Lipoid congenital adrenal hyperplasia (LCAH) is a severe genetic disorder that affects the steroid hormone biosynthesis. The production of all adrenal and gonadal steroids is significantly impaired in LCAH patients due to a defect in the conversion of cholesterol to pregnenolone - the first step in adrenal and gonadal steroidogenesis. The resultant adrenal deficiency of mineralocorticoid and glucocorticoid hormones usually presents during the first weeks of life with salt loss, shock, hyponatremia, hyperkalemia, and hypoglycemia. Immediate signs of mineralocorticoid deficiency are seen in some newborns, but others remain asymptomatic for months. Generalized hyperpigmentation due to proopiomelanocortin hypersecretion is observed in nearly all patients. In addition to adrenal insufficiency, affected patients of both sexes develop female external genitalia due to impaired testosterone synthesis during fetal development. Early intervention and treatment with appropriate mineralocorticoid and glucocorticoid replacement therapy is crucial for LCAH patients.
LCAH has been described in most ethnic groups. It is common among the Japanese, Korean, and Palestinian Arab populations, but rare elsewhere.
Mutations in STAR gene is associated with LCAH. STAR gene encodes steroidogenic acute regulatory protein (StAR), which is essential for steroid biosynthesis. Normally, StAR accelerates the transport of cholesterol (the substrate for steroid hormone biosynthesis) from the outer mitochondrial membrane to the inner mitochondrial membrane, where the cytochrome P450 side-chain cleavage (CYP11A1) enzyme converts cholesterol to pregnenolone. In patients with LCAH, mutations in the STAR gene produce a partial to non-functional StAR protein that lacks the ability to bind cholesterol and to transfer it to mitochondria, thereby impairing steroid synthesis. In addition, this leads to accumulation of cholesterol in the cytoplasm and an engorgement of the cell with lipid droplets which are toxic to cells and could lead to destruction of tissues, such as the adrenal and gonads, which actively synthesize steroids.
Gucev et al. (2013) described two siblings (46,XX and 46,XY) who presented in the first month of their lives with severe glucocorticoid and mineralocorticoid deficiency and with a normal female external genitalia. There was no evidence of adrenal hyperplasia on abdominal US, prompting a diagnosis of P450scc deficiency. However, no mutations were found in the CYP11A1 gene. Sequencing of the STAR gene identified a mutation, confirming the diagnosis of Lipoid Congenital Adrenal Hyperplasia.
Achermann et al (2001) described two sisters affected with LACH in a consanguineous family from Libya. The proband, a phenotypic female, was hyperpigmented at birth and developed vomiting and diarrhea during the first days of life. Her karyotype was 46XY. Examination revealed a complete lack of virilization. A younger sibling was also found to be hyperpigmented at birth and developed similar symptoms. Her karyotype was 46XX. Investigations were consistent with a diagnosis of primary adrenal failure, and both children responded well to glucocorticoid and mineralocorticoid replacement therapy. Direct DNA sequencing of the STAR gene revealed a homozygous T to G transversion within the splice donor site of exon 1 (IVS1+2T>G, g.66) in both affected individuals.
Bose et al. (2000) described the clinical features of a Palestinian patient with lipoid CAH. This patient was the third surviving child of a consanguineous marriage with twin premature girls, a term male who died in infancy, and two spontaneous abortions. The mother had low estradiol levels throughout pregnancy, but delivered a full-term normal appearing female infant. At two weeks of age she was hospitalized for congenital Addison's disease with electrolyte abnormalities, low cortisol, androgen, aldosterone, and 17-hydroxyprogesterone levels, and hypotensive shock. PRA was high, but adrenal steroids were minimal after ACTH infusion. Treatment with hydrocortisone and fludrocortisones was effective, but the child had poor growth. Her karyotype was XX. At molecular level, she was found to be homozygous for a novel replacement of T for C at nucleotide 703 in exon 5 of the STAR gene, resulting in the premature stop codon R193X.
Bhangoo et al. (2005) described the clinical features of two sisters with lipoid congenital adrenal hyperplasia, born to healthy consanguineous parents of Palestinian descent. The first patient, the eldest sibling in the family, was born via normal spontaneous vaginal delivery, full term, with a birth weight of 3,458 grams. She presented with adrenal insufficiency at 2 weeks of age. Karyotype was 46,XX. She was hyperpigmented, and ACTH levels were noted to be increased at about 6 years 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 days). 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. 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. The second patient, the younger sister of the first patient, was the product of a full-term pregnancy, with a birth weight of 4,370 grams. She developed hypoglycemia (21 mg/dl; 1.16 mmol/liter) within the first 2 days 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 day two confirmed adrenal insufficiency with a low response of cortisol from 3.6-4.4 microgram/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 days). The karyotype was 46,XX. MRI of the brain showed tonsillar ectopia consistent with Chiari-I malformation. 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. At the molecular level, both patients were found to be homozygous for a dinucleotide deletion (327_328delCT) in exon 3 of the STAR gene. The parents and three other sisters were found to be heterozygous for this mutation. The parents were neurologically normal.
In a family from Qatar, Achermann et al (2001) described an LACH patient with a phenotypic female who presented with pallor and failure to thrive at 3 weeks of age. She was hyponatremic (122 mmol/L) and hyperkalemic (6.1 mmol/L). Cortisol was within the normal range (19 mg/dl), but she had elevated ACTH (642 mg/dl) and plasma renin activity (5.7 mg/ml/h). Her karyotype was 46XY. Bilateral gonadectomy performed at 4 months of age revealed immature testes. At 8 years of age, she developed a mucoepidermoid adenocarcinoma of the right parotid gland. DNA sequencing revealed a homozygous R182H missense mutation in StAR in the patient, which was confirmed by MaeIII digestion. Immunohistology of the testis showed low-level StAR expression in the uncanalated seminiferous tubules, but no evidence of StAR expression in the interstitium. No StAR expression was detected in the parotid tumor in this patient by immunohistochemistry or in normal human or mouse parotid by RT-PCR.
Chen et al. (2005) described eight patients with lipoid CAH from six families of native Saudi Arabian descent. Five families are from the eastern (Ash-Sharqiyah) province, whereas one family originates from a different part of Saudi Arabia (the northern or AlHudud Ash-Shamaliyah Province). The parents in the first family with one patient are cousins. The father's brother is also married to the mother's sister, and that couple has an apparently affected 15-year-old daughter, who was not available for study. The parents in the second and third family, with two patients for each, are first cousins; furthermore, the mother in the second family is the first cousin of the father in the third family, and the father in the second family is the brother of the mother in the third family. The parents from northern Saudi Arabia (the fifth family with one patient) are also first cousins. With the exception of the patient from the fourth family, all were healthy infants who grew well for the first few months of life. The patients were first diagnosed at 1-14 months of age (median, 4-7 months; mean, 7 months). Patients from the first, second and third families are remarkable in surviving from 7-14 months of age without hormonal replacement therapy. Except for this late age of onset of clinical symptoms, the clinical and hormonal findings in these patients are wholly typical of lipoid CAH. All patients presented with a typical salt-losing crisis, evidenced by dehydration, signs of poor growth, recent weight loss, poor feeding, hyponatremia, hyperkalemia, and generalized hyperpigmentation. Hypoglycemia (glucose, <70 mg/dI) was seen in five of the patients. All had profoundly elevated ACTH values and very low cortisol values. Pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, testosterone, androstenedione, and dehydroepiandrosterone sulfate were all low in those patients in whom it was measured. Five patients were 46,XY and three were 46,XX. Four of the five 46,XY patients had palpable inguinal masses. The five 46,XY patients underwent surgical exploration, and histologically proven testes were removed in all cases. At molecular level, the patient from the fifth family was found to be homozygous for the StAR mutation M144R, and the other seven patients were found to be homozygous for the StAR mutation R182H. Each mutation was recreated in a human StAR cDNA expression vector and found to be wholly inactive in a standard assay of COS-1 cells cotransfected with the cholesterol side-chain cleavage enzyme system, indicating that the loss of all assayable activity in vitro correlated poorly with the later onset of clinical symptoms in these patients. Chen et al. (2005) concluded that Lipoid CAH may present much later in life than previously thought.
Bhangoo et al. (2005) described the clinical features of a 19-month-old phenotypic female affected with lipoid congenital adrenal hyperplasia. She was born full term to healthy consanguineous parents of Yemeni descent. 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 (2.5microgram/dl; 68.9 nmol/liter) and after ACTH stimulation (5.4 microgram/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 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. 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. At the molecular level, this patient was found to be homozygous for the R182C missense mutation in exon 5 of the StAR gene. The neurologically normal parents were found to be heterozygous for this mutation.