Abstract
Background11β-Hydroxylase deficiency (11OHD) is a common form of congenital adrenal hyperplasia that has been shown to result from inactivating CYP11B1 mutations, and pathogenic CYP11B2/CYP11B1 chimeras contribute to a minority of cases. Heterozygote cases (chimeras combined with missense mutation) are very rare, and genetic analysis of these cases is difficult.Case presentationWe describe an 11OHD patient presenting with precocious pseudopuberty and hypokalemia hypertension who harbored a chimeric CYP11B2/CYP11B1 with a novel breakage point located at g.9559–9742 of CYP11B2. Interestingly, the other allele exhibited a new mutation, p.L340P, in CYP11B1. Bioinformatics and molecular dynamics simulation indicated that p.L340P decreased the stability and changed the surface configuration of 11β-hydroxylase, indicating a disease-causing mutation. Further pedigree study, PCR and next-generation sequencing indicated that the proband carried both the chimera and p.L340P, and coexistence of the two increased the severity of 11OHD in this family. After treatment with combined medications, blood pressure and clinical parameters improved.ConclusionsOur results suggest that chimera screening and CYP11B1 mutation screening should be simultaneously conducted, and pedigree study is necessary.
Highlights
Congenital adrenal hyperplasia (CAH) is one of the most common inheritable metabolic disorders and is characterized by virilization, precocious pseudopuberty and accelerated skeletal maturation, progressing in some cases to severe dehydration, shock, and even death [1, 2]
Our results suggest that chimera screening and CYP11B1 mutation screening should be simultaneously conducted, and pedigree study is necessary
One common variant of CAH is 11β-hydroxylase deficiency (11OHD), driven by CYP11B1 inactivating mutations clustered in exons 2, 6, 7 and 8 [4], and approximately 148 mutations have been reported in the Human Gene Mutation
Summary
Congenital adrenal hyperplasia (CAH) is one of the most common inheritable metabolic disorders and is characterized by virilization, precocious pseudopuberty and accelerated skeletal maturation, progressing in some cases to severe dehydration, shock, and even death [1, 2]. Bioinformatics and molecular dynamics simulation indicated that CYP11B1mut altered the free energy, and change the stability and conformation of the protein by driving the uncoiling of a partial helical structure into a loop structure, leading to positive group migration and pocket structure enlargement (Additional file 2: Table S2, Figure 1e, f ), suggesting that the mutation could be pathogenic. His mother did not carry this pathogenic mutation (Fig. 1g), indicating the proband only carried the point mutation on one allele, with the pathogenicity of the other allele unclear. This study was approved by the ethics committees of Xinqiao Hospital, Third Military Medical University, and informed consent was obtained from the patient’s mother (Additional file 7)
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