21-hydroxylase deficiency accounts for >90% of congenital adrenal hyperplasia (CAH) cases. 11β-hydroxylase deficiency (11β-OHD) – caused by CYP11B1 mutation – accounts for 5%–8% of CAH cases worldwide and occurs in approximately 1 in 100,000 births; its prevalence is high in areas where consanguineous marriage prevails. Further, more than 50% of patients with classic 11β-OHD may present with high blood pressure, developing early in childhood. Most reported CYP11B1 mutations are missense/nonsense mutations.
Herein, we discuss a 2-year, 8-month-old male patient with 11β-OHD, presenting with pseudoprecocious puberty and hypertension. We identified a novel variant of homozygous mutation in intron 5 of CYP11B1 (NM_000497.3) (c. 955-1G>C).
A previously healthy 2-year, 8-month-old Saudi male patient was referred to our pediatric endocrinology clinic because of pubic hair development and progressive darkening of the skin color over a period of several months. He is the first child of a young consanguineous couple. The family history was negative for endocrine disorders, including CAH and precocious puberty.
Physical examination revealed a high blood pressure of 139/90 mmHg. His weight was 24.4 kg (>97th percentile, Z-score +4.8) and height was 115.4 cm (>97th percentile, Z-score +6.2).
There was obvious hyperpigmentation of the skin. Examination of his genitalia revealed Tanner stage 3 pubic hair and stretched penile length of 12 cm; however, the testes were prepubertal (2 ml bilaterally). The systemic examination was otherwise normal.
Initial biochemical parameters are shown in Table 1. Notably, the random serum 11-deoxycorticosterone (DOC) level (90.3 ng/dL) was almost thrice the upper limit of the normal range, which is 2–34 ng/dL, for his age. Despite an adrenocorticotropic hormone (ACTH) level of >2000 pg/mL, an immunoassay showed his serum cortisol as only 285 nmol/L. Basal-luteinizing hormone and follicle-stimulating hormone (FSH) levels were prepubertal. His bone age was 13 years at the diagnosis [Figure 1].
Based on the patient’s high blood pressure, which is typical in classic 11β-OHD, genetic testing for CYP11B1 was performed to further confirm the diagnosis. The genomic DNA was fragmented; the coding exons of CYP11B1 and corresponding exon-intron boundaries were enriched using the NimbleGen Sequence Capture technology (Roche, Basel, Switzerland) before being amplified and sequenced simultaneously using the HiSeq 1500 system (Illumina, San Diego, CA, USA). Genetic analysis revealed a novel mutation in intron 5 of CYP11B1 (NM_000497.3) (c. 955-1G>C), found in the homozygous state. This was further confirmed using Sanger sequencing [Figure 2]. In silico analysis predicted that this variant leads to significant alteration in mRNA splicing by introducing an altered acceptor splice site, whereby it is labeled as a “likely pathogenic” variant. Notably, this variant has not been previously reported. In our case, genetic testing confirmed the 11β-OHD diagnosis, whereas testing for 21-hydroxylase deficiency yielded negative results.
The patient was prescribed oral hydrocortisone, 5 mg in the morning and 7.5 mg in the evening (14 mg/m2/day) and followed-up in the pediatric endocrinology clinic. Due to the advanced bone age, he also received 7.5 mg leuprolide acetate injections every 4 weeks, anticipating imminent gonadotropin releasing hormone-dependent precocious puberty. His blood pressure improved to 117/67 mmHg and 113/68 mmHg during two subsequent visits, and his skin hyperpigmentation improved significantly. No further progress was observed in the pubertal development. The posttreatment DOC and testosterone levels decreased to 10.5 ng/dL and to below 0.45 nmol/L, respectively. Signed informed consent was obtained from the patient’s father for publishing this case report.
Here, we report a novel homozygous variant in intron 5 of CYP11B1 (NM_000497.3) (c. 955-1G>C) in a 2-year, 8-month-old male who presented with pseudoprecocious puberty and hypertension.
Although 11β-OHD is typically diagnosed at birth in genotypic female newborns based on ambiguous genitalia, nonclassic forms can present later in childhood with premature adrenarche or pseudoprecocious puberty and development of hypertension in young children. Until the 1950s, a small percentage of patients with CAH was considered to develop hypertension rather than mineralocorticoid deficiency. Hypertension occurs in 11β-OHD because of the accumulation of DOC and 11-deoxycortisol at supraphysiological levels. Nevertheless, salt wasting may occur in some cases, particularly in the neonatal period. Notably, individuals with the rare syndrome of glucocorticoid resistance may present with clinical features similar to those of nonclassic 11 β-OHD. A low or inappropriately normal cortisol level, along with a markedly high ACTH level, is a differentiating factor between the two conditions. In the present case, the serum cortisol level was 285 nmol/L, despite an extremely high ACTH level (>2000 pg/mL). In the most severe cases of primary generalized glucocorticoid resistance, serum cortisol concentrations may be up to seven times higher than the upper limit of the normal range. In addition, compared with liquid chromatography-tandem mass spectrometry analysis, immunoassays (particularly old-generation immunoassays) can overestimate serum cortisol levels owing to cross-reaction with cortisol precursors, specifically in the conditions of elevated serum DOC.
In a recent study, three novel CYP11B1 variants were reported. Furthermore, a recent case series from Saudi Arabia reported seven novel CYP11B1 variants; however, none of them matched the mutation identified in our case.
In conclusion, genetic testing of CYP11B1 is readily available and a useful tool to confirm 11 β-OHD diagnosis. As 11 β-OHD is the second most common form of CAH, its diagnosis should be considered in any child with pseudoprecocious puberty and hypertension. Novel CYP11B1 variants have been reported worldwide, and the novel gene mutation identified in this study adds to the database of pathogenic CYP11B1 variants.
- 11 β-Hydroxylase deficiency (11 β-OHD) is the second most common form of CAH, resulting in 5%−8% of all CAH cases
- 11 β-OHD should be considered in any child with precocious puberty or hyperandrogenism and hypertension
- Genetic analysis of CYP11B1 is readily accessible, and several recent reports of novel CYP11B1 variants occurring worldwide have been published. Our findings broaden the spectrum of the existing database of pathogenic CYP11B1 variants.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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