Richard B. Parad

Guidelines for Diagnosis of Cystic Fibrosis in Newborns through Older Adults: Cystic Fibrosis Foundation Consensus Report

Newborn screening (NBS) for cystic fibrosis (CF) is increasingly being implemented and is soon likely to be in use throughout the United States, because early detection permits access to specialized medical care and improves outcomes. The diagnosis of CF is not always straightforward, however. The sweat chloride test remains the gold standard for CF diagnosis but does not always give a clear answer. Genotype analysis also does not always provide clarity; more than 1500 mutations have been identified in the CF transmembrane conductance regulator (CFTR) gene, not all of which result in CF. Harmful mutations in the gene can present as a spectrum of pathology ranging from sinusitis in adulthood to severe lung, pancreatic, or liver disease in infancy. Thus, CF identified postnatally must remain a clinical diagnosis. To provide guidance for the diagnosis of both infants with positive NBS results and older patients presenting with an indistinct clinical picture, the Cystic Fibrosis Foundation convened a meeting of experts in the field of CF diagnosis. Their recommendations, presented herein, involve a combination of clinical presentation, laboratory testing, and genetics to confirm a diagnosis of CF.

A three-center, randomized, controlled trial of individualized developmental care for very low birth weight preterm infants: medical, neurodevelopmental, parenting, and caregiving effects.

ABSTRACT. Medical, neurodevelopmental, and parenting effects of individualized developmental care were investigated in a three-center, randomized, controlled trial. A total of 92 preterm infants, weighing less than 1250 g and aged less than 28 weeks, participated. Outcome measures included medical, neurodevelopmental and family function. Quality of care was also assessed. Multivariate analysis of variance investigated group, site, and interaction effects; correlation analysis identified individual variable contributions to significant effects. The results consistently favored the experimental groups. The following contributed to the group effects: shorter duration of parenteral feeding, transition to full oral feeding, intensive care, and hospialization; lower incidence of necrotizing enterocolitis; reduced discharge ages and hospital charges; improved weight, length, and head circumferences; enhanced autonomic, motor, state, attention, and self-regulatory functioning; reduced need for facilitation; and lowered family stress and enhanced appreciation of the infant. Quality of care was measurably improved. Very low birth weight infants and their parents, across diverse settings, may benefit from individualized developmental care.

Cystic Fibrosis Foundation Evidence-Based Guidelines for Management of Infants with Cystic Fibrosis

Newborn screening for cystic fibrosis (CF) offers the opportunity for early medical and nutritional intervention that can lead to improved outcomes. Management of the asymptomatic infant diagnosed with CF through newborn screening, prenatal diagnosis, or sibling screening is different from treatment of the symptomatically diagnosed individual. The focus of management is on maintaining health by preventing nutritional and respiratory complications. The CF Foundation convened a committee to develop recommendations based on a systematic review of the evidence and expert opinion. These guidelines encompass monitoring and treatment recommendations for infants diagnosed with CF and are intended to help guide families, primary care providers, and specialty care centers in the care of infants with CF.

Guidelines for Implementation of Cystic Fibrosis Newborn Screening Programs: Cystic Fibrosis Foundation Workshop Report

Newborn screening for cystic fibrosis offers the opportunity for early intervention and improved outcomes. This summary, resulting from a workshop sponsored by the Cystic Fibrosis Foundation to facilitate implementation of widespread high quality cystic fibrosis newborn screening, outlines the steps necessary for success based on the experience of existing programs. Planning should begin with a workgroup composed of those who will be responsible for the success of the local program, typically including the state newborn screening program director and cystic fibrosis care center directors. The workgroup must develop a screening algorithm based on program resources and goals including mechanisms available for sample collection, regional demographics, the spectrum of cystic fibrosis disease to be detected, and acceptable failure rates of the screen. The workgroup must also ensure that all necessary guidelines and resources for screening, diagnosis, and care be in place prior to cystic fibrosis newborn screening implementation. These include educational materials for parents and primary care providers; systems for screening and for providing diagnostic testing and counseling for screen-positive infants and their families; and protocols for care of this unique population. This summary explores the benefits and risks of various screening algorithms, including complex situations that can occur involving unclear diagnostic results, and provides guidelines and sample materials for state newborn screening programs to develop and implement high quality screening for cystic fibrosis.

Fetal lung masses: prenatal course and outcome.

We describe 25 cases of echogenic or complex fetal lung masses seen sonographically and suspected of being cystic adenomatoid malformations or sequestrations of the lung. On the basis of prenatal sonographic appearance, 40% of fetuses were suspected of having type 1, 20% type 2, and 40% type 3 cystic adenomatoid malformations or sequestrations. Sixteen (64%) of the 25 fetuses with lung masses survived the perinatal period, and 80% of the nonaborted fetuses survived. Eleven infants (69% of liveborns) had no respiratory symptoms at birth. Nine of the survivors underwent surgical resections of their masses after birth, whereas the other seven children are being followed conservatively. The postnatal diagnoses revealed that four of the fetuses had sequestrations, one had a sequestration with elements consistent with cystic adenomatoid malformation, and two who were thought to have type 1 cystic adenomatoid malformation had an esophageal duplication cyst and a thoracic neuroblastoma, respectively. All the other infants who had a pathologic diagnosis or postnatal imaging had cystic adenomatoid malformations. Increasing mediastinal shift was associated with decreasing survival as 90% of fetuses with no mediastinal shift are alive, whereas 50% of the nonaborted fetuses with a severe mediastinal shift survived. Follow‐up scans in utero were available in 15 cases. The size of the mass became smaller in 53% during gestation. Seventy‐one percent of pregnancies had normal amniotic fluid volumes and 29% were complicated by polyhydramnios. Survival of nonaborted fetuses was 100% in pregnancies with normal amniotic fluid compared with 50% in those with polyhydramnios. Eight percent of the fetuses with chest masses had additional structural abnormalities and were karyotypically abnormal. In conclusion, many fetuses with lung masses show improvement of the sonographic findings in utero, and many infants may not be symptomatic at birth. Of the survivors in this series, only slightly greater than half underwent surgery.

Is the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) effective for preterm infants with intrauterine growth restriction

Objective:This study investigates the effectiveness of the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) on neurobehavioral and electrophysiological functioning of preterm infants with severe intrauterine growth restriction (IUGR).Study Design:Thirty IUGR infants, 28 to 33 weeks gestational age, randomized to standard care (control/C=18), or NIDCAP (experimental/E=12), were assessed at 2 weeks corrected age (2wCA) and 9 months corrected age (9mCA) in regard to health, anthropometrics, and neurobehavior, and additionally at 2wCA in regard to electrophysiology (EEG).Result:The two groups were comparable in health and anthropometrics at 2wCA and 9mCA. The E-group at 2wCA showed significantly better autonomic, motor, and self-regulation functioning, improved motility, intensity and response thresholds, and reduced EEG connectivity among several adjacent brain regions. At 9mCA, the E-group showed significantly better mental performance.Conclusion:This is the first study to show NIDCAP effectiveness for IUGR preterm infants.

Individualized developmental care for a large sample of very preterm infants: health, neurobehaviour and neurophysiology

Aim:  To assess medical and neurodevelopmental effects of Newborn Individualized Developmental Care and Assessment Program (NIDCAP) for a large sample of very early‐born infants.

Type I C1 inhibitor deficiency with a small messenger RNA resulting from deletion of one exon.

The molecular genetic basis of C1 inhibitor (C1 INH) deficiency in a patient with type I hereditary angioneurotic edema was studied. This patient was found to have an abnormally short C1 INH mRNA together with a normal message. Restriction fragment length polymorphism of the C1 INH gene was detected by Southern blot analysis of the patients DNA after digestion with Pst I or Sac I, and hybridization with a full-length C1 INH cDNA. Hybridization of the same blot with three different fragments of the full-length cDNA suggested that exon VII and portions of both flanking introns were deleted in the C1 INH gene. Northern blot analysis of RNA from cultured monocytes, using a probe corresponding to exon VII, also indicated that the abnormal C1 INH mRNA had a deletion of these nucleotides. To confirm the hypothesis that the short C1 INH mRNA contained a deletion, the involved segment of the patients C1 INH mRNA was amplified using the polymerase chain reaction (PCR). PCR amplification yielded two C1 INH DNA fragments of different lengths (380 and 160 bp). Southern blot and sequence analysis of both DNA fragments clearly revealed that the smaller 160-bp DNA was derived from the abnormal message and had a deletion of nucleotides corresponding to exon VII.

Genetic counseling after implementation of statewide cystic fibrosis newborn screening: Two years' experience in one medical center.

Purpose: To study the follow-up of genetic counseling performed in families with a newborn detected with one cystic fibrosis (CF) mutation in a statewide newborn screening pilot program.Methods: Newborns in Massachusetts with an elevated trypsinogen level on newborn screen who are found to have one mutation for CF on a selected mutation assay undergo sweat testing for CF, and their families receive genetic counseling. The genetic counseling focuses on carrier risk for the parents of the newborn and offers carrier testing. We studied the yield of genetic counseling and the resulting genetic testing performed on the families of infants found to be CF carriers who underwent sweat testing in a single institution.Results: Of 102 newborns evaluated with a single CF mutation, 2 (twins) had sweat test results consistent with CF. A total of 101 families were counseled, and 95 were offered DNA-based CF carrier testing. Eighty-two percent of all parents chose to have CF carrier testing, and in five couples, both members were carriers. One of these couples (whose newborn was only a carrier) had an older child who was unexpectedly found to have CF.Conclusions: Sweat testing of newborns at increased risk for CF in conjunction with genetic counseling for their parents allows identification of infants with CF, finds couples at high risk for having a child with CF, identifies previously undiagnosed siblings with CF, and allows for potential identification of CF carriers in the extended family.

Early Pulmonary Manifestation of Cystic Fibrosis in Children With the ΔF508/R117H-7T Genotype

We report 3 cystic fibrosis newborn screen–positive infants with the ΔF508/R117H-7T genotype who had Pseudomonas aeruginosa detected in oropharyngeal cultures early in life and a fourth who had pulmonary symptoms and Gram-negative growth on multiple oropharyngeal cultures. All 4 patients were followed prospectively from the time of genetic diagnosis. As many regions implement newborn screening for cystic fibrosis, there is concern regarding which mutations should be included in genetic panels used to make the cystic fibrosis diagnosis. Some have recommended that mutations not specifically associated with classic cystic fibrosis be excluded. Our cases highlight the importance of considering keeping so-called mild mutations on cystic fibrosis newborn screening panels and the need to follow children with these mutations closely.