain low T3 and high rT3 serum concentrations during fetal life and that its removal at birth is responsible for most changes in iodothyronine metabolism occurring afterwards.

Binding of methyltrienolone to androgen receptors in human skin fibroblasts is enhanced by insulin.

Previous reports have suggested a relationship between hyperinsulinemia and increased androgen secretion leading to female virilization, but no report has been made of the effects of insulin on androgen receptors. The authors tested the in vitro effect of insulin on the binding of methyltrienolone (R1881) to androgen receptors of cultured genital skin fibroblasts preincubated with serum-free medium in the absence and presence of insulin (100 ng/mL, ie, 2600 microU/mL) for 18 hours at 37 degrees C. Insulin increased specific binding of R1881 by 35% (range, 13% to 75%). Scatchard analysis of androgen receptor binding demonstrated a similar increase in the number of binding sites, whereas binding affinity remained unchanged. The increase in androgen receptors was dose dependent (maximum effect at 25 ng insulin/mL) and time dependent (maximum effect occurring after 12 hours). DNA measurements indicated that insulin increased binding sites per cell rather than altering the cell number. Insulin increased total protein concentration to an extent similar to that observed for the increase in androgen receptor binding sites. Cycloheximide, but no actinomycin D, inhibited the effect of insulin on androgen receptor binding. The authors' data suggest that insulin induces an increase in the number of androgen receptors per cell as part of a general anabolic effect on cellular protein content.

A clinician looks at androgen resistance.

Androgen resistance in genetic males occurs when gonadotropins and testosterone are normal, but the physiological androgen response in androgen target organs is absent or decreased. In androgen-dependent target tissues two main defects may be found: 1) defective testosterone metabolism (5 alpha-reductase type 2 deficiency) and 2) anomalies in androgen receptors (androgen insensitivity syndrome (AIS)). The clinical manifestations of these defects vary from subjects with female external genitalia to subjects with mild forms of impaired masculinization. In particular, in the complete form of AIS (CAIS) the phenotype is feminine, and in the partial form (PAIS) the external genitalia are ambiguous with an extremely variable phenotype. The diagnosis requires clinical, hormonal, genetic, and molecular investigation for appropriate gender assignation and treatment. In AIS, cloning of androgen receptor cDNA using the polymerase chain reaction, denaturing gradient gel electrophoresis, and nucleotide sequencing have enabled a variety of molecular defects in the androgen receptor to be identified. The complexity of phenotypic presentation of AIS probably reflects the heterogeneity of androgen receptor gene mutations, but to date a relationship between genotype/phenotype has been difficult to establish, with the same point mutation reported to be associated with different phenotypic expressions. Other factors must therefore also contribute to the clinical presentation of AIS, although none have yet been identified. Establishing the functional consequences of androgen receptor mutations in vitro systems and correlating them with clinical presentation may ultimately provide an explanation for the variable clinical presentation of AIS and perhaps enable prediction of the response to androgen therapy in infants with PAIS.

Neonatal screening for congenital cytomegalovirus infection in preterm and small for gestational age infants.

Congenital cytomegalovirus (CMV) infection affects many organs: reticuloendothelial and central nervous system are particularly involved. Congenital CMV infection is the leading cause of non-genetic sensorineural hearing loss. Hearing impairment can be present at birth or it can occur months or even years after birth. It is as well an important risk factor for antenatal stillbirth, preterm birth and small for gestational age (SGA) condition. For these reasons we should early identify congenital CMV infection investigating at least at risk newborns such as preterm or SGA babies given that a simple and standardized method for a large scale screening program is lacking. In our study, we found an association between congenital CMV infection and preterm births (3.03%) and with SGA condition (3.7%). Consequently, routine CMV urine detection should be performed at least in all babies born before 37 weeks of gestational age and in term SGA newborns.

Kangaroo Mother Care: four years of experience in very low birth weight and preterm infants.

AIM: Kangaroo Mother Care (KMC) is a method of providing care for preterm infants through skin-to-skin contact with the mother and, preferably, exclusive breastfeeding. The growing interest in KMC at the Neonatology Unit of Pisa has provided the occasion for a retrospective analysis of the last four years, comparing the clinical effects of the kangaroo method vs. those obtained with conventional care (CNC) with respect to indicators of the general health of the infants (indices of growth, and duration of breastfeeding and hospitalization). METHODS: A total of 213 infants, aged <37 gestational weeks and weighing ≤1500 g were enrolled for the study; these were divided into two groups for the purpose of comparison (91 in KMC vs. 71 in CNC). RESULTS: The indices of growth and the duration of the infants in hospital were not significantly different in the two groups. Nevertheless, it is worth noting how KMC is more efficacious in the very tiny VLBW infants, and that the means of the growth parameters in the KMC infants are greater than those referring to the CNC subjects, body temperatures taken at the beginning and end of a KMC session are higher, and that the mother-child relationship facilitates better sucking-feeding. CONCLUSION: While KMC is equivalent to CNC in terms of safety, thermal protection, morbidity and auxologic development, it appears to promote humanisation of infant care and mother-child bond more quickly.

Increased incidence of esophageal atresia in northwest Tuscany: years 1994-2007.

AIM: Esophageal atresia (EA) and imperforate anus are congenital disorders with an incidence that ranges between 1/4000 and 1/5000 births. The aim of this work was to assess the incidence of these malformations in northwest Tuscany and the associated anomalies in comparison with the data published by the Tuscan Congenital Diseases Registry. METHODS: A retrospective study was made analyzing the cases of these malformations in the years 1994-2007 on a total of 25051 births at the Division of Neonatology of S. Chiara Hospital, Pisa. RESULTS: The authors found 14 cases of EA and 5 cases of imperforate anus. In these case histories of EA and imperforate anus the incidence was 1/1800 and 1/5000 respectively in comparison with the data issued by the Tuscan Congenital Diseases Registry with an incidence of 1/6644 and 1/1403 in all Tuscany. Five cases of EA (35%) and 2 cases of imperforate anus (40%) were associated with other congenital malformations. CONCLUSION: Our retrospective study shows a higher incidence of EA in northwest Tuscany than in all the rest of Tuscany unlike the incidence of imperforate anus that it is the same of the rest of Tuscany. In both cases isolated form is most frequent than syndromic one.

Fatal respiratory failure in a full-term newborn with two ABCA3 gene mutations: a case report.

Genetic mutations associated with pulmonary surfactant protein deficiency are associated with diverse clinical phenotypes. Mutations of the surfactant protein B and C genes were the first to be described. In 2004, fatal surfactant deficiency in newborns due to mutations of the gene encoding the adenosine triphosphate-binding cassette transporter A3 (ABCA3) was first reported. Few cases of lethal adenosine triphosphate-binding cassette transporter A3 mutations have been described to date. In our report, we describe a full-term newborn that died because of respiratory failure secondary to an uncommon ABCA3 genetic configuration.

Herlitz junctional epidermolysis bullosa: laminin-5 mutational profile and carrier frequency in the Italian population.

BACKGROUND: Herlitz junctional epidermolysis bullosa (HJEB; MIM 226700) is a rare epithelial adhesion disorder caused by null mutations in any of the three genes encoding the alpha3, beta3 and gamma2 chains of laminin-5, and is mainly characterized by extensive mucocutaneous blistering, recurrent infections and early lethality. OBJECTIVES: To perform immunoepitope mapping, electron microscopy and molecular analysis of five Italian patients with HJEB in order to complete the clinical and molecular characterization of patients with HJEB collected in the Italian Registry of hereditary epidermolysis bullosa (IRHEB) and to calculate the HJEB carrier frequency in this population. METHODS: Skin biopsies from perilesional skin of all patients were employed for immunoepitope mapping and electron microscopy examination. Blood genomic DNA was used for mutation analysis in the LAMA3, LAMB3 and LAMC2 genes by heteroduplex scanning, preceded by a search for Italian recurrent mutations. Carrier frequency calculation was performed assuming Hardy-Weinberg equilibrium. RESULTS: Two novel mutations in the LAMA3 (p.R782X) and LAMC2 (c.3235delA) genes, as well as three known and recurrent mutations in the LAMB3 (c.31insC and p.R81X) and LAMC2 (p.Y355X) genes were identified. Based on disease incidence reported in the IRHEB and the prevalence of mutations in each laminin-5 gene, the population carrier risk for HJEB was calculated to be one in 375. CONCLUSIONS: Our delineation of a laminin-5 mutational spectrum in the general Italian population provides a solid basis for expedited diagnosis, accurate genetic counselling and DNA-based prenatal testing for Italian families at risk for recurrence of HJEB.

Early diagnosis of 5alpha-reductase deficiency in newborns.

5Alpha-reductase-2 deficiency is a rare autosomal recessive form of 46,XY disorders of sex differentiation (DSD), caused by mutations in the steroid 5alpha-reductase type 2 gene (SRD5A2), presenting at birth with variable degrees of undervirilization. We report on three Italian newborns with 46,XY DSD in whom the evaluation of testosterone, dihydrotestosterone, testosterone/dihydrotestosterone (T/DHT) ratio and molecular analysis of the 5alpha-reductase type 2 gene was made in their first month of life. Baseline T/DHT ratio suggested 5alpha-reductase-2 deficiency; the diagnosis was confirmed by molecular genetics (homozygous mutation in exon 4 [G196S], heterozygous mutation in exon 1 and 5 [W35X/Y235F], heterozygous mutation plus polymorphism in exon 1 [G34W/A49T]). Proper investigation permitted early reassignment to male sex in two babies, assigned to female sex just after birth. In infancy, the T/DHT ratio, assessed by suitable assay methods and evaluated by age-appropriate reference values, seems to be able to select newborns affected by 5alpha-reductase-2 deficiency. Molecular analysis of the SRD5A2 gene should be warranted in newborns with abnormal ratio before sex assignment.