MON-177 CAH-X Syndrome in a German Cohort of Patients with Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is encoded by the CYP21A2 gene. The CYP21A2 gene is flanked and partially overlapped by the TNXB gene encoding an extracellular matrix protein called Tenascin-X. Deficiency of Tenascin X can cause the Ehlers-Danlos Syndrome (EDS). Deletions of CYP21A2 extending into TNXB rarely cause CAH combined with EDS. Heterozygosity of TNXB mutations causing haploinsufficiency of TNX, however, have been described in about 5-7% in a patient cohort from the US and has been named CAH-X syndrome, CAH associated with mild hypermobility form of EDS. We genetically investigated a cohort of 81 adult patients (31 males, mean age 37,8 years +/- 9,8) with classic CAH for CAH-X. Patients genetically positive for CAH-X and unaffected CAH control patients matched for sex, age and BMI underwent a thorough clinical investigation including joint examination by Beighton 9-point scale, skin and neurological examination, by a standardised protocol of thransthoracic echocardiography and muscle ultrasound. In addition serum tenascin-X has been measured. In our cohort we identified one patient with CAH and EDS and 4 patients with CAH-X syndrome. All CAH-X patients had serum concentrations of tenascin-X below the normal range, however, not different from 35 unaffected CAH patients with regard to serum concentration. All 4 patients with CAH-X syndrome showed some associated clinical symptoms. Two had joint hypermobility detected by Beighton 9-point score. Two of four CAH-X patients showed cardiac abnormalities (mild mitral regurgitation in one patient and a surgically corrected common arterial trunk type I A in the other patient). The patient with CAH and EDS showed cardiac abnormalities in addition to typical EDS symptomatology. All 5 affected patients complained about back pain and showed foot malposition. Profound changes in muscle ultrasound were found in 60 % of patients with CAH-X syndrome (3/5) and in none of the controls (0/5). In conclusion, our data confirm the previously described prevalence of CAH-X. Beighton-score seems to be a quick and cheap screening instrument for CAH-X and should be performed in all patients with classic CAH, since protein level in serum cannot be used for screening for CAH-X-Syndrome. A stronger focus needs to be made on back pain and foot malposition as symptoms of CAH-X and echocardiography should be performed in all CAH-X patients. Therapy should depend on clinical symptoms in patients.