Genotype-Phenotype Correlation and Clinical Findings in 145 Patients with Congenital Adrenal Hyperplasia: Single Centre Experience

Introduction: Congenital adrenal hyperplasia (CAH) is agroup of autosomal recessive disorders of adrenal steroidogenesis.Aim: The purpose of this study was to investigate genotypephenotypecorrelation, clinical findings and long-term outcomesin patients with CAH due to 11-hydroxylase deficiency(11-OHD) and 21-hydroxylase deficiency (21-OHD).Paients and methods: 145 genetically proven 21-OHD and11-OHD patients were included in this study.Endocrinological,clinical and molecular findings were recorded at presentation andfollow-up.Results: Out of 145 patients diagnosed with CAH,122 had(83.6%) 21OHD[66 salt wasting (SW),40 simple virilizing(SV),16 non-classic(NC)]; 23(16.4 %)had 11-OHD. SW 21-OHDwas the most common and the earliest diagnosed CAH type.Consanguinity rate was high in all groups. Due to severe virilizationand late diagnosis, some of the XX patients were raised as male.Frequency of SGA was higher in SV and NC 21-OHD(p=0.048).While 29 different mutations were detected in 21 OHD, therewere 12 different mutations in 11-OHD. The most commonmutation was IVS-2 not only in the all patients with 21-OHD,but also in the SW(34.7%)and SV(34.4%). Furthermore, the mostcommon mutation in NC 21-OHD was p.V282L(34.4%) andp.Leu299Pro(25%) in 11-OHD.Positive predictive value(PPV)for all 21-OHD patients was 78.4%. PPV in subgroups(accordingto enzyme activity) was 80.8% in group0 (‘Null’=Enzymeactivity:0%), 100% in groupA(1%), 62.5% in groupB(1-2%), and65.2% in groupC (20-50%). There was no genotype-phenotypecorrelation in patients with 11-OHD. Mean value of thedifference between the adult height and the target height for those,who have reached adult height was -0.42±0.73 in SW; -0.91±1.35 inSV, - 0,14±0,94 in NC, and -0,71±1,43 in 11-OHD. The pubertalspurt was not sufficient in classic 21-OHD. The rate of earlypuberty was 24.2% in SW, 40% in SV, 18.8% in NC 21-OHD and56.5% in 11-OHD(p=0.003 in all groups). Frequency of testicularadrenal rest tumour (TART) was 29.4% for SW, 33.3% for SV and40% for 11-OHD. While the obesity rate in all subgroups of21-OHD(32.8% in SW,33.3% in SV, 31.2% in NC) was significantlyhigh, it was low in the 11-OHD (5%)(p=0.010).Conclusion: In Turkey the rate of 11-OHD was high. The rateof mutation diversity for both 21-OHD and 11-OHD was veryhigh. The positive predictive value of genotype-phenotype correlationin 21-OHD was good

The R110C mutation in Notch3 causes variable clinical features in two Turkish families with CADASIL syndrome

Mutations in Notch3 gene are responsible for the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). It is a late onset neurological disorder recognized by recurrent strokes and dementia. We describe here the clinical and molecular findings of three unrelated Turkish families with CADASIL syndrome. Two of the families were identified to have the same mutation, p.R110C (c.C328T), located in exon 3 of the Notch3 gene. Interestingly, the phenotypic expression of the disease in these two families was markedly different in severity and age of onset implicating additional genetic and/or non-genetic modulating factors involved in the pathogenesis. In addition, we identified the novel p.C201R (c.T60IC) mutation in exon 4 of the Notch3 gene in a proband of the third family with two consecutive stroke-like episodes and typical MRI findings