Genetic and Hormonal Characterization of Cryptic 21-Hydroxylase Deficiency*

Levine, Lenore S.; Dupont, Bo; Lorenzen, Franziska; Pang, Songya; Pollack, Marilyn S.; Oberfield, Sharon E.; Kohn, Brenda; Lerner, Alan J.; Cacciari, E; Mantero, Franco; Cassio, Alessandra; Scaroni, Carla; Chiumello, G; Rondanini, G. F.; Gargantini, L; Giovannelli, G; Virdis, R; Bartolotta, E; Migliori, C; Pintor, C.; Tato, Luciano; Barboni, F; New, Maria I.

doi:10.1210/jcem-53-6-1193

Cited by 74 publications

(16 citation statements)

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“…The LO form may be either symptomatic, causing virilization in late childhood or at puberty, or asymptomatic. The latter, also called the cryptic form, was initially described in families with the classic form, the authors suggested that the asymptomatic patients were compound heterozygotes for a classic and a cryptogenic gene (Levine et al 1981;Levine and Pang 1992).…”

Section: Introductionmentioning

confidence: 99%

Point mutations in Italian patients with classic, non-classic, and cryptic forms of steroid 21-hydroxylase deficiency

et al. 1996

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Seventy-three Italian patients affected by steroid 21-hydroxylase deficiency were studied by a PCR-allele-specific oligonucleotide protocol in order to evaluate the presence of eight known point mutations. The majority of chromosomes were found to carry point gene conversions normally present in the pseudogene. Within the classic form, the most common mutations were the splicing mutation A/C-655 to G in intron 2 (34.2%), the nonsense mutation C-1993 to T in exon 8 (10.8%), and the missense mutation T-999 to A in exon 4 (10%). Within the non-classic form, the missense mutation G-1683 to T was the most common (57.7%). Other mutations were either absent, such as the three clustered missense mutations T-1380, T-1383, T-1389 to A in exon 6, or very rare, like the 1761 + T in exon 7 and the C-2108 to T in exon 8. Family genotyping revealed the presence of ten asymptomatic parents carrying mutations in both chromosomes, thus identifying the gene defect in cryptic subjects. Interestingly, the same mutations were found in both symptomatic and asymptomatic forms.

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Section: Introductionmentioning

confidence: 99%

Point mutations in Italian patients with classic, non-classic, and cryptic forms of steroid 21-hydroxylase deficiency

et al. 1996

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“…Steroid 21-hydroxylase deficiency accounts for 90 -95% of CAH cases (1,2). The symptoms of steroid 21-hydroxylase deficiency are classified into three distinct clinical phenotypes: the salt-wasting (SW), simple virilizing (SV), and nonclassical (NC) forms (1)(2)(3)(4)(5)(6)(7). SW and SV forms of steroid 21-hydroxylase deficiency produce masculinization of the external genitalia in girls and, therefore, can be detected at birth in girls by careful examination of the external genitalia.…”

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confidence: 99%

“…The NC form presents later in life as premature pubarche, hirsutism, acne, or menstrual abnormalities. The NC form may also be cryptic, which denotes asymptomatic individuals with the identical biochemical and genetic abnormalities as family members with the symptomatic NC form (2,3,(5)(6)(7).…”

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confidence: 99%

Molecular Basis of Nonclassical Steroid 21-Hydroxylase Deficiency Detected by Neonatal Mass Screening in Japan

Tajima

Fukui

Nakae

et al. 1997

The Journal of Clinical Endocrinology & Metabolism

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Since 1989, neonatal mass screening for congenital adrenal hyperplasia (CAH) has been performed in Japan, and the frequency of the classical form of 21-hydroxylase deficiency was found to be nearly identical to that in other countries. However, it has not yet been determined whether our mass screening program can detect the nonclassical (NC) form. From 1991 to 1994, about 4,500,000 infants underwent CAH mass screening in Japan. During this period, we identified by screening 2 siblings and 2 unrelated patients who had mild elevation of serum 17-hydroxyprogesterone levels at 5 days of age, but who revealed no symptoms of CAH. They were diagnosed as having probable NC steroid 21-hydroxylase deficiency. To clarify the molecular basis of NC CAH detectable by neonatal screening in Japan, the steroid 21-hydroxylase (CYP21) genes from these cases were analyzed. The 2 siblings (patients 1 and 2) had I172N and R356W mutations in 1 allele and in the other allele had local gene conversion, including the P30L mutation in exon 1. Patient 3, who was unrelated, had gene conversion encoding the same P30L mutation in 1 allele and in the other allele had an intron 2 mutation (668-12 A-->G), causing aberrant ribonucleic acid splicing, and the R356W mutation. Patient 4, also a compound heterozygote, had the R356W and 707del8 mutations. The estimated rate of detection of the NC form by mass screening (1:1,100,000) seemed low compare to the established detection rate for the classical form (1:18,000). As all of our 4 patients were compound heterozygotes with at least 1 allele bearing 1 or more mutations associated with classic CAH, it may be difficult to detect NC cases carrying only NC-associated alleles using our current neonatal mass screening methods.

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“…According to genotype, the predicted phenotype of case 2 is the more severe classic type [19,20]. These discrepancies between genotype and phenotype are often observed in nonclassical 21-OHD [18], the precise reason for this has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Clinical Course of Patients with Nonclassical 21-hydroxylase Deficiency (21-OHD) Diagnosed in Infancy and Childhood

et al. 2008

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Abstract. We report four cases of nonclassical 21-hydroxylase deficiency (21-OHD) diagnosed in neonate or early childhood. The four patients comprised a 6-year, 5-month-old male (case 1); a 3-year, 10-month-old female (case 2); a 13-year, 11-month-old female (case 3) and a 17-year, 1-month-old male (case 4). Cases 3 and 4 were siblings. None had any signs of virilization or salt wasting at birth. 21-OHD was diagnosed using ACTH loading test and other adrenal steroid evaluations. Mutations of the CYP21 gene were detected in all patients. Three patients (cases 1, 3 and 4) had positive results in neonatal mass screening. Cases 1 and 2 showed no apparent signs of virilizaton and were observed without conventional treatment. In cases 3 and 4, because of increased growth velocity and accelerated bone maturation, hydrocortisone administration was initiated from their late infantile period. In spite of hydrocortisone treatment, in case 4, the final height of 159.7 cm was less than his predicted final height. Besides he revealed adrenal insufficiency at the age of 9 years and 2 months old caused by viral infection. Hydrocortisone supplementation therapy may cause adrenal insufficiency in nonclassical patients due to suppression of the hypothalamus-pituitary-adrenal axis. The clinical courses in these cases were various, and it was difficult to predict the appearance of any symptoms of virilization. Careful observation is necessary.

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Genetic and Hormonal Characterization of Cryptic 21-Hydroxylase Deficiency*

Cited by 74 publications

References 0 publications

Point mutations in Italian patients with classic, non-classic, and cryptic forms of steroid 21-hydroxylase deficiency

Point mutations in Italian patients with classic, non-classic, and cryptic forms of steroid 21-hydroxylase deficiency

Molecular Basis of Nonclassical Steroid 21-Hydroxylase Deficiency Detected by Neonatal Mass Screening in Japan

Clinical Course of Patients with Nonclassical 21-hydroxylase Deficiency (21-OHD) Diagnosed in Infancy and Childhood

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