196 Fig. 1 Pes cavus and main en griffe in a patient with CMT1A Fig. 2 Pes cavus in a patient with CMT1A HPN associated with pes cavus Charcot–Marie–Tooth disease 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 [5]. CMT is a genetically heterogeneous disorder (Table 1), classiﬁed into demyelinating (CMT1 and CMT4), axonal (CMT2 and CMT4), and intermediate (CMT, CMTX, 123 J Orthopaed Traumatol (2010) 11:195–201 CMT2E) forms, and caused by mutations in several genes coding for structural myelin proteins, gap-junction pro- teins, cytoskeleton components, enzymes, or transcription factor. CMT is usually transmitted as an autosomal domi- nant trait, although rarer X-linked (CMTX) or recessive forms have been reported [6, 7]. CMT is a slow progressive disease, usually with onset in the second or third decade. Rarely, CMT arises in early infancy (Dejerine–Sottas and congenital hypomyelination diseases) [8] with a severe phenotype characterized by hypotonia and delay in motor milestones. CMT onset may also occur later, generally with a less aggressive clinical course [9]. 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 [12]. The most frequent ﬁndings [13] 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 [14]. Muscle cramps, cold feet, acro- cyanosis, and postural tremor are frequent complaints. Electroneurography allows classiﬁcation of CMT dis- ease 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 pre- served or only mildly slowed ([38 m/s in upper limb motor nerves) and the axon is the primary disease target [15]. 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 pres- ence of basal lamina ‘‘onion bulbs,’’ determined by con- centric proliferation of Shawn cell cytoplasmic processes during the demyelination phenomenon and the remyelina- tion tentative. In the advanced phase, loss of normal myelin covering (‘‘nude axon’’) has also been reported.