Familial Segmental Neurofibromatosis

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Journal of Child Neurology http://jcn.sagepub.com

Familial Segmental Neurofibromatosis Sibel Oguzkan, Mine Cinbis, Sükriye Ayter, Banu Anlar and Sabiha Aysun J Child Neurol 2004; 19; 392 DOI: 10.1177/088307380401900515 The online version of this article can be found at: http://jcn.sagepub.com/cgi/content/abstract/19/5/392

Published by: http://www.sagepublications.com

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392

The reasons why the lesion involves exclusively the cortex of a single hemisphere remain unclear. The infectious context suggests a

direct attack

by the virus

on

this

particular

immune process cannot be ruled out,

even

zone.

However,

13.

Raine CS, Path FRC: Demyelinating diseases, in Davis RL, Robertson DM (eds): Textbook of Neuropathology, 2nd ed. Baltimore, Williams & Wilkins, 535-620.

14.

Broich

an

in the absence of white-

matter involvement. A

perivascular swelling with secondary demyelination has been suggested by Raine and Patch. 13 A disorder producing thrombosis or embolism should be affecting well-defined vascular territories; this is not the case because different vessels are irrigating the cerebellar hemisphere. The compression of the pyramidal tract below the cerebellar decussation has been suggested as the reason for the hemiparesis.3 Nevertheless, a crossed cerebellocerebral diaschisis could also be the basis of the hemiparesis, as described in adults with cerebellar infarction.4~’4 In conclusion, hemicerebellitis is a rare entity that should be suspected in the presence of a postinfectious cerebellitis, especially if the cerebellar signs are asymmetric and hemiparesis is associated with it. The diagnosis is finally established by MRI studies. Final prognosis is good, although cerebellar hemiatrophy remains.

K, Hartmann A, Biersack HJ, Horn R: Crossed cerebellocerebral diaschisis in a patient with cerebellar infarction. Neurosci Lett

1987;83:7-12.

Familial

ABSTRACT

Segmental

neurofibromatosis is considered to be the result of

postzygotic NF1 gene mutations. We present a family in which the proband has generalized neurofibromatosis 1, whereas members of previous generations manifest segmental skin lesions. All, including the clinically asymptomatic grandmother, carry the same haplotype. This is the only case in the literature in which a parent with

segmental Angels Garcfa-Cazorla, MD Jos6 Antonio Olivdn, MD Cristina Pancho, MD Anna Sans, MD Cristina Boix, MD Jaume Campistol, PhD Pediatric Neurology Unit Hospital Sant Joan de Déu Passeig Sant Joan de Deu Barcelona, Spain

Segmental Neurofibromatosis

skin

findings has a child with full-blown neurofibrogenetic mechanisms underlying this assodiscussed. This family can be further investigated by

matosis 1 disease. The ciation

are

examination of tissue

samples from affected and unaffected sites



Received June 30, 2003. Received revised lication Sept 9, 2003.

Sept 4,

2003.

Accepted for pub-

Address correspondence to Dr Angels Garcia-Cazorla, Pediatric Neurology Unit, Hospital Sant Joan de D6u, Passeig Sant Joan de D6u, 2. 08950 Esplugues, Barcelona, Spain. Tel: 0034932804000 ext 2418; fax: 0034932033959; e-mail: [email protected].

References

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Gieron-Korthals MA, Westberry KR, Emmanuel PJ: Acute childhood ataxia: 10-year experience. J Child Neurol 1994;9:381-384.

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Connolly AM,

Dodson

E, Prensky A,

Rust R: Course and outcome of

acute cerebelar ataxia. Ann Neurol

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1994;35:673-679. Iester A, Alpiagiani MG, Franzone G, et al: Magnetic resonance imaging in right hemisphere cerebellitis associated with homolateral hemiparesis. Childs Nerv Syst 1995;11:118-120. Sékhara T, Christophe C, Christiaens F, Dan B: Hémicerebellite postinfectieuse. Rev Neurol (Paris) 2001;157:1,84-86. Jabbour P, Samaha E, Abi Lahoud G, et al: Hemicerebellitis mimicking a tumour on MRI. Childs Nerv Syst 2003;19:122-125. Batten FE: Acute cerebellar ataxia of childhood. Trans Clin Soc Lond

1907;40:276. 7.

Cottom DG: Aute cerebellar ataxia. Arch Dis Child

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Horowitz MB, Pang D, Hirsch W: Acute cerebellitis: Case report and review. Pediatr Neurosurg 1991-92;17:142-145.

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Maggi G, Varone A, Aliberti F: Acute cerebellar ataxia in children. Childs Nerv Syst 1997;13:542-545.

1957;32:181-188.

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Hayakawa H, Katoh T: Severe cerebellar atrophy cerebellitis. Pediatr Neurol 1995;12:159-161.

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Shoji H, Hirai S, Ishikawa K, et al: CT and MR imaging of acute bellar ataxia. Neuroradiology 1991;33:360-361.

12.

Tabarki B, Husson B, Landrieu P: Acute cerebellar atrophy in encephalitis. J Child Neurol 1998;13:9-12.

following

acute

cere-

for mutations.

(J Child Neurol 2004; 19:392-394).

Neurofibromatosis 1

(von Recklinghausen’s disease) is an autosomal

dominant disorder affecting 1 in 3000 to 4000 newborns. The most

frequent clinical features of the disease are the presence of cafe au lait spots, axillary or inguinal freckling, neurofibromas, and Lisch nodules of the iris. Minor disease features are macrocephaly, short stature, hypertelorism, and thorax abnormalities. Plexiform neurofibromas, orthopedic problems (scoliosis, pseudoarthrosis), and learning disabilities are frequent complications. Neurofibromatosis 1 is also associated with malignancies such as optic glioma, peripheral nerve tumors, rhabdomyosarcoma, pheochromocytoma, duodenal carcinoid, and leukemia. 1,2 The NFl gene is located on chromosome 17q11.2. The gene is large, spanning 350 kb of genomic DNA, and contains 60 exons. Three modifier genes are embedded within the NFI gene, encoded in the opposite strand. Direct mutation analysis is difficult in the

NFl gene, because of its size, the presence of intragenic repeated sequences, and the probable occurrence of interlocus gene conversion from several NF1 pseudogenes. The mutation rate of the NF1 gene is higher than observed in most human genes: approximately half of all patients with neurofibromatosis 1 have no fam-

ily history of the disease.2,3 Up to 90% of new mutations are believed to be of paternal origin4,5; however, it has recently been suggested that large deletions are more commonly maternally derived .6 Segmental neurofibromatosis 1 is a term used to describe patients in whom the features of neurofibromatosis 1 are limited to an area or segment of the body. It was initially defined as involvement of &dquo;one side of the body,&dquo; but not all cases are unilateral. Segmental neurofibromatosis occurs in four subtypes, described as a true segmental type (Riccardi’s neurofibromatosis 5), a localized type with deep involvement, a hereditary type, and a bilateral type.’ Segmental cases are explained by somatic

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393

Figure order:

1.

Pedigree of the family. Marker p11.3C4.2, pHHH202,

IVS27AAAT2.1, IVS27AC28.4, EVI-20, IVS38GT53.0, pEW206, p2F9.8, pEW207.

mutations

occurring

in late

embryonic development.7,8

At pre-

sent, 150 segmental cases of neurofibromatosis have been described in the literature.’ Familial occurrence has been reported in only seven families.9-11 We present a case with generalized neurofibromatosis 1 whose family members had

digested with the appropriate restriction enzymes.12 Digestion products electrophoresed on 3% agarose gel containing ethidium bromide and were visualized under ultraviolet fluorescence. PCR products of microsatellite markers were electrophoresed on 7% denaturing polyacrylamide gel electrophoresis. DNA bands were detected by silver staining. were

segmental disease. Results

Case

Report

This 6-year-old boy had multiple cafe au lait spots,

a

plexiform neurofibroma,

and axillary freckling. His mother had three cafe au lait spots on the left arm, left leg, and right side of the chest, all smaller than 1.6 cm. The maternal aunt had

segmental findings with right axillary freckling and small cafe au lait spots spread over a 9 X 9 cm area on the right side of the neck. The maternal uncle had similar freckling on the inner surface of the right arm, spread over an area of 5.5 X 2.5 cm. The grandmother had no symptoms of neurofibromatosis 1, and her tion, was normal.

examination, including ophthalmologic

evalua-

Materials and Method Three generations of this family were analyzed using polymorphic DNA sequences: five extragenic restriction fragment length polymorphisms (pHHH 202, pll.3C, pEW 206, pEW 207, p2F9.8) and four intragenic microsatellites was

(IVS27AAAT2.1, EVI-20, IVS27CA28.4, IVS38CA53.1). DNA extracted from peripheral blood. All polymorphisms were analyzed by

polymerase chain reaction (PCR)-based methods. PCR products

were

Genotyping of the three-generation family is shown in Figure 1. The proband and his mother, maternal aunt, maternal uncle, and maternal grandmother showed a similar haplotype. The grandmother had no features of neurofibromatosis 1, although she had the same haplotype with the other family members who had disease symptoms. Discussion

According to the segregation analysis, the interesting feature in this family is the presence of the affected chromosome in the grandmother, who had no skin lesions; in the mother, who had only a few cafe au lait spots; and in the maternal aunt and uncle, who had only segmental disease, whereas the child (proband) had generalized findings of neurofibromatosis 1. Five segmental cases whose offspring had generalized neurofibromatosis 1 have been reported, but the children had only cafe au lait spots.8 This is the first report in which an

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394

individual with segmental skin lesions has a child with full-blown dis-

4.

Segmental neurofibromatosis 1 is explained by somatic mosaicism for the NFI gene mutations: some cells in an affected indi-

5.

ease.

558-559.

vidual harbor an NFI gene mutation, whereas others do not. Because somatic mosaicism is the consequence of a mutation that has occurred in a subset of cells after conception, all cases are sporadic.

Somatic mosaicism in pure

6.

segmental neurofibromatosis 1 has not been proven at the molecular level, although it has been described

7.

in some adults with mild generalized neurofibromatosis 1. The risk

8.

of having an affected offspring is very low; however, individuals with

segmental neurofibromatosis 1 might have offspring with classic neurofibromatosis 1 if their germ cells are also mosaic for an NFI muta-

tion.12,13 Gonadal mosaicism has been thought to be

an

Jadayel D, Fain P, Upadhyaya M, et al: Paternal origin of new mutations in von Recklinghausen neurofibromatosis. Nature 1990;343:

9.

unusual

Stephans K, Kayes L, Riccardi VM, et al: Preferential mutations of the neurofibromatosis type 1 gene in paternally derived chromosomes. Hum Genet 1992;88:279-282. Viskochil D: Genetics of neurofibromatosis 1 and the NF1 gene. J Child

Neurol 2002; 17:562-570. Roth RR, Martines R, James WD: Segmental neurofibromatosis. Arch Dermatol 1987;123:917-920. Huson SM: Neurofibromatosis type 1: Historical perspective and introductory overview, in Upadhyaya M, Cooper DN (eds): Neurofibromatosis Type 1 From Genotype to Phenotype. Bios Scientific Publishers, Oxford, UK, 1998, 1-20. Huson SM, Ruggieri M: Segmental NF: More common and more variable than the literature suggests? Braz J Genet 1996;19(Suppl 2):179. Rubenstein AE, Bader JL, Aron AA, Wallace S: Familial transmission of segmental neurofibromatosis. Neurology 1993;33(Suppl 2):76. Clementi M, Boni S, Mammi I, et al: Clinical application of genetic polymorphism in neurofibromatosis type 1. Ann Genet 1996;39:92-96. Ruggieri M, Huson SM: The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology 2001;56:1433-1443. Colman SD, Rasmussen SA, Ho VT, et al: Somatic mosaicism in a patient with neurofibromatosis type 1. Am J Med Genet 1996;58:

phenomenon in neurofibromatosis 1 in light of the infrequency with which cases of unaffected parents with affected offspring have been reported. 13 According to the clinical examination, the grandmother had no signs of neurofibromatosis 1. We think that the presence of the affected chromosome suggests a germline mutation that is expressed only in certain tissues of the offspring. This can be explained by somatic mosaicism, as described above, or with variable expression: according to the literature, different clinical findings can be observed within the same family members carrying the same mutation.z~6 This is explained by modifying genes at other loci and random somatic inactivation of the normal allele. The genetic mechanisms underlying the variable clinical fmdings in this family can be further investigated by examination of tissue samples from

Bilateral Decreased Oxygenation During Focal Status Epilepticus in a Neonate With

affected and unaffected sites for mutations.

Hemimegalencephaly

Sibel

~

.

Oguzkan, PhD Department of Medical Biology University of Hacettepe Mine Cinbis, MD Department of Pediatric Neurology University of Hacettepe Sükriye Ayter, PhD Department of Medical Biology University of Hacettepe Banu Anlar, MD Sabiha Aysun, MD Department of Pediatric Neurology University of Hacettepe Ankara, Turkey

Received April 22, 2003. Received revised lication Sept 25, 2003.

Sept 24, 2003. Accepted for pub-

Address

correspondence to Prof Dr Sukriye Ayter, Department of Medical Biology, Faculty of Medicine, University of Hacettepe, 06100-Sihhiye, Ankara, Turkey. Tel: +90 312 305 25 41; fax: +90 312 309 60 60; e-mail: [email protected]. ,

.

10. 11. 12. 13.

484-490.

ABSTRACT

Early surgical removal of a dysplastic hemisphere appears to be hemimegalencephaly and medically resistant seizures. We analyzed the changes in the cerebral regional beneficial for neonates with

oxygen saturation index in

a

neonate with tuberous sclerosis and

right hemimegalencephaly (1) during seven episodes of right hemisphere electroencephalographic status epilepticus with and without clinical manifestations and (2) after right hemispherectomy. The cerebral regional oxygen saturation index demonstrated marked fluctuations and progressive decline in both hemispheres during the episodes and normal values in the remaining hemisphere after surgery. We speculate that decreased oxygenation of the nonepileptic cerebral hemisphere in patients with hemimegalencephaly and medically resistant seizures can contribute to the production of global neurologic impairments in these patients and that the benefits of early hemispherectomy are due to the improved oxygenation of the nondysplastic hemisphere following surgery. (J Child Neurol 2004; 19:394-396).

,.

References 1.

2.

3.

Rasmussen SA, Overman J, Thomson SAM, et al: Chromosome 17 loss of heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1. Genes Chromosomes Cancer 2000;28:425-431. Shen MH, Harper PS, Upadhyaya M, et al: Molecular genetics of neurofibromatosis type 1. J Med Genet 1996;33:2-17. Fahsold

R, Hoffmeyer S, Mischung C,

et al: Minor lesion mutational

spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet

2000;66:790-818.

Patients with hemimegalencephaly and medically resistant seizures

often show significant global neurologic deficit.l-3 The physiologic basis for the global dysfunction is poorly understood.

Early surgical dysplastic hemisphere appears to prevent global developmental delay in neonates with hemimegalencephaly and medically resistant seizures.4,5 Near-infrared spectroscopy is a reliable tool to evaluate cerebral oxygenation in neonate. We observed removal of the

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