ESPE Abstracts

The CYP21A2 and the TNXB genes are highly homologous with their corresponding pseudogenes (CYP21A1P and TNXA), leading to frequent homologous recombination. The TNXB includes 43 exons, the mRNA encodes tenascin-X (TNX), an extracellular matrix glycoprotein, highly expressed in connective tissue.

CAH patients with a "contiguous gene syndrome" comprising a deletion of both genes- CYP21A2 and TNXB have been described. Chimeric genes generated by large gene deletion or gene conversion events, account for 20%–30% of the common CYP21A2 pathogenic variants in CAH patients. Nine CYP21A2/CYP21A1P (CH-1 to CH-9) and one TNXA/TNXB chimera have been described. TNXA/TNXB CH-1 resulted in a contiguous CYP21A2 and TNXB deletion. TNXA/TNXB CH-1 is characterized by a 120-bp deletion crossing exon 35 and intron 35 carried over from the TNXA pseudogene.

We present a newborn with extremely severe phenotype, with lethal outcome despite early hormonal substitution. He was born after 3^rd pregnancy, at term, (BW 3100g, BL 50 cm, HC 34 cm, vaginal delivery). Severe bradycardia and bradypnea lead 8 hours later to intubation. Early hypoglycemia, hyponatremia and hyperkalemia were present, therefore methylprednisolone (GCS) was instituted early. Screening was taken on d 3, the extremely elevated 17 OHP results (>324 nmol/l) were reported immediately, 9-alfa fludrocortisone (MCS) was added (d 9) to the GCS and fluid therapy. The patient was transferred to a tertiary neonatology center (d10) with weight loss (9.7%), respiratory insufficiency, reduced muscle tonus and activity, marked hyperpigmentation, descended testis, elevated CRP, direct hyperbilirubinemia (316 mcmol/l, dBili 228), negative in the TORCH&hepatitis screen, with opened fetal communications, small left/right shunt, aneurism fossa ovale, left sided severe hydronephrosis, enlarged adrenals, no signs of atresia of the extrahepatic bile duct system, hypocholic stools and dark urine. The further clinical course was not typical for a newborn with classical CAH on therapy. The molecular genetic analysis (SANGER sequencing and MLPA) revealed homozygous deletions in CYP21A2 gene and its substitution with CYP21A1P pseudogene and chimera gene TNXA/TNXB at the intron - exon 35 boundary of the TNXB gene. The skin elasticity, the hypermobility of the joints and the aneurism fossa ovale is in line with the Ehler Danlos syndrome phenotype, but due to the small age of the patient could not be further explored. The patient represents a case of TNXA/TNXB CH-1 with extremely complex phenotype and Ehler Danlos symptoms, adding to the phenotype of the contiguous CAH syndrome and additional TNXB – related diseases.