Band 29, Heft 1 - HIGHLIGHT: INHERITED METABOLIC DISORDERS IN NEWBORNS

Background: Newborn screening comprises a paramount public health program seeking timely detection, diagnosis, and intervention for genetic disorders that may otherwise produce serious clinical consequences. Today newborn screening is part of the health care system of developed countries, whereas in India, newborn screening is still in the toddler stage. Method: We searched PubMed with the keywords newborn screening for metabolic disorders, newborn screening in India, and congenital disorder in neonates, and selected publications that seem appropriate. Results: In India, in spite of the high birth rate and high frequency of metabolic disorders, newborn screening programs are not part of the health care system. At Union Territory, Chandigarh in 2007, newborn screening was initiated and is currently ongoing for three disorders, that is, congenital hypothyroidism, congenital adrenal hyperplasia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Prevalence of these disorders is found to be 1:1400 for congenital hypothyroidism, 1:6334 for congenital adrenal hyperplasia, and 1:80 for G6PD deficiency. Conclusion: Mandatory newborn screening for congenital hypothyroidism should be implemented in India, and other disorders can be added in the screening panel on the basis of region-wise prevalence. The objective of this review is to provide insight toward present scenario of newborn screening in India along with recommendations to combat the hurdles in the pathway of mandatory newborn screening.

Background: Hawkinsinuria is a rare inborn error of tyrosine metabolism. Objectives: To study novel hawkinsinuria cases by monitoring their biochemical profile and conducting a mutation analysis. Subjects and methods: Among 92,519 newborns that underwent expanded newborn screening, two unrelated cases with high tyrosine blood levels were further investigated by chromatographic techniques and via genetic testing for 4-hydroxyphenylpyruvate dioxygenase (HPD) gene. Results: Elevated levels were monitored for blood/plasma tyrosine and for the specific diagnostic markers in urine. The two newborns were put on a special low tyrosine diet. Till completion of the 1st year of their life, liver function tests and brain MRI were normal. The mutation A33T was identified in both cases, while one neonate carried an additional novel mutation of HPD gene (V212M). Conclusions: Two mutations of HPD gene, A33T, which are associated with hawkinsinuria and a novel one (V212M) were detected for the 1st time in Greek newborns.

Aim: Several studies have investigated leptin and neuropeptide Y (NPY) levels in children, but the information for newborns in the literature is limited. The purpose of this study was to determine leptin and NPY levels in 14- to 28-day-old newborns. Materials and methods: This prospective study was performed in Atatürk University Medical Faculty Research Hospital Neonatal Clinic, Erzurum, Turkey between July and December, 2014. Sixty-two 14- to 28-day-old neonates, 26 female and 36 male, were included. Age, height, and body weight of the patients were recorded. Feeding status was also recorded. The newborns were divided into two groups – those receiving breastfeeding only and those receiving breastfeeding and formula. Plasma leptin levels were measured using enzyme amplified sensitivity immunoassay (EASIA). Results: The mean leptin level in 14- to 28-day-old female neonates was 4.25±3.08 ng/mL, and the mean NPY level was 24.79±9.87 ng/mL. The mean leptin level in 14- to 28-day male neonates was 3.49±2.52 ng/mL, and the mean NPY level was 25.80±9.58 ng/mL. No significant difference was determined between leptin (p=0.228) or NPY (p=0.144) in terms of feeding status. No significant difference was also observed between the sex in terms of leptin or NPY levels (leptin p=0.775 and NPY p=0.687). Conclusion: There were no differences in terms of feeding status and sex in leptin and NPY levels in the neonatal period.

The prospective study assessed the influence of serum leptin levels on markers of bone metabolism and bone mineral density in 2-year-old infants born preterm. A total of 57 randomized preterm Caucasian newborns (32nd–37th week of gestation) were included in the study. Bone metabolism markers were measured every 6 months. The infants were monitored prospectively up to the age of 2 years. When the infants turned 2 years of age, they were investigated by dual energy X-ray absorptiometry (lumbar spine). The median cord blood leptin levels was 3.07 μg/L. The median leptin level during check-ups before 2 years of age was 9.96 μg/L. The other laboratory markers were within the normal ranges for that age. The bone mineral density reached, on average, 0.410 g/cm 2 . Lower leptin levels in the cord blood and in the serum of preterm infants do not influence bone mineral density during the first 2 years of life.

Background: The etiology of childhood obesity and the associated morbidity is multifactorial. Recently, data suggesting a prenatal programming towards later childhood obesity and metabolic deregulation through the intrauterine environment has emerged. This study explored the concentrations of adipokines and their mutual relationship at birth in children born to non-diabetic mothers. Methods: Adiponectin, leptin and sOB-R were measured using ELISA-based commercial kits in umbilical cord blood from 60 neonates (30 born large for gestational age [LGA] and 30 born appropriate for gestational age [AGA]). Children exposed to maternal diabetes, chronic disease and preeclampsia were excluded. Results: The LGA group exhibited significantly elevated concentrations of leptin (p<0.001) and of free leptin index (p<0.001) and decreased sOB-R concentrations (p=0.005) when compared to the AGA group, which persisted in multiple regression analysis after taking the gestational age into account (p=0.048, p<0.001 and p<0.001, respectively). Only a trend towards a difference in adiponectin was demonstrated (p=0.057) regardless of adjustment (p=0.150). However, the leptin/adiponectin ratio was elevated in the LGA group (p=0.008), regardless of adjustment (p=0.039). Conclusion: The data indicate a disturbance of adipokines in macrosomic newborns and that the mutual ratios between adipokines may provide a more sensitive marker of metabolic disturbance than any isolated adipokine.

Diabetes insipidus (DI) is one of the common disorders affecting sodium and water homeostasis, and results when ADH is either inadequately produced, or unable to negotiate its actions on the renal collecting tubules through aquaporins. The diagnostic algorithm starts with exclusion of other causes of polyuria and establishing low urine osmolality in the presence of high serum osmolality. In this paper, we have reviewed the diagnosis, etiology and management of DI in children, with special emphasis on recent advances in the field.

Background: Essential oils were proven to possess analgesic activity in adults. Children with diabetes are exposed to highly painful interventions such as self-monitoring of blood glucose (SMBG). Objective: An evaluation of the analgesic properties of two essential oils during SMBG in diabetic children. Subjects: We included 73 hospitalized children (age<18 years) with well-controlled type 1 diabetes. Methods: The study extended over a period of 1 month (2 weeks for control group and 1 week for orange and lavender oil application). The measurements were performed four times per day in a shared room during SMBG. Pain intensity was evaluated by visual analog scale (VAS) and change of baseline heart rate (ΔHR%). An aromatherapy device was used to disperse essential oils in the testing room. Results: We performed 647 individual measurements of pain intensity and ΔHR%. Girls reported higher VAS scores [median, Me 0.5 (interquartile range, IQR 0–1) vs. 0 (IQR 0–0.5), p=0.0036]. Both age and duration of diabetes correlated with ΔHR% [ r =–0.14, p=0.0005; r =–0.12, p=0.0025]. Negative correlations were also noted for VAS/age [ r =–0.12, p=0.0030] and VAS/duration of diabetes [ r =–0.12, p=0.0034]. Aromatherapy did not alter the VAS score (p=0.40), while ΔHR% decreased with borderline significance (p=0.0639). After adjustment for patient’s age and sex lower ΔHR% was associated with essential oil application (p=0.0252). Aromatherapy did not have any influence on VAS scores in multivariate analysis (p=0.35). Conclusion: Aromatherapy decreased the autonomic response to a painful stimulus by lowering ΔHR%, but did not affect the perception of pain reported by VAS.

Melanocortin-4 receptor (MC4R) deficiency is the most frequent monogenic form of obesity. The contribution of MC4R mutations to the Slovak population has not been investigated as yet. We screened the coding sequence of the MC4R gene in a cohort of 210 Slovak obese children and adolescents. We identified four different mutations in four patients, giving a mutation detection rate of 0.95%. Of these, three were missense mutations previously identified and characterized by other research groups (p.R7C, p.S127L and p. R305W, respectively). One was a novel nonsense mutation p.W174* detected in a severely obese 7-year-old boy. This mutation was further analyzed in family segregation analysis and exhibited variable penetrance. Two known amino acid polymorphisms (p.V103I and p.I251L) were also identified in seven subjects of our cohort group. We also performed multifactorial statistical analysis to determine the influence of genotypes on standard biochemical blood markers. No significant influence was observed in carriers of DNA variants on tested parameters. We conclude that rare heterozygous MC4R mutations contribute to the onset of obesity only in a few cases in the Slovak population.

Objective : We examined the associations among daily cortisol, physical activity (MVPA) and continuous metabolic syndrome score (cMetS) in obese youth. Methods : Fifty adolescents (mean age 14.8±1.9 years) were recruited from medical clinics. Daily MVPA (min/day) was assessed by accelerometry. Saliva was sampled at prescribed times: immediately upon waking; 30 min after waking; and 3, 6 and 9 h after waking. Fasting lipids, glucose, waist circumference and blood pressure were used to calculate a continuous metabolic syndrome score (cMetS). Multiple linear regression analysis was used to examine associations among variables. Results : The mean cMetS score was 4.16±4.30 and did not differ by clinic or sex. No significant relationship was found between cortisol area under the curve (cAUC) and cMetS, nor did the interaction of MVPA with cAUC significantly predict cMetS. Conclusions : Physical activity, cortisol, and metabolic risk were not associated in this sample of obese adolescents. Future research should examine the role of insulin sensitivity in these relationships.

Primary congenital hypothyroidism (PCH) has an incidence of approximately 1 in each 3000–4000 live births. In the last two decades, nearly 50 types of the distinct inactivating mutations have already been described in the coding region of the tshr gene. The aim of present study was to investigate tshr gene mutations in patients with primary congenital hypothyroidism, analyzing a sample of 106 patients that were diagnosed with PCH. Genomic DNA was isolated from peripheral blood samples, and 10 exons from the TSH receptor were automatically sequenced. Five nucleotide alterations (P52T, N187N, A459A, L645L, and D727E. N187N and D727E polymorphisms) were associated with positive medical history. In view of the clinical, biochemical and molecular heterogeneity of the etiology of the PCH, the study of polymorphisms is critical for investigating the possible associations with prevailing symptoms of this disorder.

During puberty, estrogen has a biphasic effect on epiphyses; at low levels, it leads to an increase in height and bone mass, whereas at high levels, it leads to closure of the epiphysis. Tamoxifen is a selective estrogen receptor modulator that has been used in the treatment of pubertal gynecomastia. Although it has not been approved for this indication, studies have shown it to be both successful and safe. In males, the peak of pubertal bone development occurs during Tanner stage 3–4, which is also when pubertal gynecomastia reaches its highest prevalence. Thus tamoxifen treatment could potentially effect pubertal bone development. The aim of this study was to assess the effects of tamoxifen on bone mineral density (BMD) and skeletal maturation when used for pubertal gynecomastia. We evaluated 20 boys with pubertal gynecomastia receiving tamoxifen for at least 4 months. BMD was measured with dual-energy X-ray absorptiometry. Z-score and absolute BMD (g/cm 2 ) was determined at baseline and 2 months after completing tamoxifen treatment. Bone age and height was evaluated before treatment and again one year later. Using absolute BMD (g/cm 2 ), the mean difference from baseline was significant between the two groups both at spine (p=0.002) and femur (p=0.001), but not with the Z-score. This result was attributed to the expected increase during puberty according to sex and age. No significant effect on skeletal maturation was found (p=1.112). We conclude that when pubertal bone development is concerned, tamoxifen is safe for the treatment of pubertal gynecomastia as neither bone mineralization nor growth potential was affected.

The purpose of this study was to determine the levels of leptin, ghrelin, and nesfatin-1 to elucidate the causes of poor appetite and growth retardation in patients receiving methylphenidate therapy for attention deficit hyperactivity disorder. The study was performed on 89 male subjects; 48 patients and 41 healthy controls, aged 7–14 years. Following treatment, patients’ leptin levels increased and ghrelin levels decreased while no significant change was found in nesfatin-1 levels. Of the 48 patients, 34 developed lack of appetite. In patients who developed lack of appetite, body weight SDS, body mass index (BMI), and BMI SDS were statistically significantly reduced; moreover, height SDS was reduced, though not to a statistically significant extent. This study attempted to elucidate the mechanisms that mediate the association between methylphenidate and appetite and growth, for which no studies have yet to be published.

Hereditary nephrogenic diabetes iInsipidus (HNDI) is an uncommon disorder due to a resistance to anti-diuretic hormone leading to a reduced urinary concentrating ability. The X-linked form is fully expressed in hemizygous male patients, but diabetes insipidus may also present in heterozygous females where it must be distinguished from autosomal and other secondary causes. We report a mother and daughter in the same family with HNDI due to a heterozygous deletion in exon 1 of the AVPR2 gene, not previously described in the literature. A 5-year-old girl was referred for investigation of polyuria and polydipsia. The patient had a water deprivation test elsewhere at the age of 3 that was inconclusive. A degree of water restriction was imposed leading to headaches. The thyroid, cortisol, renal, and calcium profiles were normal. Her mother showed similar symptoms that had not been previously investigated. AQP2 (Aquaporin) and initial AVPR2 gene sequencing had not identified a mutation, but subsequent quantitative polymerase chain reaction analysis revealed a heterozygous large exon 1 deletion of the AVPR2 gene. The same deletion was also found in the child’s mother. The patient’s symptoms have significantly improved on appropriate treatment. Further analysis revealed skewed X inactivation in mother and daughter.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare and potentially lethal disorder. The etiology is unclear but paraneoplastic syndrome and autoimmunity secondary to neural crest tumors have been considered, even in patients without any detectable tumor due to their tendency for spontaneous remission. We are presenting a 13-year-old girl with ROHHAD syndrome and celiac disease, which may suggest further evidence for immune-mediated etiology in the pathogenesis of ROHHAD syndrome.

Introduction: Prepubertal gynecomastia is a rare condition characterized by the growth of breast tissue in males as a consequence of early exposure to sexual hormones. When this condition is present, pathological sources of testosterone/estrogen production, such as adrenal or gonadal tumors must be searched for. A few reports have described an association between gynecomastia and substances that produce stimulation of the estrogen receptor, such as lavender and tea tree oil. Methods: Here we describe the cases of three boys who presented with prepubertal gynecomastia and were chronically exposed to lavender. Two of these boys were exposed to a cologne, named agua de violetas , used by Hispanic communities in the US, and in their countries of origin. Results: We studied a sample of the cologne used by one of the patients. Analysis of the chemical composition of the agua de violetas cologne was performed using high-performance liquid chromatography as well as off-line mass spectrometric detection. All these, combined with the physical appearance and the smell, determined that the cologne had lavender as an ingredient. Conclusion: Exposure to estrogenic substances, such as lavender, should be explored in children presenting with prepubertal gynecomastia/thelarche.

Cushing syndrome and lipodystrophy syndromes share similar clinical features. This report describes an adolescent girl with newly diagnosed familial partial lipodystrophy type 2 (FPLD2) who was initially referred for Cushing syndrome. The type of abnormal fat deposition syndrome can be elucidated by careful clinical examination. FPLD2 can lead to type 2 diabetes mellitus and early cardiovascular events. Partial lipodystrophy presenting for the first time in adolescence can be mistaken for corticosteroid excess. Early diagnosis and preventative management of cardiovascular risk factors are crucial.