Laboratory of Pediatric Endocrinology

The Mount Sinai Laboratory of Pediatric Endocrinology offers direct DNA testing for 21-hydroxylase deficiency, 11beta-hydroxylase deficiency, 17alpha-hydroxylase deficiency and apparent mineralocorticoid excess. The testing for congenital adrenal hyperplasia utilizes PCR with allele specific oligonucleotides for 8 point mutations, and a Southern blot to detect a large gene deletion. Our panel of mutations picks up 95% of the mutations for 21-hydroxylase deficiency. Assuming the frequency of the classical form of the disease to be 1/13,000, the carrier frequency is 1/57. If no mutations are found by our analysis, the risk of being a carrier has been reduced to 1/1084.

Patients who are affected with 21-hydroxylase deficiency congenital adrenal hyperplasia are more likely to be compound heterozygotes than homozygotes. Thus, an individual who is affected with nonclassical 21-hydroxylase deficiency will very likely carry one nonclassical gene, and one gene for the more severe classical form of 21-hydroxylase deficiency. This presents the possibility that an offspring can inherit the classical gene from the affected parent, and if the unaffected carrier parent also has a classical gene, the offspring may present with the more severe, saltwasting or simple virilizing form of the disorder. To complicate matters further, genotype does not predict phenotype in all instances. We have seen saltwasters, simple virilizers and nonclassical affected all with the same combination of mutations.

Two of the point mutations for which we test are associated with the nonclassical, later onset, milder form of the disorder, specifically: Exon 1 (P30L) and Exon 7 (V281L). The Exon 7 (V281L) mutation is found with high frequency in the Ashkenazi Jewish population. The disease frequency is 1/27, and the carrier frequency is 1/3. Again, an affected individual is more likely to be a compound heterozygote, with an Exon 7 (V281L) mutation on one gene, and a mutation that is associated with the classical, prenatal onset, more severe form of the disorder, saltwasting or simple virilizing on the other. In the majority of cases the presentation will be that of the nonclassical form, yet in a few instances individuals have presented either with saltwasting or simple virilizing.

Prenatal samples cannot be accurately interpreted without parental and/or proband studies because of the possibility that one of the parents may carry a cluster of mutations on one allele or may carry a mutation that we cannot detect. We strongly suggest that family studies be performed prior to a pregnancy whenever possible. Prenatal studies can then be performed more quickly in most cases because the exact gene defects are known.

Dexamethasone has been shown to be effective in preventing or mitigating virilization or masculinization of the genitalia of affected female fetuses. A mother must begin taking the medication prior to 8 or 9 weeks in order to avert labial fusion, however clitoromegaly will be mitigated throughout the gestational period. The recommended protocol is to begin the medication in at risk pregnancies as early as possible, pending a determination either that the fetus is a 46XY or that the fetus is an unaffected 46XX. The dosage that we have found to be effective is calculated as follows: 20 micrograms per kilogram of pre-pregnancy weight, not to exceed .5mg three times per day (for a maximum total of 1.5mg per day).

Even if the Dexamethasone has not been started early enough to prevent labial fusion, clitoromegaly can be prevented or significantly lessened. The advantage is that where there is complete virilization, two or more surgeries are generally required to correct the problem; even when Dexamethasone is started later than 8 or 9 weeks gestational age, clitoromegaly which continues for the duration of the pregnancy can be sufficiently reduced to avoid the need for clitoral recission, leaving only a vaginoplasty to be done.

It is extremely important that the intake information forms provided to you be thoroughly filled in. Where testing is done for diagnostic purposes it is critical that biochemical values such as the results of ACTH stimulation tests be provided. If these are available for the proband, please do forward the data with any specimen sent for carrier testing. In addition to provision of background documentation, including a complete pedigree with names and birthdates for the nuclear family as well as ethnicity of both parents, it is required that payment arrangements be made prior to performance of DNA analysis. We do not bill insurance companies directly unless prior authorization has been obtained. We ask for full payment to be sent with the specimen, or that alternative arrangements be made with our biller. We do accept credit cards and are happy to do institutional billing, particularly where an out of state individual is a medicare recipient.

If you have any additional questions or concerns, please feel to call Susan Baker, PhD, at (212) 241-5070.

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