Non-alcoholic fatty liver infiltration in children: an underdiagnosed evolving disease.

Non-alcoholic fatty liver disease (NAFLD) constitutes the most common liver disease, one that is still underdiagnosed in pediatric populations (as well as in the general population), this due to the progressive increase in childhood obesity observed both in developed and developing countries during the last few decades. The pathophysiology of the disease has not been thoroughly clarified yet. The condition displays common pathways in adults and children; however, there are age-related differences. Unlike adults, children with NAFLD require extensive laboratory analysis, because underlying pathologies other than obesity may contribute to the evolution of the disease. Despite the presence of several serum markers and imaging techniques that contribute to NAFLD diagnosis, liver biopsy remains the gold standard diagnostic procedure. Early intervention and obesity prevention are mandatory, as NAFLD is reversible at an early stage. If left undiagnosed and untreated, NAFLD can progress to steatohepatitis (NASH) and subsequent liver failure, a potentially lethal complication. Of note, there are no treatment options when advanced liver fibrosis occurs. This review summarizes literature data on NAFLD in childhood indicating that this is an evolving disease and a significant component of the metabolic syndrome. Pediatricians should be aware of this entity, screening children at high risk and providing appropriate early management, in collaboration with pediatric subspecialists.

Hypovitaminosis D in Healthy Pregnant Women and their Newborns in Greece.

BACKGROUND/OBJECTIVES: The aim of this work was to evaluate the current vitamin D status in healthy pregnant women and their newborns living in Greece and assess possible associations between 25(OH)D and anthropometric features of their fetuses and newborns. MATERIALS & METHODS: 81 healthy women were monitored during pregnancy. Biochemical markers related to bone metabolism, 25(OH)D and PTH levels were measured in serum samples of mothernewborn pairs at 1st trimester of pregnancy and at delivery in mothers, in cord blood and at the 3rd day of life of newborns. RESULTS: Maternal 25(OH)D levels at the 1st trimester of pregnancy (22.6±9.2ng/ml) were significantly higher than those at delivery (19.2±9.2ng/ml) (p<0.001). Furthermore, umbilical 25(OH)D levels (21.3±9.3ng/ml) were higher than maternal at delivery (p=0.005) and neonatal levels (19.4±10.4 ng/ml) (p=0.021). Only 57.3% of the mothers at the first trimester and 46.7% at delivery as well as 55.8% of the fetuses and 38.5% of the neonates had adequate vitamin D levels (25(OH)D≥30ng/ml). A significant positive correlation was found between fetal femur length at the 22nd week of gestation and maternal 25(ΟΗ)D at the 1st trimester of pregnancy (r=0.36, p=0.048) while body length was significantly higher in newborns whose mothers had sufficient 25(OH)D levels (51.5±2.1cm) compared with those whose mothers had insufficient or deficient 25(OH)D levels at delivery (50.6±2.0cm) (p=0.047). CONCLUSION: The study confirms inadequate levels of vitamin D in pregnant women in Greece associated with inadequate vitamin D levels of their fetuses and newborns.

Expanding the spectrum of genetic mutations in antenatal Bartter syndrome type II.

Bartter syndrome (BS) is a group of genetic disorders characterized by hypokalemic metabolic alkalosis, hyponatremia and elevated renin and aldosterone plasma concentrations. BS type II is caused by mutations in the KCNJ1 gene and usually presents with transient hyperkalemia. We report here a novel KCNJ1 mutation in a male neonate, prematurely born after a pregnancy complicated by polyhydramnios. The infant presented with typical clinical and laboratory findings of BS type II, such as hyponatremia, hypochloremic metabolic alkalosis, severe weight loss, elevated renin and aldosterone levels and transient hyperkalemia in the early postnatal period, which were later normalized. Molecular analysis revealed a compound heterozygous mutation in the KCNJ1 gene, consisting of a novel K76E and an already described V315G mutation, both affecting functional domains of the channel protein. Typical manifestations of antenatal BS in combination with hyperkalemia should prompt the clinician to search for mutations in the KCNJ1 gene first.

Negativation of type 1 diabetes-associated autoantibodies to glutamic acid decarboxylase and insulin in children treated with oral calcitriol.

BACKGROUND: Based on recent knowledge of the possible involvement of 1,25-dihydroxyvitamin D in the pathogenesis of type 1 diabetes (T1D) and the results of its administration in animal models, we conducted a clinical trial by treating high-risk children, positive for T1D autoantibodies, with oral calcitriol. METHODS: The present prospective trial was performed on 12 children (1.5-13 years old) who were investigated for the potential risk of T1D because of an already diagnosed association of celiac disease and autoimmune thyroiditis (four girls), autoimmune thyroiditis at a very young age (two girls, two boys), a diagnosis of T1D in siblings (two boys), and impaired glucose tolerance (IGT; one boy, one girl). Serum autoantibody levels, including islet cell autoantibodies, anti-glutamic acid decarboxylase (GAD) 65, insulin autoantibodies (IAA), and anti-tyrosine phosphatase, and markers of calcium metabolism were evaluated prior to and at 6-monthly intervals after the initiation of 0.25 µg/day calcitriol for 1-3 years. RESULTS: In all children, persistent negativation of the anti-GAD65 antibodies and IAA was observed within 0.4-2.1 years. Of the two children with IGT, the boy proved to have maturity onset diabetes of the young (MODY) 2, whereas the glycemic profile was normalized in the girl. CONCLUSIONS: Despite the small number of subjects and the absence of a control group in the present study, 0.25 µg/day calcitriol effectively negativates anti-GAD65 antibodies and IAA after a median time of 6 months. This simple, safe, and low-cost strategy may prove effective in the prevention of T1D in the future.

Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment.

Noonan syndrome (NS) is a common multiple congenital anomaly entity, the diagnosis of which, on clinical grounds, is based on a comprehensive scoring system in order to select patients for molecular confirmation. Our aim was to evaluate the phenotypic characteristics in the light of PTPN11 mutations. The study revealed 80 patients who were referred with initial indication of NS or Noonan-like syndrome (NLS) and further assessed by a clinical geneticist; 60/80 index patients, mean age 5.9 ± 5.3 years, fulfilled the NS criteria. Molecular analysis of PTPN11 gene (exons and their flanking regions) of the total population revealed mutations in 17/80 patients, all belonging in the group of the patients screened with the scoring system. All mutations were heterozygous missense changes, mostly clustering in exon 3 (8/17), followed by exons 13 (3/17), 8 (2/17), 7 (2/17), 2 (1/17) and 4 (1/17). We conclude that (a) most of our clinically diagnosed NS cases were sporadic (b) PTPN11 analysis should be limited to those fulfilling the relevant NS criteria (c) Cardiovascular evaluation should comprise all NS patients, while pulmonary stenosis, short stature, and thorax deformities prevailed among those with PTPN11 mutations.

Characteristics of the short children referred to an academic paediatric endocrine clinic in Greece.

AIM: To describe the characteristics of short children in relation to gender and the various diagnoses. METHODS: All new patients of Greek origin that were referred to our institution in the years 2007 and 2008 for evaluation of short stature were included in the study. Children were categorized according to the severity of their short stature in those with height standard deviation score (HSDS) ≤ -3 and HSDS > -3. RESULTS: Two hundred ninety-five children (162 boys and 133 girls, ratio 1.2) were referred. HSDS of boys was -2.3 (0.6) and of girls -2.1 (0.5), P= 0.004. Girls had shorter parents, and the predicted adult HSDS was also shorter for girls -1.7 (0.8) than for boys -1.35 (0.76), P= 0.003. Seventy per cent of the children of both sexes had familial short stature (FSS), constitutional delay of growth or a combination of the two conditions. About 10% presented the auxological and biochemical criteria for growth hormone deficiency (GHD). In addition, 11.8% had a HSDS ≤ -3, the most common diagnosis being GHD (36.1%); the less severely short children most commonly presented FSS (41.2%). CONCLUSIONS: There is no gender bias in referrals for short stature in Greece. About 70% of children of both sexes presented FSS or constitutional delay of growth or a combination of the two conditions, whereas GHD was diagnosed in about 10% of the children. Normal variants of growth were present in about 80% of children with HSDS > -3, but in only 40% when HSDS was ≤ -3.

Pubertal maturation of contemporary Greek boys: no evidence of a secular trend.

PURPOSE: To examine pubertal status of contemporary Greek boys and compare the data with those of a previous study we performed in the year 1996. METHODS: We performed a cross-sectional study of 932 healthy boys, aged from 8.05 to 16.05 years. Development of the genitalia (G) and pubic hair was assessed by the method of Tanner and testicular volume (TV) was determined with a Prader orchidometer. Genitalia stage 2 (G2) was assessed by probit analysis. RESULTS: Median (95% confidence interval [CI]) age at G2, defined as TV 4 mL, was 11.3 (10.9-11.6) years, almost the same age as in our study performed in 1996, which was 11.4 (10.7-11.7) years (p = .21). When G2 was defined as change in scrotum texture and TV2 mL, median (95% CI) age at onset of puberty was 10.9 (10.5-11.3) years, again similar to the study performed in 1996 which was 11.0 (10.7-11.4) (p = .32). Median (95% CI) age of pubic hair development was 11.2 (10.8-11.6) years versus 11.5 (11.1-12.0) years in 1996, p = .015. CONCLUSIONS: Our data provide no evidence of a secular trend for gonadarche in Greek boys, although such a trend was evident for pubarche.

Constitutional advancement of growth is associated with early puberty in girls.

BACKGROUND: Constitutional advancement of growth (CAG) is the growth pattern of early growth acceleration that has been shown to be characteristic in girls with idiopathic precocious puberty (IPP). The aim of this study was to examine the growth pattern of girls with early puberty compared to girls with IPP. METHODS: We studied the growth pattern, from birth to presentation, of 61 girls with early puberty, of 40 girls with IPP and of 100 healthy girls with normal pubertal onset that served as controls. RESULTS: Height SDS (HSDS) at presentation was significantly different among the 3 groups (p < 0.001). Girls with early puberty were shorter than girls with IPP (HSDS 0.63 ± 1.09 vs. 0.98 ± 0.95, respectively, p < 0.001) and taller than control girls (HSDS 0.05 ± 0.94, p < 0.05). By comparing the linear growth pattern from birth to presentation, pairwise comparisons showed that it differed significantly between early puberty and control (p < 0.001) as well as between IPP and control girls (p < 0.001), whereas the difference between girls with IPP and early puberty was not significant (p = 0.09). CONCLUSION: Girls with early puberty present the pattern of CAG suggesting that IPP lies at the extreme of the distribution of the normal timing of puberty onset.

VPA-induced recurrent pancreatitis in a cystic fibrosis carrier.

A 4.5 years old male with myoclonic epilepsy on Valproic acid (VPA) monotherapy, developed an acute pancreatitis. The discontinuation of VPA and substitution with Levetiracetam was followed by clinical improvement but a relapse of the pancreatitis was noted one month later. The investigation excluded a structural abnormality but revealed a heterozygous CTFR mutation. The contribution of the CTFR mutation on this VPA-induced recurrent pancreatitis cannot be ignored.

Clinical review: Constitutional advancement of growth, a.k.a. early growth acceleration, predicts early puberty and childhood obesity.

CONTEXT: Constitutional advancement of growth (CAG), a.k.a. early growth acceleration, refers to a growth pattern that is characterized by growth acceleration soon after birth, reaching a zenith centile in the first 2 to 4 yr of life and followed by normalization of the growth rate until the onset of puberty, which is usually early. CAG is the mirror image of the growth pattern of constitutional delay of growth and puberty, which is characterized by growth deceleration in the first years of life that is followed by normalization of the growth rate and late onset of puberty. For a child to be considered as presenting CAG, other conditions that lead to early growth acceleration, like genetic tall stature, infant overfeeding, and intrauterine growth restraint, have to be excluded. EVIDENCE ACQUISITION: This review was based on our own data supplemented by relevant articles identified by a PubMed search. EVIDENCE SYNTHESIS: Girls with idiopathic precocious puberty almost invariably present the growth pattern of CAG. Moreover, the growth pattern of growth acceleration in the first years of life, i.e. CAG, is also present in children that become obese later in childhood; thus, it may be considered a risk factor for childhood obesity. CONCLUSIONS: Given the strong association between childhood obesity and early puberty, especially in girls, infants that present the pattern of CAG have to be monitored for the development of early puberty or/and obesity.

Coinheritance of Noonan syndrome and Becker muscular dystrophy.

We describe for the first time a case of a 9-year old boy with co-existence of dystrophinopathy and Noonan syndrome (NS). Although the patient has a severe muscular clinical phenotype, consistent with Duchenne muscular dystrophy (DMD), the diagnosis of Becker muscular dystrophy (BMD) was proposed based on family history (brother with BMD) and confirmed by muscle immunohistochemistry, and molecular study shown an in-frame DMD gene mutation. The patient also fulfilled the clinical criteria of NS and he harbors a hotspot mutation on PTPN11 gene. This genetic combination may be an explanation for the variability of clinical expression in the family.

Congenital bilateral amazia associated with bilateral choanal atresia.

Congenital absence of breast development is a very rare abnormality. It may present as an isolated finding or it may be accompanied by other congenital anomalies. Here we report on a 13.5-year-old girl presented to our pediatric endocrinology clinic because of lack of breast development. She had pubarche since the age of 10 years and was regularly menstruating since the age of 12 years. The patient's medical history was positive for bilateral complete choanal atresia that was diagnosed and corrected soon after birth. Physical examination was unremarkable except for bilateral amazia, that is, absence of palpable breast tissue and hypoplastic areolae, whereas both nipples were formed. Renal ultrasonography and chest radiography were normal. The coexistence of congenital bilateral amazia and bilateral complete choanal atresia suggests that these rare disorders may be related etiologically. The patient is scheduled for breast augmentation.

Evaluation of a rapid antigen detection test in the diagnosis of streptococcal pharyngitis in children and its impact on antibiotic prescription.

OBJECTIVES: To study the performance of the Becton-Dickinson Link 2 Strep A Rapid Test, a rapid antigen detection test (RADT) for diagnosing streptococcal pharyngitis in children presenting to private offices and to the Pediatric Outpatient Clinic of a university hospital, in relation to clinical criteria (fever, tender anterior cervical lymph nodes, tonsillar exudate and absence of cough), and its impact on antibiotic prescription. METHODS: Children were enrolled in Group A (enrolment by private-practice paediatricians; diagnosis by clinical picture only), Group B (enrolment by private-practice paediatricians; diagnosis by RADT and culture) or Group C (enrolment by hospital-affiliated paediatricians in the Pediatric Outpatient Clinic; diagnosis by RADT and culture). RESULTS: During a 2 year period, 820 children were enrolled [369 (45%) in Group A, 270 (33%) in Group B and 181 (22%) in Group C]. Streptococcal pharyngitis was diagnosed by RADT and culture in 146 (32.4%) of the 451 tested children. The sensitivity, specificity and positive and negative predictive values of the RADT were 83.1%, 93.3%, 82.4% and 93.6%, respectively. A stepwise increase in the sensitivity of the RADT was noted among children with one, two, three or four clinical criteria (60.9% to 95.8%). Paediatricians without access to laboratory tests were more likely to prescribe antibiotics compared with paediatricians with access to tests (72.2% versus 28.2%, P < 0.001). Private-practice paediatricians prescribed antibiotics more frequently compared with hospital-affiliated paediatricians (55.7% versus 19.9%, P < 0.001). CONCLUSIONS: Our findings support screening of all children with pharyngitis for Centor criteria and subsequently performing an RADT to guide decision for antibiotic administration. Such a strategy has an important impact on limiting throat culture testing and is associated with reduced antibiotic prescription.

Timing of pubertal onset in girls: evidence for non-Gaussian distribution.

CONTEXT: The timing of the onset of puberty is considered to approximate a normal distribution. However, because many more girls present with early than late puberty, we hypothesized that the distribution of the timing of the onset of puberty in girls might have changed. OBJECTIVE/SUBJECTS: The objective of the study was to examine the distribution of the timing of the onset of puberty in normal Greek girls. DESIGN: Onset of puberty, i.e. breast development (B2), was studied longitudinally in 311 prepubertal schoolgirls aged 6.4-8.2 yr until the onset of puberty. We also studied cross-sectionally 126 girls, 6-14 yr old. SETTING: Clinical examinations took place in the school setting. RESULTS: In the longitudinal study, median of the distribution of age at B2 was 10.0 yr (with the 25th and 75th centiles being 9.2 and 10.6 yr, respectively). Skewness was -0.45 (P=0.001), suggesting a negatively skewed distribution. In the cross-sectional study, 126 subjects were found at B2. The median of the age distribution at B2 was 10.1 yr (with the 25th and 75th centiles being 9.7 and 11.2 years, respectively). Skewness was -0.44 (P=0.03), suggesting a negatively skewed distribution. CONCLUSIONS: A non-Gaussian distribution of the age at the onset of puberty in girls was documented. The currently used cutoff ages for precocious and delayed puberty may not be applicable to modern children; therefore, up-to-date studies on pubertal maturation are much needed.

High incidence and allelic homogeneity of Wilson disease in 2 isolated populations: a prerequisite for efficient disease prevention programs.

OBJECTIVES: Herein we report the results of mutation-based screening for Wilson disease (WD) in 2 isolated populations of Sardinia and the Greek island of Kalymnos. PATIENTS AND METHODS: Mutation analysis was performed in 110 and 9 WD families originating respectively from Sardinia and Kalymons using single-strand conformation polymorphism and sequencing methods. In Sardinia, a limited screening was performed for -441/-427del in 5290 newborns, whereas in Kalymnos 397 newborns underwent mutation screening for H1069Q and R969Q using appropriate methods. RESULTS: In Sardinia, mutation analysis showed the presence of 6 mutations accounting for 85% of chromosomes, 1 of which (-441/-427del) is present in 61.7% of alleles. The screening for -441/-427del in 5290 newborns revealed the presence of 122 heterozygotes, which is equal to an allelic frequency of 1.15%. Assuming the same distribution of WD mutations in the general Sardinian population, we also inferred an allelic frequency of 0.77% for mutations other than -441/-427del, which accounts for an overall frequency of any WD mutation of 1.92%. Assuming Hardy-Weinberg equilibrium, these data could be translated into a WD incidence of 1 in 2707 live births. In Kalymnos, mutation analysis in 9 WD families revealed the presence of only 2 mutations. The screening of 397 newborns revealed the presence of 18 heterozygotes for H1069Q, 9 for R969Q, and 1 compound heterozygote for these mutations, which is equal to an allele frequency of 3.7%. Assuming Hardy-Weinberg equilibrium, the expected carrier rate is 7%. CONCLUSIONS: These data indicate the need for health education for WD prevention in these isolated populations.

Greek young men grow taller.

AIM: To examine whether a secular trend for greater height is still observed in young Greek men. METHOD: Height and weight of 3982 Greek conscripts, aged 18-26 years, were measured and correlated with the level of education and place of residence. Our data were collected from May 2006 to May 2007 from pre-selected army camps all over Greece. The data were compared with those of a similar study performed in 1990. RESULTS: Mean height (+/-SD) of the conscripts was 178.06 (+/-7.05) cm. From 1990 until 2006, mean height increased from 175.7 cm to 178.06 cm (p < 0.001), corresponding to 1.47 cm/decade. Height was positively correlated with the place of residence (p = 0.007) and the level of education (p < 0.001) of the conscripts. CONCLUSIONS: Our data show a further increase in the stature of young Greek men in the last 16 years. It appears that the male Greek population has still not exhausted its growth potential.

Age at menarche in contemporary Greek girls: evidence for levelling-off of the secular trend.

AIM: To examine the secular trend of menarcheal age in Greek girls during the last decade. METHODS: Seven hundred and fifty senior high schoolgirls were asked through a questionnaire to report their date of menarche, participation in physical activities and their weight status at menarche. The data were compared with those of a study of 1996. RESULTS: Mean age at menarche (+/-SD) in 2006 was 12.29 (1.19) and in 1996 it was 12.27 (1.13) years, p = 0.73. Maternal menarcheal age was 13.02 (1.32). There was a significant correlation between age at menarche of the schoolgirls and their mothers, p < 0.0001. There was a significant difference in the age at menarche according to the schoolgirls' perceived weight status. Menarcheal age of obese girls (n = 56) was 11.73 (1.21) years, of normal weight girls (n = 474) was 12.29 (1.21) years and of lean girls (n = 220) was 12.42 (1.14) years, p < 0.001. There was no significant difference in the age at menarche between the girls that participated, 12.23 (1.19), and those that did not participate in sporting activities, 12.32 (1.19), p = 0.31. CONCLUSION: Levelling-off of the age at menarche over the last 10 years occurred in Greek girls living in Athens. Menarcheal age is influenced by the weight status and maternal menarcheal age.

A novel monocarboxylate transporter 8 gene mutation as a cause of severe neonatal hypotonia and developmental delay.

Monocarboxylate transporter 8 acts as a specific cell membrane transporter for thyroxine and especially triiodothyronine into target cells. It is expressed in brain neurons and in many other tissues. The monocarboxylate transporter 8 gene resides on chromosome Xq13.2. An 11-month-old male infant was referred because of severe hypotonia from early life and global developmental delay. Thyroid-function tests showed normal thyrotropin levels and the characteristic for the disorder, including high serum triiodothyronine and low thyroxine concentrations. Molecular analysis of the monocarboxylate transporter 8 gene showed that the patient was hemizygous for a novel missense mutation P537L. This case highlights the importance of determining thyroid hormone levels, especially triiodothyronine, in infants with severe neonatal hypotonia.

Low TSH levels are not associated with osteoporosis in childhood.

INTRODUCTION: A recent study on TSH receptor (TSHR) null mice suggested that skeletal loss occurring in hyperthyroidism is caused by the low TSH rather than high thyroid hormone levels. The aim of this study was to examine whether low TSH results in osteoporosis in the human. SUBJECTS AND METHODS: We determined bone mineral density (BMD) and markers of bone metabolism in two male siblings aged 9.8 and 6.8 years with isolated TSH deficiency, due to a mutation of the TSH beta-subunit gene. BMD was measured in the lumbar spine (L1-L4) by dual-energy X-ray absorptiometry. Laboratory investigation included the determination of serum calcium, phosphate, 25-hydroxy-vitamin D, parathyroid hormone concentrations, and urine calcium (Ca)/creatinine (Cr) ratio. Osteoblast activity was measured by serum bone alkaline phosphatase and osteocalcin levels, and osteoclast activity by urine cross-linked amino-terminal, carboxy-terminal telopeptides of type I collagen and deoxypyridinoline concentrations. RESULTS: BMD of both patients was within the normal range for age and sex; z-scores were -0.55 and -0.23 for patients 1 and 2 respectively. Serum calcium, phosphate, urine Ca/Cr ratio, and specific markers of bone metabolism were also within normal range. CONCLUSION: In childhood, chronic extremely low TSH levels, in the face of normal thyroid hormone levels, are not related to bone loss.

Does exclusive breastfeeding increase after hospital discharge? A Greek study.

To monitor the rate of exclusive breastfeeding in Greek maternity wards and to investigate possible changes in infant-feeding practices during the first month after hospital discharge, the authors questioned 4310 Greek mothers from 7 hospitals on the fourth day postpartum. Odds ratios were calculated to estimate the effects of health system, demographic, psychosocial, and environmental factors. Any breastfeeding and full breastfeeding initiation rates were 85% and 23%, respectively. One month postpartum, the corresponding rates of any and exclusive breastfeeding were 79% and 61%, respectively. Mothers of infants who lacked continuous rooming-in while in the maternity ward (OR, 2.08; 95% CI, 1.27-3.40) and with previous experience of breastfeeding (OR, 1.46; 95% CI, 1.19-1.79) were more likely to reestablish exclusive breastfeeding at home despite the use of supplementation in the maternity ward. It seems women are capable of overcoming supplementation in hospital and can revert to exclusive breastfeeding at home.