Moderate congenital adrenal hyperplasia in two girls diagnosed by newborn screening

Pediatric Endocrinology, Diabetes, and Metabolism · 5 authors, 4 centres

AI SUMMARY

FIDELITY 100%

POPULATIONTwo female newborns (Patient 1: term, 3520 g; Patient 2: term, 3670 g) with atypical newborn screening results for CAH in the Wielkopolska region, Poland

INTERVENTIONNewborn screening for CAH (17-OHP by FIA from dried blood spots, followed by LC/MS/MS steroid profile, Synacthen test, 24-h urinary GC-MS steroid profile, and CYP21A2 genetic analysis)

COMPARISONNot applicable (case series without a control group)

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TL;DR

This case report describes two female newborns with moderate (simple-virilizing) congenital adrenal hyperplasia (CAH) detected through newborn screening in Poland, despite being discharged from neonatal units without clinical suspicion. Both girls had mild virilization that was initially missed, and screening with 17-OHP measurement followed by steroid profiling, Synacthen testing, and urinary GC-MS confirmed 21-hydroxylase deficiency. Early diagnosis via screening enabled prompt treatment with hydrocortisone and fludrocortisone, preventing further virilization and precocious puberty, highlighting the clinical value of newborn screening even for milder CAH forms.

Full summary

4,813 CHARS

**Background:** Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder, with 21-hydroxylase deficiency accounting for 90–95% of cases. Clinical forms range from severe salt-wasting (SW-CAH) and simple-virilizing (SV-CAH) to milder nonclassic (NC-CAH). Newborn screening for CAH, based on 17-hydroxyprogesterone (17-OHP) measurement from dried blood spots, was introduced in the Wielkopolska region of Poland in September 2016 and nationwide by the end of 2016. Screening reduces time to diagnosis, prevents life-threatening salt-wasting crises, and reduces delays in sex assignment of virilized females. The Polish screening program uses 17-OHP fluoroimmunoassay (FIA) with gestational age and day-of-sampling adjustment, followed by LC/MS/MS steroid profile (17-OHP, cortisol, 21-deoxycortisol, 11-deoxycortisol, androstenedione) and calculation of (17-OHP+androstenedione)/cortisol and (17-OHP+21-deoxycortisol)/cortisol ratios to improve specificity.

**Methods:** Two female newborns with atypical screening results are described. Both were born at term and discharged without suspicion of disease. Screening filter papers were obtained on day 3 of life and, in Patient 1, repeated on day 14. 17-OHP (FIA) and LC/MS/MS steroid profiles were performed. Upon recall, both infants underwent physical examination, electrolyte measurement, short Synacthen test (36 µg/kg), measurement of ACTH, androstenedione, testosterone, DHEA-S, and 24-hour urinary steroid profile by GC-MS. Genetic analysis of the CYP21A2 gene was performed by MLPA.

**Key Results:** Patient 1 (born at 40 weeks, 3520 g, Apgar 9–10) had slightly elevated 17-OHP by FIA (45.95 nmol/l on first filter paper, 62.02 nmol/l on second). LC/MS/MS showed normal 17-OHP but low cortisol (2.4 nmol/l, then 0.1 nmol/l), with elevated (17-OHP+androstenedione)/cortisol ratio (2.03, then 110.29; normal <1.95) and (17-OHP+21-deoxycortisol)/cortisol ratio (9.99, then 148.2; normal <1.95). On admission (day 28), weight was 3970 g, Na 132 mmol/l, K 5.31 mmol/l. Synacthen test showed insufficient cortisol rise (0': 21 ng/ml, 30': 28 ng/ml, 60': 29 ng/ml) and abnormal 17-OHP (0': 33.4 ng/ml, 30': 36.4 ng/ml, 60': 34.8 ng/ml). Androstenedione (3.47 ng/ml; normal 0.06–0.78), DHEA-S (15.24 µmol/l; normal 0.14–1), testosterone (1.85 nmol/l; normal 0.03–0.17), and ACTH (110.5 pg/ml; normal 10–60) were elevated. Urinary GC-MS showed markedly elevated pregnanetriolone (1087.1 µg/24h; normal 0.2–10) and other androgen metabolites. Genetic analysis revealed heterozygous I2G splice variant (c.293-13C>G) and heterozygous p.I172N mutation (c.515T>A).

Patient 2 (born at 40 weeks, 3670 g, Apgar 10) had elevated 17-OHP by FIA (61.71 nmol/l). LC/MS/MS showed elevated 17-OHP (30.4 nmol/l; normal 0.1–14.8) and 21-deoxycortisol (43.8 nmol/l; normal <5.9), low-normal cortisol (19.9 nmol/l), and slightly elevated (17-OHP+21-deoxycortisol)/cortisol ratio (3.73; normal <1.95). On admission (day 24), weight was 4000 g, Na 134 mmol/l, K 5.07 mmol/l. Synacthen test showed insufficient cortisol rise (0': 16 ng/ml, 30': 27 ng/ml, 60': 38 ng/ml) and abnormal 17-OHP (0': 33.9 ng/ml, 30': 37.1 ng/ml, 60': 38.68 ng/ml). Androstenedione (9.55 ng/ml), DHEA-S (12.2 µmol/l), testosterone (2.57 nmol/l), and ACTH (420.9 pg/ml) were markedly elevated. Urinary GC-MS showed elevated pregnanetriolone (427.7 µg/24h; normal 0–5). Genetic analysis showed heterozygous deletion of CYP21A2 exon 4 and heterozygous duplication of CYP21A1P pseudogene exon 4. Both patients were diagnosed with classic simple-virilizing CAH, started on intravenous then oral hydrocortisone, and fludrocortisone was added due to low-normal sodium.

**Clinical Implications:** These cases demonstrate that newborn screening can detect moderate (simple-virilizing) CAH even when clinical virilization is subtle and initially missed. Both infants were discharged without suspicion of CAH despite mild virilization (Prader stage 1 and 2). The authors note that >50% of females may have incorrect clinical evaluation of virilization features, and in Poland, 5 of 31 female CAH cases identified in the first three years of screening had no documentation of virilization in newborn records. Screening with 17-OHP alone may yield equivocal results in SV-CAH, and the addition of LC/MS/MS steroid ratios and urinary GC-MS profiling was crucial for diagnosis. The Synacthen test confirmed adrenal insufficiency with insufficient cortisol response, indicating risk in stress situations. Early diagnosis enabled prompt treatment to prevent further virilization and GnRH-independent precocious puberty. The authors emphasize that careful genital examination in newborns and communication of any virilization findings to screening laboratories can significantly reduce time to diagnosis.

PICO

PPOPULATION

Two female newborns (Patient 1: term, 3520 g; Patient 2: term, 3670 g) with atypical newborn screening results for CAH in the Wielkopolska region, Poland

IINTERVENTION

Newborn screening for CAH (17-OHP by FIA from dried blood spots, followed by LC/MS/MS steroid profile, Synacthen test, 24-h urinary GC-MS steroid profile, and CYP21A2 genetic analysis)

OOUTCOME

Diagnosis of classic simple-virilizing CAH due to 21-hydroxylase deficiency; initiation of hydrocortisone and fludrocortisone treatment; prevention of further virilization and precocious puberty

STUDY TYPE

case_report

SPECIALTY

pediatric endocrinology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10226346

Moderate congenital adrenal hyperplasia in two girls diagnosed by newborn screening

Pediatric Endocrinology, Diabetes, and Metabolism

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ABSTRACT

Introduction Congenital adrenal hyperplasia (CAH) before the introducing a newborn screening was initially diagnosed based on clinical symptoms or positive family history and thereafter confirmed hormonal profiles. Patients’ report We present two female newborns with atypical screening results born shortly after the introduction of neonatal screening for congenital adrenal hyperplasia in the Wielkopolska region. Female patients 1 and 2 were both born at term and discharged from neonatal departments without any suspicion of disease. After performing complete neonatal screening for CAH, girls were admitted to the endocrine department for further investigations. In both cases, the girls did not exhibit characteristic symptoms of the disease. Using the Synacthen test, we observed an insufficient increase in cortisol and an abnormal increase in 17-OHP concentrations. The 24-hour urinary steroid profile analyzed by GC-MS confirmed the diagnosis. In both cases, treatment with hydrocortisone and fludrocortisone was initiated. Genetic evaluation confirmed mutations in the CYP21A2 gene. Discussion and Conclusion Newborn screening for CAH is useful for revealing a moderate form of CAH and indicates the need to start treatment in cases without typical signs of disease to prevent further virilization and the generation of a GnRH-independent precocious puberty. For nonobvious screening results, clinical information, including any data on virilization, is extremely helpful. Therefore, a careful assessment of newborns’ genitalia in neonatal departments is important. The screening laboratory should be informed about any abnormalities to perform a complete screening immediately decreasing significantly the time between taking the paper sample and the final diagnosis.

CITATION EXPORT

Magdalena Banaszak-Ziemska, Elżbieta Małecka, Katarzyna Łacna et al.. Moderate congenital adrenal hyperplasia in two girls diagnosed by newborn screening. Pediatric Endocrinology, Diabetes, and Metabolism. (2021). https://doi.org/10.5114/pedm.2021.109123

AUTHORS

5 · 4 CENTRES

Magdalena Banaszak-Ziemska, Elżbieta Małecka, Katarzyna Łacna, Maria Ginalska-Malinowska, Marek Niedziela

1Karol Jonscher’s Clinical Hospital, Poznan University of Medical Sciences, Poznan, Poland
2Center of Medical Genetics GENESIS, Poznan, Poland
3Screening and Metabolic Diseases Department, Institute of Mother and Child, Warsaw, Poland
4Department of Pediatric Endocrinology and Rheumatology, Institute of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland