Is HNPP Something New?
No, Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) is not a new condition—it is a well-established autosomal dominant genetic disorder that has been recognized and studied for decades, with the genetic basis (PMP22 gene deletion on chromosome 17p11.2-12) identified in the 1990s. 1, 2
Historical Recognition and Genetic Discovery
HNPP has been documented in medical literature since well before the 1990s, though it was historically referred to as "tomaculous neuropathy" due to the characteristic sausage-like myelin formations seen on nerve biopsy. 1, 2 The genetic basis was definitively mapped in the 1990s when researchers identified that approximately 80% of HNPP cases result from a 1.5 Mb deletion on chromosome 17p11.2 that includes the peripheral myelin protein 22 (PMP22) gene. 2, 3 This is the same chromosomal region that, when duplicated rather than deleted, causes Charcot-Marie-Tooth disease type 1A (CMT1A)—representing a reciprocal dosage effect of the PMP22 gene. 1, 2
Why HNPP May Seem "New" to Clinicians
The condition is frequently underdiagnosed or misdiagnosed due to several factors that may make it appear unfamiliar or newly recognized:
Heterogeneous clinical presentation: HNPP manifests with episodic, recurrent focal neuropathies that can mimic common entrapment syndromes like carpal tunnel syndrome or peroneal palsy, leading clinicians to miss the underlying genetic disorder. 3, 4
Variable age of onset: While symptoms typically begin in adolescence or young adulthood, the condition can present in childhood or remain subclinical in some gene carriers, making recognition inconsistent across age groups. 1, 4
Overlap with other neuropathies: The mild clinical overlap with CMT1 can lead to misdiagnosis, though the episodic nature and focal distribution of HNPP are quite distinct from the progressive, symmetric polyneuropathy of CMT1. 1, 2
Modern Diagnostic Advances
Genetic testing for HNPP has become more accessible and is now recommended as part of the standard evaluation for hereditary neuropathies. 5 The American Academy of Neurology guidelines from 2009 established that initial genetic testing for hereditary neuropathies should focus on the most common abnormalities, specifically including "CMT1A duplication/HNPP deletion" as a primary target. 5 This recommendation reflects that HNPP testing should be considered alongside CMT1A evaluation in patients with appropriate clinical phenotypes.
Clinical Recognition Patterns
In pediatric populations, HNPP presents most commonly as:
- Peroneal palsy (42% of cases) 4
- Brachial plexus palsy (25% of cases) 4
- Unexplained mononeuropathy or multifocal neuropathy 4
A key diagnostic clue is bilateral or unilateral median nerve entrapment at the carpal tunnel on electrophysiological studies, which was present in 100% of pediatric cases in one series, even when not clinically symptomatic. 4
Genetic Heterogeneity Beyond the Common Deletion
While the 1.5 Mb deletion accounts for the overwhelming majority of cases, approximately 20% of HNPP patients have point mutations in the PMP22 gene rather than the classic deletion. 3, 6 New point mutations continue to be identified and reported, which may contribute to the perception that HNPP is "evolving" or newly recognized, when in fact these represent variants of a long-established condition. 6
Important Clinical Caveats
- Any unexplained mononeuropathy or multifocal neuropathy in a child or young adult should prompt consideration of PMP22 gene testing for HNPP deletion. 4
- Electrophysiological studies should be extended to all family members, even those without previous symptomatic episodes, as asymptomatic gene carriers can show reduced nerve conduction velocities. 1, 6
- Early diagnosis is critical for appropriate genetic counseling and preventive care, including avoidance of repetitive pressure on nerves and prolonged positioning that could trigger episodes. 4