Epilepsy in a Patient With Focal Dermal Hypoplasia

Hideaki Kanemura, MD, PhD*, Kazuo Hatakeyama, MD, PhD*, Kanji Sugita, MD, PhD*, and Masao Aihara, MD, PhD
Focal dermal hypoplasia is an X-linked, dominantly inherited syndrome of mesodermal and ectodermal decits. Although profound dysplasia of connective tissue, especially in the skin and skeleton, inarguably constitutes a predominant feature of focal dermal hypoplasia, the disease occurs in a variety of organs of ectodermal and mesodermal origin. However, seizure disorders with focal dermal hypoplasia and ndings of cranial magnetic resonance imaging in focal dermal hypoplasia were not previously reported. We report on a 5-year-old girl with focal dermal hypoplasia, refractory epilepsy, and suspected dysplasia of the cerebellar cortex. This case may represent a novel expression of focal dermal hypoplasia as a seizure disorder and dysplasia of the cerebellar cortex. Hence seizure disorders and dysplasia of the cerebellar cortex need to be considered in patients with focal dermal hypoplasia. 2011 Elsevier Inc. All rights reserved. Kanemura H, Hatakeyama K, Sugita K, Aihara M. Epilepsy in a patient with focal dermal hypoplasia. Pediatr Neurol 2011;44:135-138.

et al. described three new patients, coined the term focal dermal hypoplasia, and linked these patients to earlier cases [2]. More than 200 cases of focal dermal hypoplasia have since been reported in the literature or are otherwise known. In these reports, focal dermal hypoplasia syndrome may affect various organs and organ systems such as the eyes, bones, teeth, and skin. A number of lesions affecting the soft tissues continue to be reported, such as anomalies of the urinary tract and kidneys. Many patients with focal dermal hypoplasia exhibit varying degrees of mental deciency. However, severe mental retardation is rare in patients with focal dermal hypoplasia. Thus, a number of new clinical manifestations have been recognized, and considerable knowledge has been accumulated regarding methods of inheritance and pathogenetic mechanisms. Among these clinical manifestations, however, seizure disorders have not been recognized as a feature of the syndrome [3]. Furthermore, abnormal ndings of the cerebellar cortex have never been reported, although other clinical manifestations such as agenesis of the corpus callosum were described. We report on our experience with a girl manifesting focal dermal hypoplasia, who exhibited severe mental retardation and refractory epilepsy. In addition, a complication of dysplasia of the cerebellar cortex was suspected. Seizure disorders may represent an unusual manifestation in focal dermal hypoplasia. Case Report
A 5-year-old girl was born during gestational week 39 by cesarean section because of prolonged delivery. She weighed 2685 g and was 45 cm in length, and her occipital frontal circumference was 32 cm. The pregnancy was recorded as uneventful. The mother was normal and was age 27 years. The father was normal and was age 30 years. This child was their rst. The family history was unremarkable. The patient was born without asphyxia, but left hemiconvulsions were evident 13 hours after birth. Phenobarbital was immediately administered, and this treatment led to improvement in the seizures. Laboratory tests produced normal results, including a complete blood count, platelet count, electrolytes, and liver enzymes. Computed tomography of the brain demonstrated no signicant abnormalities. On examination, she exhibited an asymmetric face with patchy alopecia and apparently low-set ears. Coloboma of the iris was not present. Examination of the skin revealed multiple erythematous, crusted, atrophic macules on the neck, trunk, and limbs. On the right upper limb, these lesions displayed a linear distribution, contiguous with a white verrucous plaque. A similar plaque was evident on the left hand. Skeletal system defects of her hands and feet were apparent. Although she did not exhibit a lobster-claw deformity or syndactyly, the thumbs on both hands bent backward (Fig 1). In addition, dystrophy of the nails was evident. Based

Introduction Focal dermal hypoplasia is an uncommon congenital disorder of mesodermal and ectodermal decits. Focal dermal hypoplasia was rst described more than 80 years ago by Jessner as atrophoderma linearis maculosa et papillomatosis congenitalis [1]. Forty years later, Goltz
From the *Department of Pediatrics, and Department of Health Science and Community, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.

Communications should be addressed to: Dr. Kanemura; Department of Pediatrics, Faculty of Medicine; University of Yamanashi; 1110 Chuo, Yamanashi 409-3898, Japan. E-mail: ykimu@yamanashi.ac.jp Received April 27, 2010; accepted August 5, 2010.

2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2010.08.003  0887-8994/$ - see front matter

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on these manifestations, focal dermal hypoplasia syndrome (Goltz syndrome) was diagnosed. At age 11 months, the patient experienced a second seizure episode involving complex partial seizures with decreased responsiveness, motion arrest, staring, lip cyanosis, and oral automatism. Her head circumference at age 11 months was still small (41 cm). Ictal encephalography indicated right-sided frontal to occipital spikes, spreading to both hemispheres. An interictal electroencephalogram indicated right-sided frontal to anterotemporal spikes. Although we replaced phenobarbital with carbamazepine, her seizures remained resistant to treatment and tended to occur in clusters. Therapy with continuous intravenous midazolam (0.2-0.3 mg/kg/hour) was required to control these clusters of epileptic seizures. Treatment with valproate sodium and clobazam was added. In addition, we replaced carbamazepine with zonisamide, leading to immediate improvement. Recently, she has experienced seizure disorders once or twice a month. However, psychomotor developmental delay, including mental retardation and spasticity, was severe, and growth retardation became evident. Cranial magnetic resonance imaging demonstrated growth retardation of the whole brain, particularly the frontal and temporal regions. In addition, T2-weighted axial imaging revealed signal hyperintensity in the left cerebellar hemisphere (Fig 2), T1-weighted axial imaging indicated signal hypointensity, and coronal imaging with uid-attenuated inversion recovery revealed increased signals in that region. No contrast enhancement was evident on a subsequent contrast-enhanced scan. The lesion exhibited no changes in size or signal intensity during subsequent studies. Based on these investigations, dysplasia of the cerebellar cortex was suspected.

Figure 1. The thumb bent backward on the patients right hand.

Discussion Patients with genetic or chromosomal syndromes associated with epilepsy account for 2-3% of all cases of epilepsy. In fact, these patients are more likely to be examined rst by a pediatrician, family practitioner, or geneticist for a diagnosis and treatment of the genetic syndrome. Investigations of disorders associated with epilepsy are providing insights into the causes of epilepsy. However, from a diagnostic perspective, the classication of epilepsy simply on the basis of the clinical or electrographic appearance of seizures is insufcient, and some consideration of the underlying cause must be included [4]. Focal dermal hypoplasia is characterized by a congenital defect in the development of tissues of ectodermal and mesodermal origin. Focal dermal hypoplasia was suggested to be an X-linked dominant condition, because more than 200 cases have been reported to date, and approximately 85-90% of patients have been female. A frequent history of miscarriage of male fetuses has also been observed [5]. The X-linked locus is presumably silenced in the usual manner on the inactive X chromosome of females, and the mutant allele is recessive to the normal Y-linked homologue [6]. Functional X-chromosomal mosaicism was proposed as the genetic mechanism underlying the cutaneous anomalies in a number of X-linked skin diseases such as focal dermal hypoplasia. However, the fact that 10% of those affected are male may be attributable to genetic half-chromatid mutation. The linear patterns of skin lesions and radiographic bone ndings were attributed to X-chromosome inactivation in females [7]. The unexpectedly high proportion of males with focal dermal hypoplasia, however, argues against X-linked dominance with lethality in males. A gene locus on Xp22.31 was identied as a potential cause [8]. The

same deletion was reported in two female infants with combined partial phenotype focal dermal hypoplasia and Aicardi syndrome [9]. In contrast, Happle et al. hypothesized that only Aicardi syndrome should be assigned to Xp22.3, whereas the gene responsible for focal dermal hypoplasia syndrome could occur at an X-linked locus distant from Xp22.3 [10]. Recently it has become obvious that focal dermal hypoplasia genetic defect has been associated with at least 24 different mutations in the PORCN gene on the X chromosome. Focal dermal hypoplasia is an X - linked dominant trait with lethality in males, unless there is postzygotic somatic mosaicism. However, we have not conrmed the chromosomal abnormalities in the present patient. Further investigations are needed to clarify these points. Clinical expressions of focal dermal hypoplasia continue to be reported in adults rather than children. Skin involvement is regarded as essential for diagnosis, and is invariably present from birth [9]. Other organs, eyes, teeth, and the skeletal system can be affected to various degrees. Other

Figure 2. Findings of cranial magnetic resonance imaging. Signal intensity in the left cerebellar hemisphere was increased on T2-weighted axial imaging (arrow). No interval change was evident during the clinical course.

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Table 1. Clinical manifestations of focal dermal hypoplasia Rothmund-Thomson Syndrome Photosensitivity, blisters Mottled pigmentation + No comments + Almost normal No comments

Goltz [3] Skin atrophy Pigmentary changes Tan papillomas Syndactyly Bent ngers Dystrophic nails Mental retardation Epileptic seizures Findings of magnetic resonance imaging Atrophic scars Reticulated hyperpigmentation + + + + Mild to normal intelligence Chiari anomaly, meningomyelocele, agenesis of the corpus callosum

Giam and Khoo [8] Atrophic scars Reticulated hyperpigmentation + + No comments + No comments No comments

Our Patient Atrophic scars Reticulated hyperpigmentation + + + Severe + Dysplasia of the cerebellum

noteworthy features include facial asymmetry, pointed chin, deformed and low-set ears, and notched nasal alae. Abnormalities of the internal organs frequently include anomalies of the kidney, ureter, and heart, along with inguinal and umbilical hernias and omphalocele [8]. Similar to other genetic disorders [11], many patients with focal dermal hypoplasia demonstrate varying degrees of mental deciency, although some exhibit normal intelligence and have achieved productive careers [3]. Approximately 15% of patients are mentally retarded [12]. In other expressions involving the central nervous system, one report cited agenesis of the corpus callosum [13], whereas another described meningomyelocele, hydrocephalus, and Chiari malformation [14]. Given these complex combinations of anomalies, the genes related to normal differentiation of the eyes, skin, and brain may be contiguous. However, seizure disorders do not appear to represent a feature of the syndrome [3]. Furthermore, few ndings of cranial magnetic resonance imaging were reported in patients with focal dermal hypoplasia. In this patient, manifestations such as colobomas of the iris, anomalies of the urinary tract, absence of kidneys, dilated ureters with inammation, and cystitis were not evident. Conversely, the patient exhibited unusual features of focal dermal hypoplasia, such as seizure disorder and dysplasia of the cerebellar cortex. However, the clinical diagnosis is compatible with focal dermal hypoplasia, based on manifestations such as skin lesions and skeletal system defects. This report is the rst to identify seizure disorder as a possible feature of focal dermal hypoplasia. New expressions of focal dermal hypoplasia continue to be reported, but to the best of our knowledge, seizure disorders and dysplasia of the cerebellar cortex were not previously described. Here, seizure disorder and dysplasia of the cerebellar cortex may have been identied as new expressions of focal dermal hypoplasia. In addition, mental deciency was severe in this patient. Some neurologic and non-neurologic features for comparison with previous reports are listed in Table 1. A previous study examined epilepsy and mental retardation limited to females

(EFMR) exhibited the same inheritance pattern [6]. Assignment of the EFMR disease locus to the X chromosome indicates that a selective involvement of females in X-linked disease may in some instances result from malesparing rather than male lethality [6]. Further investigations are needed to clarify the relationship between focal dermal hypoplasia and EFMR. Despite multiple defects, most patients with focal dermal hypoplasia achieve a normal lifespan and can lead a normal life. Profound dysplasia of the connective tissue constitutes a predominant feature, especially in the skin and skeleton, and malformations or disorders of the central nervous system may affect a patients quality of life, as in this case. Taking manifestations of the central nervous system (such as seizure disorders and cortical dysplasia) into account is important in patients with focal dermal hypoplasia. Depending on the circumstances, electroencephalograms and cranial magnetic resonance imaging may be warranted. Moreover, this genetic condition is best managed by a multidisciplinary team.

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[9] Naritomi K, Izumikawa Y, Nagataki S, et al. Combined Goltz and Aicardi syndromes in a terminal Xp deletion: Are they a contiguous gene syndrome? Am J Med Genet 1992;43:839-43. [10] Happle R, Daniels O, Koopman RJJ. MIDAS syndrome (microphthalmia, dermal aplasia and sclerocornea): An X-linked phenotype distinct from Goltz syndrome. Am J Med Genet 1993;47:710-3. [11] Wolters PL, Gropman AL, Martin SC, et al. Neurodevelopment of children under 3 years of age with Smith-Magenis syndrome. Pediatr Neurol 2009;41:250-8.

[12] Temple IK, MacDowall P, Baraitser M, Atherton DJ. Focal dermal hypoplasia (Goltz syndrome). J Med Genet 1990; 27:180-7. [13] Baughman FA Jr, Worcester DD. Agenesis of the corpus callosum in a case of focal dermal hypoplasia. Mt Sinai J Med 1970;37: 702-9. [14] Almeida L, Anyane-Yeboa K, Grossman M, Rosen T. Myelomeningocele, Arnold-Chiari anomaly and hydrocephalus in focal dermal hypoplasia. Am J Med Genet 1988;30:917-23.

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