Pes cavus and hereditary neuropathies: when a relationship should be suspected
© The Author(s) 2010
Received: 7 May 2010
Accepted: 25 September 2010
Published: 21 October 2010
The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the first signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or confirm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a “spy sign,” discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases.
Frequently, pes cavus may be a sign of an underlying neurological disorder, including spinal cord and peripheral nerve pathologies, such us spino-cerebellar ataxia and hereditary peripheral neuropathies. A previous retrospective analysis of patients undergoing pes cavus surgery  revealed that almost one-third of apparently idiopathic cases suffered from a neurological disease.
Herein, we discuss the hereditary peripheral neuropathies (HPN) in which pes cavus plays a key role as a “spy sign.” A clear, complete, and detailed review of clinical and molecular features of these rare disorders may be useful in clinical management and differential diagnosis of patients who present with pes cavus as almost single sign of disease.
Hereditary peripheral neuropathies (HPN) are a heterogeneous group of peripheral nerve disorders, clinically characterized by sensorial and/or motor impairment, with reduction or absence of deep tendon reflexes .
Foot deformities, including pes cavus, hammer toes, and twisting of the ankle, are commonly present in some HPN forms, such as Charcot–Marie–Tooth (CMT) disease, hereditary neuropathy with predisposition to pressure palsies (HNPP), and distal hereditary motor neuropathy (DHMN) , but are uncommon in the other HPN. We will therefore discuss only the clinical features and genetic basis of HPN associated with pes cavus.
HPN associated with pes cavus
The most common form of HPN is hereditary motor and sensory neuropathy (HMSN), also called Charcot–Marie–Tooth (CMT) disease. Prevalence is estimated at about 17–40 per 100,000 .
Genetic classification of hereditary motor and sensory neuropathies
Neurofilament light chain
Neurofilament light chain
Lam in A/C
The most common features in classical CMT phenotype are skeletal deformities such as pes cavus with hammer toes; less frequent skeletal signs are pes planus, twisting of ankle and tripping, and painful foot callosities. Scoliosis could be present in 10% of affected people [10, 11]. Neurological examination shows characteristic signs of a sensorimotor peripheral neuropathy. Sensory signs are usually less prominent (70%) than motor ones . The most frequent findings  are ataxia, hypoesthesia, and loss of vibration, two-point discrimination, and joint position sense. Motor impairment, which usually became evident during the course of disease, is responsible for upper and lower limb weakness and atrophy, with main en griffe (Fig. 1) and “inverted champagne bottle” legs. Steppage gait and foot drop are the first most common motor signs. Deep tendon reflexes are diminished or absent . Muscle cramps, cold feet, acrocyanosis, and postural tremor are frequent complaints.
Electroneurography allows classification of CMT disease into two main forms: CMT1 or demyelinating form, characterized by a marked slowing in nerve conduction velocities (by definition, <38 m/s in upper limb motor nerves) and by a primary myelinopathy; and CMT2 or axonal form, in which nerve conduction values are preserved or only mildly slowed (>38 m/s in upper limb motor nerves) and the axon is the primary disease target . The existence of a CMT subgroup showing nerve conduction velocity (NCV) values “intermediate” between CMT1 and CMT2 has been also reported [16, 17].
As previously reported, CMT diagnosis is based on clinical examination, electrophysiological findings, and molecular testing. In selective cases, such as in patients with sporadic form or in whom molecular investigations result unable to demonstrate DNA defects, nerve biopsy might give relevant information for diagnosis and differential diagnosis. In particular, the typical histological marker of demyelinating neuropathies is represented by the presence of basal lamina “onion bulbs,” determined by concentric proliferation of Shawn cell cytoplasmic processes during the demyelination phenomenon and the remyelination tentative. In the advanced phase, loss of normal myelin covering (“nude axon”) has also been reported. Large-caliber fiber reduction and formation of isolated monostratified “simple onion bulbs” have been described in CMT2 .
There are no pharmacologic cures for CMT. A well-balanced diet and weight control can help minimize disability. Dietary supplements such as creatine, and co-enzyme Q have not been proven effective in treating CMT. Aerobic exercise and rehabilitation play an essential role in preserving quality of life of patients with CMT. A small percentage of patients with inherited neuropathy may respond to immunomodulatory therapy, such as prednisone or intravenous gammaglobulin (IVIG). Potentially neurotoxic medications, such as vincristine or cisplatinum, should be avoided . Experimental studies showed that progesterone antagonist improves neuropathy in CMT1A rats, and it represents a promising pharmacologic target for CMT1A patients [19, 20].
Dejerine–Sottas neuropathy and congenital hypomyelinating neuropathy
Dejerine–Sottas (DSN) and congenital hypomyelinating (CHN) neuropathies are rare, severe, infantile-onset, demyelinating peripheral nerve diseases.
DSN is transmitted as an autosomal dominant or recessive trait (Table 1). Clinical onset occurs at up to 2 years of age, with motor and sensory impairment and skeletal deformities, more frequently represented by scoliosis. NCV of DSN patients is greatly compromised, with values <15 m/s. Sural nerve biopsies could show marked demyelination or predominant axonal loss [8, 18].
CHN, an autosomal dominant or recessive disease (Table 1), is characterized by severe hypotonia (“floppy infant”), dysphagia, and respiratory insufficiency, usually occurring within the first year of life. NCV is very slow (<10 m/s), and sural nerve biopsy presents pathological features similar to those of DSN [16, 17].
Hereditary neuropathy with liability to pressure palsies
The prevalence of hereditary neuropathy with liability to pressure palsies (HNPP) is estimated to be at least 16 per 100,000 .
HNPP is an autosomal dominant disorder due to a deletion in chromosome 17p11.2 which codes for peripheral myelin protein (PMP22), an integral membrane protein that is a major component of myelin in the peripheral nervous system .
Patients present acute and transient episodes of focal neuropathies, commonly affecting the ulnar, radial, and peroneal nerves and the brachial plexus. These episodes are typically painless, recurrent, and occur after trauma or pressure, or with no evident precipitating factor . The palsies may be debilitating, last for days to weeks, and require installation of specific orthosis. Onset of HNPP is usually in adolescence, with a high degree of penetrance; however, clinically asymptomatic gene carriers are reported. Neurological examination could evidence hypoactive deep tendon reflexes and mild pes cavus, even in clinically asymptomatic patients .
With ageing, these patients can have a significant clinical overlap with CMT1, as the repeated injuries to the nerve can prevent full reversal.
Electrophysiological examination shows prolonged motor and sensory nerve conduction velocities (NCV)  and conduction blocks that are characteristic of the affected nerves, especially over entrapment sites. NCV abnormalities are also present in those nerves apparently unaffected by palsy and in asymptomatic gene carriers .
Histological analysis of sural nerve biopsies shows segmental area of de- and remyelination. The pathological hallmark of HNPP is presence of tomacula, consisting of massive variable myelin overfolding . In rare of HNPP patients nerve biopsy could be present only the axonal regeneration signs .
There is no specific treatment for HNPP. Current management consists of early detection and diagnosis of the disease, to reduce excessive force or repetitive movements, or to avoid static joint positions. Chemotherapeutic agents, such as vincristine, should be used with great caution .
Distal hereditary motor neuropathies
Genetic classification of distal hereditary motor neuropathies
Congenital distal SMA
dHMN usually presents as a classical peroneal muscular atrophy syndrome without sensory symptoms . The clinical picture consists of progressive weakness and wasting of the extensor muscles of the toes and feet. Later, weakness and wasting also involve the distal upper limb muscles. Foot deformity is a common feature. Additional features are represented by involvement of hands, vocal cord paralysis, diaphragm paralysis, and pyramidal tract signs .
In dHMN patients, electromyography evidences signs of chronic denervation, and motor NCV study shows an amplitude reduction of compound muscle action potentials or a moderate decrease in velocity. Sensory nerve conductions and amplitudes were normal [4, 36].
dHMN has no specific treatment. Patients need neurological follow-up to evaluate the disease’s clinical progression and for referral to rehabilitation or orthopedic service for correct management of complications.
Etiopathogenesis of pes cavus in HPN
Pes cavus in HPN derives from plantar flexion deformity of the first metatarsal due to imbalance between the intrinsic muscles of the foot and the muscles of the leg. The exact physiopathological mechanisms responsible for pes cavus genesis in HPN is not entirely clarified, even if two main hypotheses have been formulated .
The first hypothesis assigns an important role in the pathogenesis of this skeletal deformity to overaction of the peronei in comparison with the antagonist tibialis anterior, secondary to the leg muscle’s amyotrophy pattern in the disease. In particular, it has been supposed that a weak peroneus brevis is overpowered by a relatively stronger tibialis posterior, causing adduction of the forefoot and inversion of the hindfoot. In addition, a weak tibialis anterior is overpowered by a stronger peroneus longus, causing plantar-flexion of the first metatarsal and anterior pes cavus [12, 39–41]. The intrinsic foot muscles develop contractures, while the long extensor to the toe muscles, recruited to assist in ankle dorsiflexion, causes claw toes deformity.
The second hypothesis is that precocious and primary involvement of intrinsic foot muscles is responsible for the pathogenesis of pes cavus, because the deformity is observed in the early stages of the disease, also when there is not yet evidence of leg muscle weakness . A magnetic resonance imaging (MRI) study of amyotrophic leg and foot muscles performed in patients with CMT  reported precocious fatty infiltration of intrinsic foot muscles, also when leg muscles are still preserved. The authors deduced that the weakness of the lumbricals and the other intrinsic foot muscles, due to selective denervation, could cause the dorsiflexion of metatarsophalangeal joints, initially responsible for the flattening of the transverse arcus plantaris and the clawing of the toes. Dorsiflexion of metatarsophalangeal joints during gait could also determine the wrapping around the metatarsal head of the plantar aponeurosis and the contraction of the short flexors, with secondary shortening of the Achilles tendon and limitation of ankle dorsiflexion. A subsequent MRI muscle study in CMT patients also seems to confirm a possible primary role of intrinsic foot muscle in pes cavus pathogenesis . The sensitivity of MRI for detecting precocious denervation changes in early stages of HMN and CMT has been also recently confirmed .
In conclusion, the foot deformity pes cavus, secondary to plantar flexion deformity of the first metatarsal, could be associated to several neurological disorders, including spinal cord and peripheral nerve pathologies, such us spino-cerebellar ataxia and hereditary peripheral neuropathies.
In this article, we have reported the HPN in which pes cavus plays a key role as a “spy sign” [46, 47], as a precocious manifestation of HPN. Accurate clinical evaluation in patients with pes cavus is therefore necessary to exclude or confirm the presence of contemporary involvement of peripheral nerves [48, 49], especially in the early stage of the disease, when other signs of HPN may not yet be present or evident.
When should HPN be suspected in a patient with pes cavus? Clinical data suggestive of HPN are represented by evidence of: bilateral pes cavus, positive family history for pes cavus and/or gait impairment, distal muscle hypotrophy of limbs, and sensorial and/or motor dysfunction.
Conflict of interest
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
- Japas LM (1968) Surgical treatment of pes cavus by tarsal v-osteotomy: preliminary report. J Bone Joint Surg Am 50:927–944PubMedGoogle Scholar
- Brewerton DA, Sandifer PH, Sweetnam DR (1963) Idiopathic pes cavus: an investigation into its aetiology. Br Med J 14:659–661View ArticleGoogle Scholar
- Pareyson D, Marchesi C (2009) Diagnosis, natural history, and management of Charco-Marie-Tooth disease. Lancet Neurol 8:654–667PubMedView ArticleGoogle Scholar
- Irobi J, Dierick I, Jordanova A, Claeys KG, De Jonghe P, Timmerman V (2006) Unraveling the genetics of distal hereditary motor neuronopathies. Neuromolecular Med 8:131–146PubMedView ArticleGoogle Scholar
- Martyn CN, Hughes RAC (1997) Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 62:310–318PubMed CentralPubMedView ArticleGoogle Scholar
- Boerkoel CF, Takashima H, Lupski JR (2002) The genetic convergence of Charcot-Marie-Tooth disease types 1 and 2 and the role of genetics in sporadic neuropathy. Curr Neurol Neurosci Rep 2:70–77PubMedView ArticleGoogle Scholar
- Pareyson D, Testa D, Morbin M, Erbetta A, Ciano C, Lauria G, Milani M, Taroni F (2003) Does CMT1A homozygosity cause more severe disease with root hypertrophy and higher CSF proteins? Neurology 60:1721–1722PubMedView ArticleGoogle Scholar
- Chance PF, Lupski JR (1994) Inherited neuropathies: Charcot Marie Tooth disease and related disorders. Baillieres Clin Neurol 3:373–385PubMedGoogle Scholar
- Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, Shy RR, Balsamo J, Lilien J, Garbern JY, Kamholz J (2004) Phenotypic clustering in MPZ mutations. Brain 127:371–384PubMedView ArticleGoogle Scholar
- Holmes JR, Hansen ST (1993) Foot and ankle manifestations of Charcot Marie Tooth disease. Foot Ankle 14:476–486PubMedView ArticleGoogle Scholar
- Banchs I, Casasnovas C, Albertí A, De Jorge L, Povedano M, Montero J, Martínez-Matos JA, Volpini V (2009) Diagnosis of Charcot-Marie-Tooth disease. J Biomed Biotechnol 2009:985415PubMed CentralPubMedView ArticleGoogle Scholar
- Shy ME, Lupski JR, Chance PF, Klein CJ, Dyck PJ (2005) Hereditary motor and sensory neuropathies: an overview of clinical, genetic, electrophysiologic, and pathologic features. In: Dyck PJ, Thomas PK (eds) Peripheral neuropathy, 4th edn. Elsevier Saunders, Philadelphia, pp 1623–1658View ArticleGoogle Scholar
- Szigeti K, Lupski JR (2009) Charcot-Marie-Tooth disease. Eur J Hum Genet 17:703–710PubMed CentralPubMedView ArticleGoogle Scholar
- Mann RA, Missirian J (1988) Pathophysiology of Charcot Marie Tooth disease. Clin Orthop 234:221–228PubMedGoogle Scholar
- Harding AE, Thomas PK (1980) The clinical features of hereditary motor and sensory neuropathy (types I and II). Brain 103:259–280PubMedView ArticleGoogle Scholar
- Birouk N, LeGuern E, Maisonobe T, Rouger H, Gouider R, Tardieu S, Gugenheim M, Routon MC, Léger JM, Agid Y, Brice A, Bouche P (1998) X linked Charcot-Marie-Tooth disease with connexin 32 mutations: clinical and electrophysiologic study. Neurology 50:1074–1082PubMedView ArticleGoogle Scholar
- Züchner S, Noureddine M, Kennerson M, Verhoeven K, Claeys K, De Jonghe P, Merory J, Oliveira SA, Speer MC, Stenger JE, Walizada G, Zhu D, Pericak-Vance MA, Nicholson G, Timmerman V, Vance JM (2005) Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nature Genet 37:289–294PubMedView ArticleGoogle Scholar
- Grandis M, Shy ME (2005) Current therapy for Charcot-Marie-Tooth disease. Curr Treat Options Neurol 7:23–31PubMedView ArticleGoogle Scholar
- Sereda MW, Meyerzu Hörste G, Suter U, Uzma N, Nave KA (2003) Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT1A). Nat Med 9:1533–1537PubMedView ArticleGoogle Scholar
- Koenig HL, Schumacher M, Ferzaz B, Thi AN, Ressouches A, Guennoun R, Jung-Testas I, Robel P, Akwa Y, Baulieu EE (1995) Progesterone synthesis and myelin formation by Schwann cells. Science 268:1500–1503PubMedView ArticleGoogle Scholar
- Meretoja P, Silander K, Kalimo H, Aula P, Meretoja A, Savontaus ML (1997) Epidemiology of hereditary neuropathy with liability to pressure palsies (HNPP) in south western Finland. Neuromuscul Disord 7:529–532PubMedView ArticleGoogle Scholar
- Snipes GJ, Suter U, Welcher AA, Shooter EM (1992) Characterization of a novel peripheral nervous system myelin protein (PMP-22/SR13). J Cell Biol 117:225–238PubMedView ArticleGoogle Scholar
- Pareyson D, Taroni F (1996) Deletion of the PMP22 gene and hereditary liability to pressure palsies. Curr Opin Neurol 9:348–354PubMedView ArticleGoogle Scholar
- Chance PF (1999) Overview of hereditary neuropathy with liability to pressure palsies. Ann N Y Acad Sci 14(883):14–21View ArticleGoogle Scholar
- Earl CJ, Fullerton PM, Wakefield GS, Schutta HS (1964) Hereditary neuropathy with liability to pressure palsies. Q J Med 33:481–498PubMedGoogle Scholar
- Mouton P, Tardieu S, Gouider R, Birouk N, Maisonobe T, Dubourg O, Brice A, LeGuern E, Bouche P (1999) Spectrum of clinical and electrophysiological features in HNPP patients with the 17p11.2 deletion. Neurology 52:1440–1446PubMedView ArticleGoogle Scholar
- Madrid R, Bradley WG (1975) The pathology of neuropathies with focal thickening of the myelin sheath (tomaculous neuropathy): studies on the formation of the abnormal myelin sheath. J Neurol Sci 25:415–448View ArticleGoogle Scholar
- Sessa M, Nemni R, Quattrini A, Del Carro U, Wrabetz L, Canal N (1997) Atypical hereditary neuropathy with liability to pressure palsies (HNPP): the value of direct DNA diagnosis. J Med Genet 34:889–892PubMed CentralPubMedView ArticleGoogle Scholar
- Kalfakis N, Panas M, Karadima G, Floroskufi P, Kokolakis N, Vassilopoulos D (2002) Hereditary neuropathy with liability to pressure palsies emerging during vincristine treatment. Neurology 59:1470–1471PubMedView ArticleGoogle Scholar
- Radhakrishnan K, Thacker AK, Maloo JC (1988) A clinical, epidemiological and genetic study of hereditary motor neuropathies in Benghazi, Libya. J Neurol 235:422–424PubMedView ArticleGoogle Scholar
- Nelson JN, Amick LD (1966) Heredofamilial progressive spinal muscular atrophy: a clinical and electromyographic study of a kinship. Neurology 16:306Google Scholar
- Emery AEH (1971) Review: the nosology of the spinal muscular atrophies. J Med Genet 8:481–495PubMed CentralPubMedView ArticleGoogle Scholar
- Takata RI, Martins CES, Passosbueno MR, Abe KT, Nishimura AL, Da Silva MD, Monteiro A Jr, Lima MI, Kok F, Zatz M (2004) A new locus for recessive distal spinal muscular atrophy at Xq13.1–q21. J Med Genet 41:224–229PubMed CentralPubMedView ArticleGoogle Scholar
- Harding AE (1993) In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF (eds) Peripheral Neuropathy. W.B. Saunders, Philadelphia, pp 1051–1064Google Scholar
- Irobi J, De Jonghe P, Timmerman V (2004) Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet 1:195–202View ArticleGoogle Scholar
- Frequin ST, Gabreels FJ, Gabreels-Festen AA, Joosten EM (1991) Sensory axonopathy in hereditary distal spinal muscular atrophy. Clin Neurol Neurosurg 93:323–326PubMedView ArticleGoogle Scholar
- Timmerman V, Raeymaekers P, Nelis E, De Jonghe P, Muylle L, Ceuterick C, Martin JJ, Van Broeckhoven C (1992) Linkage analysis of distal hereditary motor neuropathy type II (distal HMN II) in a single pedigree. J Neurol Sci 109:41–48PubMedView ArticleGoogle Scholar
- Burns J, Ouvrier R (2006) Pes cavus pathogenesis in Charcot-Marie-Tooth disease type 1A. Brain 129:E50; author reply E51Google Scholar
- Tynan MC, Klenerman L, Helliwell TR, Edwards RH, Hayward M (1992) Investigation of muscle imbalance in the leg in symptomatic forefoot pes cavus: a multi disciplinary study. Foot Ankle 13:489–501PubMedView ArticleGoogle Scholar
- Guyton GP, Mann RA (2000) The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease. Foot Ankle Clin 5:317–326PubMedGoogle Scholar
- Berciano J, García A, Combarros O (2003) Initial semeiology in children with Charcot-Marie-Tooth disease 1A duplication. Muscle Nerve 27:34–39PubMedView ArticleGoogle Scholar
- Sabir M, Lyttle D (1983) Pathogenesis of pes cavus in Charcot-Marie-Tooth disease. Clin Orthop Relat Res 175:173–178PubMedGoogle Scholar
- Gallardo E, García A, Combarros O, Berciano J (2006) Charcot-Marie-Tooth disease type 1A duplication: spectrum of clinical and magnetic resonance imaging features in leg and foot muscles. Brain 129:426–437PubMedView ArticleGoogle Scholar
- Chung KW, Suh BC, Shy ME, Cho SY, Yoo JH, Park SW, Moon H, Park KD, Choi KG, Kim S, Kim SB, Shim DS, Kim SM, Sunwoo IN, Choi BO (2008) Different clinical and magnetic resonance imaging features between Charcot-Marie-Tooth disease type 1A and 2A. Neuromuscul Disord 18:610–618PubMedView ArticleGoogle Scholar
- Del Porto LA, Nicholson GA, Ketheswaren P (2010) Correlation between muscle atrophy on MRI and manual strength testing in hereditary neuropathies. J Clin Neurosci 2010 Apr 15 Apr 15 Epub ahead of printGoogle Scholar
- Carter GT, England JD, Chance PF (2004) Charcot-Marie-Tooth disease: electrophysiology, molecular genetics and clinical management. IDrugs 7:151–159PubMedGoogle Scholar
- Pareyson D, Scaioli V, Laura M (2006) Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med 8:3–22Google Scholar
- Berciano J, Gallardo E, García A, Infante J, Mateo I, Combarros O (2006) Charcot-Marie-Tooth disease type 1A duplication with severe paresis of the proximal lower limb muscles: a long-term follow-up study. J Neurol Neurosurg Psychiatry 77:1169–1176PubMed CentralPubMedView ArticleGoogle Scholar
- Reilly MM, Shy ME (2009) Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry 80:1304–1314PubMedView ArticleGoogle Scholar