Inheritance Pattern of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)
The inheritance pattern is autosomal recessive (Answer D). Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is one of the most common autosomal recessive inherited diseases in humans, with both parents being carriers and each affected child inheriting two mutated copies of the CYP21A2 gene 1, 2.
Genetic Basis
The CYP21A2 gene responsible for 21-hydroxylase is located on chromosome 6 (6p21.3) and is HLA-linked 1, 3.
The disease requires inheritance of two mutated alleles—one from each parent—to manifest clinically, which is the defining characteristic of autosomal recessive inheritance 1, 2.
Three alleles can be combined in various ways to produce individuals who are either unaffected, heterozygote carriers, or affected with classical or nonclassical disease 1.
Epidemiology Supporting Autosomal Recessive Pattern
The classical form appears in 1:5,000 to 1:15,000 live births in North America and Europe, consistent with autosomal recessive carrier frequencies 1.
The nonclassical form occurs in approximately 0.2% of the general white population, also following autosomal recessive inheritance patterns 1.
21-hydroxylase deficiency accounts for 95-99% of all congenital adrenal hyperplasia cases 4.
Molecular Mechanisms
Multiple mutation types occur including complete gene deletions, large gene conversions, and pseudogene-derived mutations 1, 3.
The most frequent mutations identified include Intron 2, G318X, and 8 bp deletion 4.
Compound heterozygotes (two different mutations) are found in affected patients, all corresponding to classic forms of the disease 4.
Clinical Correlation with Inheritance
The syndrome demonstrates considerable genotype-phenotype correlation, with the type of CYP21A2 gene mutation affecting the severity of 21-hydroxylase deficiency 2.
A male newborn presenting with hyponatremia (112 mmol/L), hyperkalemia (9.3 mmol/L), and metabolic acidosis represents the salt-wasting form, which requires two severe mutations for manifestation 5.
The laboratory findings in the question—sodium 127 mmol/L, potassium 6.8 mmol/L, bicarbonate 15 mmol/L, and hypoglycemia—are classic for salt-wasting congenital adrenal hyperplasia requiring bilateral gene mutations 6, 5.
Genetic Counseling Implications
Both parents of an affected child are obligate carriers (heterozygotes) 1, 2.
Each subsequent pregnancy has a 25% risk of producing an affected child, 50% risk of a carrier, and 25% risk of an unaffected non-carrier 1.
Molecular diagnosis offers confirmation of diagnosis, prediction of phenotype, and enables accurate genetic counseling 4.