Fryns syndrome: another example of non-lethal outcome with severe mental handicap.

In this report we present clinical data of a patient with Fryns syndrome who survived the neonatal period. Two sibs died intra-uterine. The syndrome is characterized by craniofacial dysmorphism, diaphragmatic hernia and distal limb hypoplasia. Lethality in most cases is caused by the diaphragmatic hernia with concomitant lung hypoplasia. In patients with Fryns syndrome presenting without the diaphragmatic defect and lung-hypoplasia, survival beyond the neonatal period is possible; mental retardation is present in all four patients described so far. This report illustrates, once more, the great intrafamilial variation of the syndrome and emphasises its important consequences for genetic counseling and prenatal diagnosis.     

Granulomatous skin lesions complicating Varicella infection in a patient with Rothmund-Thomson syndrome and immune deficiency: case report

Acro-cardio-facial syndrome (ACFS) is a rare genetic disorder characterized by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and mental retardation. Up to now, 9 patients have been described, and most of the reported cases were not surviving the first days or months of age. The spectrum of defects occurring in ACFS is wide, and both interindividual variability and clinical differences among sibs have been reported. The diagnosis is based on clinical criteria, since the genetic mechanism underlying ACFS is still unknown. The differential diagnosis includes other disorders with ectrodactyly, and clefting conditions associated with genital anomalies and heart defects. An autosomal recessive pattern of inheritance has been suggested, based on parental consanguinity and disease's recurrence in sibs in some families. The more appropriate recurrence risk of transmitting the disease for the parents of an affected child seems to be up to one in four. Management of affected patients includes treatment of cardiac, respiratory, and feeding problems by neonatal pediatricians and other specialists. Prognosis of ACFS is poor.     

Joubert syndrome. Review of the fifty-three cases so far published

Joubert's syndrome (JS) is an autosomal recessive disorder, which is characterised by a variable combination of central nervous, respiratory and eye anomalies. We review the clinical characteristics of the 53 so far reported children with Joubert's syndrome, stressing the importance of recognising the syndrome in the neonatal period, in order that specific and effective therapeutic measures be started as soon as possible.     

Postnatal development of some membrane-bound enzymes of rat liver and kidney

1. The development of rat liver acyl-CoA:sn-glycerol-3-phosphate-O-acyl-transferase (EC 2.3.1.15) is characterized by an increase and decrease in activity during the neonatal period, followed by a second increase and decrease during the late weaning period. Kidney acyltransferase exhibits a similar peak in activity during the neonatal period before increasing to adult levels of activity during the late weaning period. 2. Nucleosidediphosphatase activity increases rapidly during the neonatal period and thereafter gradually rises to adult levels in both liver and kidney. The latency of the enzyme increases rapidly after birth and thereafter shows little change with age. The enzyme appears to be more latent in the liver than in the kidney at all ages studied. 3. NADPH-cytochrome c reductase of liver has a single steep maximum and minimum in activity during the neonatal period, before increasing again to adult levels during the late weaning period. The enzyme in kidney shows a similar developmental pattern but at much lower levels of specific activity. 4. sn-Glycerol-3-phosphate acyltransferase activity was significantly higher in rough than in smooth membranes throughout the neonatal period of rapid smooth membrane proliferation. This distribution of enzyme activity is unlike that reported by others in phenobarbital-induced smooth membrane proliferation and suggests a major role for rough membranes in phospholipid synthesis during the neonatal period. 5. The qualitative similarity in development in rough and smooth microsomal subfractions for each of these enzymes is in distinct contrast with results previously reported for glucose-6-phosphatase.     

Congenital pulmonary lymphangiectasia

Congenital pulmonary lymphangiectasia (PL) is a rare developmental disorder involving the lung, and characterized by pulmonary subpleural, interlobar, perivascular and peribronchial lymphatic dilatation. The prevalence is unknown. PL presents at birth with severe respiratory distress, tachypnea and cyanosis, with a very high mortality rate at or within a few hours of birth. Most reported cases are sporadic and the etiology is not completely understood. It has been suggested that PL lymphatic channels of the fetal lung do not undergo the normal regression process at 20 weeks of gestation. Secondary PL may be caused by a cardiac lesion. The diagnostic approach includes complete family and obstetric history, conventional radiologic studies, ultrasound and magnetic resonance studies, lymphoscintigraphy, lung functionality tests, lung biopsy, bronchoscopy, and pleural effusion examination. During the prenatal period, all causes leading to hydrops fetalis should be considered in the diagnosis of PL. Fetal ultrasound evaluation plays a key role in the antenatal diagnosis of PL. At birth, mechanical ventilation and pleural drainage are nearly always necessary to obtain a favorable outcome of respiratory distress. Home supplemental oxygen therapy and symptomatic treatment of recurrent cough and wheeze are often necessary during childhood, sometimes associated with prolonged pleural drainage. Recent advances in intensive neonatal care have changed the previously nearly fatal outcome of PL at birth. Patients affected by PL who survive infancy, present medical problems which are characteristic of chronic lung disease.     

A progeroid syndrome with neonatal presentation and long survival maps to 19p13.3p13.2

We report on a Palestinian family with three affected individuals exhibiting progeroid syndrome characterized by intrauterine growth retardation, a progeroid appearance, failure to thrive, short stature, and hypotonia. The progeroid features were evident at birth. All the affected members of this family have survived beyond the neonatal period and one of them is currently a 27‐year‐old adult. As parental consanguinity suggested an autosomal recessive mode of inheritance, we employed homozygosity mapping using single nucleotide polymorphism arrays followed by next generation whole exome sequencing to identify the disease‐causing gene. We were able to identify a single block of homozygosity shared between all the affected members of the studied family spanning 2.3 Mb on chromosome 19p13.3p13.2. However, Sanger sequencing of known genes and whole exome sequencing of the three affected sibs did not reveal a convincing causal mutation. These findings are anticipated to open the way for the identification of the molecular causes underlying this syndrome. Birth Defects Research (Part A) 97:456–462, 2013. © 2013 Wiley Periodicals, Inc.     

Identification and distribution of Flavobacterium meningosepticum in clinical material

During the 19 year period ending December 1984, 82 (1.7%) of 4840 strains of Gram-negative non-fermentative bacteria submitted to the National Collection of Type Cultures (NCTC) for computer-assisted identification were Flavobacterium meningosepticum. These figures suggest either that F. meningosepticum occurs only rarely in clinical material in the UK, or that when it does occur it is not always recognized. The sources from which the NCTC strains were isolated are reported and also the characteristics by which the species may be identified. The clinical significance of F. meningosepticum is reviewed, particularly its role in neonatal meningitis, of which there have been but two reported cases in the UK, both imported. The susceptibility of the species to antimicrobial agents is discussed and also antimicrobial therapy of neonatal meningitis due to this species.     

Identification and distribution of Flavobacterium meningosepticum in clinical material

During the 19 year period ending December 1984, 82 (1.7%) of 4840 strains of Gram-negative non-fermentative bacteria submitted to the National Collection of Type Cultures (NCTC) for computer-assisted identification were Flavobacterium meningosepticum. These figures suggest either that F. meningosepticum occurs only rarely in clinical material in the UK, or that when it does occur it is not always recognized. The sources from which the NCTC strains were isolated are reported and also the characteristics by which the species may be identified. The clinical significance of F. meningosepticum is reviewed, particularly its role in neonatal meningitis, of which there have been but two reported cases in the UK, both imported. The susceptibility of the species to antimicrobial agents is discussed and also antimicrobial therapy of neonatal meningitis due to this species.     

Hyperparathyroidism in pregnancy: case report and review of the literature.

The apparent incidence of hyperparathyroidism (HPT) is low in pregnancy but will likely increase now that more asymptomatic HPT is being diagnosed. However, since the serum calcium levels are decreased in pregnant women, mild primary HPT may go unrecognized. In untreated cases of HPT, complications during pregnancy or during the neonatal period have included spontaneous abortion, stillbirth, neonatal death, neonatal tetany and hypercalcemia. A review of the literature indicates a substantial improvement in fetal outcome when parathyroidectomy is done during pregnancy, as in the case reported here. Therefore, parathyroidectomy is the treatment of choice when the diagnosis is made during pregnancy, although oral phosphate therapy may be an alternative if surgery is contraindicated.     

A FIVE-YEAR STUDY OF PREMATURITY

To get a comprehensive picture of prematurity and neonatal death or survival, all factors on the maternal and fetal records that might be pertinent were recorded. This information, having to do with factors such as age, gravida of the mother, blood group incompatibility, period of gestation, weight at birth, type of delivery, medication and anesthesia administered to the mother, is presented in tabular form.In the study of perinatal mortality it was noted that failure to establish normal pulmonary ventilation is the most common cause of death in the neonatal period. Maternal history of relative infertility, that is, previous abortions, stillbirths and premature deliveries, was the most impressive finding in the stillborn series.In the follow-up study of premature infants who survived the neonatal period, 8.5 per cent were found to be severely handicapped. In four cases the handicap was due to congenital anomalies, in two others probably to infection, leaving 12 with complications possibly ascribable to prematurity. Six of these had retrolental fibroplasia as a major handicap. In seven, mental retardation was the presenting problem. Most of the handicapped children had multiple handicaps, which included spasticity, delayed motor development, strabismus, etc. The incidence of the necessity for corrective measures for feet and legs appeared relatively high.In general, survivors compared favorably with the rest of the childhood population. Complications and twinning were associated inordinately often.     

A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males

Heterozygous mutations in the X-linked MECP2 gene cause Rett syndrome, a severe neurodevelopmental disorder of young females. Only one male presenting an MECP2 mutation has been reported; he survived only to age 1 year, suggesting that mutations in MECP2 are male lethal. Here we report a three-generation family in which two affected males showed severe mental retardation and progressive spasticity, previously mapped in Xq27.2-qter. Two obligate carrier females showed either normal or borderline intelligence, simulating an X-linked recessive trait. The two males and the two obligate carrier females presented a mutation in the MECP2 gene, demonstrating that, in males, MECP2 can be responsible for severe mental retardation associated with neurological disorders.     

Neonatal glutaric aciduria type II: An X-linked recessive inherited disorder

Summary A new case of neonatal glutaric aciduria type II is reported. Neonatal acidosis, hypoglycemia, and hyperammonemia were characteristic. The baby died at four days of age. Organic acid analysis revealed massive glutaric aciduria with elevated concentrations of butyric, isobutyric, n-butyric, and isovaleric acid in his urine. The baby's pedigree suggested strongly an X-linked recessive mode of inheritance. Clinically, biochemically, and genetically glutaric aciduria type II is an heterogeneous disorder. The neonatal form is an X-linked inherited disorder which presents early in life, and is associated with metabolic acidosis, hypoglycemia, and hyperammonemia, and leads to death in the neonatal period. The mild form is an autosomal recessive inherited disease which may present even in adults, and is associated with recurrent hypoglycemia without ketosis and usually improves. Nevertheless the same unusual organic acid pattern is observed in both forms. The basic biochemical defect must be distinct and has not been elucidated.     

The effect of neonatal starvation on the growth,development and survival of larvae of the pine beauty moth,Panolis flammea (D & S)

Summary Mortality of neonatal pine beauty moth larvae varied from 0% to 100% depending on the duration of food deprivation and temperature. At 20°C and 100% RH all larvae had died by the fourth day of food deprivation, whereas at 10°C and 100% RH larvae survived for twelve days without food. Although larvae were able to survive at 15°C for up to seven days without food, establishment on thier host at this temperature was seriously affected by three days of starvation. No establishment took place after four days of starvation at 15°C. At 10°C establishment was significantly affected by starvation but not to such a marked degree. Establishment at both 15°C and 10°C was enhanced if the larvae were presented with a highly suitable host. The mean relative growth rate of those larvae reaching fifth instar was unaffected by the duration of their prefeeding starvation period. However, overall mean relative growth rates of the larvae were significantly affected by the duration of the starvation period. The implications of these results are discussed in relation to the population dynamics of this insect.     

Clinical and molecular findings in children with complex I deficiency

Isolated complex I deficiency, the most frequent OXPHOS disorder in infants and children, is genetically heterogeneous. Mutations have been found in seven mitochondrial DNA (mtDNA) and eight nuclear DNA encoded subunits, respectively, but in most of the cases the genetic basis of the biochemical defect is unknown. We analyzed the entire mtDNA and 11 nuclear encoded complex I subunits in 23 isolated complex I-deficient children, classified into five clinical groups: Leigh syndrome, progressive leukoencephalopathy, neonatal cardiomyopathy, severe infantile lactic acidosis, and a miscellaneous group of unspecified encephalomyopathies. A genetic definition was reached in eight patients (35%). Mutations in mtDNA were found in six out of eight children with Leigh syndrome, indicating a prevalent association between this phenotype and abnormalities in ND genes. In two patients with leukoencephalopathy, homozygous mutations were detected in two different nuclear-encoded complex I genes, including a novel transition in NDUFS1 subunit. In addition to these, a child affected by mitochondrial encephalomyopathy had heterozygous mutations in NDUFA8 and NDUFS2 genes, while another child with neonatal cardiomyopathy had a complex rearrangement in a single NDUFS7 allele. The latter cases suggest the possibility of unconventional patterns of inheritance in complex I defects.     

Metacarpal morphometry in adults with osteogenesis imperfecta.

Osteogenesis imperfecta is often regarded as a form of osteoporosis. In many cases, particularly those in whom the first fracture occurs outside the neonatal period, bones that have not been fractured may appear radiologically normal. In a group of 24 adults with osteogenesis imperfecta the thickness of the metacarpal cortex was normal but their bones were often slender. Osteoporosis is probably not an inevitable feature of such cases, and some of the radiological abnormalities reported may be the results of previous fractures and their treatment.     

Induction of Labour for Prevention of Stillbirth from Rh Hemolytic Disease

The fate of 80 infants delivered after induction of labour in 72 Rh-sensitized mothers was studied to determine whether the stillbirth rate could be reduced. Labour was induced at 32 to 39 weeks of gestation; the criteria for induction were based on the history of previously affected infants, and a maternal Rh-antibody titre of 1/40 or greater, using an indirect antiglobulin technique. Nine mothers were delivered by Cesarean section. It was estimated that 26 infants were so severely affected as to be unlikely to have survived to term. However, only seven died, and one was stillborn. Two of these would normally have survived, one being Rh-negative. These two cases demonstrated the main danger in this method of management. There was a probable saving of 18 infants. In 22 mothers there was no history of previous delivery of an affected infant; in all 22 the infants survived, though six probably would not have survived to term. In 15 pregnancies in which the mothers had had a previous stillbirth, 12 infants survived. Sixty-seven infants required a total of 116 exchange transfusions. Despite the hazards it is concluded that early induction has an important place in management of Rh hemolytic disease.     

Silver-Russell syndrome: genetic basis and molecular genetic testing

Hereditary combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX and X as well as natural anticoagulants protein C, protein S and protein Z. The spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases. The bleeding symptoms are often life-threatening, occur both spontaneously and in a surgical setting, and usually involve the skin and mucosae. A range of non-haemostatic symptoms are often present, including developmental and skeletal anomalies. VKCFD is an autosomal recessive disorder caused by mutations in the genes of either gamma-glutamyl carboxylase or vitamin K2,3-epoxide reductase complex. These two proteins are necessary for gamma-carboxylation, a post-synthetic modification that allows coagulation proteins to display their proper function. The developmental and skeletal anomalies seen in VKCFD are the result of defective gamma-carboxylation of a number of non-haemostatic proteins. Diagnostic differentiation from other conditions, both congenital and acquired, is mandatory and genotype analysis is needed to confirm the defect. Vitamin K administration is the mainstay of therapy in VKCFD, with plasma supplementation during surgery or severe bleeding episodes. In addition, prothrombin complex concentrates and combination therapy with recombinant activated FVII and vitamin K supplementation may constitute alternative treatment options. The overall prognosis is good and with the availability of several effective therapeutic options, VKCFD has only a small impact on the quality of life of affected patients.     

Neonatal Maternal Deprivation Response and Developmental Changes in Gene Expression Revealed by Hypothalamic Gene Expression Profiling in Mice

Neonatal feeding problems are observed in several genetic diseases including Prader-Willi syndrome (PWS). Later in life, individuals with PWS develop hyperphagia and obesity due to lack of appetite control. We hypothesized that failure to thrive in infancy and later-onset hyperphagia are related and could be due to a defect in the hypothalamus. In this study, we performed gene expression microarray analysis of the hypothalamic response to maternal deprivation in neonatal wild-type and Snord116del mice, a mouse model for PWS in which a cluster of imprinted C/D box snoRNAs is deleted. The neonatal starvation response in both strains was dramatically different from that reported in adult rodents. Genes that are affected by adult starvation showed no expression change in the hypothalamus of 5 day-old pups after 6 hours of maternal deprivation. Unlike in adult rodents, expression levels of Nanos2 and Pdk4 were increased, and those of Pgpep1, Ndp, Brms1l, Mett10d, and Snx1 were decreased after neonatal deprivation. In addition, we compared hypothalamic gene expression profiles at postnatal days 5 and 13 and observed significant developmental changes. Notably, the gene expression profiles of Snord116del deletion mice and wild-type littermates were very similar at all time points and conditions, arguing against a role of Snord116 in feeding regulation in the neonatal period.