Syndromes Causing Blue Skin
The two primary syndromes causing blue skin are methemoglobinemia (a blood disorder causing lavender-blue discoloration) and argyria (permanent slate-gray skin from chronic silver exposure), with methemoglobinemia being medically significant and potentially life-threatening, while argyria is cosmetically permanent but generally benign. 1, 2
Methemoglobinemia
Clinical Presentation
Methemoglobinemia causes a characteristic lavender-blue or slate-gray appearance of the skin that does NOT improve with supplemental oxygen, distinguishing it from cardiac or pulmonary causes of cyanosis. 1, 3
- The blue discoloration appears most prominently on the lips, nose, cheeks, and buccal mucosa 1
- Blood appears dark brown rather than the normal red color 1
- Cyanosis becomes visible when methemoglobin levels exceed 10%, with typical levels in hereditary cases ranging 20-30% 1, 3
Types and Inheritance Patterns
Type I (Recessive Methemoglobinemia):
- Autosomal recessive inheritance pattern with cytochrome b5 reductase deficiency 1, 3
- Patients are generally asymptomatic despite dramatic blue appearance at methemoglobin levels of 20-30% 1, 3
- May experience mild symptoms including headaches, tachycardia, and dyspnea 1
- Some patients develop mild compensatory polycythemia due to chronic tissue hypoxia 4
Type II (Recessive Methemoglobinemia with Neurological Disease):
- Same enzyme deficiency but with severe neurological manifestations 1
- Presents with profound developmental delay, microcephaly, dystonia, and seizures typically by 9 months of age 1
- Life expectancy significantly reduced, with death typically in the first decade 1
M-Hemoglobinopathies:
- Autosomal dominant inheritance (though many are de novo mutations) 1
- Caused by specific hemoglobin variants (Hb M-Iwate, Hb M-Saskatoon) 1
- Historically recognized in Japan as "Kochikuro" (black mouth) since the 1800s 1
- Patients have isolated skin discoloration without other symptoms 1
Diagnostic Approach
The American Journal of Hematology recommends molecular testing as the gold standard for diagnosis of hereditary methemoglobinemia. 1
Key diagnostic tests include:
- Co-oximetry measurement of methemoglobin levels - essential first step 1, 3
- Cytochrome b5 reductase enzymatic activity measurement using ferricyanide substrate 1
- DNA analysis via targeted NGS panels for CYB5R3 and globin genes 1
- Detailed exposure history to distinguish acquired from congenital causes 3
Critical distinguishing features from other causes:
- No respiratory distress despite dramatic cyanosis 3, 5
- Cyanosis present from birth and persistent without variation 1
- Pulse oximetry may show discordant results compared to clinical assessment 1
- Normal cardiac examination without tachypnea or increased work of breathing 3
Treatment Considerations
Management depends on whether methemoglobinemia is acquired versus hereditary, symptom severity, and absolute methemoglobin levels. 1
Treatment thresholds for ACQUIRED methemoglobinemia:
- Treat at 20% if symptomatic 1
- Treat at 30% if asymptomatic 1
- Treat at 10-30% if additional factors compromise oxygen delivery (cardiac disease, lung disease, anemia, CO poisoning) 1
- Levels >70% are potentially lethal 1
Treatment thresholds for HEREDITARY methemoglobinemia:
- Higher levels are better tolerated - patients may be asymptomatic even at 30-40% 1
- Most children with Type I require no acute treatment despite dramatic appearance 3
- Consider treatment only if symptomatic or levels exceed 30% 3
Methylene Blue (Methylthioninium chloride) - Primary Treatment:
- Acts by accepting electrons from NADPH to reduce ferric iron back to ferrous state 1
- Requires adequate glucose for effectiveness 1
- Critical pitfall: Contraindicated in G6PD deficiency patients 1
Supportive measures:
- Intravenous hydration and oxygen supplementation 1
- Glucose administration to support endogenous reducing enzymes 1
- For infants with methemoglobinemia from diarrhea/acidosis: aggressive hydration and bicarbonate if MetHb <20% 1
Prevention and Counseling
Patients with hereditary methemoglobinemia should:
- Avoid oxidant drugs and chemical substances in food, drinks, and well water 1
- Use medical alert systems 1
- Receive genetic counseling - siblings have 25% risk if both parents are carriers of Type I 3
- Promptly treat infections that may increase methemoglobin levels 1
Special populations at higher risk:
- Infants have 50-60% of adult cytochrome b5 reductase activity 1
- Infants have higher HbF levels which oxidize more readily 1
- Well water contaminated with nitrates poses risk to infants 1
- Local anesthetics (lidocaine, benzocaine) can trigger methemoglobinemia in young children 1
Argyria
Clinical Presentation
Argyria causes permanent slate-gray or blue-gray skin discoloration from chronic silver exposure, most prominent in sun-exposed areas. 2, 6
- Affects skin, nails, and mucous membranes 6, 7
- Discoloration is irreversible and permanent 8
- Increased pigmentation in sun-exposed areas of face and neck 6, 9
Causes
Most common modern cause is ingestion of colloidal silver supplements:
- Patients typically consume colloidal silver for years (7-10 years reported) as alternative medicine 2, 6, 9
- Historical causes include occupational exposure and silver-containing medications 6
- Silver sulfadiazine absorption from extensive burns/wounds 6
Diagnosis
Skin biopsy showing brown-black silver granules in basement membranes of sweat gland epithelia is diagnostic. 8
Associated Complications
While primarily cosmetic, argyria can have systemic effects:
- May cause microcytic anemia secondary to silver-induced copper deficiency 2
- Case reports of associated polyneuropathy and myopathy 8
- Can cause pseudocyanosis that mimics methemoglobinemia 2
Critical pitfall: When evaluating patients with blue-gray skin and anemia, differentiate between argyria-induced copper deficiency versus iron deficiency or other causes. 2