When Monozygotic Twins Are Not Identical: Phenotype Discordance in Twins with Congenital Adrenal Hyperplasia

Presentation Number: LB SUN 50
Date of Presentation: April 2nd, 2017

Kathryn Foley*1, Michelle Kluge2 and Evan Graber1
1Nemours/AI Dupont Hospital for Children, Wilmington, DE, 2Mayo Clinic, Rochester, MN



Congenital adrenal hyperplasia (CAH) is most commonly caused by 21-hydroxylase deficiency due to biallelic mutations in the CYP21A2 gene. There are three clinical forms (salt-wasting, simple-virilizing and non-classical) which represent varying degrees of enzymatic deficiency. Reports have shown genotype to be a reasonable predictor of phenotype. Our case demonstrates the phenotypic variability of genetically identical twins due to apparent somatic mosaicism.

Clinical Case: 7-day-old female presented with elevated 17OHP (86.4 ng/mL, n <30) on newborn screen. Serum studies were consistent with salt-wasting CAH: 17OHP 7840 ng/dL (<630), Na 131 mEq/L (133-145), K 9.7 mEq/L (3.6-5.2). She was started on hydrocortisone and fludrocortisone with resolution of hyperkalemia and gradual improvement of 17OHP. Physical examination revealed hyperpigmentation of the labia majora, a urogenital sinus, and no clitoromegaly. Her sister had negative newborn screen, normal electrolytes, and normal serum 17OHP on numerous occasions. She had a urogenital sinus on physical examination.

The patients were reported to be monochorionic, diamniotic twins. Zygosity testing confirmed that the twins were monozygotic. Genetic testing for CYP21A2 mutations using mini-sequencing revealed that both twins were heterozygous for the Int2G mutation. CYP21A2 full gene sequencing by Sanger followed by multiplex ligation-dependent probe amplification (MLPA) of blood samples from both patients and their parents revealed that the patients are apparently mosaic for two different genotypes: Cell line 1: Int2G and a wildtype copy of the CYP21A2 gene, Cell line 2: Int2G and a CYP21A1P/CYP21A2 hybrid. The hybrid most commonly results from the 30 kb deletion mutation commonly seen in CAH. The mother’s analysis revealed heterozygosity for the Int2G mutation. Father’s analysis revealed no evidence of disease-causing mutations. The first cell line is associated with CAH carrier status. The most common phenotype associated with the second cell line is salt-wasting CAH, though a minority of cases of simple-virilizing CAH has been reported (1).

Since both twins were mosaic for these two cell lines, the deletion of the paternal CYP21A2 gene most likely occurred during postzygotic cell division, but prior to twinning. The differing phenotypes are most likely due to either the amount of each cell line present in each twin or the cell line that gave rise to critical tissue (such as the adrenal glands) in each twin.

Conclusion: This is the first reported case of monozygotic twins presenting with discordant CAH phenotypes due to somatic mosaicsm. This case reinforces genotype-phenotype variability seen in CAH and demonstrates the importance of full gene analysis follow-up when targeted testing does not demonstrate genotype-phenotype concordance. The importance of family studies is also highlighted by this case.


Nothing to Disclose: KF, MK, EG