Newborn Screening.

The goal of newborn screening is to identify medical conditions that can cause significant morbidity and/or mortality if not treated early in life. Pediatricians often play a vital role in the initial disclosure of newborn screening results and coordination of confirmatory testing, treatment, and referral to specialty care. The goal of this article is to provide an overview of current newborn screening in the United States, focusing on the various disorders, their manifestations, the newborn screening process, the confirmatory testing, and treatments. Some practical considerations will be discussed as well.

Transcobalamin receptor deficiency in seven asymptomatic patients ascertained through newborn screening.

We report seven cases from our clinic with transcobalamin receptor deficiency (TCRD). None of our cases have experienced health issues or metabolic decompensation. All have experienced typical growth and development throughout childhood, with our oldest case now 10 years old. Every case has had normalization of initial biochemical abnormalities following parenteral hydroxocobalamin administration. Several cases had trace elevations of methylmalonic acid throughout childhood, all which normalized without further hydroxocobalamin administration. Population data from our state's newborn screening program suggest the incidence of TCRD is comparable to other metabolic disorders associated with elevations of C3 acylcarnitine including propionic academia, isolated methylmalonic academia and combined methylmalonic academia and hyperhomocysteinemia due to cobalamin metabolism disorders. Based on the generally benign nature of this condition, we assert that TCRD may be considered an incidental finding on newborn screen. However, additional long-term data are needed to ascertain the long term outcomes of children identified with TCRD.

A cautionary tale of pyridoxine toxicity in cystathionine beta-synthase deficiency detected by two-tier newborn screening highlights the need for clear pyridoxine dosing guidelines.

Classic homocystinuria is due to deficiency of cystathionine beta-synthase (CBS), a pyridoxine-dependent enzyme that, depending on the molecular variants, may be co-factor responsive. Elevated methionine is often used as the primary analyte to detect CBS deficiency (CBSD) on newborn screening (NBS), but is limited by increased detection of other biochemical disorders with less clear clinical significance such as methionine aminotransferase (MAT) I/III heterozygotes. Our state has implemented a two-tier NBS algorithm for CBSD that successfully reduced the number of MATI/III heterozygotes, yet effectively detected a mild, co-factor responsive form of CBSD. After initial diagnosis, newborns with CBSD often undergo a pyridoxine challenge with high-dose pyridoxine to determine responsiveness. Here we describe our NBS-identified patient with a mild form of pyridoxine responsive CBSD who developed respiratory failure and rhabdomyolysis consistent with pyridoxine toxicity during a pyridoxine challenge. This case highlights the need for weight-based dosing and duration recommendations for pyridoxine challenge in neonates.

The Current State of Newborn Screening in the United States.

Newborn screening has evolved since its introduction in 1963. The disorders that are being screened for continue to evolve as new treatments and new technologies advance. In this review, the authors discuss the current state of newborn screening in the United States, including the disorders currently being screened for and how newborn screening is performed. They also discuss the special considerations and limitations of newborn screening in sick and premature infants and as well as some ethical issues related to newborn screening. Finally, new disorders being considered for testing and new technologies that may be used in the future of newborn screening are discussed.

Gender role across development in adults with 46,XY disorders of sex development including perineoscrotal hypospadias and small phallus raised male or female.

Self-rated degree of femininity and masculinity across development were evaluated for 40 adults affected by 46,XY disorders of sex development (DSDs) who presented at birth with a small phallus and perineoscrotal hypospadias, raised either male (n = 22) or female (n = 18). Most participants were confirmed or presumed to be affected by partial androgen insensitivity syndrome (n = 14), partial gonadal dysgenesis (n = 11), or were considered to have a poorly defined case of 46,XY DSD including ambiguous external genitalia (n = 15). Participants retrospectively evaluated their degree of masculinity and femininity during their childhood, adolescence, adulthood, and in the past 12 months of filling out a questionnaire pertaining to their psychosexual development. Participants raised male reported more masculinity than those raised female due to an increase in masculinization during adolescence and adulthood. Participants raised male also reported less femininity than those raised female throughout development. Participants raised female reported more femininity than those raised male due to an increase in feminization during adolescence and adulthood. Participants raised female also reported less masculinity than those raised male throughout development. These data support the proposition that some aspects of gender role (GR), such as masculinity and femininity, are capable of proceeding along female- or male-typic patterns depending on sex of rearing among individuals affected by specific types of 46,XY DSD. Furthermore, regardless of male or female rearing, GR increasingly corresponds with assigned sex as individuals proceed through sexual maturity and into adulthood. These results are consistent with the idea that socialization/learning contributes to GR development in humans in addition to data from others demonstrating endocrine influences.