Salt-Losing 21-Hydroxylase Deficiency Caused by Double Homozygosity for Two 'Mild' Mutations
- Resource Type
- Authors
- Richard J. Auchus; Ephrat Levy-Lahad; JJ Liu; Haike Reznik-Wolf; Christoph Welsch; Jacob Ilany
- Source
- The Journal of clinical endocrinology and metabolism. 106(2)
- Subject
- 0301 basic medicine
Adult
Male
medicine.medical_specialty
Genotype
Endocrinology, Diabetes and Metabolism
Genetic counseling
Clinical Biochemistry
Mutation, Missense
Water-Electrolyte Imbalance
030209 endocrinology & metabolism
Context (language use)
Biochemistry
Severity of Illness Index
03 medical and health sciences
Consanguinity
0302 clinical medicine
Endocrinology
Internal medicine
medicine
Humans
Congenital adrenal hyperplasia
Family
Allele
Israel
Genetics
biology
Adrenal Hyperplasia, Congenital
Biochemistry (medical)
Homozygote
21-Hydroxylase
Heterozygote advantage
medicine.disease
Phenotype
Pedigree
030104 developmental biology
HEK293 Cells
biology.protein
Salts
Steroid 21-Hydroxylase
- Language
- ISSN
- 1945-7197
Context Congenital adrenal hyperplasia due to 21-hydroxylase deficiency presents with different severities that correlate with the genotype. The salt-losing phenotype requires 2 alleles with “severe” mutations. Case Description We present a case of salt-losing 21-hydroxylase deficiency that was found to be homozygous for 2 “mild” pathogenic variants: V281L and S301Y. Both in silico and heterologous expression functional analysis demonstrated that co-occurrence of these 2 mutations in cis severely impairs the function of the 21-hydroxylase enzyme. Conclusions This case has important implications for genetic counseling. Regarding this combination of 2 “mild” variants as having mild phenotypic effects could lead to inappropriate counseling of heterozygote carriers.