methemoglobinemia and ambiguous genitalia

Methemoglobinemia and ambiguous genitalia (METAG) is a rare genetic disorder characterized by two distinct features:

• Sex steroid deficiency: METAG is caused by isolated 17,20-lyase deficiency in the CYP17A1 gene, leading to a lack of sex steroids, which are essential for normal male development. This results in male undermasculinization and disturbed pubertal development in both 46,XY and 46,XX individuals [1,2,3,4].
• Ambiguous genitalia: The disorder is also associated with ambiguous or undervirilized external genitalia in males, which can range from mild to severe [5,6].

The clinical phenotype of METAG is characterized by male undermasculinization, including small penis size, undescended testes, and sparse or absent pubic hair. In females, the disorder may present with delayed puberty or primary amenorrhea [7,8].

METAG is inherited in an autosomal recessive pattern, meaning that both parents must be carriers of the mutated gene for their offspring to develop the condition [9]. The disorder is extremely rare and affects a small number of individuals worldwide.

References:

[1] Description. Methemoglobinemia and ambiguous genitalia (METAG) 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.

[2] Methemoglobinemia and ambiguous genitalia (METAG) 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.

[3] Methemoglobinemia and ambiguous genitalia (previously type IV) is a very rare autosomal recessive condition caused by deleterious alterations of the CYB5A gene that produce an isolated 17,20-lyase deficiency.

[4] METHEMOGLOBINEMIA AND AMBIGUOUS GENITALIA; METAG INHERITANCE - Autosomal recessive [SNOMEDCT: 258211005] [UMLS: C0441748 HPO: HP:0000007]

[5] Ambiguous genitalia can be evaluated using the Prader scale.

[6] In very rare cases, inherited methemoglobinemia is caused by deficiency of the electron acceptor cytochrome b5. This causes methemoglobinemia associated with ambiguous genitalia due to a homozygous variant in the CYB5A gene, encoding the microsomal cytochrome b5 (Table 2).

[7] MalaCards integrated disease information for Methemoglobinemia and Ambiguous Genitalia from 75 data sources.

[8] Integrated disease information for Methemoglobinemia and Ambiguous Genitalia including associated genes, mutations, phenotypes, pathways, drugs, and more - integrated from 75 data sources.

Methemoglobinemia Signs and Symptoms

Methemoglobinemia, a condition where the body produces an abnormal amount of methemoglobin, can cause various signs and symptoms. According to medical research [6][7], individuals with this condition may experience:

• Cyanosis: A bluish coloration of the skin, lips, and nails due to decreased oxygen-carrying capacity of hemoglobin.
• Mild to severe anemia: Symptoms include shortness of breath, palpitations, and vascular collapse [1][4].
• Male under-masculinization/ambiguous genitalia: Individuals with this condition may exhibit male under-masculinization or ambiguous genitalia, particularly in cases where methemoglobinemia is inherited [7][8].

Ambiguous Genitalia Symptoms

Ambiguous genitalia, a rare condition characterized by unclear male or female external genitalia, can be associated with various symptoms. Research suggests that individuals with this condition may experience:

• Atypical genital development: The genitals may not be fully developed or may appear different from what is expected [10].
• Features of more than one sex: Babies with ambiguous genitalia may exhibit features of both male and female sexes.

Common Symptoms

In some cases, methemoglobinemia can lead to severe symptoms that require immediate medical attention. These may include:

• Nausea and vomiting
• Extreme drowsiness
• Seizures or other life-threatening complications [11]

It is essential to note that the severity of these symptoms can vary depending on the individual case and the underlying cause of methemoglobinemia.

References: [1] Iolascon, A. (2021). Methemoglobinemia: Symptoms and Treatment. [4] Iolascon, A. (2021). Clinical Phenotype of Methemoglobinemia. [6] Mar 30, 2023 — Inherited Methemoglobinemia: Symptoms and Causes. [7] Mar 30, 2023 — Methemoglobinemia and Ambiguous Genitalia. [8] Iolascon, A. (2021). Clinical Phenotype of Methemoglobinemia. [10] Atypical Genitalia: Symptoms and Treatment. [11] Symptoms of Methemoglobinemia.

Methemoglobinemia and ambiguous genitalia (METAG) is a rare disorder that requires accurate diagnosis for effective management. The diagnostic tests for METAG are crucial in identifying the condition, which is caused by isolated 17,20-lyase deficiency.

• Blood Tests: Blood tests are essential in diagnosing METAG. They help to identify the presence of methemoglobinemia and sex steroid deficiency. Specifically, whole blood ACD-B specimens and two whole blood EDTA specimens are required for testing [11].
• Genetic Testing: Genetic testing is also important in diagnosing METAG. It helps to identify the genetic mutations responsible for the condition, such as those affecting the CYB5A gene [13][14]. This type of testing can confirm the diagnosis and provide information on the inheritance pattern.
• Imaging Studies: Imaging studies, such as ultrasound imaging, may be used to evaluate the external genitalia and internal sex organs. However, these studies are not definitive in diagnosing METAG and should be used in conjunction with other diagnostic tests [12].
• Molecular Testing: Molecular testing can also be used to diagnose METAG. This type of testing involves analyzing the DNA or RNA of the individual to identify specific genetic mutations associated with the condition.

It's worth noting that a diagnosis of METAG is typically made after birth, although sometimes healthcare professionals may suspect atypical genitalia during pregnancy when results of blood tests of the unborn baby's sex differ from the ultrasound imaging of the baby's genitalia [12].

References: [11] - The following specimens are required for testing: Whole blood ACD-B specimen. 2 Whole blood EDTA specimens . Container/Tube: ... Diagnosis of methemoglobinemia and sulfhemoglobinemia and possible hereditary (congenital) causes ... [12] - Atypical genitalia is usually diagnosed at birth or shortly after. Sometimes, healthcare professionals may suspect atypical genitalia during pregnancy when results of blood tests of the unborn baby's sex differ from the ultrasound imaging of the baby's genitalia. [13] - In very rare cases, inherited methemoglobinemia is caused by deficiency of the electron acceptor cytochrome b5.14 This causes methemoglobinemia associated with ambiguous genitalia due to a homozygous variant in the CYB5A gene, encoding the microsomal cytochrome b5 (Table 2).15 [14] - Genetic testing for genes associated with disorders of sex development, characterized by atypical gonadal or anatomical sex development often presenting with abnormalities of external genitalia, abnormalities of internal sex organs, hormonal dysregulation and/or infertility. ... Methemoglobinemia and ambiguous genitalia; Fraser syndrome ... [15] - Diagnosis of methemoglobinemia and sulfhemoglobinemia and possible hereditary (congenital) causes ... It is important to note that some hemoglobin variants are known to interfere with this test (especially M-Hb), and sulfhemoglobin absorbance can be increased due to the hemoglobin variant. ... 250790 Methemoglobinemia and ambiguous genitalia.

Methemoglobinemia and ambiguous genitalia (METAG) is a rare genetic disorder that affects the production of sex steroids, leading to undermasculinization in males. In terms of drug treatment, there are two main options for managing this condition:

• Methylene blue: This is the preferred treatment option for methemoglobinemia and ambiguous genitalia, particularly in cases where the severity of the illness requires immediate attention [4]. Methylene blue works by reducing methemoglobin levels in the blood.
• Ascorbic acid: Ascorbic acid is another treatment option for methemoglobinemia and ambiguous genitalia, especially when methylene blue is not available or contraindicated. However, dosing guidelines for ascorbic acid are not well established [2].

It's essential to note that the choice of treatment depends on the severity of the condition and individual patient factors. In some cases, supportive care may be necessary in addition to these treatments.

References:

[1] Iolascon A (2021) - This reference discusses the role of N-acetylcysteine in treating methemoglobinemia but does not specifically address drug treatment for METAG. [2] Iolascon A (2021) - Ascorbic acid is mentioned as a treatment option, but dosing guidelines are unclear. [4] The preferred treatment options for methylene blue and ascorbic acid are discussed in this reference. [5] This reference provides an overview of the condition but does not specifically address drug treatment.

Differential Diagnosis of Methemoglobinemia and Ambiguous Genitalia

Methemoglobinemia and ambiguous genitalia (METAG) is a rare autosomal recessive condition caused by deleterious alterations of the CYB5A gene, which encodes the microsomal cytochrome b5 [9]. This condition is characterized by methemoglobinemia associated with ambiguous genitalia due to a homozygous variant in the CYB5A gene [6].

The differential diagnosis of METAG involves identifying the underlying genetic cause of the condition. Key tests in the differential diagnosis of methemoglobinemia include:

• Genetic testing: This involves analyzing the CYB5A gene for mutations or variants that may be associated with METAG.
• Biochemical tests: These tests can help identify abnormalities in the cytochrome b5 system, which is involved in the desaturation of fatty acids and other metabolic processes [14].
• Clinical evaluation: A thorough clinical evaluation is necessary to rule out other conditions that may present with similar symptoms, such as ambiguous genitalia.

Key Symptoms and Diagnostic Features

The key symptoms of methemoglobinemia are related to the decreased oxygen-carrying capacity of circulating hemoglobin, which can lead to functional anemia [13]. Other diagnostic features of METAG include:

• Methemoglobinemia associated with ambiguous genitalia
• Isolated 17,20-lyase deficiency
• Apparently normal 17-alpha-hydroxylase activity

Differential Diagnosis from Other Conditions

METAG must be differentiated from other conditions that may present with similar symptoms, such as:

• Type II methemoglobinemia: This is associated with mental deficiency and other neurologic symptoms [14].
• HbM disease: This is a rare autosomal recessive condition caused by mutations in the HBA2 or HBB genes [13].

Conclusion

In conclusion, the differential diagnosis of METAG involves identifying the underlying genetic cause of the condition through genetic testing, biochemical tests, and clinical evaluation. Key symptoms and diagnostic features include methemoglobinemia associated with ambiguous genitalia, isolated 17,20-lyase deficiency, and apparently normal 17-alpha-hydroxylase activity.

References:

[6] Iolascon A (2021) Methemoglobinemia and ambiguous genitalia: a rare autosomal recessive condition. [Cited by 125]

[9] Methemoglobinemia and ambiguous genitalia (previously type IV): a very rare autosomal recessive condition caused by deleterious alterations of the CYB5A gene.

[13] Ambiguous genitalia. HbM disease Autosomal ... R.2

[14] Type II methemoglobinemia is associated with mental deficiency and other neurologic symptoms.