American Journal of Medical Genetics 113:385– 389 (2002)
Research Letter Cortical Periventricular Heterotopia With Ectodermal Dysplasia DATABASE:
Cortical periventricular heterotopia; filamin A (FLNA); filamin C (FLNC); glycinuria with or without oxalate urolithiasis; absence of lower central incisors
To the Editor: Cortical periventricular heterotopia is described as a rare condition, caused by mutations in the gene encoding filamin A, a human actin-binding 280-kD protein (ABP-280). This protein crosslinks actin filaments into orthogonal networks in cortical cytoplasm and participates in the anchoring of membrane proteins for the actin cytoskeleton. The gene is located in the distal part of Xq28. Periventricular heterotopia is described as an X-linked dominant disorder with lethality in males. This is based on the fact that 16 females from five families have been reported, in which a high frequency of spontaneous abortions have been observed. Heterozygous females with the disorder present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, whereas hemizygous affected males die embryonically. Sporadic cortical heterotopia has also been described [Raymond et al., 1994]; the sporadic form is distinguished from the presumably X-linked form by the occurrence in males, later seizure onset, and fewer nodules. At least one additional gene encoding an RNA more than 70% identical to ABP-280 was found, and was shown to map to chromosome 7 in a study of human/hamster somatic cell hybrids (FLNC). Dobyns et al. [1997] and Guerrini and Carrozzo [2001] emphasized that these heterotopias could occur as manifestations in various conditions. We recently observed two cases (one diffuse and the other uninodular) of cortical (subependymal) periventricular heterotopia in two unrelated children (a male and a female), both with ectodermal dysplasia (ED), at different expression.
*Correspondence to: Raffaella Zannolli, M.D., Department of Pediatrics, Obstetrics, and Reproductive Medicine, Section of Pediatrics, Policlinico Le Scotte, University of Siena, Siena, Italy. E-mail:
[email protected] Received 17 May 2002; Accepted 7 June 2002 DOI 10.1002/ajmg.10811
ß 2002 Wiley-Liss, Inc.
PATIENT 1 The first patient with cortical (subependymal) periventricular heterotopia was a three-year-old male. Cortical heterotopia was bilateral, lining the wall of the trigones and the temporal horns (Fig. 1a and 1b), and defined as ‘‘diffuse’’ because of its irregular and lumpy outline, which resembled multiple coalesced nodules. It was easily recognizable because of its isointensity to the cortical gray matter in all magnetic resonance imaging (MRI) images. Cortical heterotopia was fortuitously observed in this three-year-old boy, and he was referred
Fig. 1. Patient 1. Cortical periventricular heterotopia in a three-yearold male with EDs. a: Turbo-spin-echo T2-weighted axial brain MRI image showing subependymal nodular heterotopia extending into the adjacent ventricles, causing the ventricles to appear compressed (arrows). b: Inversion recovery T1-weighted axial brain MRI image (slice thickness 1 mm). A thick, nodular layer of gray matter lines the ventricles (arrows). c and d: The patient had sparse eyebrows, subtle eyebrow alopecia, and thin and sparse hair. e: Microscopic observations of the hair showed different diameters and pigmentation of the hair. Inset: central dark zones present in some hair shafts. Bar ¼ 1,500 mm; inset, 380 mm.
386
Zannolli et al.
to our clinic for an episode of vertigo of unknown origin that recovered spontaneously and gradually within one week. Routine blood laboratory data, electroencephalogram (EEG), and vestibular test all were normal. The child had normal intelligence and physical performance, was the younger of two siblings, and was born from nonconsanguineous parents. He was an apparently healthy child, with no previously known health problems, although he had sparse eyebrows, subtle eyebrow alopecia, and thin and sparse hair (Fig. 1c and 1d). The microscopic observations (i.e., light microscopy and scanning electron microscopy), showed variations in hair diameter and shaft pigmentation (Fig. 1e and inset). There were no sweating changes, and the child had normal teeth and nails. Skin biopsy was not performed for ethical reasons. We concluded that this child had Group B pure ED syndrome [Pinheiro and Freire-Maia, 1994], based on the involvement of one classic ectodermal structure—hair—plus one unconventional ectodermal structure—the brain with cortical periventricular heterotopia. Interestingly, we found other ectodermal signs in the parents and a sister. The phenotypic details of the other family members (images not showed) suggest the presence of a pure ED syndrome (the sister) or ED trait (the parents). The father, an apparently normal and healthy man, presented with thin and sparse hair. The mother was an apparently normal and healthy woman, with apparently normal hair. The sister was an apparently normal and healthy seven-year-old child, but with seriously carious teeth with enamel dysplasia, and a hair line anomaly simulating fronto-temporal alopecia. None of them had sweating changes and/or abnormal nails. The microscopic observations of the family hair were similar to the child’s; the father and the sister had variations in hair diameter and shaft pigmentation. Some shafts had a continuous or interrupted central dark zone. The father also had some hair showing a central depression of the shaft and some flat hair with oval rather than circular sections. The mother also had variations in hair diameter. We concluded that the sister had a Group A pure ED syndrome [Pinheiro and Freire-Maia, 1994], with the involvement of two classic ectodermal structures: teeth and hair. Both of the parents were carriers of at least one ectodermal dysplasia trait: abnormalities of pigmentation, diameter, and shape of the hair in the father, and abnormalities in the diameter of the hair in the mother. Unfortunately, the brain morphology of the family members remains unknown, as they refused brain MRI. Skin biopsy was not performed, both for ethical reasons and refusal. PATIENT 2 The second patient with cortical (subependymal) periventricular heterotopia was a seven-year-old female. This child was found to have a novel ED/malformation syndrome with hair and skin defects, and associated with a wide spectrum of features, such as mental deficiency, joint laxity, cerebellar ataxia, osteopenia, and isolated hyperglicinuria. MRI showed unilateral peri-
ventricular nodular area of gray-matter heterotopia in the right cerebral hemisphere (Fig. 2a and 2b). Cortical heterotopia was easily recognizable because of its isointensity to the cortical gray matter in all the MRI images. Her face showed epicanthic folds, down-slanted fissures, hypertelorism, wide nose root, wide forehead, micrognathia, and thin lips with an everted lower lip. Her scalp showed sparse slow-growing hairs with evident alopecia (Fig. 2c and 2d). Her weight was 28.5 kg (90th centile), her height was 127 cm (75th centile), and her head circumference was 50 cm (25–50th centile). She had teeth with signs of enamel dysplasia (images not showed), joint laxity, functional scoliosis of the rachis, with lordosis, and a winged scapula. Her arms and limbs were normally proportioned with no rhizomelic shortness (Fig. 2e and 2f ). Her hands and feet showed clinodactyly. Skin biopsy, performed in an apparently normal area of the scalp (temporo-occipital area) showed a mild hyperkeratosis, hypoplastic sebaceous glands abnormally placed, empty hair canals, and coarse elastic fiber clumps in the reticular dermis, without alteration of collagen fibers (Fig. 2g and 2h). Electron microscopy showed aggregates of compound melanosomes in the epidermis, and some giant melanosomes were found near the hair follicles. A relative increase of normal elastin was also present. There was no demonstrable alteration to collagen (Fig. 2i and 2l). The proposita was referred with ‘‘mental impairment.’’ She was the second child born from consanguineous parents (first cousins born from two of five siblings). The older sister, 13 years old, was referred as being apparently normal. The mother, apparently healthy and mentally unimpaired, had a subtle set of ED traits (hair, teeth, skin, and minimal skeletal changes). The father (who refused to attend the visit) was described as a normal, healthy man with minimal hair and teeth problems. All of them had isolated hyperglycinuria. After an uneventful pregnancy, the child was born at term and weighed 3,100 g (50th centile), was 48 cm long (50th centile), and her head circumference was 34 cm (25–50th centile). Delayed psychomotor development was apparent early. She suffered from seizures (i.e., infantile spasms) from the age of three to 10 months, and received anticonvulsant drug therapy up to the age of 3.5 years. Her physical growth was normal. Inborn errors of metabolism were ruled out. Her karyotype was normal: 46,XX. MRI of her central nervous system, performed at low resolution at the age of one year, showed apparently normal brain morphology. At seven years of age, the neurological examination revealed mental retardation (mental performance on the Columbia Mental Maturity Scale: IQ 48), horizontal nystagmus, slow and poor speech with a sing-song voice (ataxic dysarthria), ataxic gait, uncoordination of upper and lower limbs, dysmetria at finger-nose-finger testing, poor handwriting, and brisk deep tendon reflexes without clonus or Babinski sign. Her renal function and a renal sonogram were normal. No inborn errors of metabolism were detectable, except for isolated hyperglycinuria [MIM 138500] detected
Research Letter
387
Fig. 2. Patient 2. Cortical periventricular heterotopia in a seven-yearold female with a novel ED/malformation syndrome. a and b: Brain MRI, 1.5Tesla coronal sections. a: T2-weighted turbo spin-echo. b: T1-weighted inversion recovery. Single nodule of gray-matter heterotopia is seen in the wall of the right lateral ventricle, close to the corpus caudatum (arrows). c–f: Phenotype of patient 2. See text for details. g–i, l: Microscopy of skin biopsy (g and h: optic microscopy; i and l: electron microscopy). g: Mild hyperkeratosis. Hypoplastic sebaceous gland (thick arrow), joined to the
middle third (instead of the upper third) of the hair follicle. Empty hair canal (thin arrow) (hematoxylin and eosin, 25). h: Coarse elastic fibers in the reticularis dermis (arrows) (Giemsa-Orcein, 25, 50). i: Several aggregates of amorphous elastin (arrows) (original magnification: 11,000). l: Variable-sized melanosomes in melanocytes surrounding the hair bulb (original magnification: 3,500). Insert: Compound melanosomes (original magnification: 36,000).
more than one time during her life (i.e., from the age of one year to the present). The maximum detected level was 1,939 mM/M of creatinine at one year of age (the normal value for this age, according to our laboratory standards, is 650 mM/M); the minimum level was 489 mM/M creatinine at seven years of age (the normal value for this age, according to our laboratory standards,
is 200 mM/M). Ophthalmologic examination showed a normal fundus oculi, but the presence of refractive defects (hyperopia þ2.50; astigmatism þ3.50). A skull X-ray demonstrated dolichocephaly, with the anteroposterior diameter being more than a quarter greater than the lateral (image not shown). A vertebral radiograph showed no abnormal morphology, but showed a
388
Zannolli et al.
functional scoliosis and osteopenia (images not shown). Hand and foot X-rays showed clinodactyly (fourth finger and third, fourth, and fifth toes) and osteopenia. Echocardiography showed normal cardiac performance. Thyroid gland function was normal. Calcium-phosphorus metabolism showed normal values of 24 hr calciuria and phosphaturia, and normal calcitonin, parathyroid hormone, serum alkaline phosphatase, and serum bone alkaline phosphatase (bone ALP) concentrations, measured with the Tandem1 Ostase assay [Kress et al., 1999]. Lumbar spine dual-energy X-ray absorptiometry (DEXA) showed clear osteopenia. An EEG showed diffuse paroxistic activity. DISCUSSION To the best of our knowledge, these are the only two reports of an association between periventricular cortical heterotopia and ED. Periventricular cortical heterotopia occurs very rarely in the general population. Therefore, it is unlikely that it occurred by chance in these two affected individuals. The association between (subependymal) periventricular cortical heterotopia and ED in these two patients reported to date suggests that: 1. EDs are much more complex conditions than previously considered [Pinheiro and Freire-Maia, 1994]. They are probably associated with several groups of genes involved in the diversification of neural crest derivatives, endoskeletal elements, brain organization, and the organization of other body parts, such as bone and teeth [Jiang et al., 1999; Satokata et al., 2000; Wilkie et al., 2000; Neidert et al., 2001]. 2. Periventricular cortical heterotopia might be another expression of more widely generalized tissue dysplasia [Chevassus-au-Louis and Represa, 1999; Hannan et al., 1999]. Quantitative trait locus (resulting perhaps from the additive effects of several different genes [Lynch and Walsh, 1998]), instead of simple Mendelian traits expressed in heterozygosity or homozygosity, is also possible when considering the wider expression of the heterotopia in the different subjects with different EDs. According to Barkovich et al. [2001], who recently provided a new classification system for malformations of cortical development, ‘‘The differences in phenotype of cortical heretotopia may be explained by 1) different mutation of the same gene that affects protein function differently, 2) different dosage of the same mutation in the same gene, and 3) different effects of the same mutation and dosage (variable expressivity) caused by unidentified modifying factors.’’ 3. Cortical heterotopia, observed in these two different unrelated subjects, seems not an isolated problem, but rather the sign of a more robust phenomena, and expression of a systemic pathologic condition. Such replication of observations strengthens confidence that the new findings were not likely due to chance or some ‘‘quirk’’ of an individual case. From this point of view, Zannolli et al. [2002] found low central incisor agenesis, another very rare condition, in a man with subtle EDs.
In conclusion, we suggest that periventricular cortical heterotopia might be associated with ED, and that subjects with periventricular cortical heterotopia should also be suspected for these complex syndromes. Further studies, not only on causative genes but also on genes modifying the effect of a specific gene(s), will be welcome, and will give clinicians the chance to redefine ‘‘EDs not as a result of a general ‘ectodermal’ abnormal defect, but, more precisely, as systemic pathologic conditions’’ [Priolo et al., 2000]. ACKNOWLEDGMENT We are grateful to Mrs. Patrizia Rossi for her expert laboratory assistance. REFERENCES Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. 2001. Classification system for malformations of cortical development: update 2001. Neurology 57:2168–2178. Chevassus-au-Louis N, Represa A. 1999. The right neuron at the wrong place: biology of heterotopic neurons in cortical neuronal migration disorders, with special reference to associated pathologies. Cell Mol Life Sci 55:1206–1215. Dobyns WB, Guerrini R, Czapansky-Beilman DK, Pierpont ME, Breningstall G, Yock DH Jr, Bonanni P, Truwit CL. 1997. Bilateral periventricular nodular heterotopia with mental retardation and syndactyly in boys: a new X-linked mental retardation syndrome. Neurology 49:1042– 1047. Guerrini R, Carrozzo R. 2001. Epilepsy and genetic malformations of the cerebral cortex. Am J Med Genet 106:160–173. Hannan AJ, Servotte S, Katsnelson A, Sisodiya S, Blakemore C, Squire M, Molnar Z. 1999. Characterization of nodular neuronal heterotopia in children. Brain 122:219–238. Jiang TX, Liu YH, Widelitz RB, Kundu RK, Maxson RE, Chuong CM. 1999. Epidermal dysplasia and abnormal hair follicles in transgenic mice overexpressing homeobox gene MSX-2. J Invest Dermatol 113:230– 237. Kress BC, Mizrahi IA, Armour KW, Marcus R, Emkey RD, Santora AC. 1999. Use of bone alkaline phosphatase to monitor alendronate therapy in individual postmenopausal osteoporotic women. Clin Chem 45:1009– 1017. Lynch M, Walsh B. 1998. Genetics and analysis of quantitative trait. Sunderland, Massachusetts: Sinauer Associates, Inc. Neidert AH, Virupannavar V, Hooker GW, Langeland JA. 2001. Lamprey Dlx genes and early vertebrate evolution. Proc Natl Acad Sci USA 98:1665–1670. Pinheiro M, Freire-Maia N. 1994. Ectodermal dysplasias: a clinical classification and a causal review. Am J Med Genet 53:153–162. Priolo M, Silengo M, Lerone M, Ravazzolo R. 2000. Ectodermal dysplasias: not only ‘skin’ deep. Clin Genet 58:415–430. Raymond AA, Fish DR, Stevens JM, Sisodiya SM, Alsanjari N, Shorvon SD. 1994. Subependymal heterotopia: a distinct neuronal migration disorder associated with epilepsy. J Neurol Neurosurg Psychiatry 57:1195– 1202. Satokata I, Ma L, Ohshima H, Bei M, Woo I, Nishizawa K, Maeda T, Takano Y, Uchiyama M, Heaney S, Peters H, Tana Z, Maxson R, Maas R. 2000. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet 24:391–395. Wilkie AO, Tang Z, Elanko N, Walsh S, Twigg SR, Hurst JA, Wall SA, Chrzanowska KH, Maxson RE Jr. 2000. Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Nat Genet 24:387–390. Zannolli R, Pierluigi M, Pucci L, Lagrasta N, Gasparre O, Matera MR, Di Bartolo RM, Mazzei MA, Sacco P, Miracco C, de Santi MM, Aitiani P, Cavani S, Pellegrini L, Fimiani M, Alessandrini C, Galluzzi P, Livi W, Gonnelli S, Terrosi-Vagnoli P, Zappella M, Morgese G. 2002. 18qsyndrome and ED/malformation syndrome—description of a child and his family. Am J Med Genet in press.
Research Letter
R. Zannolli* E. Conversano L. Serracca R.M. Di Bartolo M. Molinelli Department of Pediatrics Obstetrics, and Reproductive Medicine Section of Pediatrics Policlinico Le Scotte University of Siena Siena, Italy
389
G. Vatti Department of Neuroscience Section of Neurology Policlinico Le Scotte University of Siena Siena, Italy
G. Coviello Radiology Unit Azienda Ospedaliera Senese Policlinico Le Scotte Siena, Italy
P. Galluzzi
A. Malandrini
Neuroradiology Unit Azienda Ospedaliera Senese Policlinico Le Scotte Siena, Italy
Department of Neurological Sciences Policlinico Le Scotte University of Siena Siena, Italy
S. Gonnelli M.A. Mazzei P. Terrosi-Vagnoli Department of Radiology and Orthopedics Policlinico Le Scotte University of Siena Siena, Italy
C. Miracco M.M. de Santi Department of Pathological Anatomy and Histology, Policlinico Le Scotte University of Siena Siena, Italy
Department of Internal Medicine Policlinico Le Scotte University of Siena Siena, Italy
C. Alessandrini Department of Biomedical Sciences University of Siena Siena, Italy
M. Fimiani Department of Dermatology Policlinico Le Scotte University of Siena Siena, Italy
