What are the causes of palmoplantar hyperhidrosis?

Causes of Palmoplantar Hyperhidrosis

Palmoplantar hyperhidrosis is primarily a hereditary disorder with autosomal dominant inheritance and variable penetrance, affecting approximately 1-3% of the population, though secondary causes including medications, neurological conditions, and genetic syndromes must be excluded.

Primary (Idiopathic) Palmoplantar Hyperhidrosis

Genetic Basis:

• Strong hereditary component with 65% of patients reporting positive family history 1
• Autosomal dominant inheritance pattern with variable penetrance (approximately 25%) 1
• Disease allele present in about 5% of the general population 1
• Parent-child transmission most common (58%), followed by sibling cases (18%) 2
• No evidence of sex-linked transmission 1

Pathophysiology:

• Results from localized hyperactivity of the sympathetic autonomic nervous system 3
• Characterized by excessive emotional sweating not related to thermoregulation 3
• Dysfunction involves both parasympathetic and sympathetic nervous system components 4

Secondary Causes of Palmoplantar Hyperhidrosis

Medication-Induced:

• Isoniazid - can cause palmoplantar hyperhidrosis through peripheral neuropathy mechanism; reversible with pyridoxine supplementation 4

Neurological Conditions:

• Peripheral neuropathies (particularly diabetic neuropathy) 4
• Central or peripheral neuronal defects 4
• Sudomotor dysfunction associated with autonomic neuropathy 5

Genetic Syndromes:

• Cardio-facio-cutaneous syndrome (CFC) - patients develop heat intolerance, excessive sweating, and axillary body odor due to hyperkeratosis 6
• 22q11.2 Deletion Syndrome - palmoplantar keratoderma can be an associated feature 7
• Palmoplantar keratoderma of Bothnian type - caused by AQP5 gene mutations affecting aquaporin 5 water channel protein, presenting with pronounced hyperhidrosis along with keratoderma 8
• Fabry disease - commonly presents with hypohidrosis rather than hyperhidrosis, but dermatological disturbances are characteristic 9

Drug-Related Palmoplantar Reactions (Distinct from True Hyperhidrosis):

• BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) cause palmoplantar keratoderma with calluses, not classic hyperhidrosis 10
• MEK inhibitors cause hand-foot skin reaction (HFSR) with hyperkeratosis at pressure points 10
• Chemotherapy agents cause palmar-plantar erythrodysesthesia syndrome (PPES), characterized by erythema and swelling rather than hyperhidrosis 10

Clinical Pearls and Pitfalls

Important Distinctions:

• True palmoplantar hyperhidrosis involves excessive sweating without structural skin changes
• Palmoplantar keratoderma presents with thickened skin and may have associated hyperhidrosis as a secondary feature 8
• Drug-induced palmoplantar reactions (HFSR, PPES) are distinct entities from primary hyperhidrosis 10

Evaluation Approach:

• Obtain detailed family history - positive in approximately 36-65% of primary cases 2, 1
• Review medication history, particularly isoniazid, anticancer agents
• Assess for associated features suggesting genetic syndromes (dysmorphic features, cardiac abnormalities, developmental delay)
• Screen for diabetic neuropathy and other peripheral neuropathies in appropriate clinical contexts 5

Age and Onset Patterns:

• Primary hyperhidrosis typically begins in childhood or adolescence 3
• Later onset should prompt investigation for secondary causes
• In genetic syndromes like CFC, hyperhidrosis manifestations may evolve over time and become more prominent in adolescence 6