www.elsevier.com/locate/braindev

Brain & Development 33 (2011) 683–686

Case report

Rud syndrome with focal cortical dysplasia: A case report

Sara Marconi a, Gaetano Cantalupo b, Federica Marliani c, Francesco Toni c,Giuseppe Capovilla d, Elena Lorenzetti d, Antonino Romeo e, Roberto Michelucci f,

Guido Rubboli f,⇑

a Department of Neurological Sciences, Institute of Neurology, University of Bologna, Via Ugo Foscolo 7, 40131 Bologna, Italyb Child Neuropsychiatry Unit, University of Parma, Viale Gramsci 14, 43100 Parma, Italy

c Neuroradiology Unit, Department of Neurosciences, Bellaria Hospital, Via Altura, 3 40139 Bologna, Italyd Child Neuropsychiatry Unit, “C. Poma” Hospital, Viale Albertoni, 46100 Mantova, Italy

e Child Neuropsychiatry Unit, Fatebenefratelli Hospital, Corso di Porta Nuova, 20121 Milan, Italyf Neurology Unit, Department of Neurosciences, Bellaria Hospital, Via Altura, 3 40139 Bologna, Italy

Received 21 July 2010; received in revised form 7 October 2010; accepted 11 October 2010

Abstract

We report a female patient with ichthyosis, epilepsy, mental retardation, hypergonadotrophic hypogonadism, polyneuropathy,and cranial dysmorphisms. This clinical picture may satisfy the main diagnostic criteria that characterize Rud syndrome (RS), a rareneurocutaneous disease. The patient underwent extensive clinical evaluation, neurophysiological studies (wakefulness and sleepEEG, EMG), dermatological and endocrinological evaluation and neuroimaging study (3 Tesla brain MRI). Interestingly, brainMRI unveiled a malformation of cortical development, never reported previously in RS. Although seizure semiology and EEG fea-tures could not provide clear cut information suggesting a focal onset, the role of this MRI finding in the genesis of the epilepticseizures cannot be ruled out. The finding of a focal cortical dysplasia in RS might be related to genetic abnormalities affectingthe development of both epidermis and neural structures with the same embryological origin.� 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Rud syndrome; Congenital ichthyosis; Epilepsy; Mental retardation; Focal cortical dysplasia

1. Introduction

The designation “Rud syndrome” (RS-OMIM#308200) has been used to describe a peculiar associationof ichthyosis, epilepsy, mental retardation, and, in mostcases, hypogonadism [1,2]. Other associated findings suchas retinitis pigmentosa, polyneuropathy, neuro-sensorydeafness, short stature, cranial and facial dysmorphisms,hyperchromic macrocytic anemia and alopecia have beenreported in various combinations [1,3]. In the literature,

0387-7604/$ - see front matter � 2010 The Japanese Society of Child Neuro

doi:10.1016/j.braindev.2010.10.011

⇑ Corresponding author. Tel.: +39 051 6225738; fax: +39 0516225680.

E-mail address: guido.rubboli@ausl.bo.it (G. Rubboli).

descriptions of the clinical features and laboratory findingsof RS, particularly in adulthood, are scanty. In this reportwe describe the clinical, neurophysiological and neurora-diological aspects of an adult female patient presentingwith a condition that might fit the clinical diagnostic cri-teria of RS, interestingly associated with a malformationof cortical development, never reported in previous cases.

2. Case report

A 30-year-old female patient was diagnosed as suffer-ing from Rud syndrome since the age of 4. Since theearly months of life, she started to present withslightly-moderate vulgar ichthyosis, generalized tonic–clonic seizures and “absence-like” episodes, associated

logy. Published by Elsevier B.V. All rights reserved.

684 S. Marconi et al. / Brain & Development 33 (2011) 683–686

with a severe delay of psychomotor development and nolanguage acquisition. At 10 years, she started to sufferfrom bronco-pulmonary infections and dysphagia; amegaesophagus with achalasia was diagnosed and sheunderwent several surgical interventions. At 27 and29 years, she was operated on for breast fibroadenoma.Generalized tonic–clonic seizures kept occurring untilthe time of our examination with variable frequency(from 2 seizure/year to monthly clusters of manyseizures per day for 3–4 days); she was on phenobarbi-tal 150 mg/day, phenytoin 300 mg/day, nitrazepam15 mg/day. At the admission in our hospital, sheunderwent extensive clinical evaluation, including neu-rological, dermatological, endocrinological and ophthal-mological assessment, neurophysiological investigations(wakefulness and sleep EEG, EMG), and neuroimagingstudy (3 Tesla brain MRI). Neurological examinationshowed cranio-facial dysmorphisms such as biparietalmicrocephaly with tight biparietal, horizontal palpebralfissures with blepharophimosis, prominent root andnasal bridge, bulbous nasal tip with hypoplastic nasalwings, hypertelorism, thin upper lip, fleshy and evertedlower lip (Fig. 1). Wakefulness and sleep EEG studiesrevealed a waxing and waning low amplitude posteriorbackground activity, fast rhythmic activities in the ante-rior leads, sporadic diffuse fast spike–polyspike-waveabnormalities, occasionally prevailing on the left hemi-sphere (Fig. 2). EMG studies showed sensitive-motor,mainly axonal, polyneuropathy. Dermatological evalua-tion concluded for moderate ichthyosis. Endocrinologi-cal assessment revealed oligo-amenorrhoea associated

Fig. 1. (A and B) Cranio-facial dysmorphisms such as biparietalmicrocephaly, horizontal palpebral fissures with blepharophimosis,prominent root and nasal bridge, bulbous nasal tip with hypoplasticnasal wings, hypertelorism, thin upper lip, fleshy and everted lower lip,are illustrated. (C and D) Moderate ichthyosis at the lower limbs.

with abnormal values of gonadotropic hormones (inthe follicular phase, FSH: 14.2 mU/ml – normal range(n.r.): 2.0–13.5 mU/ml; LH: 22.4 mUI/ml – n.r.: 1.5–13.0 mU/ml; progesterone: 0.15 ng/ml – n.r.: 0.1–1.5;estradiol: 98 pg/ml – n.r.: 20–100 pg/ml), consistent withmild hypergonadotrophic hypogonadism. 3 Tesla brainMRI showed a thickening of the left temporo-polar cor-tical mantle around an abnormally deep sulcus, andblurring of the boundary between the white and the graymatter, compatible with a left temporal cortical dyspla-sia (Fig. 3). No retinitis pigmentosa was found.

3. Discussion

In the literature, reports of adult cases diagnosed assuffering from RS are rare [1,2]. We describe a adultfemale patient in whom the main clinical characteristics,i.e. mental retardation, hypergonadotrophic hypogo-nadism, congenital ichthyosis, epilepsy met the majordiagnostic criteria of RS [1,2]. Polyneuropathy, micro-cephaly and cranio-facial dysmorphisms observed inour patient can be features of RS as well [3–5]. Pheno-typic and genetic variability of the cases reported inthe literature have questioned the existence of thissyndrome [6,7]; indeed, the present ichthyosis classifica-tion does not include RS as a distinct entity and mostcases previously reported as RS should now be reas-signed in the broader context of ichthyosis with hypogo-nadism, with and without others neurological deficits[4,8]. In fact, congenital ichthyosis is common in severalneurological disorders, such as Sjogren and Larssonsyndrome, Refsum disease, Netherton syndrome,X-linked recessive ichthyosis and associated X-linkedSTS deficiency, however these diseases have distinctcharacteristics that are absent in our patient [8,9].Sjogren and Larsson syndrome differs from RS by thedevelopment of a spastic paraplegia and the absence ofhypogonadism. In Refsum disease, hypogonadism, men-tal retardation and cranial dysmorphisms are notdescribed, whereas cerebellar ataxia, peripheral polyneu-ropathy, anosmia, central deafness as well cranial nerveinvolvement are common; furthermore large amounts ofphitanic acid are found in plasma and urine. Nethertonsyndrome unlike RS has a distinct hair defect (trichor-rhexis invaginata) which gives the hair shaft the appear-ance of a bamboo stick, and ichthyosis may present aslinearis circumflexa, with typical annular and polycycliclesions [9]. Finally, a group of X-linked ichthyosis, i.e.X-linked recessive ichthyosis, associated with STSdeficiency, due to complete or partial deletion of STSgene mapped to the distal part of the short arm the Xchromosome (Xp22.3,) are characterized by eitherichthyosis as the only clinical manifestation or by theassociation with extracutaneous manifestations such ascorneal opacity, cryptorchidism, epileptic seizures, andreactive psychological disorders [10].

Fig. 2. EEG recordings showed a waxing and waning low amplitude posterior background activity, fast rhythmic activities in the anterior leads, andsporadic diffuse fast spike–polyspike-wave abnormalities.

Fig. 3. (a–c) Axial reformatted SPGR T1 weighed images, (d–e) coronal reformatted SPGR T1 and (f) FSE IR T1 weighted images. The lefttemporal bone is thickened (arrowhead) as well as the underlying temporo-polar cortical mantle around an abnormally deep fissure (arrows). Thecerebral cortex on the right side is normal.

S. Marconi et al. / Brain & Development 33 (2011) 683–686 685

686 S. Marconi et al. / Brain & Development 33 (2011) 683–686

Interestingly, in our patient brain MRI demonstrateda focal cortical dysplasia in the anterior portion of theleft temporal lobe. Although the description of seizuresemiology and the EEG features could not provide clearcut information suggesting a focal onset, the role of thisMRI finding in the genesis of the epileptic seizures can-not be ruled out, particularly considering the poorresponse to antiepileptic treatment of our patient;indeed, drug-resistance is not uncommon in epilepto-genic malformations of cortical development. Neurora-diological findings reported in RS syndrome includecranial dysmorphism, i.e. oxycephalic skull deformity,scaphocephaly, microcephaly, and cortical atrophy, pre-dominantly asymmetric [4,6], whereas malformation ofcortical development have never been reported so far.

In conclusion, in our patient the association of men-tal retardation, congenital ichthyosis, epilepsy, hypergo-nadotrophic hypogonadism, polyneuropathy, cranialand facial dysmorphisms constitutes a peculiar constel-lation of clinical features that may be consistent withthe clinical picture attributed to RS, presently includedin the broad group of ichthyosis with hypogonadism,and neurological deficits. The finding of a focal corticaldysplasia might be related to genetic abnormalities, notyet completely identified, affecting the development ofboth epidermis and neural structures with the sameembryological origin.

Conflict of interest statement

The authors have no conflict of interest.

References

[1] Rud E. Et Tilf�lde af Infantilisme med Tetani, Epilepsi,Polyneuritis, Ichthyosis og An�mi af perniciøs Type. Hospitalst-idende 1927;70:525–38.

[2] Marxmiller J, Trenkle I, Ashwal S. Rud syndrome revisited:ichthyosis, mental retardation, epilepsy and hypogonadism. DevMed Child Neurol 1985;27:335–43.

[3] Larbrisseau A, Carpenter S. Rud syndrome: congenital ichthyo-sis, hypogonadism, mental retardation, retinitis pigmentosa andhypertrophic polyneuropathy. Neuropediatrics 1982;13:95–8.

[4] Kaufman LM. A syndrome of retinitis pigmentosa, congenitalichthyosis, hypergonadotropic hypogonadism, small stature,mental retardation, cranial dysmorphism, and abnormal electro-encephalogram. Ophthal Genet 1998;19:69–79.

[5] Stoll C, Eyer D. A syndrome of congenital ichthyosis, hypogo-nadism, small stature, facial dysmorphism, scoliosis and myogenicdystrophy. Ann Genet 1999;42:45–50.

[6] Munke M, Kruse K, Goos M, Ropers HH, Tolksdorf M. Geneticheterogeneity of the ichthyosis, hypogonadism, mental retarda-tion, and epilepsy syndrome. Clinical and biochemical investiga-tions on two patients with Rud syndrome and review of theliterature. Eur J Pediatr 1983;141:8–13.

[7] Traupe H, Muller-Migl CR, Kolde G, Happle R, Kovary PM,Hameister H, et al. Ichthyosis vulgaris with hypogenitalism andhypogonadism: evidence for different genotypes by lipoproteinelectrophoresis and steroid sulfatase testing. Clin Genet1984;25:42–51.

[8] Oji V, Traupe H. Ichthyosis. Clinical manifestations and practicaltreatment options. Am J Clin Dermatol 2009;10:351–64.

[9] Krug M, Oji V, Traupe H, Berneburg M. Ichthyoses – Part 2:congenital ichthyoses. J Dtsch Dermatol Ges 2009;7:577–88.

[10] Hernandez-Martın A, Gonzalez-Sarmiento R, De Unamuno P.X-linked ichthyosis: an update. Br J Dermatol 1999;141:617–27.