P450scc deficiency is a rare disorder that can present as acute adrenal insufficiency in infancy or childhood. ACTH and plasma renin activity are grossly elevated and adrenal steroids are inappropriately low or absent; the 46,XY patients have female ... P450scc deficiency is a rare disorder that can present as acute adrenal insufficiency in infancy or childhood. ACTH and plasma renin activity are grossly elevated and adrenal steroids are inappropriately low or absent; the 46,XY patients have female external genitalia, sometimes with clitoromegaly. The phenotypic spectrum ranges from prematurity, complete underandrogenization, and severe early-onset adrenal failure to term birth with clitoromegaly and later-onset adrenal failure (summary by Kim et al., 2008). Although hormonal and phenotypic features can resemble those of congenital lipoid adrenal hyperplasia (lipoid CAH; 201710), no patient with P450scc deficiency has been described with the massive adrenal enlargement typical of lipoid CAH (summary by Sahakitrungruang et al., 2011).
In studying patients with clinical features of lipoid CAH, Tajima et al. (2001) encountered an individual with a heterozygous mutation in P450scc. The patient presented at 4 years of age with lethargy and hyperpigmentation. Serum sodium and potassium ... In studying patients with clinical features of lipoid CAH, Tajima et al. (2001) encountered an individual with a heterozygous mutation in P450scc. The patient presented at 4 years of age with lethargy and hyperpigmentation. Serum sodium and potassium were both normal, but ACTH was extremely elevated, plasma aldosterone was elevated, and cortisol was low. The karyotype was 46,XY; the patient had clitoromegaly, no labial fusion, and separate vaginal and urethral openings. Computed tomographic and ultrasonographic examinations revealed no hypertrophy of the adrenal glands, and no uterus. Inguinal hernias had been diagnosed at 2 years of age, and inguinal masses had been resected at another clinic; Tajima et al. (2001) remarked that these were probably testes. Vaginography demonstrated a blind vaginal pouch. The patient was treated with hydrocortisone and 9-alpha-fluorocortisone; she became more active and the hyperpigmentation disappeared. Tajima et al. (2001) noted that the slower, more insidious onset of adrenal insufficiency and absence of enlarged adrenals were atypical of lipoid CAH. Katsumata et al. (2002) reported a child with congenital adrenal insufficiency who at the age of 7 months presented with hyperpigmentation and markedly elevated ACTH levels. At the age of 9 months, endocrinologic investigation revealed increased levels of ACTH and inappropriately normal levels of cortisol, aldosterone (high normal), and 17-alpha-hydroxyprogesterone. Electrolyte and plasma glucose levels were normal. The karyotype was 46,XX. Serum FSH (136530) approached the upper limit of normal, suggesting to Katsumata et al. (2002) the possibility of early ovarian insufficiency. The patient was successfully treated with hydrocortisone and fludrocortisone. Hiort et al. (2005) described a patient who presented with severe adrenal insufficiency in the first days of life. The child was born at 31 weeks' gestation. The karyotype was 46,XY; the baby's phenotype was unequivocally female with an unusual bronze skin color. Severe salt wasting was present in the neonatal period. Plasma ACTH and renin activity were extremely elevated. Plasma cortisol and 17-hydroxyprogesterone were undetectable. The child developed respiratory failure and was put on a respiratory ventilator. Treatment with hydrocortisone and fludrocortisone produced rapid improvement. Urinary steroid analysis at the age of 2 months did not demonstrate any excretion of 3-beta-hydroxy-5-ene steroids, suggesting complete loss of steroidogenesis. Ultrasound and magnetic resonance imaging failed to demonstrate gonads or adrenal tissue, and no uterus was seen. Al Kandari et al. (2006) reported a 46,XY phenotypic female who presented with life-threatening adrenal insufficiency at the age of 1 year 9 months. Generalized tanning of skin was present with markedly increased pigmentation of lips and gums, nape of neck, and abdomen. ACTH and plasma renin activity were extremely elevated, with very low or undetectable aldosterone. Treatment with hydrocortisone and fludrocortisone produced dramatic improvement. External genitalia were those of a normal female. Ultrasound and magnetic resonance imaging identified bilateral small gonads in inguinal regions, and adrenal glands of normal size. Genitogram showed short, blunt-ended vagina. Computed tomography revealed complete agenesis of the corpus callosum. Developmental milestones had been normal to this time. Kim et al. (2008) reviewed the findings in all patients reported to that time with P450scc deficiency, including the patients described by Tajima et al. (2001), Katsumata et al. (2002), Hiort et al. (2005), and Al Kandari et al. (2006), as well as 2 new patients. They noted that the phenotypic spectrum ranged from prematurity, complete underandrogenization, and severe early-onset adrenal failure resulting from severe loss-of-function mutations (Hiort et al., 2005) to term birth with clitoromegaly and later-onset adrenal failure resulting from partial deficiency (Tajima et al., 2001). In all cases ACTH and plasma renin activity were grossly elevated and adrenal steroids were inappropriately low or absent. In contradistinction to the massive adrenal enlargement typically seen in lipoid CAH, caused by mutation in StAR (600617), none of the 6 patients with P450scc deficiency had been reported to have adrenal hyperplasia. Rubtsov et al. (2009) described a patient with P450scc deficiency who showed no overt signs of adrenal insufficiency until the age of 9 years, when he began to experience episodes of weakness, dizziness, and vomiting. At birth he presented with bilateral cryptorchidism with inguinal testes, midshaft hypospadias, and bilateral talipes equinovarus. Karyotype was 46,XY. Ultrasound and magnetic resonance imaging showed normal-sized adrenals. The patient's twin, a phenotypic female, had died at age 2.5 years after an unknown illness presenting with weakness and cyanosis. Sahakitrungruang et al. (2011) described 2 sibs with hormonal findings suggesting nonclassic lipoid CAH who had mutations in P450scc that retained partial function. A 46,XY male presented with underdeveloped genitalia and partial adrenal insufficiency; his 46,XX sister presented with adrenal insufficiency. Both sibs had small adrenals with calcifications. Sahakitrungruang et al. (2011) noted that most cases of P450scc deficiency reported to that time had presented with the hormonal and phenotypic features of classic lipoid CAH, although none had been described with the massive adrenal enlargement typical of lipoid CAH. Patients with the 'classic' forms of both P450scc deficiency and lipoid CAH typically present with adrenal failure and salt wasting in infancy and are phenotypically female irrespective of genetic sex. The nonclassic forms of the disorders present with varying degrees of retained adrenal function and sexual development.
In studying patients with lipoid CAH (201710), Tajima et al. (2001) identified an individual with normal STAR (600617) and SF1 (184757) genes and a heterozygous mutation in CYP11A1 (118485.0001). The CYP11A1 mutation, an in-frame insertion of gly and ... In studying patients with lipoid CAH (201710), Tajima et al. (2001) identified an individual with normal STAR (600617) and SF1 (184757) genes and a heterozygous mutation in CYP11A1 (118485.0001). The CYP11A1 mutation, an in-frame insertion of gly and asp between asp271 and val272, was inserted into a catalytically active fusion protein of the CYP11A1 system and completely inactivated enzymatic activity. Because P450scc is normally a slow and inefficient enzyme, the authors proposed that P450scc haploinsufficiency resulted in subnormal responses to ACTH, so that recurrent ACTH stimulation led to a slow accumulation of adrenal cholesterol, eventually causing cellular damage. Thus, although homozygous absence of P450scc should be incompatible with term gestation, haploinsufficiency of P450scc causes a late-onset form of congenital lipoid adrenal hyperplasia that can be explained by the same 2-hit model that has been validated for congenital lipoid adrenal hyperplasia caused by STAR deficiency. Katsumata et al. (2002) identified compound heterozygosity for missense mutations in the CYP11A1 gene in a patient with congenital adrenal insufficiency. The patient's healthy mother was heterozygous for one of the mutations; the other mutation occurred de novo. Hiort et al. (2005) described a 46,XY patient with homozygosity for a single-nucleotide deletion in CYP11A1 (118485.0004), predicted to lead to a nonfunctional protein. In a 46,XY phenotypic female with adrenal insufficiency, the child of healthy consanguineous Syrian parents, Al Kandari et al. (2006) detected homozygosity for a missense mutation in the CYP11A1 gene. The mutant enzyme was shown to retain approximately 11% residual activity. Kim et al. (2008) screened nine 46,XY infants with adrenal failure and disordered sexual differentiation for mutations in the CYP11A1 gene and identified 2 patients, both compound heterozygotes, bringing the total number of patients with CYP11A1 mutations to 6. One carried the missense mutations L141W (118485.0007) and V415E (118485.0008), which retained 38% and 0% activity, respectively. The other carried the CYP11A1 frameshift mutation 835delA (118485.0004) (0% activity) and a splice site mutation, IVS3+(2-3)insT (118485.0006) that prevented correct splicing of P450scc mRNA. Rubtsov et al. (2009) reported a patient with P450scc deficiency with a mild phenotype who was homozygous for a missense mutation (118485.0009). He showed no signs of adrenal insufficiency until 9 years of age. Midshaft hypospadias and cryptorchidism were present at birth. That the hypospadias was midshaft led Rubtsov et al. (2009) to infer that androgen production had been substantial until at least the 14th week of gestation.