Iron Nutrition, Erythrocytes, and Erythropoietin in the NICU: Erythropoietic and Neuroprotective Effects.

Prematurity, maternal diabetes, maternal smoking, being medically underserved, and small size for gestational age are common characteristics of neonates in the NICU and can predispose them to develop congenital iron deficiency. Iron is critical for organ development. In the fetus and newborn, iron is prioritized for red blood cell production, sometimes at the expense of other tissues, including the brain. It is critical to optimize iron levels in newborns to support erythropoiesis, growth, and brain development. Available studies support improved neurodevelopmental outcomes with either iron supplementation or delayed umbilical cord clamping at birth. Erythropoietic doses of erythropoietin/erythrocyte-stimulating agents may also improve neurocognitive outcomes. However, the literature on the effect of liberal red blood cell transfusions on long-term neurodevelopment is mixed. Understanding age-specific normal values and monitoring of iron indices can help individualize and optimize the iron status of patients in the NICU.

Perinatal iron and copper deficiencies alter neonatal rat circulating and brain thyroid hormone concentrations.

Copper (Cu), iron (Fe), and iodine/thyroid hormone (TH) deficiencies lead to similar defects in late brain development, suggesting that these micronutrient deficiencies share a common mechanism contributing to the observed derangements. Previous studies in rodents (postweanling and adult) and humans (adolescent and adult) indicate that Cu and Fe deficiencies affect the hypothalamic-pituitary-thyroid axis, leading to altered TH status. Importantly, however, relationships between Fe and Cu deficiencies and thyroidal status have not been assessed in the most vulnerable population, the developing fetus/neonate. We hypothesized that Cu and Fe deficiencies reduce circulating and brain TH levels during development, contributing to the defects in brain development associated with these deficiencies. To test this hypothesis, pregnant rat dams were rendered Cu deficient (CuD), FeD, or TH deficient from early gestation through weaning. Serum thyroxine (T(4)) and triiodothyronine (T(3)), and brain T(3) levels, were subsequently measured in postnatal d 12 (P12) pups. Cu deficiency reduced serum total T(3) by 48%, serum total T(4) by 21%, and whole-brain T(3) by 10% at P12. Fe deficiency reduced serum total T(3) by 43%, serum total T(4) by 67%, and whole-brain T(3) by 25% at P12. Brain mRNA analysis revealed that expression of several TH-responsive genes were altered in CuD or FeD neonates, suggesting that reduced TH concentrations were sensed by the FeD and CuD neonatal brain. These results indicate that at least some of the brain defects associated with neonatal Fe and Cu deficiencies are mediated through reductions in circulating and brain TH levels.

Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus.

Iodine is essential for the synthesis of triiodothyronine (T(3)) and thyroxine (T(4)). Iodine deficiency leads to inadequate thyroid hormone. Thyroid hormones deficiency during brain development affects cognitive functions, such as attention, learning, and memory. However, the mechanism underlying these deficits is unclear. To investigate the role of iodine deficiency and hypothyroidism in synaptic plasticity, this study examined the induction of long-term synaptic plasticity (LTP) and expression of immediate early (IEA) gene proteins in rat hippocampus following congenital iodine deficiency or hypothyroidism. Through gestation and lactation, iodine-deficient or hypothyroid dam rats were administered with either iodine-deficient diet or methimazole-added drinking water. Exposure was terminated on postnatal day (PN) 30. In hippocampus of pup rats, the induction of LTP in area CA1 was determined on PN60 and the expression of c-fos and c-jun proteins was examined on PN20, PN30 and PN60. Compared to control pups, both treated groups have shown: (1) significantly lower concentrations of serum FT(3) and FT(4), (2) much smaller population spike (PS) amplitude (p<0.01) and field-excitatory postsynaptic potential (f-EPSP) slope induced by high-frequency stimulation (HFS) (P<0.01), and (3) significantly lower integrated optical density (IOD) total of c-fos and c-jun expression (P<0.05 or P<0.01). In summary, iodine deficiency and hypothyroidism during critical periods of brain development impair LTP induction and decrease the expression of c-fos and c-jun proteins in hippocampus.

Congenital deficiency of alpha feto-protein.

Alpha-fetoprotein (AFP) is the main fetus serum glycoprotein with a very low concentration in the adult. AFP deficiency is a rare phenomenon. We studied two families with congenital AFP deficiency and searched for mutations in the AFP gene. We identified one mutation of 2 base deletion in exon 8, in both families, that leads to the congenital deficiency of AFP. The mutation nt930-931delCT (T294fs25X) creates a frameshift after codon 294 that leads to a stop codon after 24 amino acids, thus truncating the normal length of AFP of 609 amino acids. All the affected children were found to be homozygous for the mutation as was one of the fathers. The affected individuals were asymptomatic and presented normal development. This first identification of a mutation in the AFP gene demonstrates for the first time that deficiency of AFP is compatible with human normal fetal development and further reproduction in males.

Surfactant protein B deficiency in infants with respiratory failure.

Surfactant Protein B (SP-B) deficiency has been recently identified as an uncommon, autosomal recessive lung disorder in term infants. This inability to produce SP-B leads to progressive, lethal, hypoxemic respiratory failure in the first year of life. A frameshift mutation (121 ins 2) is the predominant but not exclusive cause. The clue to diagnosis is to have a high suspicion of SP-B deficiency in any term infant with severe respiratory distress without any apparent cause. SP-B deficiency can be diagnosed prenatally or postnatally. The only current treatment options available include lung transplantation or compassionate care. Current developments in gene therapy offer hope for future treatment.

Very low alpha-fetoprotein in Down syndrome maternal serum screening.

OBJECTIVE: To establish the frequency of very low maternal serum AFP and to differentiate congenital AFP deficiency from those diseases known to be associated with low AFP. METHODS: AFP values below 2 microg/L and borderline values up to 3 microg/L were retrospectively analysed in 839 773 singleton pregnancies included in a programme for routine screening of trisomy 21 maternal serum markers. RESULTS: Serum AFP was undetectable (< or =2 microg/L) in 8 cases, giving a frequency of 1/105 000. The calculated risk of Down syndrome was > or =1/250 in 5 cases. Fetal karyotype was normal. Seven of these pregnancies went to term (39-41 weeks) uneventfully, and birth weight was normal (3050-4110 g). In the 8th case, fetal death occurred at 35 weeks due to severe maternal diabetes. AFP levels between 2.1 and 3.0 microg/L were noted in 7 other cases. The calculated risk of Down syndrome was > or =1/250 in 5 cases, and fetal karyotype was normal. Pregnancies went to term in 4 cases (33-41 weeks), and birth weight was normal (3000-3380 g). In 3 cases, low hCG (<0.6 MoM) was associated with low AFP, and fetal death occurred at 15 to 16 weeks. CONCLUSION: Once technical errors have been excluded (repeat assay in a second run, calcium assayed to exclude the interference of EDTA for fluorimetric methods, dilution to exclude interfering antibodies, running on an alternative analyser, checking a second sample), very low second-trimester maternal serum AFP should prompt ultrasound examination in order to check fetal viability. Congenital AFP deficiency, an extremely rare disorder (1/100 000), should be suspected. It has no consequences for fetal and infant development, and parents should be reassured.

A novel mutation in neonatal isolated sulphite oxidase deficiency.

Isolated sulphite oxidase deficiency (ISOD) is a very rare hereditary metabolic disorder. Imaging findings of the neonatal form of ISOD, including multicystic leukoencephalopathy with brain atrophy, resemble those of severe ischemic changes of the brain. We report the case of a ten-month-old boy who exhibited neonatal seizures on the 24th day after birth. Excessive quantities of sulphite and S-sulphocysteine in the urine and normal blood uric acid were noted. These findings were consistent with those of ISOD. Point mutations were found in two alleles of the sulphite oxidase (SUOX) gene. One of the mutations was a 1029 C > G mutation, which resulted in an amino acid substitution of tyrosine to a stop code (Y343 X); and the other was a 479 G > A mutation, which resulted in an amino acid substitution of arginine to glutamine (R160 Q). Y343 X is a novel SUOX gene mutation. A review of the literature, including data from this report, showed that 3 of 6 cases had typical imaging findings characterized by initial cerebral edema followed by dramatic multicystic leukoencephalopathy. We emphasize that neonatal ISOD should be included in the differential diagnosis of neonates with unexplained hypoxic-ischemic changes on neuroimaging studies.

Transtibial amputation with plantar flap for congenital deficiency of the tibia.

Disarticulation of the knee has been the preferred treatment for the severe type (Type Ia and Type Ib classification of Jones et al) of congenital deficiency of the tibia because of marked flexion contracture of the knee and loss of quadriceps function. In such cases, the disarticulated stump is often small and poorly covered by soft tissues because of dysplastic femoral condyles and calf muscles. Therefore, stump complications after disarticulation may prevent early aggressive walking exercises and delay independent ambulation. To overcome this problem, a greater weightbearing surface was created by a transtibial amputation with a short stump of the fibula using the flexed knee. By this method, the distal femoral condyle and the anterior surface of the fibula were used for weightbearing. In addition, coverage of the new weightbearing area by a neurovascular pedicled sensate plantar flap provided a more tolerable weightbearing site. The purpose of the current study was to report a 5-year-old boy with bilateral congenital total deficiency of both tibias, who was treated using this technique. The patient was ambulating independently 15 weeks after surgery. A transtibial amputation with a plantar flap is an alternative procedure to knee disarticulation for the severe type of congenital deficiency of the tibia.

Long-term follow up of carbonic anhydrase II deficiency syndrome.

OBJECTIVE: To describe the long term clinical, biochemical and radiological features of 35 Saudi Arabian children with carbonic anhydrase II deficiency syndrome who have been followed at King Faisal Specialist Hospital and Research Center, Riyadh since 1979. METHODS: The records of these patients were retrospectively evaluated. The diagnosis was based on the clinical and the radiological evidence of the disease. Carbonic anhydrase II level was measured in 9 patients. RESULTS: Clinically, these patients had typical facial features, growth failure and varying degrees of psychomotor retardation. Biochemically, all children had renal tubular acidosis that was of distal type in the majority of them. Radiologically, this syndrome was characterized by metyphyseal osteopetrosis and intracranial calcification that was progressive in 2 patients. Five patients were blind secondary to optic nerve entrapment and 2 patients developed anemia and secondary erythropoesis due to bone marrow involvement. Nineteen patients had attained the final adult height; the mean adult height was 146 cm (-3 standard deviation) in 11 females and 152 cm (-4 standard deviation) in 8 males. Two patients were married and had clinically and radiologically normal children. CONCLUSION: The syndrome of carbonic anhydrase II deficiency is usually benign in nature and compatible with long term survival, however it can progress and involve the cranial nerves. Close clinical and neurological assessment of these patients is mandatory to early detect and manage potential serious complications.

High-frequency oscillation and paralysis stabilize surfactant protein-B--deficient infants.

OBJECTIVE: To determine if high-frequency oscillatory ventilation and neuromuscular blockade improve oxygenation and chest radiographic appearance more effectively than high-frequency oscillation alone for surfactant protein-B (SP-B)--deficient infants. STUDY DESIGN: We reviewed medical records and chest radiographs of five SP-B--deficient infants awaiting lung transplantation. Changes in FiO2 and radiographic scores were analyzed with respect to neuromuscular blockade status. RESULTS: FiO2 consistently increased 0.20 (SD 0.11) during high-frequency ventilation without neuromuscular blockade (p = 0.02) and decreased 0.14 (SD 0.11) during high-frequency ventilation with neuromuscular blockade (p = 0.05). Chest radiographic appearance, quantified by an expansion/aeration index, consistently deteriorated without neuromuscular blockade (p = 0.01) and consistently improved with neuromuscular blockade (p = 0.03). Changes in FiO2 correlated with changes in radiograph scores (r = 0.7, p < 0.001). CONCLUSIONS: High-frequency ventilation with neuromuscular blockade optimizes oxygenation for SP-B--deficient infants. This ventilatory strategy should be considered while awaiting the diagnosis of SP-B deficiency or lung transplantation.

[The physician faced with an iodine deficiency: individual management of a public health problem]. / Le praticien face à la carence iodée: prise en charge individuelle d'un problème de santé publique.

Urinary iodine was measured in samples collected during the first week of life in newborns from the areas of Liège in Belgium and Cluj in Romania. In Liège, severe iodine deficiency was seen in 1 out of 8 newborns and mild iodine deficiency in 1 out of 3. A greater proportion of newborns showed iodine deficiency in Cluj. Since public health measures to prevent iodine deficiency have not been set up yet by belgian authorities, the practitioner has to ensure individually optimal iodine intake, particularly in pregnant women, in newborns and during infancy.

Neonatal thyroid screening as a monitoring tool for the control of iodine deficiency.

In conditions of iodine deficiency, the frequency distribution of neonatal thyroid-stimulating hormone (TSH) is shifted towards elevated values. Elevated serum TSH in the neonate indicates insufficient supply of thyroid hormones to the developing brain, and therefore constitutes the only indicator that allows prediction of brain damage, which is the main complication of iodine deficiency. This paper reviews studies on neonatal thyroid function in iodine deficiency and confirms the former statement by WHO/UNICEF/ICCIDD that the frequency of neonatal TSH above 5 mU/L blood is below 3% in conditions of normal iodine supply, that a frequency of 3-19.9% indicates mild iodine deficiency and that frequencies of 20-39.9% and above 40% indicate moderate to severe iodine deficiency, respectively. Neonatal thyroid screening appears as a particularly sensitive index in the monitoring of iodine supply at a population level.

Prevalence of congenital deficiency in serum cholinesterase.

The most economical blood test for the monitoring of workers who are exposed to organophosphate pesticides is serum cholinesterase; however, serum cholinesterase can be affected by conditions other than pesticide exposure. The results of studies in Europe indicate a 4% prevalence of congenital serum cholinesterase deficiency. Prevalence rates in the United States have not been reported. In this study, 127 workers who were part of an employee health program were evaluated. Workers who had decreased serum cholinesterase levels on baseline testing before pesticide exposure were evaluated for a congenital deficit in serum cholinesterase. Five (3.9%) individuals had baseline measurements below the laboratory normal reference value: 4 (3.1 %) were heterozygote for the deficiency, and the remaining individual did not return to test for the genetic deficiency. No one was found to have the homozygote deficiency. The prevalence of congenital deficiency in serum cholinesterase in a midwestern population was 3.1-3.9%. We found it useful to incorporate the knowledge of who has a congenital deficiency into our employee health program, the purpose of which is to monitor workers who spray organophosphates.

[Mesenteric vein infarction associated with congenital antithrombin III (ATIII) deficiency]. / Infarctus veineux mésentérique associé à un déficit congénital en antithrombine III (ATIII).

A venous mesenteric infarction in a 27-year-old patient is reported. This patient presented a genetic quantitative AT-III deficiency without anticoagulation therapy. Ultrasonography revealed portal vein thrombosis and laparoscopy showed mesenteric vein infarction. Laparotomy was performed mmediately and revealed segmental infarction of 60 cm of the jejunum which was resected; the portal vein was considered to be partially occluded on palpation. No strangulation or mechanical factors were identified. Immediately postoperatively the patient received therapeutic doses of heparin with AT-III concentrates to increase AT-III levels; no recurrent thrombotic episode was observed. A systematic second-look operation 24 hours postoperatively showed good bowel viability. Five days later, long-term anticoagulation with acenocoumarol was decided. Twelve days later, ultrasonography showed complete portal revascularization which was confirmed by a third surgical operation on D60.

Congenital angiotensin-converting enzyme deficiency presenting as recurrent angioedema of upper airway in adult life.

In summary, a rare case of congenital ACE deficiency is presented. This disorder is of concern to the otolaryngologist because the patient in question had episodes of recurrent upper airway angioedema. Management of angioedema generally consists of self-administered epinephrine because these patients respond poorly to steroids.

[Prolonged neuromuscular block after administration of mivacurium caused by plasma psueudocholinesterase deficiency]. / Curarisation prolongée après mivacurium par déficit en pseudocholinestérases plasmatiques.

Mivacurium is a new neuromuscular blocking agent with a short acting time of about 30 min, due to a fast hydrolysis by pseudocholinesterases. This metabolism carries a risk for prolonged neuromuscular block in case of an acquired or congenital pseudocholinesterase deficiency. We report the case of a 75-year-old woman who experienced a neuromuscular block prolonged for 10 h after a single dose of 0.35 mg.kg-1 of mivacurium, because of a major pseudocholinesterase (1800 UI.L-1, normal value: 5400-13200 UI.L-1). The likely cause was a congenital deficiency by a homozygote genetic mutation, as usual causes of an acquired deficiency had been eliminated.