Abstract
Congenital lipoid adrenal hyperplasia (lipoid CAH) is a rare autosomal recessive disorder of adrenal and gonadal steroidogenesis. It is most frequently caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. Patients with lipoid CAH typically present with adrenal crisis in early infancy, and those with a 46,XY karyotype have female genitalia. However, it has been recently recognized that the phenotype can be quite variable, in that adrenal insufficiency is detected later in life and patients may have partially masculinized or even normal male genitalia. We report a patient assigned and reared as a female with a 46,XY karyotype and with a homozygous intron 2 (c.178+1G>C) splice site mutation of the StAR gene, which is a novel mutation that causes lipoid CAH. Her clinical presentation was somewhat atypical for a patient with classic lipoid CAH, marked by mild masculinization of the genitalia, detectable adrenal steroids at baseline, and ability to tolerate the stress of a surgical procedure with anesthesia without receiving glucocorticoid treatment. Conclusion: There is significant phenotypic variability among patients with lipoid CAH. While splice site mutations in the StAR gene lead to premature translational termination, resulting in truncated and non-functional proteins, there is phenotypic variability among patients with such mutations. Our patient appears to have the more atypical phenotype compared to reported patients with similar mutations. The molecular mechanism underlying this heterogeneity remains unclear.
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Achermann JC, Meeks JJ, Jeffs B, Das U, Clayton PE, Brook CG, Jameson JL (2001) Molecular and structural analysis of two novel StAR mutations in patients with lipoid congenital adrenal hyperplasia. Mol Genet Metab 73:354–357
Arakane F, Sugawara T, Nishino H, Liu Z, Holt JA, Pain D, Stocco DM, Miller WL, Strauss JF 3rd (1996) Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial import sequence: implications for the mechanism of StAR action. Proc Natl Acad Sci U S A 93:13731–13736
Arakane F, Kallen CB, Watari H, Foster JA, Sepuri NB, Pain D, Stayrook SE, Lewis M, Gerton GL, Strauss JF 3rd (1998) The mechanism of action of steroidogenic acute regulatory protein (StAR). StAR acts on the outside of mitochondria to stimulate steroidogenesis. J Biol Chem 273:16339–16345
Baker BY, Lin L, Kim CJ, Raza J, Smith CP, Miller WL, Achermann JC (2006) Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab 91:4781–4785
Bens S, Mohn A, Yuksel B, Kulle AE, Michalek M, Chiarelli F, Nuri Ozbek M, Leuschner I, Grotzinger J, Holterhus PM, Riepe FG (2010) Congenital lipoid adrenal hyperplasia: functional characterization of three novel mutations in the STAR gene. J Clin Endocrinol Metab 95:1301–1308
Bhangoo A, Gu WX, Pavlakis S, Anhalt H, Heier L, Ten S, Jameson JL (2005) Phenotypic features associated with mutations in steroidogenic acute regulatory protein. J Clin Endocrinol Metab 90:6303–6309
Bose HS, Sugawara T, Strauss JF 3rd, Miller WL (1996) The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med 335:1870–1878
Bose HS, Sato S, Aisenberg J, Shalev SA, Matsuo N, Miller WL (2000) Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 85:3636–3639
Caron KM, Soo SC, Wetsel WC, Stocco DM, Clark BJ, Parker KL (1997) Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Proc Natl Acad Sci U S A 94:11540–11545
Chen X, Baker BY, Abduljabbar MA, Miller WL (2005) A genetic isolate of congenital lipoid adrenal hyperplasia with atypical clinical findings. J Clin Endocrinol Metab 90:835–840
Fluck CE, Maret A, Mallet D, Portrat-Doyen S, Achermann JC, Leheup B, Theintz GE, Mullis PE, Morel Y (2005) A novel mutation L260P of the steroidogenic acute regulatory protein gene in three unrelated patients of Swiss ancestry with congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 90:5304–5308
Gassner HL, Toppari J, Quinteiro Gonzalez S, Miller WL (2004) Near-miss apparent SIDS from adrenal crisis. J Pediatr 145:178–183
Gonzalez AA, Reyes ML, Carvajal CA, Tobar JA, Mosso LM, Baquedano P, Solar A, Venegas A, Fardella CE (2004) Congenital lipoid adrenal hyperplasia caused by a novel splicing mutation in the gene for the steroidogenic acute regulatory protein. J Clin Endocrinol Metab 89:946–951
Hiort O, Holterhus PM, Werner R, Marschke C, Hoppe U, Partsch CJ, Riepe FG, Achermann JC, Struve D (2005) Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46, XY sex reversal, and severe adrenal failure. J Clin Endocrinol Metab 90:538–541
Katsumata N, Tanae A, Shinagawa T, Nagashima-Miyokawa A, Shimizu M, Yasunaga T, Tanaka T, Hibi I (1997) Homozygous Q258X mutation in the steroidogenic acute regulatory gene in a Japanese patient with congenital lipoid adrenal hyperplasia. Endocr J 44:441–446
Katsumata N, Kawada Y, Yamamoto Y, Noda M, Nimura A, Horikawa R, Tanaka T (1999) A novel compound heterozygous mutation in the steroidogenic acute regulatory protein gene in a patient with congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 84:3983–3987
Katsumata N, Ohtake M, Hojo T, Ogawa E, Hara T, Sato N, Tanaka T (2002) Compound heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans. J Clin Endocrinol Metab 87:3808–3813
Kim CJ, Lin Z, Huang N, Quigley CA, AvRuskin TW, Achermann JC, Miller WL (2008) Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. J Clin Endocrinol Metab 93:696–702
Krawczak M, Reiss J, Cooper DN (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 90:41–54
Lin D, Sugawara T, Strauss JF 3rd, Clark BJ, Stocco DM, Saenger P, Rogol A, Miller WL (1995) Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267:1828–1831
Miller WL, Strauss JF 3rd (1999) Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR. J Steroid Biochem Mol Biol 69:131–141
Miller WL (2007) Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochim Biophys Acta 1771:663–676
Mount SM (1982) A catalogue of splice junction sequences. Nucleic Acids Res 10:459–472
Nakae J, Tajima T, Sugawara T, Arakane F, Hanaki K, Hotsubo T, Igarashi N, Igarashi Y, Ishii T, Koda N, Kondo T, Kohno H, Nakagawa Y, Tachibana K, Takeshima Y, Tsubouchi K, Strauss JF 3rd, Fujieda K (1997) Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia. Hum Mol Genet 6:571–576
Okuyama E, Nishi N, Onishi S, Itoh S, Ishii Y, Miyanaka H, Fujita K, Ichikawa Y (1997) A novel splicing junction mutation in the gene for the steroidogenic acute regulatory protein causes congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 82:2337–2342
Sahakitrungruang T, Soccio RE, Lang-Muritano M, Walker JM, Achermann JC, Miller WL (2010) Clinical, genetic, and functional characterization of four patients carrying partial loss-of-function mutations in the steroidogenic acute regulatory protein (StAR). J Clin Endocrinol Metab 95:3352–3359
Tajima T, Fujieda K, Kouda N, Nakae J, Miller WL (2001) Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc) gene in a patient with 46, XY sex reversal and adrenal insufficiency. J Clin Endocrinol Metab 86:3820–3825
Tee MK, Lin D, Sugawara T, Holt JA, Guiguen Y, Buckingham B, Strauss JF 3rd, Miller WL (1995) T–>A transversion 11 bp from a splice acceptor site in the human gene for steroidogenic acute regulatory protein causes congenital lipoid adrenal hyperplasia. Hum Mol Genet 4:2299–2305
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Lekarev, O., Mallet, D., Yuen, T. et al. Congenital lipoid adrenal hyperplasia (a rare form of adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory protein gene. Eur J Pediatr 171, 787–793 (2012). https://doi.org/10.1007/s00431-011-1620-5
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DOI: https://doi.org/10.1007/s00431-011-1620-5