SHORT REPORT ABSTRACT: The nosologic boundary of neuropathic scapuloperoneal syn-drome (Davidenkow’s syndrome) remains ill defined and its genetic basis isunknown. A case of Davidenkow’s syndrome with the monochromosomic17p11.2 deletion that often is associated with hereditary neuropathy withliability to pressure palsies (HNPP) is described. The other allele at chro-mosome 17p11.2 locus was of normal length, and direct sequencing of thecoding region of the peripheral nerve protein-22 gene in this allele revealedno additional mutation. The deleted allele in the proband was inherited fromthe paternal line in which the affected members had a late onset Charcot–Marie–Tooth type 1 clinical phenotype. This observation suggests that therare Davidenkow’s syndrome is clinically related to HNPP and its genotypecould be a chromosome 17p11.2 deletion.

Muscle Nerve 32: 668–671, 2005

NEUROPATHIC SCAPULOPERONEAL SYNDROME(DAVIDENKOW’S SYNDROME) WITHCHROMOSOME 17p11.2 DELETION

ASHOK VERMA, MD

Department of Neurology, University of Miami Miller School of Medicine,1150 NW Street, Suite 701, Miami, Florida 33136, USA

Accepted 26 May 2005

Davidenkow2 in 1939 published his experience with13 patients (12 patients in 4 families and 1 sporadiccase) in order to describe an entity with overlappingfeatures of Charcot–Marie–Tooth disease (CMT)and neurogenic (amyotrophic) scapuloperoneal syn-drome (SPS). The chief characteristics of the condi-tion were autosomal-dominant inheritance, latechildhood or later age of onset, weakness and atro-phy in the proximal upper and distal lower extrem-ities, distal sensory impairment in the legs, and atendency toward pes cavus and hammertoes. Davi-denkow2 stressed that despite the similarity to CMT,the two disorders—neuropathic SPS and CMT—didnot occur in the same family and that they weredistinct entities. Subsequent authors agreed9 orquestioned4,10,13 whether Davidenkow’s syndromewas a distinct entity. Wilson13 reported his own ex-perience and commented that Davidenkow’s pa-tients were suffering from an unusual form of CMTdisease. Harding and Thomas4 and others10 de-

scribed families with affected members of the samefamily demonstrating phenotypes of CMT or Davi-denkow’s syndrome and favored the clinical relation-ship between these two entities. Ricker et al.,9 in alarge series of families with CMT, failed to identify asingle case of SPS and dismissed any relationshipwith Davidenkow’s syndrome. The nosologic statusof Davidenkow’s syndrome continues to be unclear.

CMT is genetically heterogeneous and the mostcommon form, CMT1A, is linked to the chromo-some 17p11.2 locus duplication that harbors theperipheral myelin protein-22 (PMP-22) gene. Dele-tion of the chromosome 17p11.2 locus is generallyassociated with another phenotype, hereditary neu-ropathy with liability to pressure palsies1 (HNPP).Our experience in one family with members afflictedwith Davidenkow’s syndrome and CMT1 phenotypesand with chromosome 17p11.2 locus mutation sug-gests that these two entities are indeed related.

CASE REPORT

Index Case. This 11-year-old girl first noticed diffi-culty in keeping her arms over her head duringballet lessons at the age of 4 years. At 6 years of age,she began to experience difficulty in running. Clin-ical examination then revealed asymmetric weaknessof the dorsiflexor muscles (Medical Research Coun-cil, MRC, grade 4) of ankles bilaterally, right hip

Abbreviations: CMT, Charcot–Marie–Tooth disease; HNPP, hereditary neu-ropathy with liability to pressure palsies; MRC, Medical Research Council;PMP-22, peripheral myelin protein-22; SPS, scapuloperoneal syndromeKey words: Davidenkow’s syndrome; HNPP; neuropathy; PMP-22; scapu-loperoneal syndromeCorrespondence to: A. Verma; e-mail: averma@med.miami.edu

© 2005 Wiley Periodicals, Inc.Published online 8 July 2005 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.20402

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flexor muscles (grade 4), and mild diffuse weaknessof the right upper extremity (grade 4�). Tendonreflexes were sluggish except for the left quadricepsand left biceps reflexes, which were normal. Sensoryexamination was normal. Blood investigations, in-cluding serum creatine kinase, lactate, pyruvate, andcreatine, and metabolic screen for inherited organicaciduria, were normal. Right gluteus muscle andsural nerve biopsies revealed only nonspecific find-ings. Immunocytochemistry for the following sar-colemmal proteins were normal: dystrophin; alpha,beta, gamma, and delta sarcoglycans; spectrin; andmerosin. Gene testing for facioscapulohumeral mus-cular dystrophy (chromosome 4q35-locus deletion)was normal. Brain magnetic resonance imaging withand without gadolinium was normal.

Over the ensuing 4 years, the limb weakness pro-gressed in an asymmetric fashion, right greater thanleft. She had particular difficulty in raising the armsand she developed foot drop, followed by weaknessof the arm and forearm muscles. Limited neurophys-iological testing under sedation at age 8 yearsshowed slow nerve conduction (right peroneal mo-tor velocity in leg, 33.4 m/s). A second muscle biopsyfrom the quadriceps revealed grouped fiber atrophywith regions of fiber type grouping. At age 9 years,she required lengthening of the Achilles tendon.

Neurological examination at 11 years of ageshowed spontaneous winging of scapulae (greateron left, Fig. 1a) and bilateral foot drop with highplantar arches and tendency to hammertoes (Fig.1b). Objective muscle strength was difficult to quan-tify in proximal upper extremities, but she had asym-metric (weaker right side, except serratus anterior)and less than gravity strength (grade 2) at the rhom-boids, supraspinatus, infraspinatus, deltoids, biceps,and triceps. Extensors of the wrist and fingers andintrinsic hand muscles were grade 4 (each muscle sotested was about half an MRC grade better on theleft than right). In the right lower extremity, she

could lift the iliopsoas, hamstrings, thigh adductorsand abductors against slight resistance (grade 4�).Right quadriceps and hamstrings were grade 4�,and tibialis anterior, extensor hallucis longus, andextensor digitorum were grade 2. Right toe flexorswere grade 3, and tibialis posterior and gastrocne-mius–soleus complex were grade 4. In the left lowerextremity, muscle strength was normal at hip flexors,adductors and abductors and at quadriceps andhamstrings; tibialis anterior and extensor hallucislongus were weak (grade 3), as also were tibialisposterior and the gastrocnemius–soleus complex(grade 4). All tendon reflexes were absent. Percep-tion of touch, pinprick, and vibration was impairedin the feet, and joint position was impaired at thetoes. The peripheral nerves were not thickened.

Family History. The proband’s father, current ageof 43 years, had had pes cavus and hammer toes(Fig.1c) since late childhood. Clinical examinationat age 41 years showed a symmetric weakness oftibialis anterior and peroneus longus (grade 4�),extensor hallucis longus (4), tibialis posterior (4�),and intrinsic hand muscles (4�) bilaterally. He hada distal sensory impairment in the legs with proxi-mal-to-distal gradient. Nerve conduction study re-vealed prolonged distal latencies (right peronealand right ulnar motor latencies were 6.5 ms and 4.4ms, respectively; right sural sensory was unrecord-able) and asymmetric slowing of motor nerve con-duction, particularly across the potential compres-sion sites. Thus, motor velocity of right peronealnerve in the leg and across the fibular head were30.5 m/s and 15.0 m/s, respectively; right medianmotor velocity in the forearm and across the wristwere 46.1 m/s and 35.9 m/s, respectively; and rightulnar motor velocity in the forearm and across theelbow were 55.0 m/s and 33.3 m/s, respectively.

The proband has three paternal aunts. One (41years of age) has similar feet deformity without weak-

FIGURE 1. Periscapular muscle weakness and asymmetric winging (a) and foot drop (b) in proband, and feet deformity in her father (c).

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ness but asymmetric slow nerve conduction (left me-dian and left ulnar distal motor latencies, 5.0 ms and3.8 ms, respectively; right tibial motor velocity in leg,left ulnar motor velocity in forearm, and left ulnarmotor velocity across elbow, 31.9 m/s, 49.4 m/s, and17.8 m/s, respectively; left sural distal latency, 5.8ms). Another aunt (39 years of age, not examined byauthor) had prolonged distal motor and sensorylatencies of the median nerves (left median motorand sensory latencies were 5.3 ms and 4.6 ms, respec-tively) but otherwise normal nerve conduction in thelimbs. The third paternal half-aunt was normal onclinical examination (electrophysiology not per-formed). The paternal grandmother had higharches and hammer toes without significant clinicaldeficit. The proband has a brother, aged 13 years,who is normal.

DNA Test. Direct testing from genomic DNA for theCMT1A mutation (duplication of the 17p11.2 alleleharboring PMP-22 gene) and for the so-called HNPPmutation (17p11.2 deletion) was performed byrestriction endonuclease digestion and Southernblot analysis after pulsed-field gel electrophoresis(Athena Diagnostics, Worcester, Massachusetts).The father tested positive for a 1.5 mb chromosomel7pll.2 deletion. The proband inherited this allele.The other 17p11.2 allele harboring the PMP-22 genewas of normal length, and direct sequencing of thecoding region of the nondeleted PMP-22 gene de-tected no additional mutation in the proband. Themother of the proband had two normal chromo-some 17p11.2 alleles.

DISCUSSION

Weakness and atrophy in a scapuloperoneal distri-bution may have a myopathic or neurogenic basis.Myopathic scapuloperoneal syndrome may occur inpatients with muscular dystrophy, congenital myop-athy, myopathy with cardiomyopathy, and inflamma-tory myopathy.3,11 Most neurogenic cases of SPS havebeen considered secondary to anterior horn celldisease.5 However, scapuloperoneal amyotrophymay be associated with distal sensory impairment(Davidenkow’s syndrome). Davidenkow2 and others9

assumed that neuropathic SPS was clinically and ge-netically distinct from CMT.

CMT1 is a dominantly inherited demyelinatingmotorsensory neuropathy. In most patients withCMT1, the disease locus is on chromosome 17p11.2(CMT1A) and the most common genetic defect inthese patients is an approximately 1.5 mb duplica-tion.1,6 This duplication at the chromosome 17p11.2

locus harbors the gene that codes for PMP-22 pro-tein. Additional reports of inherited and de novomutations of the PMP-22 gene in patients with CMT1provide compelling evidence that the PMP-22 geneis the disease-gene in CMT1A.6,8

The reciprocal event to chromosome 17p11.2duplication is 17p11.2 deletion, which is usually as-sociated with a different clinical phenotype (HNPP).HNPP cases without deletion but with a frame shiftor point mutation in the PMP-22 gene have alsobeen reported.1 It is postulated that unequal cross-over between chromosome 17p11.2 homologuesduring meiosis generates both the duplication andthe deletion. Identification of HNPP pedigrees thatdo not demonstrate linkage to the chromosome17p11.2 region indicates genetic heterogeneity ofHNPP itself.1

Although the clinical picture in CMT1A is fairlyuniform, the clinical spectrum of HNPP is broad.1,7

The clinical spectrum of HNPP includes asymptom-atic nerve conduction abnormalities, isolated acutemononeuropathy, subacute multiple mononeuropa-thies, brachial plexus neuropathy, acute onset neu-ropathy followed by progressive deficit, chronic pro-gressive demyelinating neuropathy, patchy axonalneuropathy, and a mild smoldering neuropathy. Inthe family described, autosomal-dominant inheri-tance, chromosome 17p11.2 deletion with CMT1and Davidenkow’s syndrome phenotypes in familymembers, and the normal sequence of the otherPMP-22 gene in the proband, who had the Daviden-kow’s syndrome phenotype, indicate that Daviden-kow’s syndrome is clinically and genetically relatedto the HNPP. The mode of disease inheritance andclinical features in the patient were similar to thosedescribed in Davidenkow’s syndrome in the pre-genetic test era.2,4,10 In one recent review of 24HNPP cases with documented chromosome 17p11.2deletion mutation,12 one patient probably had ascapuloperoneal distribution of the neuropathic def-icit (case 19). The asymmetric weakness reported inDavidenkow’s syndrome,4,10,12 similar to our case,also suggests the relationship of Davidenkow’s syn-drome to the usually asymmetric HNPP.

The Davidenkow’s syndrome phenotype ofHNPP is arguably rare; only about a dozen cases ofDavidenkow’s syndrome have been documented af-ter Davidenkow’s original report. What determinesDavidenkow’s syndrome phenotype with chromo-some 17p11.2 deletion is unknown. Compound het-erozygous mutations involving the PMP-22 gene areknown to cause atypical or more severe neuropa-thies.1 However, in the present case, a normal cod-ing sequence of PMP-22 gene on the other chromo-

670 Short Reports MUSCLE & NERVE November 2005

some excludes this possibility. The other possibilitiesfor this rare phenotype include an intronic or pro-moter region mutation involving the PMP-22 geneor some modifier gene or environmental factor.Nonetheless, the case described here indicates thatsome patients with Davidenkow’s syndrome are ge-netically related to the HNPP mutation and that adefinite DNA diagnostic test in patients with Davi-denkow’s syndrome can help in counseling regard-ing the disease prognosis and prevention.

The author thanks Dr. Walter G. Bradley for helpful clinicaldiscussion and advice.

REFERENCES

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4. Harding AE, Thomas PK. Distal and scapuloperoneal distri-bution of muscle involvement occurring within a family withtype 1 hereditary motor and sensory neuropathy. J Neurol1980;224:17–23.

5. Kaeser HE. Scapuloperoneal muscular atrophy. Brain 1965;88:407–418.

6. Keller MP, Chance PF. Inherited peripheral neuropathy. Se-min Neurol 1999;19:353–363.

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8. Marrosu MG, Vaccargiu S, Marrosu G, Vannelli A, CianchettiC, Muntoni F. A novel point mutation in the peripheralmyelin protein 22 (PMP22) gene associated with Charcot–Marie–Tooth disease type 1A. Neurology 1997;48:489–493

9. Ricker K, Mertens HG, Schimrigk K. The neurogenic scapu-loperoneal syndrome. Eur Neurol 1968;1:257–274

10. Ronen GM, Lowry N, Wedge JH, Sarnat HB, Hill A. Heredi-tary motor sensory neuropathy type 1 presenting as scapu-loperoneal atrophy (Davidenkow’s syndrome): electrodiag-nostic and pathological studies. Can J Neurosci 1986;13:264–266.

11. Serratrice G, Pellissier JF, Pouget J, Gastaut JL, Cros D. Lessyndromes scapulo-peroniers. Rev Neurol (Paris) 1982;138:691–711.

12. Tyson J, Malcolm S, Thomas PK, Harding AE. Deletion ofchromosome 17p11.2 in multifocal neuropathies. Ann Neu-rol 1996;39:180–186.

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