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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0434
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 11 6303-6309
Copyright © 2005 by The Endocrine Society

CLINICAL CASE SEMINAR

Phenotypic Features Associated with Mutations in Steroidogenic Acute Regulatory Protein

Amrit Bhangoo, Wen-Xia Gu, Steven Pavlakis, Henry Anhalt, Linda Heier, Svetlana Ten and J. Larry Jameson

Pediatric Endocrinology Division (A.B., S.T.) and Pediatric Neurology Division (S.P.), Infant’s and Children’s Hospital of Brooklyn at Maimonides, Brooklyn, New York 11219; Division of Endocrinology, Metabolism, and Molecular Medicine (W.-X.G., J.L.J.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Pediatric Endocrinology Division (H.A.), Saint Barnabas Medical Center, Livingston, New Jersey 07039; and Department of Radiology (L.H.), Weill Medical College of Cornell University, New York, New York 10021

Address all correspondence and requests for reprints to: Dr. Svetlana Ten, Pediatric Endocrinology Division, Infant’s and Children’s Hospital of Brooklyn at Maimonides, 977 48th Street, Brooklyn, New York 11219. E-mail: tenlana{at}aol.com.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Mutations in the gene encoding steroidogenic acute regulatory protein (StAR) are the most common cause of lipoid congenital adrenal hyperplasia (lipoid CAH), a disorder characterized by adrenal insufficiency and deficient gonadal steroid synthesis, resulting in female external genitalia in both genetic sexes.

Objective: We describe three new cases of lipoid CAH caused by novel mutations in the StAR gene.

Patients: An XY subject of Yemeni descent presented with adrenal insufficiency and severe undervirilization. Magnetic resonance imaging (MRI) of the brain showed enlarged subarachnoid spaces consistent with frontal and temporal atrophy. Two XX siblings of Palestinian descent presented with neonatal adrenal insufficiency. One had a borderline intelligence quotient and features of attention deficit hyperactivity disorder. MRI showed areas of supratentorial white matter lesions. In her sister, MRI revealed a Chiari-I malformation.

Results: The XY subject was found to have a missense mutation (R182C). Both XX siblings had a dinucleotide deletion at nucleotides 327–328 that induces a frame shift that truncates the StAR protein after 68 amino acids.

Conclusions: These cases broaden the spectrum of known StAR mutations and suggest that disorders of central nervous system development may arise because of StAR deficiency and/or the metabolic consequences of neonatal adrenal deficiency.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
LIPOID CONGENITAL ADRENAL hyperplasia (lipoid CAH) is a severe form of congenital adrenal insufficiency. It is characterized by lipid droplet accumulation in the cytoplasm of the adrenocortical cells and deficient production of glucocorticoids and mineralocorticoids. Most cases of lipoid CAH are caused by recessive mutations in the gene encoding steroidogenic acute regulatory protein (StAR), a protein that plays an essential role in cholesterol transfer from the outer to the inner mitochondrial membrane, thus providing the substrate for steroid hormone biosynthesis (1, 2, 3, 4). Once in the mitochondria, cholesterol is converted to pregnenolone by the cytochrome P450 side-chain cleavage (CYP11A1) enzyme, thereby initiating steroid biosynthesis. StAR mutations have been described most frequently in the Japanese and Palestinian populations, in part because certain mutations occur repeatedly, probably reflecting a founder effect (3, 5, 6). Although less common than mutations in StAR, mutations in CYP11A1 can also cause lipoid CAH (7, 8, 9).

The pathogenesis of lipoid CAH is thought to involve two distinct steps. The loss of StAR inhibits steroidogenesis because of impaired cholesterol transport. In addition, the accumulation of lipids is toxic to cells, ultimately leading to destruction of tissues, such as the adrenal and gonads, which actively synthesize steroids (3). In addition to adrenal insufficiency, XY subjects with StAR mutations develop as phenotypic females because testosterone synthesis is impaired during fetal development. The ovary in XX subjects is initially spared damage because steroidogenesis is delayed until the time of puberty, after which stimulation of steroidogenesis by the tropic hormones LH and FSH causes progressive damage to the ovary (10, 11).

In this report we describe the clinical features of three patients with StAR mutations. In addition to recognized features of lipoid CAH, each of these individuals has evidence of central nervous system (CNS) abnormalities. Although these abnormalities may be independent of StAR deficiency, the expression of StAR in the brain raises the possibility that it may play a role in brain development or function (12, 13, 14, 15).


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Hormonal testing

ACTH stimulation tests were performed with 0.25 mg Cortrosyn as previously described (16). Human chorionic gonadotropin stimulation tests were performed to assess the functional capacity of the testes as previously described (17). Steroids were analyzed by RIA after selective solvent extraction, column chromatography, hydrolysis, and HPLC tandem mass spectrometry (Esoterix, Calabasas Hill, CA).

DNA isolation and sequencing

DNA was extracted from peripheral leukocytes, and all seven exons of the StAR gene were amplified by PCR using primer pairs and conditions described previously (3). Direct DNA sequencing was performed using a dRhodamine sequencing kit and ABI 377 automated DNA sequencer (Applied Biosystems, Foster City, CA). Written informed consent was obtained from the parents to perform the mutational analysis.

Patient descriptions

Patient 1. A 19-month-old phenotypic female was born full term to healthy consanguineous parents of Yemeni descent (Fig. 1AGo). The infant was healthy until 5 months of age, when she presented to an emergency room with features of adrenal insufficiency, including severe dehydration, vomiting, hypotension, hypoglycemia (20 mg/dl; 1.1 mmol/liter), hyponatremia (114 mEq/liter), hyperkalemia (8 mEq/liter), and hyperpigmentation. She had normal female external genitalia without any signs of virilization. Testis-like structures were palpable bilaterally in the lower inguinal region. Cortisol measurements were low at baseline (2.5 µg/dl; 68.9 nmol/liter) and after ACTH stimulation (5.4 µg/dl; 148.9 nmol/liter). The basal ACTH level was elevated [769 pg/ml (170.8 pmol/liter); normal range, 10–60 (2.2–13.3)], consistent with primary adrenal insufficiency. An ultrasound of the abdomen revealed the absence of a uterus and no adrenal gland enlargement. A karyotype was 46,XY. The testosterone response to human chorionic gonadotropin stimulation was low (<3 ng/dl; 104 pmol/liter). Testicular biopsy (Fig. 2Go) revealed a normal tunica albuginea, and seminiferous tubules were reduced in size. There was an increased amount of cytoplasm in Sertoli cells (reminiscent of a Sertoli-only pattern) and a marked reduction in the number of germ cells. Magnetic resonance imaging (MRI) of the brain revealed enlarged subarachnoid spaces consistent with frontal and temporal atrophy (Fig. 3AGo). MR spectroscopy of the brain was normal. She had features of static encephalopathy and developmental delay. At age 19 months, she could stand only with support, could not walk, was hypotonic, and was unable to speak.



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  		FIG. 1. Pedigrees of families with StAR mutations. A, Pedigree of patient 1; B, pedigree of patients 2 and 3.

 


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  		FIG. 2. Testis histology in patient 1. A, Left testis shows reduced seminiferous tubule volume (arrow); B, right testis shows junction of semiferous tubules to epididymis; C and D, right testis shows reduced seminiferous tubule volume at high and low resolutions (arrow).

 


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  		FIG. 3. A, Patient 1; MRI axial T1 showing enlarged bifrontal subarachnoid spaces consistent with frontal atrophy (arrow). B, Patient 2; MRI axial T2 showing a white matter lesion (arrow). C, Patient 2; MRI axial T2 showing white matter lesion without interval change (arrow). D, Patient 3; MRI sagittal T1 showing tonsillar ectopia consistent with Chiari-I malformation (arrow).

 
Patients 2 and 3. These two patients are sisters born to healthy consanguineous parents of Palestinian descent (Fig. 1BGo).

Patient 2 was born via normal spontaneous vaginal delivery, full term, with a birth weight of 3458 g. She presented with adrenal insufficiency at 2 wk of age. Karyotype was 46,XX. She was hyperpigmented, and ACTH levels were noted to be increased at about 6 yr of age (ACTH, 936-3208 pg/ml; 207.9–712.8 pmol/liter). The ACTH level was suppressed to 44 pg/ml (9.7 pmol/liter) after administration of low-dose dexamethasone (0.5 mg, four times a day, for 2 d). She grew normally after hydrocortisone and florinef replacement. MRI of the brain showed focal supratentorial white matter lesions consistent with demyelination, dysmyelination, ischemic damage, or gliosis (Fig. 3Go, B and C). She has a full-scale intelligence quotient of 80 (2 SD below the mean) by the Wechsler Intelligence Scale for Children-Revised test, and met the criteria for attention deficit hyperactivity disorder on a Connor scale. Her neurological examination was otherwise normal.

Patient 3, the younger sister of patient 2, was the product of a full-term pregnancy, with a birth weight of 4370 g. She developed hypoglycemia (21 mg/dl; 1.16 mmol/liter) within the first 2 d of life and was started on glucocorticoids and mineralocorticoids when hyponatremia (127 mEq/liter) and hyperkalemia (7.8 mEq/liter) developed. An ACTH stimulation test performed on d 2 confirmed adrenal insufficiency with a low response of cortisol from 3.6–4.4 µg/dl (99.3–121.3 nmol/liter). ACTH had been elevated since birth (1041–5200 pg/ml; 231-1155.4 pmol/liter) and suppressed normally to 15 pg/ml (3.3 pmol/liter) after low-dose dexamethasone (0.5 mg, four times a day, for 2 d). The karyotype was 46,XX. MRI of the brain showed tonsillar ectopia consistent with Chiari-I malformation (Fig. 3DGo). Physical examination was notable for hyperpigmentation and a normal neurological exam, aside from the presence of a tic disorder. Academic achievement was normal for her age. Adrenal glands were of normal size on MRI in both sisters.

Parents and siblings of the three patients are heterozygotes. They are neurologically normal; MRI studies of the brain were not performed in the heterozygotes.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Mutation analysis of the StAR gene in patient 1 revealed a homozygous missense mutation in exon 5 at nucleotide 670 CGT->TGT, which changes the amino acid at position 182 from arginine to cysteine (GenBank accession no. DQ194261). Both parents are heterozygous for the nucleotide 670 C to T mutation (Fig. 1AGo). The steroidogenic factor-1 (SF-1) gene was also analyzed and the DNA sequence was normal.

Patients 2 and 3 have a deletion from nucleotide 327 to 328 (327_328delCT) in exon 3 of the StAR gene (GenBank accession no. DQ194260). This mutation predicts a truncation of the StAR protein after 68 amino acids, which eliminates key functional domains of the protein. Both parents and three other sisters are heterozygous for the same mutation (Fig. 1BGo).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Mutations in StAR are one of several causes of neonatal adrenal insufficiency (18). In addition to adrenal insufficiency, XY subjects with StAR deficiency are phenotypically female because of Leydig cell destruction and impaired testosterone production (3). Other genetic disorders can cause similar features. For example, mutations of SF-1 cause adrenal insufficiency and XY sex reversal (19, 20). SF-1 is a nuclear receptor required for adrenal and gonadal development, and it also regulates the expression of multiple steroidogenic enzyme genes (21). Mutations of the cholesterol side-chain cleavage enzyme gene (CYP11A1) result in blockage of steroidogenesis in both the adrenal gland and the gonad (7, 8, 9). Similarly, mutations of the 3ß-hydroxysteroid dehydrogenase gene (HSD3B2) impair cortisol and testosterone synthesis. Although DAX1 (dosage-sensitive sex reversal, AHC, critical region on the X chromosome, gene 1) mutations are associated with gonadotropin deficiency and testicular dysgenesis (22, 23), they do not cause severe undervirilization. Thus, the differential diagnosis of adrenal insufficiency and sex reversal includes multiple genetic disorders.

The phenotypic features of patients with reported StAR mutations are summarized in Table 1GoGo, allowing the features of the patients reported here to be placed into a broader context. A few observations emerge from this summary. As previously documented (3, 5, 24), StAR mutations are found in multiple ethnic groups, but are most commonly reported in individuals of Japanese, Korean, and Palestinian origin. The high prevalence of certain mutations (i.e. Q258X in Japanese and R182L in Palestinians) suggests a founder effect. In addition, certain regions of the StAR gene appear to be hot spots for new mutations. For example, R182 has been mutated to Leu, His, and Cys (3, 25, 26). R182 is proposed to form critical hydrogen bonds between two ß-sheet strands that stabilize the cholesterol-binding pocket (26). Most patients present within the first weeks of life, although there are examples where the diagnosis is not made until 1 yr of age (26, 27). Of the 85 reported cases, only 35 (41%) are in XX subjects, even though autosomal recessive transmission predicts an equal sex distribution. This finding may reflect an ascertainment bias, because XY subjects who present with undervirilization as well as adrenal insufficiency may be more likely to be considered for StAR mutations than XX subjects who only have adrenal insufficiency in infancy. Alternatively, there may be unrecognized differences in survival in utero or in the neonatal period before the diagnosis is made.


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  		TABLE 1. Characteristics of patients with mutations in the gene for StAR

 

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  		TABLE 1A. Continued

 
We identified neurological features in each of the three patients reported here. However, these features varied among the affected patients. Patient 1 has evidence of frontal and temporal atrophy and is developmentally delayed. Patient 2 has reduced intelligence quotient, attention deficit hyperactivity disorder, and white matter lesions consistent with demyelination. Patient 3 has Chiari-I malformation. Among the 82 patients in the published literature, two patients were described with mental retardation (28, 29). Two additional patients had neurological findings: one patient had cerebral atrophy, cerebral palsy, seizures, and mental retardation, and the twin sibling had hemiatrophy of the cerebrum in conjunction with other congenital anomalies (10).

StAR mRNA expression has been found in rat and human brains (12, 13, 14, 15). StAR protein is expressed in the glia and neurons in the pons, medium spiny neurons of the striatum, Purkinje cells of the cerebellum, multiple areas of the hippocampus and neocortex, and specific cell types in the thalamus. The neurosteroids are thought to play an important role in memory and sexual function (14). Neurosteroids also serve as trophic and survival factors in the nervous system (30). StAR is up-regulated in response to injury (15). These features raise the possibility that StAR may serve an important function in brain development or function. The Star gene has been knocked out in mice (31), but detailed studies of CNS histology or function have not been reported. However, Star may have important CNS functions that remain incompletely characterized. There have been few reported MRI studies in patients with other defects in steroidogenesis. Children with classic 21{alpha}-hydroxylase deficiency have been found to have smaller amygdala volumes compared with age- and sex-matched healthy children. White matter abnormalities and temporal lobe atrophy have also been noted on MRI images in children with CAH (32, 33), although these could be secondary to electrolyte abnormalities rather than a direct consequence of steroid deficiency. Thus, although the identified neurological abnormalities in the patients reported in this and other studies (10) could be related to loss of StAR activity, it is also possible that extreme electrolyte shifts or hypoglycemia, perhaps unrecognized, could secondarily affect neural development. Pending future studies, the cases reported here suggest that neurological function should be more closely evaluated in patients with StAR mutations, because CNS abnormalities may be an unrecognized feature of the lipoid CAH.


   Footnotes
 
This work was supported in part by National Institutes of Health Grant RO1-HD-044801 (to J.L.J.).

First Published Online August 23, 2005

Abbreviations: lipoid CAH, Congenital lipoid adrenal hyperplasia; CNS, central nervous system; MRI, magnetic resonance imaging; SF-1, steroidogenic factor-1; StAR, steroidogenic acute regulatory protein.

Received February 28, 2005.

Accepted August 11, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Stocco DM, Sodeman TC 1991 The 30-kDa mitochondrial proteins induced by hormone stimulation in MA-10 mouse Leydig tumor cells are processed from larger precursors. J Biol Chem 266:19731–19738[Abstract/Free Full Text]
  2. Clark BJ, Wells J, King SR, Stocco DM 1994 The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 269:28314–28322[Abstract/Free Full Text]
  3. Bose HS, Sugawara T, Strauss III JF, Miller WL 1996 The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med 335:1870–1878[Abstract/Free Full Text]
  4. Lin D, Sugawara T, Strauss III JF, 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[Abstract/Free Full Text]
  5. 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 III JF, 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[Abstract/Free Full Text]
  6. 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[Medline]
  7. 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[Abstract/Free Full Text]
  8. 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[Abstract/Free Full Text]
  9. Hiort O, Holterhus PM, Werner R, Marschke C, Hoppe U, Partsch CJ, Riepe FG, Achermann JC, Struve D 2005 Homozygous disruption of P450scc (CYP11A1) is associated with prematurity, complete 46,XY sex reversal and severe adrenal failure. J Clin Endocrinol Metab 90:538–541[Abstract/Free Full Text]
  10. Bose HS, Pescovitz OH, Miller WL 1997 Spontaneous feminization in a 46,XX female patient with congenital lipoid adrenal hyperplasia due to a homozygous frameshift mutation in the steroidogenic acute regulatory protein. J Clin Endocrinol Metab 82:1511–1515[Abstract/Free Full Text]
  11. Fujieda K, Tajima T, Nakae J, Sageshima S, Tachibana K, Suwa S, Sugawara T, Strauss III JF 1997 Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene. J Clin Invest 99:1265–1271[Medline]
  12. Furukawa A, Miyatake A, Ohnishi T, Ichikawa Y 1998 Steroidogenic acute regulatory protein (StAR) transcripts constitutively expressed in the adult rat central nervous system: colocalization of StAR, cytochrome P-450SCC (CYP XIA1), and 3ß-hydroxysteroid dehydrogenase in the rat brain. J Neurochem 71:2231–2238[Medline]
  13. Inoue T, Akahira J, Takashi S, Darnel AD, Kaneko C, Takahashi K, Hatori M, Shirane R, Kumabe T, Kurokawa Y, Satomi S, Sasano H 2002 Progesterone production and actions in the human central nervous system and neurogenic tumors. J Clin Endocrinol Metab 87:5325–5331[Abstract/Free Full Text]
  14. King SR, Manna PR, Ishii T, Syapin PJ, Ginsberg SD, Wilson K, Walsh LP, Parker KL, Stocco DM, Smith RG, Lamb DJ 2002 An essential component in steroid synthesis, the steroidogenic acute regulatory protein, is expressed in discrete regions of the brain. J Neurosci 22:10613–10620[Abstract/Free Full Text]
  15. Sierra A, Lavaque E, Perez-Martin M, Azcoitia I, Hales DB, Garcia-Segura LM 2003 Steroidogenic acute regulatory protein in the rat brain: cellular distribution, developmental regulation and overexpression after injury. Eur J Neurosci 18:1458–1467[CrossRef][Medline]
  16. Fisher DA 1998 Endocrinology test selection and interpretation. 2nd ed. San Juan Capistrano: Quest Diagnostics; 297
  17. Scurry MT, Bruton J, Barry KG 1971 The effect of chorionic gonadotropin on steroid excretion. Arch Intern Med 128:561–565[Abstract/Free Full Text]
  18. Ten S, New M, Maclaren NK 2001 Clinical review 130: Addison’s disease. J Clin Endocrinol Metab 86:2909–2922[Abstract/Free Full Text]
  19. Achermann JC, Ito M, Hindmarsh PC, Jameson JL 1999 A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 22:125–126[CrossRef][Medline]
  20. Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, Gurakan B, Jameson JL 2002 Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J Clin Endocrinol Metab 87:1829–1833[Abstract/Free Full Text]
  21. Luo X, Ikeda Y, Lala DS, Baity LA, Meade JC, Parker KL 1995 A cell-specific nuclear receptor plays essential roles in adrenal and gonadal development. Endocr Res 21:517–524[Medline]
  22. Kawabe K, Shikayama T, Tsuboi H, Oka S, Oba K, Yanase T, Nawata H, Morohashi K 1999 Dax-1 as one of the target genes of Ad4BP/SF-1. Mol Endocrinol 13:1267–1284[Abstract/Free Full Text]
  23. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ER, Meitingerm T, Monaco AP, Sassone-Corsi P, Camerino G 1994 An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372:635–641[CrossRef][Medline]
  24. 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[Abstract/Free Full Text]
  25. 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[CrossRef][Medline]
  26. 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[Abstract/Free Full Text]
  27. 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[Abstract/Free Full Text]
  28. Korsch E, Peter M, Hiort O, Sippell WG, Ure BM, Hauffa BP, Bergmann M 1999 Gonadal histology with testicular carcinoma in situ in a 15-year-old 46,XY female patient with a premature termination in the steroidogenic acute regulatory protein causing congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 84:1628–1632[Abstract/Free Full Text]
  29. Yoo HW, Kim GH 1998 Molecular and clinical characterization of Korean patients with congenital lipoid adrenal hyperplasia. J Pediatr Endocrinol Metab 11:707–711[Medline]
  30. Sierra A 2004 Neurosteroids: the StAR protein in the brain. J Neuroendocrinol 16:787–793[CrossRef][Medline]
  31. 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 USA 94:11540–11545[Abstract/Free Full Text]
  32. Merke DP, Fields JD, Keil MF, Vaituzis AC, Chrousos GP, Giedd JN 2003 Children with classic congenital adrenal hyperplasia have decreased amygdala volume: potential prenatal and postnatal hormonal effects. J Clin Endocrinol Metab 88:1760–1765[Abstract/Free Full Text]
  33. Nass R, Heier L, Moshang T, Oberfield S, George A, New MI, Speiser PW 1997 Magnetic resonance imaging in the congenital adrenal hyperplasia population: increased frequency of white-matter abnormalities and temporal lobe atrophy. J Child Neurol 12:181–186[Abstract/Free Full Text]
  34. Tee MK, Lin D, Sugawara T, Holt JA, Guiguen Y, Buckingham B, Strauss III JF, 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[Abstract/Free Full Text]
  35. 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[Abstract/Free Full Text]
  36. Katsumata N, Tanae A, Shinagawa T, Nagashima-Miyokawa A, Shimizu M, Yasunaga T, Tanaka T, Hibi I 1998 A novel frameshift mutation 840delA and a novel polymorphism D203A in the steroidogenic acute regulatory protein gene in a Japanese patient with congenital lipoid adrenal hyperplasia. Hum Mutat 11:331
  37. Katsumata N, Tanae A, Shinagawa T, Nagashima-Miyokawa A, Shimizu M, Yasunaga T, Tanaka T, Hibi I 1997 Detection of the missense mutation A218V in the steroidogenic acute regulatory protein gene of a Japanese patient with congenital lipoid adrenal hyperplasia. Clin Pediatr Endocrinol 6:33–37
  38. 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[Abstract/Free Full Text]
  39. Gassner HL, Toppari J, González SQ, Miller WL 2004 Near-miss apparent SIDS from adrenal crisis. J Pediatr 145:178–183[CrossRef][Medline]
  40. Nakarai T, Saikawa Y, Niida Y, Kanegane C, Honke K, Koizumi S 1999 Spontaneous feminization in a female patient with congenital adrenal lipoid hyperplasia due to a homozygous Q258X mutation in the steroidogenic acute regulatory protein gene. Pediatr Int 41:682–684[Medline]
  41. Shima M, Tanae A, Miki K, Katsumata N, Matsumoto S, Nakajima S, Harada T, Shinagawa T, Tanaka T, Okada S 2000 Mechanism for the development of ovarian cysts in patients with congenital lipoid adrenal hyperplasia. Eur J Endocrinol 142:274–279[Abstract]
  42. Tanae A, Katsumata N, Sato N, Horikawa R, Tanaka T 2000 Genetic and endocrinological evaluations of three 46,XX patients with congenital lipoid adrenal hyperplasia previously reported as having presented spontaneous puberty. Endocr J 47:629–634[Medline]
  43. Qiu WJ, Ye J, Han B, Han LS, Gu XF 2004 Molecular genetic analysis of congenital lipoid adrenal hyperplasia. Zhonghua Er Ke Za Zhi 42:585–588[Medline]
  44. Khoury K, Ducharme L, LeHoux JG 2004 Family of two patients with congenital lipoid adrenal hyperplasia due to StAR mutation. Endocr Res 30:925–929[CrossRef][Medline]



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D. Seto-Young, D. Avtanski, M. Strizhevsky, G. Parikh, P. Patel, J. Kaplun, K. Holcomb, Z. Rosenwaks, and L. Poretsky
Interactions among Peroxisome Proliferator Activated Receptor-{gamma}, Insulin Signaling Pathways, and Steroidogenic Acute Regulatory Protein in Human Ovarian Cells
J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2232 - 2239.
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