Methemoglobinemia And Ambiguous Genitalia

A number sign (#) is used with this entry because of evidence that methemoglobinemia and ambiguous genitalia is caused by homozygous mutation in the microsomal cytochrome b5 gene (CYB5A; 613218) on chromosome 18q22.

Description

Methemoglobinemia and ambiguous genitalia is due to isolated 17,20-lyase deficiency, defined by apparently normal 17-alpha-hydroxylase activity but severely reduced 17,20-lyase activity of the CYP17A1 enzyme (609300), which results in sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve. The clinical phenotype is characterized by male undermasculinization, with absent or disturbed pubertal development in both 46,XY and 46,XX individuals. Mild to severe methemoglobinemia has been reported in these patients (Idkowiak et al., 2012).

Other autosomal recessive methemoglobinemias include types I and II (see 250800), caused by mutation in the CYB5R3 gene (613213). Isolated 17,20-lyase deficiency can also be caused by mutation in the CYP17A1 gene (609300), and mutation in the POR gene can manifest clinically as isolated 17,20-lyase deficiency (see 124015.0016).

Clinical Features

Hegesh et al. (1986) described the highly instructive case of a female Yemenite Jewish baby who turned blue at 7 days of age and was persistently cyanotic for her 26 years to the time of report. There were no neurologic symptoms. Giordano et al. (1994) reported in full on the findings in this patient, who they stated exhibited female genitalia at birth but was subsequently determined to be a male pseudohermaphrodite. The patient was said to be the only example of 'type IV methemoglobinemia' that had been described. Hegesh et al. (1986) had reported that the parents and 6 sibs had normal methemoglobin levels, whereas those in the patient varied between 12% and 19%. The patient's erythrocyte cytochrome b5 levels were about 25% of those found in other family members. Polyacrylamide gel electrophoresis of cytochrome b5 from the patient and family members demonstrated no differences in mobility. Giordano et al. (1994) suggested that the pseudohermaphroditism was also caused by the cytochrome b5 defect. Androgen deficiencies due to defects in 17-alpha-hydroxylase activity are a known cause of pseudohermaphroditism in males (202110), and cytochrome b5 has been shown to participate in 17-alpha hydroxylation in adrenal steroidogenesis by serving as an electron donor.

Kok et al. (2010) reported a 46,XY infant, born to consanguineous parents, who had ambiguous genitalia at birth. The phallus measured 1.5 cm, and there was a bifid scrotum with bilateral palpable gonads and a scrotal urethral meatus. Ultrasound did not visualize a uterus or vagina. The patient was given a diagnosis of 46,XY disorder of sexual differentiation (DSD) and male gender was assigned. Hormone analysis at age 3 months showed markedly elevated luteinizing hormone (LH; see 152780) with a subnormal rise of testosterone after human chorionic gonadotropin (hCG; see 118860) stimulation. Cortisol levels were normal and rose appropriately after adrenocorticotropic hormone (ACTH) stimulation; 17-hydroxyprogesterone levels were basally elevated and rose significantly with ACTH, whereas levels of androstenedione and dehydroepiandrosterone (DHEA) were normal and did not increase. Plasma ACTH was normal and serum DHEA sulfate was nondetectable. In addition, at age 11 months, the patient had a methemoglobin level that was 4 times the upper limit of normal, but he showed no clinical signs of methemoglobinemia. His unaffected first-cousin parents had normal responses to ACTH stimulation testing. A presumptive diagnosis of isolated 17,20-lyase deficiency was made in the proband.

Idkowiak et al. (2012) studied 3 Pakistani sibs with 46,XY karyotypes and varying degrees of undermasculinization, ranging from clitoral enlargement and intraabdominal testes in an affected sib raised as female, to ambiguous genitalia including micropenis, hypospadias, bifid scrotum, and inguinal testes in 2 affected sibs raised as male. All 3 sibs had elevated methemoglobin levels that were at least 4 times the upper limit of normal, but their methemoglobinemia was clinically inapparent, with no evidence of cyanosis, dyspnea, or respiratory distress. Quantitative gas chromatography/mass spectrometry analysis of urinary steroid metabolites showed low androgen metabolite excretion with increased excretion of the 17-alpha-hydroxypregnenolone metabolite pregnenetriol, suggestive of 17,20-lyase deficiency; concurrently, mineralocorticoid and glucocorticoid metabolite excretion appeared normal, suggesting preserved 17-alpha-hydroxylase activity. In addition, the ratio of corticosterone over cortisol metabolites was normal, whereas the ratio of 17-alpha-hydroxyprogesterone over androgen metabolites was significantly elevated, consistent with isolated 17,20-lyase deficiency.

Biochemical Features

Laboratory studies of the patient reported by Hegesh et al. (1986) showed that adding the cofactor cytochrome b5 restored methemoglobin reductase activity. Cytochrome b5 was very low in the patient's red cells but was normal in the healthy unrelated parents and in the sibs. No abnormality of electrophoresis or heat stability was found. The findings in this patient provided confirmation for the conclusion of Hultquist and Passon (1971) that cytochrome b5 is required for methemoglobin reduction in vivo. The lack of neurologic symptoms in the patient suggested that membrane-bound cytochrome b5 levels in nucleated cells, at least those of the brain, were normal (Charache, 1986).

Molecular Genetics

In a patient with methemoglobinemia and ambiguous genitalia, originally reported by Hegesh et al. (1986), Steggles et al. (1992) identified a homozygous splice site mutation in the CYB5A gene (613218.0001), resulting in premature termination of the protein. Steggles et al. (1992) indicated that whereas more than 300 patients had been reported with hereditary methemoglobinemia types I or II (250800), this patient represented the only reported case of what they designated 'methemoglobinemia type IV.'

In a 46,XY infant with elevated methemoglobin and ambiguous genitalia due to apparent isolated 17,20-lyase deficiency, Kok et al. (2010) sequenced the CYP17A1 and CYB5A genes and identified homozygosity for a nonsense mutation in the CYB5A gene (W27X; 613218.0002) for which his unaffected first-cousin parents were heterozygous.

In 3 Pakistani sibs who were 46,XY and exhibited methemoglobinemia with ambiguous genitalia, Idkowiak et al. (2012) sequenced the CYP17A1, POR, and CYB5A genes, and identified homozygosity for a missense mutation in CYB5A (H44L; 613218.0003) that segregated fully with disease in the family. Functional analysis demonstrated greatly reduced CYP17A1 17,20-lyase activity in the presence of the H44L mutant.