Faculty

Atsumi Tsuji Hosokawa

VIEW CV

Adrenal disorders and DSD

The thirty-year lesson from the newborn screening for congenital adrenal hyperplasia in Tokyo.

Congenital adrenal hyperplasia (CAH) is an inherited disorder caused by impairment of steroidogenic enzymes involved in cortisol biosynthesis. More than 90 percent of cases result from 21-hydroxylase deficiency (21OHD). To prevent life-threatening adrenal crisis and to help perform appropriate sex assignments for affected female patients, newborn screening (NBS) programs for CAH have been introduced in numerous countries. In Japan, the NBS for CAH was introduced in 1989. Although the basis of the NBS system are identical in all local governments, the NBS in Japan was introduced individually into the prefectural administration. Tokyo is the largest city with more than ten million people, and to date, more than two million neonates have been screened. In this presentation, we aim to summarize the experience of the past 30 years of the NBS for CAH in Tokyo.

The incidence of 21OHD was approximately 1:19,000, and the mean age at diagnosis of 21OHD was 7.6 days. All the cases with 46,XX DSD was reared as female, and no false negative cases were reported. Further analysis revealed two concerns of the CAH screening, limited impact of stratified cut-off values for reducing high false positive rate and development of severe salt wasting at diagnosis in substantial number of patients.

Although the Tokyo screening program is conducted with cutoff points stratified by birth weight and gestational age which improved positive predictive value (PPV) of 25.6%, PPV for preterm infants (=<36 weeks of gestational age) remained low of 2%, suggesting the efficiency of stratified cutoff points are limited. A major cause of false positive in preterm infants are a cross reaction to non 17ɑOHP steroids synthesized from fetal adrenal gland in ELISA measurement. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been recommended as the best option for the screening, and from April 2021, LC-MS/MS was introduced to the CAH screening in Tokyo. Our pilot study demonstrated LC-MS/MS would remarkably increase PPV.

Based on our follow-up survey, 37.4% of 21OHD patients displayed severe salt wasting (Na <130mEq/L or K>7.0mEq/L) at diagnosis. Serum sodium and serum potassium was linearly deteriorated with age in days, and the intervention must be started ideally during the first week of life. Hence, earlier sampling can be discussed for the prevention of severe salt wasting. In line with this, timeline of the NBS becomes earlier worldwide as the inborn metabolic disease were added to screening panel recently. However, we must consider the evidence of false negatives associated with the earlier sampling. Additionally, our survey revealed changes in body weight was a useful index for triaging neonates with positive CAH screening. The cases showing decrease of body weight from birth are likely to have classical 21OHD, and even in cases of 21OHD, the possibility of developing severe salt wasting is extremely low without loss of body weight during their second week of life.

The NBS for CAH was efficient and provided important insights. Continuous evaluation of the NBS and long-term follow up of the patients must be considered for further improvement in the practice of CAH.

Return to Faculty List