Biotin Deficiency

Etiology

Although biotin deficiency is uncommon due to its presence in a wide range of foods and endogenous synthesis by intestinal microbiota, it should be considered in patients with identifiable risk factors. These include prolonged use of medications such as anticonvulsants or antibiotics and undernutrition (see Tables. Acquired Causes and Inherited Causes). In addition, both acquired and inherited disorders can impair biotin absorption, metabolism, or utilization, potentially resulting in clinical deficiency. Early recognition and supplementation are typically effective in reversing symptoms and preventing long-term complications.

Table. Acquired Causes 

Table. Inherited Causes

Note: Both inherited conditions are detectable via newborn screening and are treatable with lifelong biotin supplementation.

Epidemiology

According to the worldwide neonatal screening survey, profound biotinidase deficiency occurs in approximately 1 in 112,000 live births, while partial deficiency occurs in about 1 in 129,000 live births. The combined incidence of profound and partial deficiency is 1 case per 61,067 live births (see Table. Causes and Incidences of Deficiencies).[10] Biotinidase deficiency is more frequently diagnosed in children of European descent, and studies have observed a higher incidence of biotin deficiency in Brazil, Türkiye, and Saudi Arabia.[11][12] People who consume alcohol excessively have a higher incidence of low biotin levels compared to the general population.[13] Holocarboxylase synthetase deficiency occurs at a rate of approximately 1 in 87,000 live births.[14]

 Table. Causes and Incidences of Deficiencies

Pathophysiology

Biotin is a vital cofactor for several biotin-dependent carboxylases initially synthesized as inactive apoenzymes. In addition to its classical role in carboxylation reactions, emerging evidence suggests that biotin contributes to gene regulation and modulation of the immune system.[1]

There are 5 known human biotin-dependent carboxylases:

• Pyruvate carboxylase: Essential for gluconeogenesis, the tricarboxylic acid cycle, and lipogenesis
• Propionyl-CoA carboxylase: Involved in the catabolism of specific amino acids and odd-chain fatty acids
• 3-Methylcrotonyl-CoA carboxylase: Plays a role in leucine degradation
• Acetyl-CoA carboxylase 1: Catalyzes the conversion of acetyl-CoA to malonyl-CoA, a key step in fatty acid synthesis
• Acetyl-CoA carboxylase 2: Regulates fatty acid oxidation in muscle and other tissues [15]

In biotin deficiency, the reduced activity of these enzymes results in metabolic dysfunction, including impaired energy production and the accumulation of toxic organic acids, leading to lactic acidosis, ketoacidosis, and other metabolic derangements that impact multiple organ systems, particularly the skin, nervous system, and immune function.[9]

History and Physical

Biotin deficiency presents variable clinical features, most commonly neurological symptoms and dermatologic abnormalities. The patient history should include assessment of risk factors for biotin deficiency. Dermal abnormalities in biotin deficiency are caused by impaired fatty acid metabolism. Clinical findings include alopecia and periorificial dermatitis, a scaly, erythematous rash around the eyes, nose, and mouth (also called "biotin-deficient face"). The facial rash resembles that of zinc deficiency.[1]

Neurological symptoms include hypotonia, seizures, ataxia, numbness and tingling of the extremities, intellectual disability, and developmental delay in children. The patients may exhibit depression, lethargy, or report a history of hallucinations. Additional neurological abnormalities include optic atrophy and sensorineural hearing loss in untreated patients.[9] Intestinal symptoms such as nausea, vomiting, and anorexia may also develop in patients with biotin deficiency. Other presenting signs include ketoacidosis, lactic acidosis, and organic aciduria.[9]

A detailed history should focus on identifying risk factors:

• Dietary intake: Low consumption of biotin-rich foods or excessive ingestion of raw egg whites (due to avidin binding)
• Medication use: Prolonged treatment with antibiotics, anticonvulsants (eg, phenytoin, carbamazepine, or phenobarbital), or other drugs that interfere with biotin metabolism, such as isotretinoin
• Parenteral nutrition: Use of total parenteral nutrition without adequate biotin supplementation
• Family history: Relevant for inherited disorders like biotinidase deficiency or holocarboxylase synthetase deficiency
• Developmental history
  • In infants and children, a history of developmental delay, hypotonia, or seizures may be reported. Biotinidase deficiency typically presents symptoms between the ages of 1 week and 1 year and may also exhibit additional symptoms, such as hearing loss and optic atrophy.

Common complaints include:

• Fatigue and generalized weakness
• Hair loss or thinning
• Skin changes such as rash, especially around orifices
• Neurologic symptoms such as paresthesias, muscle pain, or seizures in severe cases

The physical examination findings reflect multisystem involvement and may include:

• Dermatologic:
  • Diffuse or patchy alopecia 
  • Seborrheic, eczematous, or scaly rash, often involving periorificial areas (around eyes, nose, mouth) and intertriginous zones
  • Conjunctivitis or red eyes
• Neurologic:
  • Hypotonia and decreased muscle tone
  • Peripheral neuropathy signs, such as reduced sensation or paresthesia
  • Developmental delay or cognitive impairment in infants and young children
  • Seizures in severe or untreated cases
• Other findings:
  • Signs of metabolic acidosis in severe cases (tachypnea, lethargy)
  • Generalized weakness and poor feeding in infants

Evaluation

The diagnosis of biotin deficiency relies on a combination of clinical suspicion, biochemical markers, and genetic testing in cases of inherited disorders. Biotin-dependent carboxylases in human lymphocytes are reliable markers for determining biotin status.[16] Decreased beta-methylcrotonyl-CoA carboxylase activity shunts the catabolism to alternative pathways, leading to the elevated formation of 3-hydroxyisovaleric acid. The most reliable marker of biotin deficiency is increased excretion of 3-hydroxyisovaleric acid in the urine (over 195 micromol/24 hours). Evidence shows that serum biotin concentration does not decrease in biotin-deficient patients receiving biotin-free total parenteral nutrition. Therefore, serum biotin levels are not reliable indicators of marginal biotin deficiency.[1][13][17] 

A thorough neurological examination and other investigations, including vision and hearing tests, are warranted if biotin deficiency is suspected. Biotinidase deficiency confirmation is typically performed through DNA analysis, using either allele-targeted methods or full-gene sequencing. All newborn screening programs in the United States and more than 30 other countries carry out screening for biotinidase deficiency.[9][12]

Biochemical Testing

• Urinary 3-Hydroxyisovaleric Acid:
  • The most reliable marker of biotin deficiency.
  • Levels above 195 µmol/24 hours are strongly suggestive.
  • Elevated due to decreased activity of β-methylcrotonyl-CoA carboxylase, which shunts leucine catabolism into alternative pathways.
• Biotinidase and Propionyl-CoA Carboxylase Activity (in lymphocytes):
  • Measurement of biotin-dependent carboxylase activity in lymphocytes is a reliable method to assess biotin status.
  • Propionyl-CoA carboxylase deficiency may also indicate impaired biotin utilization.
• Serum Biotin Levels:
  • Not a reliable indicator of marginal biotin deficiency, particularly in patients receiving biotin-free total parenteral nutrition.
  • Serum levels may remain falsely normal despite clinical deficiency.

Genetic Testing

• Biotinidase Deficiency Diagnosis:
  • Confirmed by DNA analysis, including either allele-specific assays or full-gene sequencing.
  • Recommended in cases with early onset symptoms, especially in neonates or infants.
  • All states in the United States and more than 30 other countries include biotinidase deficiency in their newborn screening programs.

Neurological and Imaging Evaluation

• Patients with suspected or confirmed biotinidase deficiency should undergo a comprehensive neurologic examination and vision and hearing tests to assess for early neurologic sequelae.
• Neuroimaging (eg, magnetic resonance imaging) findings may include:
  • Encephalopathy
  • Low cerebral volume
  • Ventriculomegaly
  • Widened extracerebral cerebrospinal fluid spaces

Treatment / Management

Management of biotin deficiency primarily involves addressing the underlying cause of the deficiency. Lifelong treatment with biotin supplements is necessary for patients with genetic disorders that disrupt biotin metabolism, such as holocarboxylase synthetase deficiency and biotinidase deficiency. Usually, a dose of 5 mg daily is prescribed regardless of the etiology of biotin deficiency.[13] The Food and Nutrition Board of the National Research Council recommends a range of 5 mcg per day in newborn infants to 35 mcg per day in lactating women. Clinicians should be aware that biotin requirements may increase during anticonvulsant therapy.[1] (B3)

Biotin Supplementation

• Acquired Biotin Deficiency
  • Dose: 5 to 10 mg per day orally, varies based on the severity of the deficiency
  • Rapid clinical improvement is often observed within days to weeks after treatment initiation.
  • Continued supplementation may be necessary if underlying risk factors persist (eg, long-term total parenteral nutrition or anticonvulsant therapy) [11][18]
• Biotinidase Deficiency
  • Profound deficiency: Lifelong biotin therapy at 5 to 20 mg per day orally
  • Partial deficiency: Typically managed with lower doses, with adjustments made during periods of physiologic stress
  • Early diagnosis and treatment prevent irreversible neurologic damage, including hearing and vision loss, seizures, and developmental delay.
• Holocarboxylase Synthetase Deficiency
  • Higher doses may be required: 10 to 60 mg per day orally
  • Treatment typically begins early in life and is often lifelong.
(A1)

Monitoring and Follow-Up

• Clinical Monitoring:
  • Resolution of symptoms (rash, alopecia, hypotonia, seizures)
  • Growth and neurodevelopmental milestones in infants and children
• Biochemical Monitoring (in selected cases):
  • Urinary 3-hydroxyisovaleric acid
  • Plasma organic acids
  • Repeat genetic counseling/testing as appropriate for family planning

Supportive Measures

• Address underlying causes:
  • Modify or monitor medications interfering with biotin metabolism (eg, anticonvulsants)
  • Ensure proper micronutrient formulation in total parenteral nutrition
  • Educate patients to avoid excessive raw egg white intake

Genetic Counseling

• Recommended for families affected by biotinidase or holocarboxylase synthetase deficiency
• Important in regions with high rates of consanguinity or a positive family history

Clinical Insight

• When clinical suspicion is high, a therapeutic trial of biotin at a dose of 5 to 10 mg per day orally can serve both diagnostic and therapeutic purposes, especially while awaiting biochemical or genetic confirmation.

Differential Diagnosis

Key differential diagnoses include the following:

Sodium-Dependent Multivitamin Transporter Deficiency

• A rare inborn error of metabolism involving mutations in the SLC5A6 gene.
• Results in defective intestinal absorption of biotin, pantothenic acid, and lipoate.
• Clinical presentation mimics biotinidase deficiency, with:
  • Neurologic dysfunction
  • Immune compromise
  • Dermatitis and alopecia
• Diagnosis requires molecular genetic testing; management includes high-dose multivitamin supplementation.

Acrodermatitis Enteropathica (zinc deficiency)

• An autosomal recessive disorder of zinc absorption, or acquired deficiency due to malnutrition or chronic diarrhea.
• Similar features to biotin deficiency:
  • Periorificial and acral dermatitis
  • Alopecia
  • Pediatric undernutrition with growth faltering
  • Distinguishing Features:
  • The rash associated with zinc deficiency is often bullous, scaly, and localized to facial orifices and pressure/friction areas (eg, perineum, elbows, knees).
• Associated findings include angular cheilitis, paronychia, and diarrhea.
• Serum zinc levels and clinical response to zinc supplementation help confirm the diagnosis.
• Biotin also plays a role in zinc homeostasis in the skin, though the mechanism is not fully understood. Thus, zinc and biotin deficiency symptoms may overlap, particularly in cases of combined deficiencies.

Other Considerations

• Essential fatty acid deficiency: May present with eczematous rash and poor wound healing
• Multiple carboxylase deficiency: Encompasses both biotinidase and holocarboxylase synthetase deficiencies
• Seborrheic dermatitis: May resemble the rash of biotin deficiency but typically spares the periorificial areas and lacks systemic features
• Protein-energy malnutrition (eg, Kwashiorkor): Can present with hair changes and dermatitis, but usually in generalized malnutrition [19][20]

Prognosis

Children diagnosed with biotinidase deficiency require early intervention and lifelong biotin treatment. Children who discontinue therapy develop symptoms within weeks to months. When neonates diagnosed through neonatal screening receive biotin, they grow normally and remain asymptomatic; those with symptoms quickly improve with biotin treatment. Failure to evaluate and manage biotinidase deficiency at an early stage can cause irreversible neurodevelopmental abnormalities and lead to developmental delay and autistic behavior.[21]

Prognosis of Biotin Deficiency

• Inherited biotinidase deficiency requires early diagnosis and lifelong biotin supplementation to prevent irreversible complications.
• Children who discontinue biotin therapy typically experience symptom recurrence within weeks to months, underscoring the necessity of treatment adherence.
• Neonates identified through newborn screening who promptly begin biotin therapy usually develop normally without clinical symptoms. Individuals presenting with symptoms generally respond rapidly and effectively to treatment.
• Delayed or missed diagnosis can cause permanent neurodevelopmental impairments, including developmental delay, seizures, hearing loss, and autistic behaviors.

Complications

Biotin deficiency can lead to dermatologic, neurological, immunological, and developmental complications if left untreated. Since biotin plays a crucial role in maintaining cell-mediated and humoral immunity, biotin deficiency due to inborn metabolic errors can cause skin candidal infections in infants and children. Affected individuals may exhibit immunoglobulin A deficiency and low percentages of T lymphocytes. They may also show absent or delayed hypersensitivity skin-test responses.[1][11] Additionally, biotin deficiency can cause encephalopathies. Patients usually respond well to large doses of biotin. Evidence shows that biotin deficiency is teratogenic in animal models. In genetic models of biotin deficiency, mice have exhibited fetal malformations, most commonly including cleft palate, micrognathia, and micromelia.[22]

Neurologic Complications

• Encephalopathy and seizures are serious consequences, particularly in infants and young children.
• Untreated deficiency can cause irreversible developmental delay, hypotonia, hearing loss, and autistic features, especially in cases of biotinidase deficiency.
• These manifestations often resolve or significantly improve with high-dose biotin therapy, but delays in treatment may result in permanent damage.

Immunologic Complications

• Biotin is critical for cell-mediated and humoral immunity.
• Deficiency—especially in inherited metabolic disorders—has been associated with:
  • Skin candidiasis
  • Immunoglobulin A deficiency
  • Reduced T-lymphocyte percentages
  • Absent delayed-type hypersensitivity responses
• These immune abnormalities predispose infants and children to recurrent infections and poor immune regulation.

Developmental and Teratogenic Risks

• Animal studies have demonstrated that biotin deficiency is teratogenic, particularly in murine models.
• Reported fetal malformations in mice include:
  • Cleft palate
  • Micrognathia 
  • Micromelia 
• Although human data are limited, adequate maternal biotin intake during pregnancy is recommended to help reduce potential risks to fetal development associated with biotin deficiency.