The maintenance of human pregnancy requires progesterone, which suppresses uterine contractility, permitting gestation to proceed to term (25
), and interruption of the action of progesterone will induce abortion. As P450scc is the only known enzyme that can convert cholesterol to pregnenolone (1
), it has been thought that inactivating mutations of P450scc or of any other factor required for placental synthesis of progesterone would be incompatible with term human gestation (26
). Consistent with this, no mutations have been reported in ferredoxin, ferredoxin reductase, or the placental isozyme of 3β-hydroxysteroid dehydrogenase (3βHSDI). However, four previous patients with mutations in P450scc have been described, to which we now add two more. Review of these cases shows imprecise correlation between the clinical findings and the enzymology of the P450scc mutations identified in these individuals (). Patients 1 (27
), 2 (28
) and 4 (30
) all came to medical attention well after the newborn period (9 months to 4 years of age) and all had P450scc lesions that retained substantial activity: Patient 1 was a manifesting heterozygote for a mutation devoid of activity and hence would be predicted to have about 50% of activity (from the normal allele). Patient 2 carried a missense mutation (R353W) with about 8% of activity on one allele and the other allele carried a P450scc mRNA splicing defect that generated a small amount of correctly spliced RNA, but the proportion of correctly to incorrectly spliced RNA was not quantitated. Patient 4 had two missense mutations, A359V and R353W, reported to retain 11.7 and 2.8% of activity, respectively, even though the same group reported that R353W retained 8.1% of activity in their report of Patient 2. By contrast, Patient 3 was homozygous for the frameshift mutation c835delA, predicted to cause the premature stop codon L288X; we have now tested this frameshift in vitro,
as it was also found in Patient 6, and have shown that it is devoid of detectable activity. Consistent with the lack of detectable enzymatic activity using an in vitro
assay, Patient 3 had the most severe clinical course, being born at 31 weeks and having profound neonatal adrenal failure.
Summary of six reported patients with P450scc deficiency.
Patients 5 and 6, reported here, also had adrenal failure in the first week of life, but had succeeded in reaching term gestation, suggesting that some placental progesterone was synthesized throughout pregnancy. Patient 6 had mutations that eliminated detectable activity, yet she reached term gestation. However, the functional data in Patient 5 are more confusing. The L141W mutation retained 38.5% of activity so that in the heterozygous state one would expect about 19% of net activity. This is substantially greater activity than was seen in Patients 2 and 4, yet the clinical presentation was substantially more severe. In sum, the data in the six reported patients with P450scc deficiency () show a spectrum of clinical presentations from intractable early labor and prematurity to adrenal insufficiency in early childhood. The phenotype/genotype correlations are poor, but the precise reasons for this are unknown.
P450scc deficiency is a novel, rare disorder that can present as acute adrenal insufficiency at any time from infancy to early childhood. In all cases, 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. In contradistinction to the massive adrenal enlargement typically seen in congenital lipoid adrenal hyperplasia caused by mutations in StAR (7
), none of the six patients with P450scc deficiency has been reported to have adrenal hyperplasia. Although a small number of patients with StAR mutations have normal-sized adrenals (42
), this may be useful in distinguishing these disorders. Affected tissue has not been available to determine whether P450scc-deficient adrenals can respond to ACTH. With the exception of Patient 3 (29
) and Patient 6, described here, other reported patients have had at least one allele that conferred some activity. This would seem to explain the term gestation, as P450scc is needed to make the progesterone required to maintain pregnancy. Patient 3 (29
) remains enigmatic; the survival of that pregnancy to 31 weeks may have been caused by an unusually long survival of the progesterone biosynthetic capacity of the maternal corpus luteum, which eventually involuted, causing premature labor. Several patients have had other clinical problems (absent corpus callosum in Patient 4, tethered spinal cord in Patient 6, short stature in Patients 3 (O. Hiort, personal communication) and 6, but a link to P450scc deficiency is not established for any of these conditions. Additional cases, especially those studied hormonally during pregnancy, may provide further information about the hormonal control of parturition and illuminate the pathophysiology of P450scc deficiency.