Clinical Outcomes and Correlation With Biochemical Control in Hydroxocobalamin-Treated Patients With Early-Onset Cobalamin C Disease.

Early morphologic changes in the lungs of asymptomatic infants and young children with cystic fibrosis

ABSTRACTCobalamin C (CblC) disease is the most common inborn error of cobalamin metabolism and recent data has indicated a higher prevalence among children of Hispanic heritage in particular. The purpose of this study was to (a) describe the neuropsychological characteristics of a pilot sample of Hispanic children with CblC disease and (b) explore potential differences in outcome based on underlying genetic mutation(s) and biochemical levels. Six Hispanic children (ages 2–10) diagnosed with CblC disease through newborn screening (NBS) underwent neuropsychological evaluation with a bilingual examiner. Biochemical levels and underlying mutation(s) were obtained through medical records. The overall sample performed below normative expectations across neuropsychological domains, including general cognition, adaptive functioning, language ability, and visual-motor integration. Underlying mutations and associative clinical phenotypes were found to significantly predict general cognitive abilities, while plasma methionine and Hcy at the time of diagnosis were significantly correlated with language outcomes. Despite limited sample size, results indicate that Hispanic children with CblC disease detected through NBS and treated early experience neuropsychological deficits even when treated with current standard treatments. However, consistent with prior research in non-Hispanic children with CblC disease, underlying mutations and early biochemical levels may predict better outcomes in this population as well.

1. Michael J. Goldberg, MD* 1. 2. *Tufts University School of Medicine, New England Medical Center, Boston, MA. This article provides a summary of the practice parameter of early detection of developmental dysplasia of the hip. The reader is urged to refer to the original document for a more thorough presentation.(1) Developmental dysplasia of the hip (DDH) is the preferred term to describe the condition in which the femoral head has an abnormal relationship to the acetabulum. DDH encompasses frank dislocation (luxation), partial dislocation (subluxation), instability wherein the femoral head moves in and out of the socket, and an array of radiographic abnormalities that reflect inadequate formation of the acetabulum. Because many of these findings may not be present at birth, the term “developmental” more accurately reflects the biologic features than does the term “congenital.” DDH may occur in utero, perinatally, or during infancy and childhood. The disorder is uncommon. Treatment is simpler and more effective when the dislocation is detected early. Despite newborn screening programs, dislocated hips continue to be diagnosed later in infancy and childhood. Late detection often delays appropriate therapy and frequently leads to a malpractice claim. The true incidence of DDH can only be presumed. There is no gold standard for diagnosis among newborns. Physical examination, plane radiography, and ultrasonography all are fraught with false-positive and false-negative results. The reported incidence of DDH is influenced by genetic and racial factors, diagnostic criteria, the experience and training of the examiner, and the age of the child at the time of examination. Some newborn screening surveys suggest evidence of instability in as many as 1 in 100 newborns and 1 to 1.5 cases of dislocation per 1,000 newborns. Regardless of the screening method used for the newborn, DDH is detected in 1 of 5,000 infants at 18 months of age. The object of this guideline is to reduce the number of dislocated hips detected …

Infantile hemangiomas are arrested in an early developmental vascular differentiation state

The importance of identifying congenital hearing loss during the first few months of life has been recognized for almost 60 years. Unfortunately, until more effective newborn hearing screening equipment and procedures were developed in the late 1980s, it was not practical to implement programs for identifying hearing loss during the first few months of life. This paper reviews the activities implemented by the federal government in the last 15 years to promote more effective Early Hearing Detection and Intervention (EHDI) programs, and summarizes legislation passed by states related to universal newborn hearing screening. In surveys conducted in 1998 and 2001, State EHDI Coordinators were asked to rate the degree to which various issues were obstacles to implementing effective EHDI programs. The most serious obstacles are the shortage of qualified pediatric audiologists, inadequate reimbursement for screening and diagnosis, and lack of knowledge among primary health care providers about EHDI issues. Opposition to EHDI programs by hospital administrators was rated substantially lower in 2001 than in 1998. State EHDI Coordinators were also surveyed about how well their EHDI program is addressing issues related to screening, diagnosis, early intervention, linkages to medical home providers, tracking and data management, and family support programs. Although substantial progress has been made, many gaps remain with current EHDI programs.

BackgroundThe aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene (MMACHC) c.482G > A mutation in 195 Chinese cases with CblC disease.MethodsWe carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months.ResultsAmong 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower (P < 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower (P > 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels (P < 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group).ConclusionsThe c.482G > A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes.CNU96JjhPhuCQHh9ViZTVJVideo (MP4 136794 kb)

AimSpinal Muscular Atrophy (SMA) is a rare genetic disorder that causes muscle weakness and atrophy due to the impact on motor neurons in the spinal cord. It is the leading...

Purpose: To describe the association between retinal degeneration and cobalamin C (cblC) disease and to review previously published ophthalmic data regarding cblC disease. Methods: Descriptive case series of three patients and compilation of all previously reported cases of cblC disease in the ophthalmic literature. Results: All three new cases presented with macular pigmentary changes and showed attenuation of electroretinographic responses. Sequential ERG (electroretinogram) testing in Case 1 demonstrated ERGs that began at the lower limits of normal and became progressively attenuated over time. Conclusions: Cobalamin C disease results in progressive retinal degeneration with its onset in the first few months of life and progressing rapidly over the first few years of life.

Thyroid Disorders.

Severe combined immunodeficiency (SCID) is a group of syndromes resulting from genetic defects causing severe deficiency in T cell and B cell function. These conditions are life-threatening and result in susceptibility to serious infections. SCID is often fatal in the first year of life if not detected and properly treated. SCID and related T cell lymphopenias can be detected in newborns by a simple screening test, the T cell receptor excision circle (TREC) assay, using the same dried blood spot samples already collected from newborns to screen for other genetic disorders. The TREC assay facilitates the earliest possible identification of cases of SCID before opportunistic infections, irreversible organ damage, or death, thus allowing for the possibility of curative treatment through hematopoietic stem cell transplant and gene therapy. Infants receiving hematopoietic stem cell transplant in the first few months of life, after being identified through screening, have a high probability of survival (95-100%), along with lower morbidity. The TREC assay has proven to have outstanding specificity and sensitivity to accurately identify almost all infants with SCID (the primary targets) as well as additional infants having other select immunologic abnormalities (secondary targets). The TREC assay is inexpensive and has been effectively integrated into many public health programs. Without timely treatment, SCID is a fatal disease that causes accrual of exorbitant healthcare costs even in just 1year of life. The cost of care for just one infant with SCID, not diagnosed through newborn screening, could be more than the cost of screening for an entire state or regional population. Continued implementation of TREC screening will undoubtedly enhance early diagnosis, application of treatment, and healthcare cost savings. The Jeffrey Modell Foundation helped initiate newborn screening for SCID in the USA in 2008 and continues its efforts to advocate for SCID screening worldwide. Today, all 50 states and Puerto Rico are screening for SCID and T cell lymphopenia, with 27 million newborns screened to date, and hundreds diagnosed and treated. Additionally, there are at least 20 countries around the world currently conducting screening for SCID at various stages. Newborn screening for SCID and related T cell lymphopenia is cost-effective, and most importantly, it is lifesaving and allows children with SCID the opportunity to live a healthy life.

The primary objective of population-based newborn screening is the early identification of asymptomatic infants with a range of severe diseases, for which effective treatment is available and where early diagnosis and intervention prevent serious sequelae. Primary immunodeficiency diseases (PID) are a heterogeneous group of inborn errors of immunity. Severe combined immunodeficiency (SCID) is one form of PID which is uniformly fatal without early, definitive therapy, and outcomes are significantly improved if infants are diagnosed and treated within the first few months of life. Screening for SCID using T cell receptor excision circle (TREC) analysis has been introduced in many countries worldwide. The utility of additional screening with kappa recombining excision circles (KREC) has also been described, enabling identification of infants with severe forms of PID manifested by T and B cell lymphopenia. Here, we review the early origins of newborn screening and the evolution of screening methodologies. We discuss current strategies employed in newborn screening programs for PID, including TREC and TREC/KREC-based screening, and consider the potential future role of protein-based assays, targeted sequencing, and next generation sequencing (NGS) technologies, including whole genome sequencing (WGS).

The objective is to develop methods to utilize newborn reflectance measures for the identification of middle-ear transient conditions (e.g., middle-ear fluid) during the newborn period and ultimately during the first few months of life. Transient middle-ear conditions are a suspected source of failure to pass a newborn hearing screening. The ability to identify a conductive loss during the screening procedure could enable the referred ear to be either (1) cleared of a middle-ear condition and recommended for more extensive hearing assessment as soon as possible, or (2) suspected of a transient middle-ear condition, and if desired, be rescreened before more extensive hearing assessment. Reflectance measurements are reported from full-term, healthy, newborn babies in which one ear referred and one ear passed an initial auditory brainstem response newborn hearing screening and a subsequent distortion product otoacoustic emission screening on the same day. These same subjects returned for a detailed follow-up evaluation at age 1 month (range 14 to 35 days). In total, measurements were made on 30 subjects who had a unilateral refer near birth (during their first 2 days of life) and bilateral normal hearing at follow-up (about 1 month old). Three specific comparisons were made: (1) Association of ear's state with power reflectance near birth (referred versus passed ear), (2) Changes in power reflectance of normal ears between newborn and 1 month old (maturation effects), and (3) Association of ear's newborn state (referred versus passed) with ear's power reflectance at 1 month. In addition to these measurements, a set of preliminary data selection criteria were developed to ensure that analyzed data were not corrupted by acoustic leaks and other measurement problems. Within 2 days of birth, the power reflectance measured in newborn ears with transient middle-ear conditions (referred newborn hearing screening and passed hearing assessment at age 1 month) was significantly greater than power reflectance on newborn ears that passed the newborn hearing screening across all frequencies (500 to 6000 Hz). Changes in power reflectance in normal ears from newborn to 1 month appear in approximately the 2000 to 5000 Hz range but are not present at other frequencies. The power reflectance at age 1 month does not depend significantly on the ear's state near birth (refer or pass hearing screening) for frequencies above 700 Hz; there might be small differences at lower frequencies. Power reflectance measurements are significantly different for ears that pass newborn hearing screening and ears that refer with middle-ear transient conditions. At age 1 month, about 90% of ears that referred at birth passed an auditory brainstem response hearing evaluation; within these ears the power reflectance at 1 month did not differ between the ear that initially referred at birth and the ear that passed the hearing screening at birth for frequencies above 700 Hz. This study also proposes a preliminary set of criteria for determining when reflectance measures on young babies are corrupted by acoustic leaks, probes against the ear canal, or other measurement problems. Specifically proposed are "data selection criteria" that depend on the power reflectance, impedance magnitude, and impedance angle. Additional data collected in the future are needed to improve and test these proposed criteria.

We have previously reported that despite neonatal screening, children with severe congenital hypothyroidism treated at 5 weeks of age with 6 micrograms/kg.day levothyroxine have clinically significant intellectual impairment, whereas those with the moderate form of the disease are indistinguishable from controls. The developmental outcome of children with severe congenital hypothyroidism treated earlier with higher initial doses of levothyroxine remained to be determined. In the present study, 45 infants with permanent congenital hypothyroidism detected by neonatal screening are described. For the group, the median age at starting treatment was 14 days, and the median initial dose of levothyroxine was 11.6 micrograms/kg.day. Based on the area of their knee epiphyses at diagnosis, the patients were divided into 2 subgroups: severe (< 0.05 cm2; n = 10) and moderate (> or = 0.05 cm2; n = 35). The psychomotor development of 8 patients in each subgroup, matched for the socioeducational level of their families, was assessed at 18 months. Mean plasma free T4 levels were supraphysiological during the first few months of life, but mean plasma T3 levels remained within the normal range, and there were no signs or symptoms of hyperthyroidism. The mean plasma TSH concentration was less than 4.5 mIU/L 4 weeks after starting treatment. Bone maturation remained delayed at 12 months in the severe cases and was not unduly advanced in the moderate cases. The mean (+/- SD) developmental quotients at 18 months were similar in severe and moderate cases (107 +/- 10 and 110 +/- 5, respectively). We conclude that with earlier treatment and a higher initial dose of levothyroxine, the early developmental outcome of infants with severe congenital hypothyroidism is now indistinguishable from that of infants with the moderate form of the disease who were used as controls.

An Unusual Pigmented Plaque in a Newborn.

Congenital hypothyroidism presents with characteristic symptoms within the first few months of life: constipation, jaundice, poor feeding, hoarse cry, macroglossia, and hypotonia. However, these symptoms are rare immediately upon delivery, as most neonates are asymptomatic at birth. Therefore, the newborn screens are essential in detecting congenital hypothyroidism, but there are rare cases in which congenital hypothyroidism can be missed or present before the first newborn screen. This paper presents a case of respiratory distress syndrome in a term neonate as the presenting symptom of congenital hypothyroidism. Overall, clinicians should be aware that neonatal respiratory distress can indeed be caused by congenital hypothyroidism, though more common etiologies should be ruled out following stabilization of the patient. Congenital hypothyroidism is an endocrinopathy that may present prior to the onset of symptoms at 3 months or may even present as respiratory distress syndrome prior to the results of the newborn screens. A discussion of this rare case may help physicians in the recognition and treatment of respiratory distress syndrome due to hypothyroidism.