Mutational Analysis of Uncommon Forms of Congenital Adrenal Hyperplasia

Program: Abstracts - Orals, Poster Previews, and Posters
Session: SUN 203-235-Steroid Hormone Actions, Biosynthesis and Metabolism (posters)
Bench to Bedside
Sunday, April 3, 2016: 1:15 PM-3:15 PM
Exhibit/Poster Hall (BCEC)

Poster Board SUN 209
Meshael Alswailem1, Ebtesam Qassem2, Afaf S Alsagheir3, Bassam Bin Abbas2 and Ali Saeed Alzahrani*4
1King Faisal Specialist Hospital & Research Centre, Riyadh, 2King Faisal Specialist Hospital & Research Centre, 3king Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, 4King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

Congenital adrenal hyperplasia (CAH) is a common hereditary condition.  It is caused by 21-Hydroxylase deficiency (CYP21A2) in > 90% of cases.  Other forms are much less common. Consanguinity and genetic diseases are common in Saudi Arabia and mutational patterns of genetic disorders are frequently unique.  In this report, we present our findings of mutational analysis of a large series of non-21 hydroxylase CAH

Patients and Methods

We studied patients (pts) with uncommon forms of CAH.   Diagnosis of these cases was based on clinical features, hormonal profile, radiological findings and chromosomal karyotyping.  Mutational analysis was performed on genomic DNA isolated from peripheral leucocytes using PCR and Dideoxy Termination Sanger sequencing method.  For each gene, we designed primers or used previously published primers to amplify all exons and exon-intron boundaries. The sequence was analyzed using Mutation Surveyor and compared with NCBI and Ensemble.  We also used HGMD to check novelty of mutations and Polyphen2, Mutation Taster and Provean programs to check the potential damaging effect on the protein.  We also screened 200 healthy controls for any novel mutation detected to exclude possibility of polymorphisms.


 A total of 27 pts was studied as follows: 3 with lipoid CAH (StAR), 9 with 3-β hydroxysteroid dehydrogenase type 2 (HSD3B2), 11 with 11-β hydroxylase (CYP11B1), 3 siblings (sibs) with 17 hydroxysteroid dehydrogenase type 3 (HSD17B3) and 1 with 17-α hydroxylase. Mutational testing revealed:

Lipoid CAH (StAR):2 unrelated pts had a previously reported missense homozygous mutation c.545G>A (p.182 R>A) and one pt had a novel non-sense homozygous mutation c.790C>T (p.264Q>X)

HSD3B2 mutations:family 1 (3 sibs) and the unrelated family 2 ( 4 sibs) had a previously described homozygous mutation c.1000C>T (P.334Q>X).  Family 3 (2 sibs) had a previously described homozygous non-sense mutation c.1003C>T (p. 335R>X).

CYP11B1 mutations:  Family 1 (4 sibs) had a novel insertion mutation (c. 53_54insT).  This insertion of Thiamine leads to frameshift and truncation downstream.  Three unrelated families with 4 children had a previously described missense homozygous mutation c.1343G>C (p. 488R>P). Another family with 2 sibs had a previously described missense mutation c. 1394A>T (p.465 H>L).  Another family with one child had a nonsense homozygous mutation (p.260W>X).

HSD17B3 mutations: One family with 3 sibs had a previously described missense mutation c.238C>T (p.80R>W)

CYP17A1 mutations: One pt had a homozygous missense mutation c.1247G>A (p.416R>H).  This mutation was described in a heterozygous form in a pt with 17-α hydroxylase deficiency with combined heterozygous mutation.

Conclusions:  The mutational pattern of uncommon forms of CAH is characterized by a number of novel mutations and recurrent mutations in some unrelated families that might be founder mutations.

Nothing to Disclose: MA, EQ, ASA, BB, ASA

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