Hereditary motor and sensory neuropathy I, associated with aplasia cutis conizenita: possible X-Med hheritance U
Castle D, Isaacs H, Ramsay M, Bernstein R. Hereditary motor and sensory neuropathy type I, associated with aplasia cutis congenita: possible X-linked inheritance. Clin Genet 1992: 41: 108-1 10. We report a family with possible X-linked recessive HMSN I with minor signs of the disease and abnormal sensory conduction studies evident in female carriers. There is a previously undescribed association with aplasia cutis congenita in both affected males, and a history of a severe skull defect in a third male child, who died at birth. The latter defect usually shows an autosomal dominant pattern of inheritance.
David Castid, Hyarn Isaacs', Michele Ramsay' and Renue Bumstein' 'MRC Human Ecogenetics Research Unit, Department of Human Genetics, School of Pathology, South African Institute for Medical Research and University of the Witwatersrand; and 'Clinical Neuromuscular Research Laboratory, Department of Physiology, University of the Witwatersrand, Johannesburg, South Africa
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Key words: aplasia cutis congenita CharcotMarie-Tooth disease congenital motor and sensory neuropathy X-linked
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Dr David Castle, Genetics Section, Institute of Psychiatry, Denmark Hill, London, SE5 8AF, England Received 9 June 1989, revised 9 September, accepted 17 September 1991
Type I and I1 hereditary motor and sensory neuropathies (Charcot-Marie-Tooth disease) (HMSN I and 11) are usually inherited in an autosomal dominant fashion. Type I1 disease is differentiated from Type I on the basis of normal or near-normal nerve conduction velocities. Rarely, autosomal recessive and X-linked dominant and recessive forms of HMSN have been described (Skre 1974, Fryns & Van Den Berghe 1980, Gal et a]. 1985, Phillips et al. 1985, Rozear et al. 1987). X-linked recessive inheritance occurring in HMSN I disease is characterised by delayed nerve conduction with minimal clinical manifestation of the disease in the female carriers (Fryns & Van Den Berghe 1980, Rozear et al. 1987). We report a family with possible X-linked recessive HMSN I, in which both affected male maternal cousins also exhibit aplasia cutis congenita, a defect of scalp and underlying calvaria, previously described as an autosomal dominant condition (McKusick 1986). An association between HMSN and aplasia cutis congenita has not hitherto been described. Presumed female carriers of the HMSN I gene were detected on neurophysiological testing. Case report
The proband, 111.9 in Fig. 1, was born with a 10 cm midline skull and scalp defect over the vertex 108
and occiput (Fig. 2). The brain was covered only by dura in portions of the affected area, but this gradually epithelialised. The bony defect was closed in a series of 8 operations. The repeated surgery and hospitalisations resulted in intellectual and emotional difficulties, but with remedial teaching he progressed well. At the age of 11 years his parents noticed that he walked on the outer edges of his feet and his gait became clumsy. On examination he was found to have highly arched feet and wasting of the distal musculature of the legs. There was early loss of muscle bulk in the forearms and small muscles of the hands, with good preservation of strength. There were no palpable nerves. Motor nerve conduction velocities (median, ulnar) were significantly delayed. Sensory responses (median, ulnar) were unobtainable. Electromyography (EMG) of distal musculature (anterior tibial, peroneal) confirmed denervation. A biopsy of affected muscle revealed abnormal variation in fibre size, with centralisation of nuclei. Histochemistry revealed grouping of both fibre types, type 1 fibres being mainly involved. Nerve biopsy (sural) showed primary myelin involvement affecting larger axons with onion-peeling, while unmyelinated fibres were relatively normal. These findings confirm a diagnosis of a peripheral neuropathy of the HMSN I type. High resolution chromosome analysis was normal. He has subsequently under-
X-linked HMSNI
I
III 1.
2.
3
4.
5.
6.
X
a
j
9.
m.
Fig. 1. Pedigree of Family
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male cousins affected by HMSN-I and aplasia cutis congenita. infant with a gross skull defect. females with minimal signs of HMSN-I
gone several operations to his feet and is still mobile at 17 years of age. He has two brothers, both of whom are normal, clinically and on neurophysiological testing. His mother had an early miscarriage, but no details were available. The proband's maternal first cousin, 111.6, was born with a similar skull and scalp defect, though not as severe. He also manifested with distal muscle weakness of the legs in his early teens, and clinical findings were similar to those in his cousin. Motor nerve conduction velocities were again markedly delayed, with absent sensory responses, and EMG of distal musculature revealed a denervation pattern. Chromosome analysis was normal. 111.6 has one brother and two sisters, all of whom are asymptomatic and clinically normal. Neurophysiological testing was normal in 111.4 and 111.7, but 111.5 showed flat abnormal sensory peaks (ulnar, median) with prolonged peak latencies. Motor conduction velocities were within the normal range. She is thus marked as a carrier. Neither mother of the two affected boys was aware of any muscle weakness or disability. On careful examination, however, both showed some minor distal muscle wasting and some degree of denervation was evidenced by high-voltage polyphasic activity in these muscles. Motor nerve conduction velocities were normal, but sensory testing revealed flat abnormal peaks with prolonged peak delay in both. The third sister, 11.1, her daughter and two sons, were fully investigated and showed no evidence of HMSN on either clinical or neurophysiological grounds. None of the 3 sisters, 11.1, 2 and 3, had any detectable scalp defects. Neither husband of 11.2 or 11.3 had either muscle weakness or a scalp defect. They were not related to their respective wives nor to each another. Examination of the grandparents (I. 1 and 1.2) revealed that the grandmother also had evidence of
Fig. 2. Posterior view of large scalp defect in proband, 111.9.
before a series of surgical corrections of underlying skull defect.
distal muscle wasting with electrophysiologicalevidence of denervation; sensory nerve conduction studies were again abnormal. She and her husband had no obvious scalp defects. She had had two male mid-trimester abortions, but details were not available. Her brother (1.3) was still alive and active at 80 years of age, with no evident muscle weakness. Her sister (1.4) had died at 93 years of age and there was no history of muscle weakness; she had had a son who died at birth, with a gross skull defect (11.4). Linkage analysis Linkage studies performed in families with Xlinked HMSN have shown that the gene locus maps on the proximal long arm of the X-chromosome (Haites et al. 1989, Mostacciuolo et al. 1991). In the current family, we used the markers L1.28, PGK and pDP34, which map to regions of the Xchromosome which have been implicated in previous reported pedigrees with X-linked HMSN I (see Mostacciuolo et al. 1991). DNA was extracted from blood samples, by 109
Castle et al. Table 1. X-chromosome DNA genotypes associated with HMSN I Fig. 1) Individual'
Status
11-1 Husband Of 11-1 11-2 11-3 Husband of 11-3 Ill-1 111-2 111-3 111-4 111-6 111-8 111-9
normal female carrier temale carrier female normal male normal ternale normal male normal temale affected male normal male affected male
refer to
Probe L1.28
Probe pDP34
Probe PGK
1I1 1 1I1 1I 1 1 1 1I1 1 112 1 1 1
112 1 112 112 2 1
212 2 212 a2 1 2 212 2 212 2 2 2
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2 112 1 2 1
standard methods, from those members of the pedigree who were available and willing to be tested. Southern blotting was performed and hybridised to the probes L1.28, pDP34 and PGK, which map to X p l l , Xq21.1 and Xq13, respectively (Mostacciuolo et al. 1991). The results are shown in Table 1. Discussion
As a rule males, with HMSN I are more severely affected than females and some writers have considered the pedigrees reported as X-linked dominant or recessive merely to reflect this trend (Harding & Thomas 1980). However, it now well accepted that X-linked form(s) of HMSN do exist (e.g. Gal et al. 1985, Haites et al. 1989, Mostacciuolo et al. 1991). As far as we are aware, aplasia cutis congenita has only ever been reported as an autosomal condition (McKusick 1986). We consider that the inheritance of HMSN I and aplasia cutis congenita in the present family is most compatible with an X-linked recessive mode. Autosoma1 dominant inheritance is unlikely in that three mothers and a daughter from three generations showed minimal expression of HMSN I and no scalp defect. Autosomal recessive inheritance would imply that both carrier mothers married unrelated men who were both themselves carriers, which would be a highly unlikely event. X-linked dominant inheritance is excluded by the minimal expression in the female carriers. In the DNA analysis, two of the probes (L1.28 and PGK) were uninformative. For the pDP34 probe, all three sisters (11.1, 11.2 and 11.3) were heterozygotes, but without a sample from 1.2 (she declined testing), it is not possible to determine
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whether they inherited the same X-chromosome from their mother. The two affected boys each inherited allele 1, whereas the unaffected brother (111.8) inherited allele 2, indicating segregation of HMSN with allele 1. It is possible that 11.1 inherited a different X-chromosome from 1.2, explaining how the two unaffected sons (111.1 and 111.3) inherited different X-chromosomes. Thus, although the DNA studies are inconclusive, they are compatible with an X-linked pattern of inheritance. The association of HMSN I with aplasia cutis congenita in both affected males probably implies linked genes; coincidental association would be highly unlikely. Alternatively, this might be the first report of a unique monogenic syndrome characterised by a peripheral neuropathy in association with a scalp defect. Acknowlsdgrmants We thank Professor Pierre Bill of Wentworth Hospital, Durban, for testing 11.1 and 1.3, and for his useful comments. We also thank Dr Alex Cort who supplied details of the skull defect of 111.9, and photographs thereof. Dr Jennifer Rosendorff performed the chromosome analysis. Melyn Glass and Helen Walters kindly collected the blood samples. The support of the Medical Research Council of South Africa and the Muscular Dystrophy Research Foundation is gratefully acknowledged.
Rrferrncrs Fryns JP, Van Den Berghe H. Sex-linked recessive inheritance in Charcot-Mane-Tooth disease with partial clinical manifestations in female carriers. Hum Genet 1980: 55: 413-415. Gal A, Mucke J, Theile H, Wieacker PF, Ropers HH, Wienker TF. X-linked dominant Charcot-Marie-Tooth disease: suggestion of linkage with a cloned DNA sequence from the proximal Xq. Hum Genet 1985: 70: 3842. Harding AE, Thomas PK. Genetic aspects of hereditary motor and sensory neuropathy (types I & 11). J Med Genet 1980: 17: 329-336. Haites N, Fairweather N, Clark C, Kelly KF, Simpson S, Johnston AW. Linkage in a family with X-linked Charcot-MarieTooth disease. Clin Genet 1989: 35: 399403. McKusick MA. Mendelian inheritance in man, 7th ed. Baltimore: Johns Hopkins University Press, 1986. Mostacciuolo ML, Muller E, Fardin P,MicagIio GF, Bardoni B. Guioli S, Camerino G , Danieli GA. X-linked CharcotMarie-Tooth disease: a linkage study in a large family by using 12 probes of the pericentromeric region. Hum Genet 1991: 87: 23-27. Phillips LH, Kelly TE, Schnatterly P, Parker D. Hereditary motor-sensory neuropathy (HMSN):possible X-linked dominant inheritance. Neurology 1985: 35: 498-502. Rozear MP, Pericak-Vance MA, Fischbeck K, Stajich JM, Gaskell, PC, Krendel DA, Graham DG. Dawson DV, Roses AD. Hereditary motor and sensory neuropathy, X-linked: A half century follow-up. Neurology 1987 37: 140-1465, Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth's disease. Clin Genet 1974: 6: 98-1 18.