Autism spectrum disorder in Kabuki syndrome: clinical, diagnostic and rehabilitative aspects assessed through the presentation of three cases

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2 CASE REPORTS MINERVA PEDIATR 2015;67: Autism spectrum disorder in Kabuki syndrome: clinical, diagnostic and rehabilitative aspects assessed through the presentation of three cases L. PARISI, T. DI FILIPPO, M. ROCCELLA Kabuki syndrome (KS) (Kabuki make-up syndrome, Niikawa-Kuroki syndrome) is a rare genetic disorder first diagnosed in Kabuki make-up syndrome (KMS) is a multiple malformation/intellectual disability syndrome that was first described in Japan but is now reported in many other ethnic groups. KMS is characterized by multiple congenital abnormalities: craniofacial, skeletal, and dermatoglyphic abnormalities; intellectual disability; and short stature. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. The KS is associated with mutations in the MLL2 gene in some cases were also observed deletions of KDM6A. This study describes three children with autism spectrum disorders (ASDs) and KS and rehabilitative intervention that must be implemented. Key words: Kabuki Syndrome - Child development disorders, pervasive - Intellectual disability. Kabuki syndrome (KS) (Kabuki make-up syndrome, Niikawa-Kuroki syndrome) is a rare genetic disorder first diagnosed in Kabuki make-up syndrome (KMS) is a multiple malformation/intellectual disability syndrome that was first described in Japan but is now reported in many other ethnic groups. 1-3 KS is a congenital syndrome with an estimated prevalence of 1 Corresponding author: M. Roccella, corso dei Mille 972, Palermo, Italy. michele.roccella@unipa.it Department of Psychological Sciences, Pedagogical and Educational (SPPF), University of Palermo, Palermo, Italy in 32, This syndrome is characterized by postnatal growth retardation, distinctive facial features, dermatoglyphic anomalies, skeletal dysplasia, intellectual disability, central nervous system malformation, and immunological defects. 1, 4 Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. 1-5 Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities including isolated premature thelarche in females, feeding problems, and hearing loss. 4 Moreover, Kabuki syndrome denoted hyperactivity and autistic traits, as showed by other studies. 1, 5-7 Point mutations and large intragenic deletions and duplications of the mixed lineage leukemia 2 (MLL2) and exons deletions of lysine demethylase 6A (-KDM6A) genes have been identified as its underlying causes. 2, 8-13 This study describes three children with autism spectrum disorders (ASDs) and KS and rehabilitative intervention that must be implemented. Vol No. 4 MINERVA PEDIATRICA 369

3 PARISI Autism spectrum disorder in Kabuki syndrome Clinical series Case 1. This case concerns a female patient (age 5 years and 2 months) by psychomotor development retardation and postnatal growth retardation. She was the first-born of healthy and nonconsanguineous parents with a negative history of genetic diseases. Natural delivery was at the end of the ninth month. The birth weight was 2780 g, the length was 44 cm, and the cranial circumference was 33 cm. The neonatal period was uneventful. Since the first months of life she presented retardation of psychomotor development, feeding difficulties and repeated episodes of airway infection. On physical examination, the stature was 95 cm, the weight was 12 kg, the cranial circumference was 46 cm; examination showed a characteristic facial features: eversion of the lower lateral eyelid, arched eyebrows with the lateral one-third dispersed or sparse, depressed nasal tip, and prominent ears, cleft palate, anomalies of the teeth, blue sclera; skeletal anomalies: clinodactyly of the fifth finger; dermatoglyphic abnormalities: ulnar loops on the fingertips. Neurologic examination showed esotropia (convergent strabismus), generalized hypotonia, joint laxity. On psychological examination, evaluation according to the WPPSI, showed a verbal IQ=45 and a performance IQ of 51. Atypical behaviors included preference to be alone, selective interest in privileged objects used in a stereotyped manner and attention instability. To evaluate and identify the presence and intensity of autistic symptoms, the CARS, the ADOS and ADI-R scales have been used. The submission of these scales confirmed the presence of an autism spectrum disorder. CARS has achieved an overall score of 24/60. The first module of the ADOS was used. In language and communication the child got a score of 4 (cut-off for autism=4; cut-off for the autistic spectrum=2), i.e., she has occasionally echolalia and limited use of gestures restrictive. Reciprocal social interaction got a score of 6 (cut-off for autism=7; cut-off for the autistic spectrum=4), that means the child makes little use of eye contact to start and end the social interaction, shows an adequate integration to request certain objects. In the game the child got a score of 2, which means she has a beginning game with functional objects, but does not use the objects as symbolic substitutes. Stereotyped behaviors and restricted interests got a score of 2, i.e., the subject has a particular interest in some materials, no mannerisms of the hands and fingers, or aggressive behaviors. She revealed no other abnormal behavior, only moderate signs of anxiety. The ADI-R has detected anomalies both in the diagnostic and the current behavior in the algorithm is compatible with an autism spectrum disorder. A mutation of the gene MLL2 was identified. The results of neurologic imaging (CT and brain MRI) were normal, as well as ECG, EMG, and brain stem auditory evoked potential and visual evoked potential tests. Case 2. This case concerns a male patient (age 5 years and 7 months) affected by generalized epilepsy and intellectual disability. He was born after second pregnancy; the parents were non-consanguineous and their history was positive for neurologic and psychological disorders. Natural delivery was at the end of the ninth month. The neonatal period was uneventful. The birth weight was 2970 g, the length was 48 cm, and cranial circumference was 35 cm. Psychomotor and language development were delayed. On physical examination, the height was 97 cm, the weight was 17 kg, the cranial circumference was 48 cm; examination showed characteristic facial features: eversion of the lower lateral eyelid, arched eyebrows with the lateral one-third dispersed or sparse, depressed nasal tip, and prominent ears, cleft palate, hypodontia, bilateral cryptorchidism, brachydactyly, clinodactyly, dermatoglyphic abnormalities (ulnar loops on the fingertips). Neurologic examination showed generalized hypotonia and lax joints. On psychological examination, evaluation according to the WPPSI, showed a verbal IQ=54 and a performance IQ of 66. Motor stereotypes and preference to be alone were present. To evaluate and identify the presence and intensity of autistic symptoms the CARS, ADOS and ADI-R scales were used. CARS has achieved an overall score of 32/60. The first module of the ADOS was also used. In language and communication the child got a score of 2 (cut-off for autism=4; cut-off for the autistic spectrum=2), i.e., he presents with echolalia and gesture to indicate accompanied by verbal language. Reciprocal social interaction got a score of 5 (cut-off for autism=7; cut-off for the autistic spectrum=4), he makes little use of eye contact and shows a limited range of facial expressions. The game got a score of 3, he does not use the objects as symbolic substitutes. Stereotyped behaviors and restricted interests got a score of 2, the subject has a particular interest in some materials, no self aggressive behaviors. There is no clinical signs of hyperactivity and aggression, only moderate signs of anxiety. The ADI-R has detected anomalies both in the diagnostic and the current behavior in the algorithm is compatible with an autism spectrum disorder. These scales confirmed the presence of an autism spectrum disorder. A mutation of the gene MLL2 was identified. The brain MRI scan showed cerebellar vermis atrophy, as well as ECG, EMG, and brain stem auditory evoked potential and visual evoked potential tests. The EEG showed atypical waves on the bilateral center-front derivations. Case 3. This case concerns a male patient (age 4 years and 7 months) affected by autism spectrum disorders. He was born after second pregnancy; the parents were non-consanguineous and their history was positive for neurologic and psychological disorders. The neonatal period was uneventful. The birth weight was 3050 g the length was 49 cm, and cranial circumference was 36 cm. Psychomotor and 370 MINERVA PEDIATRICA August 2015

4 Autism spectrum disorder in Kabuki syndrome PARISI language development were delayed. On physical examination, the stature was 101 cm, the weight was 13 kg, the cranial circumference was 46 cm; examination showed characteristic facial features: eversion of the lower lateral eyelid, arched eyebrows with the lateral one-third dispersed or sparse, depressed nasal tip, and prominent ears, cleft palate, anomalies of the teeth; skeletal anomalies: clinodactyly of the fifth finger; dermatoglyphic abnormalities: ulnar loops on the fingertips. Neurologic examination showed visual-motor coordination difficulty. On psychological examination, evaluation according to the WPPSI, showed a verbal IQ=58 and a performance IQ of 62. Atypical behaviors included: preference to be alone, selective interest in privileged objects used in a stereotyped manner and attention instability. To evaluate and identify the presence and intensity of autistic symptoms the CARS, the ADOS and ADI-R scales have been used. CARS has achieved an overall score of 26/60. The first module of the ADOS was used. In language and communication the child got a score of 3 (cutoff for autism=4; cut-off for the autistic spectrum=2), and echolalia has limited use of gestures restrictive. Reciprocal social interaction got a score of 7 (cut-off for autism=7; cut-off for the autistic spectrum=4), the child makes little use of eye contact, does not show proper integration to request certain objects. The game got a score of 2, he does not use the objects as symbolic substitutes. Stereotyped behaviors and restricted interests got a score of 3, the subject has a particular interest in some materials, presents some stereo hands, no self-aggressive behaviors. No other abnormal behaviors were detected. The ADI- R detected anomalies both in the diagnostic and the current behavior in the algorithm is compatible with an autism spectrum disorder. The submission of these scales confirmed the presence of an autism spectrum disorder. A mutation of the gene MLL2 was also identified. The results of neurologic imaging (CT and brain MRI) were normal, as were ECG, EMG, and brain stem auditory evoked potential and visual evoked potential tests. Discussion The Kabuki (Niikawa-Kuroki) syndrome was reported in 1981 by Niikawa et al. and Kuroki et al. in a total of ten unrelated Japanese children with a characteristic array of multiple congenital anomalies and intellectual disability. 1-3, 5 The syndrome is characterized by a distinct face, mild to moderate intellectual disability, postnatal growth retardation, dermatoglyphic and skeletal abnormalities. In Japan, the syndrome appears to have an incidence of about 1:32,000 newborns. 1-5 The signs include craniofacial elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched eyebrows and wide, with the third side thinned or presence of notches; short columella with depressed tip of the nose; large ears, prominent or loop; cleft lip/palate or high arched palate; anomalies of the teeth (hypodontia), hypoplasia of the mastoid processes; the microcephaly is not constant. 1-7 Rare are the ocular signs: blue sclera, strabismus, ptosis, coloboma and abnormalities of the cornea The length is normal at birth, infants immediately after presenting growth retardation and frequent growth retardation of varying severity. The microcephaly is not constant. 5, 8-20 Musculoskeletal abnormalities including brachydactyly of the fifth fingers, brachimesofalangia, clinodactyly of the fifth finger, abnormalities of the spine, joint hypermobility and dislocations, hip dislocation. 2 Abnormalities fickle, but reported a high frequency, are: heart defects (single ventricle with inter-atrial communication, tetralogy of Fallot, coarctation of the great arteries, ventricular septal defect); horseshoe kidney; double renal pelvis; megalouretere; rectovaginal fistula with anal atresia. 2, 6-21 An anomaly of dermatoglyphics is the presence of a number of ulnar loops on the fingertips. This is unique fold decline in the fourth and fifth fingers and excess of the flexion crease of the palm smaller, high frequency of ulnar loop configurations in the fourth interdigital area. 2, 21 Other occasional findings were severe autoimmune thrombopenia, cerebellar vermis atrophy, and myopathic features It has been reported immune disease, autoimmune disorders and increased susceptibility to infections, especially in adolescents; there are frequent infections in childhood, particularly those affecting the urinary tract, pneumonia, recurrent otitis media. 2 In females, one can observe a premature thelarche, which does not require treatment, unless there are no other signs of premature puberty These individuals have intellectual disabilities, a delay in the acquisition of psychomotor developmental milestones, head control at 4-5 Vol No. 4 MINERVA PEDIATRICA 371

5 PARISI Autism spectrum disorder in Kabuki syndrome months, months independent ambulation, poorly structured language that begins with the first disyllables at about three years and remains poor with thick, distinct and connected words. 6-12, 21 According to a review of the literature, in the absence of major structural brain anomalies, the average intelligence quotient (IQ) in patients with this condition falls within the mild mental retardation range, however, specific developmental outcomes are widely variable, ranging from severe MR to normal intelligence. 6-15, 21 The presence or absence of hearing loss or major malformations, other than those involving the brain, was not predictive of developmental outcome. 6, 16 These children may have autism spectrum disorders and hyperactivity, but the problems does not seem to have a higher incidence than in the general population Kabuki syndrome (also known as Niikawa- Kuroki syndrome) is a rare autosomal disorder. 8, 9 KMT2D-related KS is inherited in an autosomal dominant manner. Each child of an individual with KMT2D-related KS has a 50% chance of inheriting the mutation. Today only the cases of six individuals with mutations or deletions of KDM6A have been reported; all have had a proven or apparent de novo mutation. While X-linked inheritance is theoretically possible, no familial cases of KS resulting from mutations in KDM6A have been reported. The proportion of KS caused by de novo mutations is unknown, but it is likely high based on clinical experience. 4, 8, 9 The cause of KS has been unidentified, even by whole-genome scan with array comparative genomic hybridization (CGH). 11 The diagnosis is primarily established by clinical findings. KS is caused by mutation in KMT2D (formerly MLL2) or KDM6A. 4 The identification of de novo dominant mutations in KMT2D (MLL2) as the main cause of Kabuki syndrome (KS) has shed new light on the pathogenesis of this well-delineated condition consisting of a peculiar facial appearance, short stature, organ malformations and a varying degree of intellectual disability. Mutation screening studies have confirmed KMT2D as the major causative gene for KS and have at the same time provided evidence for its genetic heterogeneity Point mutations and large intragenic deletions and duplications of the mixed lineage leukemia 2 (MLL2) and exons deletions of lysine demethylase 6A (-KDM6A) genes have been identified as its underlying causes. 8, De novo point mutations are also known to be responsible for many sporadic cases of rare dominant mendelian disorders such as Kabuki syndrome, Schinzel-Giedion syndrome and Bohring- Opitz syndrome. 9 A study of 17 patients with KS showed seven copy number variants, three deleted regions and four duplicated regions among the patients, with the exception of registered copy number variants (CNVs). Among the seven loci, only the region of 9q21.11-q21.12 (approximately 1.27 Mb) involved coding genes, namely, transient receptor potential cation channel, subfamily M, member 3 (TRPM3), Kruppellike factor 9 (KLF9), structural maintenance of chromosomes protein 5 (SMC5) and MAM domain containing 2 (MAMDC2). Mutation screening for the genes detected 10 base substitutions consisting of seven single-nucleotide polymorphisms (SNPs) and three silent mutations in 41 patients with KS. Our study could not show the causative genes for KS, but the locus of 9q q21.12, in association with a cleft palate, may contribute to the manifestation of KS in the patient Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in an affected family member is known. 4 The orchestrated organization of epigenetic factors that control chromatin dynamism, including DNA methylation, histone marks, non-coding RNAs (ncrnas) and chromatin-remodeling proteins, is essential for the proper function of tissue homeostasis, cell identity and development. 12 Epigenetic marks are modifications of DNA and histones. They are considered to be permanent within a single cell during development, and are heritable across cell division. Programming of neurons through epigenetic mechanisms is believed to be critical in neural development. Disruption or alteration in this process causes an array of neurodevelopmental dis- 372 MINERVA PEDIATRICA August 2015

6 Autism spectrum disorder in Kabuki syndrome PARISI orders, including autism spectrum disorders (ASDs). Recent studies have provided evidence for an altered epigenetic landscape in ASDs and demonstrated the central role of epigenetic mechanisms in their pathogenesis Many of the genes linked to the ASDs encode proteins that are involved in transcriptional regulation and chromatin remodeling. In this paper, we highlight selected neurodevelopmental disorders in which epigenetic dysregulation plays an important role. 7, These include Rett syndrome, fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, and Kabuki syndrome. For each of these disorders, we discuss how advances in our understanding of epigenetic mechanisms may lead to novel therapeutic approaches Prenatal diagnosis is available for families with a previous child affected heterozygous for a known disease-causing mutation The differential diagnosis is with CHARGE syndrome, branchio-oto-renal, Ehlers-Danlos syndrome (hypermobile form), and Hardikar, diseases associated with IRF6 and the 22q11 deletion syndrome. In addition, several chromosomal abnormalities may manifest clinical signs similar to those of the clinical spectrum of KS The prognosis is quite favorable. Life expectancy depends mostly from heart complications and immunology This study describes three children with Ks with various features of the clinical spectrum of the syndrome. An intellectual disability was present in all cases, in addiction to autism In these subjects made an evaluation of symptoms of autistic disorder. This assessment allows us to strengthen the presence and intensity of the symptoms presented by the child. This assessment should be carried out through the scales: Childhood Autism Rating Scale (CARS), Autism Diagnostic Observation Schedule (ADOS), Autism Diagnostic Interview, Revised (ADI-R). The CARS scale is compiled on the basis of the observation of the behavior within the context unstructured. The behavior is compared to that of a peer without difficulty. The ADOS is a semi-structured and standardized assessment of communication, social interaction, play and imaginative use of materials for individuals with ASD. The ADOS consists of standardized activities that allow the examiner to observe those behaviors that are important for the diagnosis of autism spectrum disorder in different chronological age and for different levels of development. Through this tools you can assess the child s behaviors in response to situations and stimulus activities predetermined by the test in order to obtain information on the characteristics of interpersonal and communication. The test is based on an evaluation framework designed to generate interactive situations that provide stimuli at the social level, through play and verbal exchanges. The ADOS includes four different modules depending on the age and level of expressive language of the subject. In all our cases, we used the module 1. In most of the activities of this module, the focus is directed to the use of observation fun toys and other materials are particularly important for children with an age of development under three years. The first module consists of 10 activities (free play, response to name, response shared attention, game bubbles, anticipation of a routine with objects, social smile response, anticipation of a social routine, imitation functional and symbolic feast birthday, snacks). Scores are organized into five main groups: A. Language and Communication, B. Reciprocal social interaction, C. Game, D. Stereotyped behaviors and restricted interests and E. other vices. The ADI-R is addressed to parents and teachers of subjects, from early childhood to adulthood. It focuses on the observation of systemic and standardized behaviors that are rarely found in non-clinical subjects. The ADI-R is articulated in an interview protocol and five algorithms. It is useful in formulating a formal diagnosis, referring to the entire history of the subject development, for an overall estimate of the disease severity. It is used to schedule a treatment or an educational project on the basis of surveys carried out. KS is a multisystem disorder, which is why there is no specific therapy and the treatment has to be adapted to the individual patient: antiepileptic Vol No. 4 MINERVA PEDIATRICA 373

7 PARISI Autism spectrum disorder in Kabuki syndrome therapy for seizers; psychomotor treatment for intellectual disability; early cognitivebehavior treatment for autism (among which, applied behavior analysis); and other appropriate treatments to improve the quality of life of patients, as well as the direct contact with nature and enjoyment of the rural landscape In the cases described here have recommended intervention of psycho-educational and cognitivebehavioral with several times a week. To further increase the capacity of understanding (receptive communication), we suggested to provide a structure and a clarification of the physical environment: each place has to be dedicated to a single activity. Different places have been organized offering visual information of the task. To facilitate the understanding of environmental stimuli, it has been suggested as a permanent constant use of visual, verbal communications riots that accompanied the subject. Intentionality in spontaneous communication with strangers (expressive communication) has been improved. To increase the capacity of expression storybooks that use images have been used, before describing the images and then turning to the child of comprehension questions. In this way child gradually describes and explains a situation, as much as possible. We helped the children to grasp the meaning and use of descriptive gestures by imitation Some of the cases were referred for psychomotor therapy as part of an integrated neuropsychological and psychomotor treatment support program. Conclusions In this view, psychomotor treatment aims to promote the emotional-relational component, to overcome rigid divisions, and to integrate learning-related cognitive aspects with psychodynamic concepts. Finally, the goals of psychological and social support are to help the parents accept their child s handicap, understand the child s behavior, plan future pregnancies, and foster an environment for their child s integration. 22 References 1. Kasdon BD, Fox JE. Kabuki syndrome: diagnostic and treatment considerations. Ment Health Fam Med 2012;9: Bokinni Y. Kabuki syndrome revisited. J Human Genet 2012;57: Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I. A new malformation syndrome of lon palpebral fissures, large ears, depressed nasal tip and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr 1981;99: Adam MP, Hudgins L. Kabuki syndrome: a review. Clinic Genet 2005;67: Schrander-Stumpel CT, Spruy L, Curfs LM, Defloor T, Scrander JJ. Kabuki syndrome: Clinical data in 20 patients, literature review, and further guidelines for preventive management. Am J Med A 2005;132A: Vaux KK, Jones KL, Jones MC, Schelley S, Hudgins L. Developmental outcome Kabuki syndrome. Am J Med Genet A 2005;132A: Rangasamy S, D Mello SR, Narayanan V. Epigenetics, autism spectrum, and neurodevelopmental disorders. Neurotherapeutics 2013;10: Ratbi I, Fejjal N, Micale L, Augello B, Fusco C, Lyahyai J et al. Report of the first clinical Case of a Moroccan Kabuki patient with a novel MLL2 mutation. Mol Syndromol 2013;4: Ku CS, Polychronakos C, Tan EK, Naidoo N, Pawitan Y, Roukos DH et al. A new paradigm emerges from the study of de novo mutations in the context of neurodevelopmental disease. Mol Psychiatry 2013;18: Banka S, Veeramachaneni R, Reardon W, Howard E, Bunstone S, Ragge N et al. How genetically heterogenous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum. Eur J Hum Genet 2012;20: Kuniba H, Yoshiura K, Kondoh T, Ohashi H, Kurosawa K, Tonoki H et al. Molecular karyotyping in 17 patients and mutation screening in 41 patients with Kabuki syndrome. J Hum Genet 2009;54: Scrander-Stumpel C, Meinecke P, Wilson G, Gillessen-Kaesbach G, Tinschert S, Konig R et al. The Kabuki (niikawa-kutoki) syndrome: further delineation of the phenotype in 29 non-japanese patients. Eur J Pediatr 1994;153: Berdasco M, Esteller M. Genetic syndromes caused by mutations in epigenetic genes. Hum Genet 2013;132A: Bogershausen N, Wollnik B. Unmasking Kabuki syndrome. Clin Genet 2013;83: Huh JK, Chung MS, Baek GH, Oh JH, Lee YH, Gong HS. Cleft hand in Kabuki make-up syndrome: case report. J Hand Surg Am 2011;36: Vecchio D, Salzano E, Vecchio A, Roccella M. A case a femoral-facial syndrome in a patient with autism spectrumdisorders. Minerva Pediatr 2011;63: Montalbano R, Roccella M. The quality of life of children with pervasive developmental disorders. Minerva Pediatr 2009;61: Akin Sari B, Karaer K, Bodur S, Soysal AS. Case report: autistic disorder in Kabuki syndrome. J Autism Dev Disord 2008;38: Esposito M, Marotta R, Roccella M, Gallai B, Parisi L, Lavano SM et al. Pediatric neurofibromatosis 1and parental stress: a multi center study. Neuropsychlogical Dis Treat 2014;10: Esposito M, Gallai B, Parisi L, Roccella M, Marotta 374 MINERVA PEDIATRICA August 2015

8 This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher. Autism spectrum disorder in Kabuki syndrome R, Lavano SM et al. Maternal stress and childhood migraine: a new perspective on management. Neuropsychlogical Dis Treat 2013;9: Adam MP, Hudgins L, Hannibal M. Kabuki syndrome. In: Panagon RA, Adam MP, Bird TD, Dolan CR, Stephens K, editors. Gene Reviews (Internet). Seattle, WA: University of Washington; Parisi L, Di Filippo T, Roccella M. Hypomelanosis of Ito: neurological and psychlogical pictures in developmental age. Minerva Pediatr 2012;64: Genevieve D, Amiel J, Viot G, Le Merrer M, Sanlaville D, Urtizberea A et al. Atypical findings in Kabuki syndrome: report of 8 patients in a series of 20 and review of the literature. Am J Med Genet A 2004;129A: Di Trapani AM, Squatrito R, Foderà M, Testa R, Tudisca S, Sgroi F. Payment for environmental service for the sustainable development of the territory. Am J Environ Sci 2014;10: Vol No. 4 MINERVA PEDIATRICA 375 PARISI 25. Sgroi F, Tudisca S, Di Trapani AM, Testa R. The rural tourism as development opportunity of farms. The case of direct sales in Sicily. American Journal of Agricultural and Biological Sciences 2014;9: Testa R, Di Trapani AM, Sgroi F, Tudisca S. Economic sustainability of Italian greenhouse cherry tomato. Sustainability 2014;6: Testa R, Di Trapani AM, Foderà M, Sgroi F, Tudisca S. Economic evaluation of introduction of poplar as biomass crop in Italy. Renewable and Sustainable Energy Reviews 2014;38: Conflicts of interest. The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. Received on August 7, Accepted for publication on January 30, 2015.